WO2024051741A1 - Compound for inhibiting bcl-2 or bcl-xl and use thereof in medicine - Google Patents

Compound for inhibiting bcl-2 or bcl-xl and use thereof in medicine Download PDF

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WO2024051741A1
WO2024051741A1 PCT/CN2023/117251 CN2023117251W WO2024051741A1 WO 2024051741 A1 WO2024051741 A1 WO 2024051741A1 CN 2023117251 W CN2023117251 W CN 2023117251W WO 2024051741 A1 WO2024051741 A1 WO 2024051741A1
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alkyl
substituted
cyano
group
halogen
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PCT/CN2023/117251
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French (fr)
Chinese (zh)
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张晨
何平
黄清平
秦林
魏琦
唐平明
余彦
李瑶
严庞科
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西藏海思科制药有限公司
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Publication of WO2024051741A1 publication Critical patent/WO2024051741A1/en

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a compound described in general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, as well as intermediates and preparation methods thereof , and application in the preparation of drugs for treating diseases related to Bcl-2 or Bcl-xL activity or expression.
  • Apoptosis is a gene-regulated, autonomous and orderly death process of most cells in organisms at a certain developmental stage. It plays an important role in tissue evolution, organ development and the maintenance of the body's own stability. In malignant tumors, anti-apoptotic effects are considered a key feature. Therefore, specifically targeting anti-apoptotic pathways has potential applications in cancer treatment.
  • the Bcl-2 protein family consists of pro-apoptotic proteins and anti-apoptotic proteins, which can regulate the intrinsic apoptotic pathway of cancer cells. Among them, the Bcl-2 protein family members Bcl-2, Bcl-xL and Mcl-1 have been identified as anti-tumor targets.
  • Inhibiting these proteins can promote Bax/Bak oligomerization and ultimately induce mitochondrial outer membrane permeability, which subsequently causes The release of cytochrome c and the activation of caspases, thereby executing cancer cell apoptosis.
  • Bcl-2 cannot improve ischemic retinopathy, while selective inhibition of Bcl-xL can selectively kill senescent cells, inhibit the resulting aging-related secretory phenotype, inhibit pathological angiogenesis and enhance avascularity.
  • Cell Metabolism 33, 818–832, April 6, 2021 because Bcl-2 is a molecule that many cells depend on for survival, if Bcl-xL and Bcl-2 are inhibited at the same time, it may cause damage to normal tissues and cells in the eye. Apoptosis, causing further eye disease; therefore, the development of selective Bcl-xL inhibitors for the treatment of retinopathy-related eye diseases is expected to bring greater clinical benefits and relatively less toxic side effects.
  • the object of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which can be used as Bcl-2 or Bcl-xL inhibitors.
  • the compounds of the present invention can effectively inhibit Bcl-2 or Bcl-xL and can be used to treat tumors, eye diseases and other diseases.
  • the compound of the present invention has the effect of selectively inhibiting Bcl-xL, and has good inhibitory activity on WI-38 senescent cells stained with SA- ⁇ -galactosidase induced by mitomycin C.
  • the compound of the present invention has good pharmacokinetic properties (such as better exposure, better t 1/2 , CL, etc.) in mice, rats, dogs, and monkeys, and has better liver microsome stability.
  • the compound of the present invention has good proliferation inhibitory activity on MOLT-4 cells, NCI-H446 cells, and Kasumi-1 cells and has no obvious hERG and CYP inhibitory activity.
  • the present invention provides a compound described in general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
  • Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, and Ring A is optionally substituted by 1 to 4 Ra , so The ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
  • Ring A, Ring C, and Ring D are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 9 to 10 membered heteroaryl, the ring A is optionally substituted by 1 to 4 R a , the ring C is optionally substituted by 1 to 4 R c , the ring D is optionally substituted by 1 to 4 R d replace;
  • Ring A is selected from The ring A is optionally substituted by 1 to 4 Ra ;
  • Ring C and Ring D are each independently selected from The ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
  • B is selected from -B 1 -, -N(R n )-B 1 -, -B 1 -N(R n )-;
  • B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
  • B is selected from 4 to 12 membered heterocyclyl, which is optionally substituted by 1 to 10 R b ;
  • B 1 is selected from the group consisting of 4- to 7-membered nitrogen-containing monocyclic heterocyclyl, 5- to 10-membered nitrogen-containing paracyclic heterocyclyl, 5- to 11-membered nitrogen-containing spirocyclic heterocyclyl, 5- to 11-membered nitrogen-containing spirocyclic heterocyclyl, Nitrogen-containing bridged ring heterocyclyl, the B 1 is optionally substituted by 1 to 8 R b ;
  • B is selected from azetidinyl, azetipentyl, azehexyl, azepanyl, azepanyl, azetidinylspirocyclopropyl, Azetidinylspirocyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidine cyclobutylspirocyclopentyl, azetidinylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirohexyl, azetidinylspirocyclohexyl, azet
  • B1 is selected from The B 1 is optionally substituted by 1 to 8 R b ;
  • Selected from The left side is connected to ring A;
  • Selected from The left side is connected to ring C;
  • K is selected from 5-membered heteroaryl, and K is substituted by 1 to 3 R k1 , 1 R k2 ;
  • K is selected from
  • Rx is selected from H, C 1-6 alkyl, or C 3-6 cycloalkyl
  • Rx is selected from H
  • Rn is selected from H, C 1-6 alkyl, -C 1-4 alkylene-C 3-6 cycloalkyl, and the alkyl, alkylene or cycloalkyl is any Selected from 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C Substituted with 1-6 alkyl and C 1-6 alkoxy substituents;
  • Rn is selected from H, C 1-4 alkyl
  • Rn is selected from H, methyl, ethyl
  • any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • any R b and R c are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 R a1 ;
  • any R b and R a are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 R a1 ;
  • R a1 is each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propyl Alkynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclohexyl Butyl, cyclopentyl, and cyclohexyl are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl,
  • Rkla is selected from COOH
  • R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propyne base, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene group, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , substituted by hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloal
  • R k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl;
  • Rk1c is selected from deuterium, CD3 , H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl Propyl, butyl, and cyclopropyl are optionally selected from 1 to 4 deuterium, CD 3 , halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2- Substituted with 4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
  • R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • R 1 , R 2 , and R 3 are each independently selected from H, C 1-6 alkyl, C 3-10 carbocyclyl, or 4 to 10-membered heterocyclyl, and the alkyl,
  • the carbocyclyl or heterocyclic group is optionally substituted by 1 to 4 carbon atoms selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and hydroxyl-substituted C 1-6 Substituted by alkyl, cyano-substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents;
  • R 1 , R 2 , and R 3 are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclic ring, or 4 to 7-membered heterocyclic ring, and the alkyl group, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano Substituted with substituents of C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
  • Z is selected from -CH(R z1 )CH 2 -SR z2 or -CH(R z1 )CH 2 -Se-R z2 ;
  • R z1 is selected from -C 1-4alkylene -Z 1 -R z3 ;
  • R z1 is selected from -CH 2 CH 2 -Z 1 -R z3 ;
  • Z 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, Azetidinylspirocyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidine cyclobutylspirocyclopentyl, azetidinylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirohexyl, azetidinylspirohexyl, aze
  • R k2 and R z2 are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, and the R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 optionally substituted by 1 to 4 R z2a ;
  • R k2 and R z2 are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 9 to 10 Metaheteroaryl, the R k2 is optionally substituted by 1 to 4 R k2a , the R z2 is optionally substituted by 1 to 4 R z2a ;
  • R k2 and R z2 are each independently selected from phenyl, pyridine, The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
  • R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy group, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10 membered heterocyclic ring, the -CH 2 -, alkyl group, alkenyl group, alkynyl group, The alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1 groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-6 alkyl group, and hydroxyl group. -6 alkyl, cyano substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy
  • R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy group, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl group, alkenyl group, alkynyl group, The alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1 groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-4 alkyl group, and hydroxyl group. -4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alk
  • R z1a , R k2a , R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl , tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl optionally 1 to 4 selected from halogen, OH Substituted with substituents of , cyano, NH 2 , CF 3 , hydroxymethyl, C
  • R z1a , R k2a , R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl , tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • each q is independently selected from 0, 1, 2, 3, or 4;
  • q is each independently selected from 0, 1, and 2;
  • p1, p2, and p3 are each independently 0, 1, 2, or 3;
  • the compounds of general formula (I) are optionally substituted by 1 to 20 deuteriums.
  • Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, the ring A is optionally substituted by 1 to 4 R a , and the ring C is optionally substituted by 1 to 4 R c substitutes, and the ring D is optionally substituted with 1 to 4 R d ;
  • B is selected from -B 1 -, -N(R n )-B 1 -, -B 1 -N(R n )-;
  • B 1 is selected from 4 to 12 membered heterocyclyl groups, which are optionally substituted by 1 to 10 R b ;
  • K is selected from a 5-membered heteroaryl group, and the K is substituted by 1 to 3 R k1 and 1 R k2 ;
  • R x is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl
  • R n is selected from H, C 1-6 alkyl, -C 1-4 alkylene-C 3-6 cycloalkyl, and the alkyl, alkylene or cycloalkyl is optionally substituted by 1 to 4 Selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, Substituted with C 1-6 alkoxy substituents;
  • the oxygen group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1-6 alkyl groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-6 alkyl group, and hydroxyl group. Substituted by 6 alkyl, cyano substituted C 1-6 alkyl, C 2-6 alkynyl,
  • any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • R 1 , R 2 , and R 3 are each independently selected from H, C 1-6 alkyl, C 3-10 carbocyclyl, or 4 to 10-membered heterocyclyl.
  • the alkyl, carbocyclyl, or heterocyclic The group is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano Substituted with substituents of C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl;
  • Z is selected from -CH(R z1 )CH 2 -SR z2 or -CH(R z1 )CH 2 -Se-R z2 ;
  • R z1 is selected from -C 1-4 alkylene -Z 1 -R z3 ;
  • R k2 and R z2 are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, the R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a substitution;
  • R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, - (CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10 membered heterocyclic ring, the -CH 2 -, alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano Substituted with substituents of C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy,
  • q is independently selected from 0, 1, 2, 3 or 4;
  • the compounds of general formula (I) are optionally substituted by 1 to 20 deuteriums.
  • Ring A, ring C, and ring D are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and 9- to 10-membered heteroaryl base, the ring A is optionally substituted by 1 to 4 R a , the ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
  • B 1 is selected from the group consisting of 4 to 7-membered nitrogen-containing monocyclic heterocyclyl, 5- to 10-membered nitrogen-containing paracyclic heterocyclyl, 5- to 11-membered nitrogen-containing spirocyclic heterocyclyl, and 5- to 11-membered nitrogen-containing bridged heterocyclic ring. group, the B 1 is optionally substituted by 1 to 8 R b ;
  • R n is selected from H, C 1-4 alkyl
  • the oxygen group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-4 alkyl group, and hydroxyl group. Substituted by 4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl
  • any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
  • R 1 , R 2 , and R 3 are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclic ring or 4 to 7-membered heterocyclic ring.
  • the alkyl group, carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1- Substituted with a substituent of 4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
  • R k2 and R z2 are each independently selected from phenyl, benzo C 4-6 carbocyclic group, benzo 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, and 9- to 10-membered heteroaryl group, so The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
  • R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, - (CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano Substituted with substituents of C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6
  • q is independently selected from 0, 1, and 2;
  • B 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, azetidinylspiro Cyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl base, azetipentylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl,
  • Z 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, azetidinylspiro Cyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl base, azetipentylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl,
  • the alkyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-4 alkyl selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, and halogen.
  • B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
  • B 1 selected from The B 1 is optionally substituted by 1 to 8 R b ;
  • Ring A is selected from The ring A is optionally substituted by 1 to 4 Ra ;
  • Ring C and Ring D are each independently selected from The ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
  • R a1 is each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, Ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, Butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally selected from 1 to 4 halogen , OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloal
  • R z1 is selected from -CH 2 CH 2 -Z 1 -R z3 ;
  • R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, Methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, Propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, and cyclopentyl are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C Substituted with substituents of 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy
  • R k1c is selected from deuterium, CD 3 , H, methyl, ethyl, propyl, isopropyl, butyl, and cyclopropyl, and the methyl, ethyl, propyl, isopropyl, butyl,
  • the cyclopropyl group is optionally selected from 1 to 4 deuterium, CD 3 , halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1 Substituted with -4 alkoxy and C 3-6 cycloalkyl substituents;
  • R k2 and R z2 are each independently selected from phenyl, pyridine, The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
  • R z1a , R k2a , and R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene base, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl base, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C
  • p1, p2 and p3 are each independently 0, 1, 2 or 3;
  • R k1a is selected from COOH
  • R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • R k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl;
  • R z1a , R k2a , and R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene base, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal wherein
  • the compound represented by formula (I) is selected from the compounds represented by general formula (II-a),
  • B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
  • B 1 selected from The B 1 is optionally substituted by 1 to 8 R b ;
  • R b are each independently selected from deuterium and F;
  • Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 F;
  • R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • Rk2a is selected from F, Cl, methyl, ethyl, and cyclopropyl
  • the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal wherein
  • the compound represented by formula (I) is selected from the compounds represented by general formula (III-a) or (III-b),
  • R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 F;
  • Rk2a is selected from F, Cl, methyl, ethyl, and cyclopropyl
  • the present invention relates to the compound shown below or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one;
  • the present invention relates to a pharmaceutical composition, including any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutically acceptable carriers,
  • the pharmaceutical composition contains 1-1500 mg of the aforementioned compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal.
  • the present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
  • Effective amount or “therapeutically effective amount” as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or disorder being treated (e.g., inhibiting Bcl-2 or Bcl- One or more symptoms of an xL-related disease such as a tumor or eye disease).
  • the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of 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, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-
  • the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
  • a method for treating diseases in mammals comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable
  • the therapeutically effective amount of the salt or co-crystal is preferably 1-1500 mg, and the disease preferably inhibits Bcl-2 or Bcl-xL related diseases (such as tumors or eye diseases).
  • a method for treating diseases in mammals includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose.
  • the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
  • the present invention relates to a kit, which may include a composition in a single dose or multiple dose form.
  • the kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical
  • the amount of the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as that in the above pharmaceutical composition. The amount is the same.
  • the present invention relates to any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals for use in the preparation of treatments with Bcl-2 or Bcl-xL activity or Application in medicines for diseases related to expression levels.
  • the diseases are selected from tumors or eye diseases.
  • the present invention relates to the application of the above pharmaceutical composition in the preparation of drugs for the treatment of diseases related to the activity or expression of Bcl-2 or Bcl-xL.
  • the disease is selected from tumors or eye diseases, more preferably , the disease is selected from retinopathy-related eye diseases.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14 C
  • Halogen means F, Cl, Br or I.
  • Halo-substituted means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted” is simply referred to as "halogenated.”
  • Alkyl refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition.
  • Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Heteroalkyl refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replacement.
  • Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )vH (v is an integer from 1 to 5, each , O or S, and at least 1 X is selected from heteroatoms, and N or S in the heteroatoms can be oxidized to various oxidation states).
  • Heteroalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.
  • Heteroalkylene refers to a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) substitution.
  • Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )v-, v is an integer from 1 to 5, 1 X is selected from N, O or S.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or
  • the heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms
  • alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl
  • alkynyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
  • Carbocyclyl or “carbocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Bicyclic or 10 to 15-membered tricyclic system the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” may be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Sexually substituted N and S can be oxidized into various oxidation states.
  • the heterocyclyl group can be connected to a heteroatom or a carbon atom.
  • the heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclyl group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl
  • Spirocyclic or “spirocyclyl” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • Non-limiting examples include: "Spiro" or “spiryl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10.
  • Non-limiting examples include: "And ring” or "and ring group” can be monovalent, divalent, trivalent or tetravalent.
  • the "bridging ring” or “bridging ring base” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbospirocycle “spirocarbocyclyl”, “spirocarbocyclyl” or “carbospirocyclyl” appearing in this article have the same definition as spirocycle.
  • Carbocyclic ring refers to a “carbocyclic ring” in which the ring system only consists of carbon atoms.
  • the definition of “carbocyclic ring”, “carbocyclic ring group”, “carbocyclic ring group” or “carbocyclic ring group” appearing in this article is consistent with that of carbocyclic ring.
  • Carbon bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • the definitions of “carbon bridged ring”, “bridged carbocyclic ring group”, “bridged carbocyclic ring group” or “carbon bridged ring group” appearing in this article are consistent with those of the bridged ring.
  • Heteromonocycle refers to the “heterocyclyl” or “heterocycle” of a monocyclic system.
  • Heterocyclic ring refers to a “heterocyclic ring” containing heteroatoms.
  • heterocyclic ring refers to a “heterocyclic ring” containing heteroatoms.
  • the definitions of heterocyclic ring, “heterocyclic ring group”, “heterocyclic heterocyclyl group” or “heterocyclic ring group” appearing in this article are consistent with those of the heterocyclic ring group.
  • Heterospirocycle refers to a “spirocycle” containing heteroatoms. Heterospirocycle, “heterospirocyclyl”, “spirocycloheterocyclyl” or “heterospirocyclyl” appearing in this article have the same definition as spirocycle.
  • Heterobridged ring refers to a “bridged ring” containing heteroatoms.
  • the definition of hetero-bridged ring, “hetero-bridged cyclyl”, “bridged-ring heterocyclyl” or “hetero-bridged cyclyl” appearing in this article is consistent with that of bridged ring.
  • Aryl or "aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring.
  • the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms.
  • the aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring.
  • Non-limiting examples include benzene ring, naphthalene ring, "Aryl” or “aryl ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • Non-limiting examples include Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
  • 5-membered 5-membered heteroaromatic ring refers to a 5-membered fused heteroaromatic ring. At least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, Pyrazolothiophene ring.
  • 5-6-membered heteroaromatic ring refers to a 5-6-membered fused heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.
  • Constant 1 to 5 heteroatoms selected from O, S, and N means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.
  • Substituted by 1 to X substituents selected from means substituted by 1, 2, 3...
  • substituted by 1 to X substituents selected from means substituted by 1, 2, 3 or 4 substituents selected from....
  • substituted with 1 to 5 substituents means substituted with 1, 2, 3, 4 or 5 substituents.
  • the heterobridged ring is optionally substituted by 1 to 4 substituents selected from F means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from F.
  • X-Y element rings (3 ⁇ X ⁇ Y, Y is selected from any integer between 4 and 12) include X, X+1, X+2, X+3, X+4....Y element rings.
  • Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings.
  • “4-7 membered heteromonocyclic ring” refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings
  • 5-10-membered heterocyclic ring refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
  • alkyl optionally substituted by F means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body.
  • the prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF co-crystal form
  • the pure states of API and CCF are both Solids, and there are fixed stoichiometric ratios between the components.
  • a eutectic is a multicomponent crystal that includes both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed between a neutral solid and a salt or solvate.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
  • Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
  • IC 50 is the amount required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.) the concentration of the drug or inhibitor.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
  • HPLC HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Chemicals” were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXia ( Shanghai) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
  • THF tetrahydrofuran
  • DMF N,N-dimethylformamide
  • DIPEA N,N-diisopropylethylamine
  • HATU CAS148893-10-1.
  • Dissolve 1b (1.8g, 5.43mmol) in 20mL acetonitrile, add 4mL 4N dioxane hydrochloride solution, and react at room temperature for 2 hours. Concentrate under reduced pressure, add 5 mL of sodium bicarbonate aqueous solution to adjust the pH to about 8, extract 5 times with dichloromethane, combine the organic phases, and concentrate under reduced pressure to obtain 1c (1.0 g, yield: 79.61%).
  • Dissolve intermediate A (0.45g, 1.52mmol) in 20mL dichloromethane, add 3a (0.18g, 1.52mmol), add triethylamine (0.62g, 6.08mmol) in an ice-water bath under nitrogen protection, and stir at 0°C. 30 minutes; add sodium triacetoxyborohydride (0.48g, 2.28mmol), and stir at room temperature overnight.
  • 5A (1.0g, 1.91mmol), 5A-1 (530mg, 2.29mmol), copper iodide (36mg, 0.19mmol), [(2,6-dimethylphenyl)amino](oxy)acetic acid (110mg, 0.57mmol) and potassium carbonate (790mg, 5.73mmol) were dissolved in 20mL dimethyl sulfoxide, and the tube was sealed at 130°C for 12 hours. Water was added, the reaction was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5B (651 mg, 50.48%).
  • Dissolve 7A (5.0g, 22.19mmol) in 30mL methanol under nitrogen protection, add sodium borohydride (1.26g, 33.29mmol) in batches at 0°C, and react at 0°C for 1 hour.
  • Dissolve 7B (1.8g, 7.92mmol) in 20mL acetonitrile, add 4mL 4N dioxane hydrochloride solution, and react at room temperature for 2 hours. Concentrate under reduced pressure, add 5 ml of sodium bicarbonate aqueous solution to adjust the pH to about 8, extract 5 times with dichloromethane, combine the organic phases, and concentrate under reduced pressure to obtain 7C (1.0 g, yield: 99.28%).
  • Dissolve intermediate B (50 mg, 0.061 mmol) in 2 mL DMF, add compound 8D (27 mg, 0.09 mmol), DIPEA (23 mg, 0.18 mmol), and stir at room temperature for 2 h.
  • the crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 8. (20mg, yield: 29.87%).
  • Dissolve intermediate B (50 mg, 0.061 mmol) in 3 mL DMF, add compound 9D (28 mg, 0.091 mmol), DIPEA (24 mg, 0.18 mmol), and react at room temperature for 2 h.
  • the crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 9. (21 mg, yield: 31.13%).
  • Dissolve intermediate B (50 mg, 0.061 mmol) in 3 mL DMF, add compound 10E (29 mg, 0.091 mmol), DIPEA (23 mg, 0.18 mmol), and stir at room temperature for 2 h.
  • the crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 10 (18 mg, yield: 26.35%).
  • Dissolve intermediate B (50 mg, 0.061 mmol) in 2 mL DMF, add 12d (28 mg, 0.091 mmol), DIPEA (24 mg, 0.18 mmol), and stir at room temperature for 2 h.
  • the crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 12. trifluoroacetate (25 mg, yield: 37.06%).
  • Place 20A (5.0g, 46.24mmol) in a sealed tube, dissolve it in 100mL N,N-dimethylformamide, add DIPEA (9g, 50.86mmol) and 3,4-difluoronitrobenzene (4.05g, 50.86mmol).
  • DIPEA 9g, 50.86mmol
  • 3,4-difluoronitrobenzene 4.05g, 50.86mmol.
  • the system was heated to 120°C overnight under nitrogen protection, and 300 mL of ethyl acetate was added to the system to dilute it, then the organic phase was washed three times with 150 mL of water and once with 150 mL of saturated brine, the organic phase was dried and spin-dried, and the residue was purified by column chromatography to obtain Compound 20B (3.0 g, yield: 36.5%).
  • the raw material compound 5C-1 (0.21g, 0.64mmol) was dissolved in 20mL of methylene chloride, protected by nitrogen, cooled to 0°C, added pyridine (0.21g, 2.65mmol), and then added 21H (0.31g, 0.53mmol) in methylene chloride. 10 mL of solution was added and the reaction was continued for 1 hour. Directly concentrate under reduced pressure, and the residue is subjected to column chromatography to obtain product 21I (0.15g, yield: 32%).
  • compound 23A (1.5g, 3.26mmol), 23B (1.21g, 6.52mmol), copper iodide (370mg, 1.96mmol), [(2,6-xylyl)amino] (oxygen) Acetic acid (1.26g, 6.52mmol) and potassium carbonate (2.25g, 16.3mmol) were dissolved in 20 mL of DMSO and reacted in a pressure-resistant bottle at 130°C for 10 hours. The reaction was quenched by adding water, extracted with EA (30 mL ⁇ 2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 23C (1.1 g, 59.6%).
  • Dissolve 22E 60 mg, 0.076 mmol and intermediate 24A (21 mg, 0.076 mmol) in 3 mL DMF, slowly add DIPEA (49 mg, 0.38 mmol), and stir at room temperature for 2 hours.
  • DIPEA 49 mg, 0.38 mmol
  • the crude product is subjected to silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5 % NH 4 HCO 3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% to 40% A in B solution) to obtain compound 24 (23 mg, 28.05%).
  • Dissolve 26E (55 mg, 0.066 mmol) in 2 mL DMF, add intermediate 24A (56 mg, 0.20 mmol) and DIPEA (43 mg, 0.33 mmol), and stir at room temperature for 2 h.
  • Add 30 mL of ethyl acetate wash the organic layer twice with water (20 mL : 0.5% NH 4 HCO 3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% to 40% A of B solution) to obtain compound 26 (13 mg, 18.11%).
  • Dissolve 27A (5g, 49.43mmol) in 50mL THF and 5mL water, slowly add sodium carbonate (15.72g, 148.23mmol), and slowly add 9-fluorenylmethyl chloroformate (15.35g, 59.34mmol) under an ice bath. , warmed to room temperature and stirred for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL ⁇ 3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 27B (11.2 g, 70.06%).
  • Dissolve 27B (5g, 15.47mmol) in 15mL pyridine, slowly add carbon tetrabromide (10.26g, 30.94mmol), replace nitrogen three times, stir for 30 minutes, slowly add trimethoxyphosphorus (4.03g, 32.49mmol), heated to room temperature and stirred for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL ⁇ 3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 27C (4.5 g, 67.43%).
  • HPLC preparation method Instrument: SHIMADZU LC-20AP; Preparation column: C18; Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile;
  • Elution method 32% to 62% A solution of B, gradient elution for 15 minutes; flow rate: 25mL/min; column temperature: room temperature; detection wavelength: 220nm;
  • the crude intermediate 28D (89 mg, 0.241 mmol) was dissolved in a mixed solvent of 3 mL ultra-dry 1.2-dichloroethane and 3 mL ultra-dry methanol, and then sodium acetate (79 mg, 0.964 mmol) and acetic acid ( 0.1mL) and Molecular sieve (50 mg), stirred at room temperature for 15 min, then added intermediate A (107 mg, 0.362 mmol), and then the system reacted at room temperature for 1 h. Sodium triacetoxyborohydride (153 mg, 0.723 mmol) was added and stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and product 28D (124 mg, two-step yield: 97%) was obtained through column chromatography.
  • intermediate 28D (124 mg, 0.235 mmol) was dissolved in 5 mL of ultra-dry dichloromethane, then trimethyliodosilane (0.2 mL, 1.41 mmol) was slowly added dropwise, stirred at room temperature for 2 h, concentrated, and the residue was added Dissolve 10 mL of dichloromethane, concentrate again, and repeat twice to obtain crude product 28E (210 mg), which is directly used in the next step of the reaction.
  • A is 0.1% TFA aqueous solution
  • B is acetonitrile
  • HPLC preparation method Instrument: SHIMADZU LC-20AP; Preparation column: C18; Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile; Elution method: 25% to 60% A solution of B, gradient elution for 15 minutes ;Flow rate: 25mL/min; Column temperature: room temperature; Detection wavelength: 220nm;
  • test compounds were diluted 3 times in a 384 dilution plate using DMSO (Sigma, D4540). The final starting concentration of the test compounds was 10000 nM. Transfer 75nL of diluted compounds of different concentrations to the 384 reaction plate, ensuring that the DMSO content is 0.5%. Then add 5 ⁇ L of diluted 3 ⁇ Bcl-xL enzyme (BPS, 50273) solution to the 384 reaction plate to ensure the final reaction concentration is 5 nM, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min.
  • BPS 3 ⁇ Bcl-xL enzyme
  • the positive compound (A-1210477) and the test compound were serially diluted 3-fold with DMSO (Sigma, D4540) in a 384 dilution plate, so that the final starting concentrations of the positive compound and the test compound were 1000 nM and 10000 nM respectively. Transfer 75nL of diluted compounds of different concentrations to the 384 reaction plate, ensuring that the DMSO content is 0.5%. Then transfer 5 ⁇ L/well 3 ⁇ BCL-2 enzyme (BPS, 50272) solution to the 384 reaction plate to ensure the final concentration of the reaction is 2 nM, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min.
  • DMSO Sigma, D4540
  • the compounds of the present invention have high binding ability to the Bcl-xL target. Relative to the Bcl-2 target, the compound of the present invention has high selectivity for the Bcl-xL target. Compared with the trifluoroacetate salt of Compound 1 and Compound 2, the compound of the present invention has better selectivity.
  • the target affinity of compound 25 for the Bcl-xL target is 1207 times that of the Bcl-2 target.
  • the target affinity of compound 22 for Bcl-xL is 893 times that of the Bcl-2 target.
  • Compounds 21 and 24 The affinity of 27 trifluoroacetate and 28 trifluoroacetate to the Bcl-xL target was 295 times higher than the affinity to the Bcl-2 target.
  • Human fibroblast primary cell line WI-38 cells are derived from ATCC (Product No.: CCL-75), cultured in EMEM+10% FBS+1% double antibody medium, 37°C, 5% CO 2 incubator . When the cells are in the exponential growth phase, collect the cells, count them, and plate them on a 10cm2 dish. After the cells adhere to the wall, treat the cells with 200nM mitomycin C (MMC, manufacturer: Absin, product number: 47029279) for 48 hours, and construct In the cell senescence model, a DMSO-treated cell group was also set as a vehicle control to ensure that the final concentration of DMSO was less than 0.1%.
  • MMC mitomycin C
  • the cells treated with MMC/DMSO were digested, centrifuged, resuspended, and plated into a 384-well plate at a density of 5000 cells/well (MMC) and 1000 cells/well (DMSO) for 5 days, and then the prepared different concentrations were added.
  • MMC cells/well
  • DMSO cells/well
  • the compounds of the present invention such as the example compounds, especially compound 22, have good inhibitory activity against mitomycin C-induced SA- ⁇ -galactosidase-stained WI-38 senescent cells.
  • Human fibroblast primary cell line WI-38 cells are derived from ATCC (Product No.: CCL-75), cultured in EMEM+10% FBS+1% double antibody medium, 37°C, 5% CO 2 incubator . When the cells are in the exponential growth phase, collect the cells, count them, and plate them on a 10cm2 dish. After the cells adhere to the wall, treat the cells with 200nM mitomycin C (MMC, manufacturer: Absin, product number: 47029279) for 48 hours, and construct In the cell senescence model, a DMSO-treated cell group was also set up as a vehicle control to ensure that the DMSO The concentration is 0.1% or less.
  • MMC mitomycin C
  • the CTG detection steps are as follows:
  • Luminescence readings use GraphPad Prism 8.0 software to calculate the IC 50 value and maximum inhibition rate of compounds inhibiting cell proliferation according to formula (1) and formula (2) respectively.
  • T administration is the signal reading after 7 days of incubation with the compound, and T vehicle is the cell signal reading after 7 days of incubation with the vehicle control.
  • Growth% (T administration /T vehicle ⁇ 100)% Formula (1)
  • the compound of the present invention has good inhibitory activity on WI-38 senescent cells induced by mitomycin C.
  • the purpose of this study is to use an in vitro test system to evaluate the effect of the test substance on the activity of two isoenzymes (CYP2C9 and CYP2D6) of human liver microsomal cytochrome P450 (CYP).
  • CYP2C9 and CYP2D6 human liver microsomal cytochrome P450
  • the specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the compounds of the present invention such as the example compounds, especially compounds 22, 24, and 26, inhibit CYP2C9 and CYP2D6 weaker than the control compound 1, and the risk of drug interactions caused by the metabolism of CYP2C9 and CYP2D6 is lower.
  • the compound of the present invention has no obvious inhibitory effect on each subtype of CYP enzyme.
  • MOLT-4 cells are a human acute lymphoblastic leukemia cell line. Purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator. Cells were plated in a 96-well plate at 5 ⁇ 10 3 cells/well. After plating, compounds of different concentrations were added and cultured for 72 hours in a 37°C, 5% CO 2 incubator. After the culture, add cell viability detection reagent (Promega, G7573), mix for 2 minutes, incubate at room temperature for 10 minutes, and use a multifunctional microplate reader (BMG, PHERAstar FSX) to detect the luminescence signal.
  • BMG PHERAstar FSX
  • the compounds of the present invention especially the compounds of the examples, have good proliferation inhibitory activity on MOLT-4 cells.
  • NCI-H446 cells human small cell lung cancer cell line
  • ATCC culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator.
  • Cells were plated in a 96-well plate at a density of 1 ⁇ 10 3 cells/well.
  • compounds of different concentrations compound starting concentration 10 ⁇ M, 5-fold dilution, 9 concentration gradients
  • T administration is the cell signal reading value after 72 hours of incubation with the compound
  • T vehicle is the cell signal reading value after 72 hours of incubation with the vehicle control.
  • the compounds of the present invention especially the compounds of the examples, have good proliferation inhibitory activity on NCI-H446 cells.
  • Kasumi-1 cells human acute myelocytic leukemia cell line
  • ATCC culture conditions: RPMI-1640+20% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator.
  • Cells were plated in a 96-well plate with a seed plate density of 1.2 ⁇ 10 4 cells/well. After plating, compounds of different concentrations (compound starting concentration 10 ⁇ M, 5-fold dilution, 9 concentration gradients) were added, and the culture was continued for 72 h in a 37°C, 5% CO 2 incubator.
  • the compounds of the present invention especially the compounds of the examples, have good proliferation inhibitory activity on Kasumi-1 cells.
  • compounds containing phosphate esters require quantitative analysis of both the test substance itself and its corresponding hydrolyzed compound (original drug). For example, compound 27 needs to be detected simultaneously with its corresponding original drug compound 24.
  • Test animals male C57Mice mice, 20 ⁇ 25g, 3-6/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, mice were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
  • Intravenous administration vehicle 5% DMSO+95% (3% Tween 80 in PBS)
  • the original drug has a good exposure in mice.
  • the original drugs are 24, 22, and 26, respectively. Have better exposure.
  • Test animals male SD rats, about 220g, 6 to 8 weeks old, 3-6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, rats were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
  • Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline; or 5% DMSO+95% (3% Tween 80in PBS) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline)
  • the original drug When the compounds of the present invention, especially the example compounds, are administered intravenously, the original drug has a good exposure in rats. For example, after hydrolysis of compounds 27, 28, and 29, the original drugs are 24, 22, and 26 respectively, which have better exposure.
  • mice male beagles, about 8-11kg, 3-6/compound, purchased from Beijing Mas Biotechnology Co., Ltd.
  • Test method On the day of the test, the beagle dogs were randomly divided into groups according to their weight. No food or water for 12 to 14 hours one day before administration, and food 4 hours after administration. Dosage according to Table 1.
  • the original drug When the compounds of the present invention, especially the compounds of the examples, are administered intravenously, the original drug has a good exposure in the body of beagle dogs. For example, after hydrolysis of compounds 27, 28, and 29, the original drugs are 24, 22, and 26 respectively, which have better exposure.
  • Test animals male cynomolgus monkey, 3-5kg, 3-6 years old, 3-6 animals/compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
  • 1.0 mL of blood was taken from the veins of the limbs and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5min, 15min, 30min, 1, 2, 4, 6, 8, 10, 12, and 24h. Before analysis and detection, all samples were stored at -80°C, and LC-MS/MS was used to quantitatively analyze the samples. If the test compound is a prodrug molecule, quantitative analysis of the prodrug and original drug was performed on the sample at the same time.
  • the original drug has a good exposure in monkeys.
  • the original drugs are 24, 22, and 26 respectively, which have better exposure.
  • This experiment uses five types of hepatic microsomes from humans, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substance.
  • LC-MS/ The MS method detects the concentration of the test substance in the sample, and calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the liver microsome intrinsic clearance rate CL int (mic) and the liver intrinsic clearance rate CL int(Liver) .
  • the compounds of the present invention especially the compounds in the examples, have good liver microsome stability.

Abstract

The present invention relates to a compound represented by general formula (I) or a stereoisomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal, and an intermediate thereof, a preparation method therefor, and a use thereof in the preparation of a drug for treating diseases related to Bcl-2 or Bcl-xL activity or expression quantity.

Description

一种抑制Bcl-2或Bcl-xL的化合物及其在医药上的应用A compound that inhibits Bcl-2 or Bcl-xL and its application in medicine 技术领域Technical field
本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与Bcl-2或Bcl-xL活性或表达量相关疾病的药物中的应用。The present invention relates to a compound described in general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, as well as intermediates and preparation methods thereof , and application in the preparation of drugs for treating diseases related to Bcl-2 or Bcl-xL activity or expression.
背景技术Background technique
细胞凋亡是生物体内绝大多数细胞在一定发育阶段由基因调控的、自主的、有序的死亡过程，它对于组织进化、器官发育和机体自身稳定的维持起着重要作用。在恶性肿瘤中，抗凋亡作用被认为是一个关键的特征。因此，特异性地靶向抗凋亡通路在癌症治疗方面具有潜在的应用前景。Bcl-2蛋白家族由促凋亡蛋白和抗凋亡蛋白组成，能调节癌细胞内在的凋亡途径。其中，Bcl-2蛋白家族成员Bcl-2、Bcl-xL和Mcl-1已被确认为抗肿瘤靶点，抑制这些蛋白能够促进Bax/Bak齐聚化并最终诱导线粒体外膜渗透化，随后引起细胞色素C的释放和半胱天冬氨酸蛋白酶的激活，从而执行癌细胞凋亡。Apoptosis is a gene-regulated, autonomous and orderly death process of most cells in organisms at a certain developmental stage. It plays an important role in tissue evolution, organ development and the maintenance of the body's own stability. In malignant tumors, anti-apoptotic effects are considered a key feature. Therefore, specifically targeting anti-apoptotic pathways has potential applications in cancer treatment. The Bcl-2 protein family consists of pro-apoptotic proteins and anti-apoptotic proteins, which can regulate the intrinsic apoptotic pathway of cancer cells. Among them, the Bcl-2 protein family members Bcl-2, Bcl-xL and Mcl-1 have been identified as anti-tumor targets. Inhibiting these proteins can promote Bax/Bak oligomerization and ultimately induce mitochondrial outer membrane permeability, which subsequently causes The release of cytochrome c and the activation of caspases, thereby executing cancer cell apoptosis.
临床前研究表明抑制Bcl-2不能改善缺血性视网膜病变，而选择性抑制Bcl-xL可选择性杀伤衰老细胞，抑制由此引发的衰老相关分泌表型，抑制病理性血管新生和增强无血管区的血管恢复(Cell Metabolism 33,818–832,April 6,2021)；同时由于Bcl-2是多种细胞生存依赖的分子，若同时抑制Bcl-xL和Bcl-2可能引起眼部正常组织和细胞的凋亡，引起眼部进一步病变；因此开发选择性Bcl-xL抑制剂用于治疗视网膜病变相关眼部疾病有望带来更大的临床获益和相对更小的毒副作用。Preclinical studies have shown that inhibiting Bcl-2 cannot improve ischemic retinopathy, while selective inhibition of Bcl-xL can selectively kill senescent cells, inhibit the resulting aging-related secretory phenotype, inhibit pathological angiogenesis and enhance avascularity. (Cell Metabolism 33, 818–832, April 6, 2021); at the same time, because Bcl-2 is a molecule that many cells depend on for survival, if Bcl-xL and Bcl-2 are inhibited at the same time, it may cause damage to normal tissues and cells in the eye. Apoptosis, causing further eye disease; therefore, the development of selective Bcl-xL inhibitors for the treatment of retinopathy-related eye diseases is expected to bring greater clinical benefits and relatively less toxic side effects.
因此，有必要开发新型的Bcl-xL抑制剂药物，用于治疗与细胞凋亡相关的疾病。Therefore, it is necessary to develop new Bcl-xL inhibitor drugs for the treatment of apoptosis-related diseases.
发明内容Contents of the invention
本发明的目的就是提供一类杂环类化合物或其药学上可接受的盐，将其应用于Bcl-2或Bcl-xL抑制剂。本发明中的化合物能有效抑制Bcl-2或Bcl-xL并可用于治疗肿瘤或眼部疾病等疾病。The object of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which can be used as Bcl-2 or Bcl-xL inhibitors. The compounds of the present invention can effectively inhibit Bcl-2 or Bcl-xL and can be used to treat tumors, eye diseases and other diseases.
本发明化合物具有选择性抑制Bcl-xL的作用，对丝裂霉素C诱导的SA-β-半乳糖苷酶染色的WI-38衰老细胞具有较好的抑制活性。本发明化合物在小鼠、大鼠、犬、猴中具有良好的药代动力学性能(如暴露量更好、更优的t1/2、CL等)，具有更好的肝微粒体稳定性。本发明化合物对MOLT-4细胞、NCI-H446细胞、Kasumi-1细胞有较好的增殖抑制活性且无明显的hERG和CYP抑制活性。The compound of the present invention has the effect of selectively inhibiting Bcl-xL, and has good inhibitory activity on WI-38 senescent cells stained with SA-β-galactosidase induced by mitomycin C. The compound of the present invention has good pharmacokinetic properties (such as better exposure, better t 1/2 , CL, etc.) in mice, rats, dogs, and monkeys, and has better liver microsome stability. . The compound of the present invention has good proliferation inhibitory activity on MOLT-4 cells, NCI-H446 cells, and Kasumi-1 cells and has no obvious hERG and CYP inhibitory activity.
本发明提供一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中
The present invention provides a compound described in general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
在一些实施方案中，环A、环C、环D各自独立的选自C6-10芳基或5至10元杂芳基，所述环A任选被1至4个Ra取代，所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代；In some embodiments, Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, and Ring A is optionally substituted by 1 to 4 Ra , so The ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
在一些实施方案中，环A、环C、环D各自独立的选自苯基、苯并C4-6碳环基、苯并5至6元杂环基、5至6元杂芳基、9至10元杂芳基，所述环A任选被1至4个Ra取代，所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代；In some embodiments, Ring A, Ring C, and Ring D are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 9 to 10 membered heteroaryl, the ring A is optionally substituted by 1 to 4 R a , the ring C is optionally substituted by 1 to 4 R c , the ring D is optionally substituted by 1 to 4 R d replace;
在一些实施方案中，环A选自 所述环A任选被1至4个Ra取代；In some embodiments, Ring A is selected from The ring A is optionally substituted by 1 to 4 Ra ;
在一些实施方案中，环C、环D各自独立的选自 所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代；In some embodiments, Ring C and Ring D are each independently selected from The ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
在一些实施方案中，B选自-B1-、-N(Rn)-B1-、-B1-N(Rn)-；In some embodiments, B is selected from -B 1 -, -N(R n )-B 1 -, -B 1 -N(R n )-;
在一些实施方案中，B选自-B1-、-N(CH3)-B1-、-B1-N(CH3)-；In some embodiments, B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
在一些实施方案中，B1选自4至12元杂环基，所述杂环基任选被1至10个Rb取代；In some embodiments, B is selected from 4 to 12 membered heterocyclyl, which is optionally substituted by 1 to 10 R b ;
在一些实施方案中，B1选自4至7元含氮单环杂环基、5至10元含氮并环杂环基、5至11元含氮螺环杂环基、5至11元含氮桥环杂环基，所述B1任选被1至8个Rb取代；In some embodiments, B 1 is selected from the group consisting of 4- to 7-membered nitrogen-containing monocyclic heterocyclyl, 5- to 10-membered nitrogen-containing paracyclic heterocyclyl, 5- to 11-membered nitrogen-containing spirocyclic heterocyclyl, 5- to 11-membered nitrogen-containing spirocyclic heterocyclyl, Nitrogen-containing bridged ring heterocyclyl, the B 1 is optionally substituted by 1 to 8 R b ;
在一些实施方案中，B1选自氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环己烯基、氮杂环庚基、氮杂环丁基螺环丙基、氮杂环戊基螺环丙基、氮杂环己基螺环丙基、氮杂环丁基螺环丁基、氮杂环戊基螺环丁基、氮杂环己基螺环丁基、氮杂环丁基螺环戊基、氮杂环戊基螺环戊基、氮杂环己基螺环戊基、氮杂环丁基螺环己基、氮杂环戊基螺环己基、氮杂环己基螺环己基、氮杂环丁基螺氮杂环丁基、氮杂环戊基螺氮杂环丁基、氮杂环己基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环戊基螺氮杂环戊基、氮杂环己基螺氮杂环戊基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环己基螺氮杂环己基、哌嗪螺环丙基、哌嗪螺环丁基、哌嗪螺环戊基、哌嗪螺环己基、哌嗪螺氮杂环丙基、哌嗪螺氮杂环丁基、哌嗪螺氮杂环戊基、哌嗪螺氮杂环己基、氮杂环丁基并环丙基、氮杂环戊基并环丙基、氮杂环己基并环丙基、氮杂环丁基并环丁基、氮杂 环戊基并环丁基、氮杂环己基并环丁基、氮杂环丁基并环戊基、氮杂环戊基并环戊基、氮杂环己基并环戊基、氮杂环丁基并环己基、氮杂环戊基并环己基、氮杂环己基并环己基、氮杂环丁基并氮杂环丁基、氮杂环戊基并氮杂环丁基、氮杂环己基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环戊基并氮杂环戊基、氮杂环己基并氮杂环戊基、氮杂环丁基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环己基并氮杂环己基、哌嗪并环丙基、哌嗪并环丁基、哌嗪并环戊基、哌嗪并环己基、哌嗪螺并杂环丙基、哌嗪并氮杂环丁基、哌嗪并氮杂环戊基、哌嗪并氮杂环己基、3,8-二氮杂双环[3.2.1]辛烷基、3-氮杂双环[3.2.1]辛烷基、8-氮杂双环[3.2.1]辛烷基、2,5-二氮杂双环[2.2.1]庚烷基、2-氮杂双环[2.2.1]庚烷基、5-氮杂双环[2.2.1]庚烷基、3-氮杂双环[3.1.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、3,6-二氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.3.1]壬烷基、3,7-二氮杂双环[3.3.1]壬烷基，所述B1任选被1至8个Rb取代；In some embodiments, B is selected from azetidinyl, azetipentyl, azehexyl, azepanyl, azepanyl, azetidinylspirocyclopropyl, Azetidinylspirocyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidine cyclobutylspirocyclopentyl, azetidinylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl Cyclohexyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, Azetidine spiroazepinyl, azetidinyl spiroazepinyl, azetidinyl spiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl Azepanyl, piperazinespirocyclopropyl, piperazinespirocyclobutyl, piperazinespirocyclopentyl, piperazinespirocyclohexyl, piperazinespiroazetipropyl, piperazinespiroazetidinyl, Piperazinespiroazepinyl, piperazinespiroazepinyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidine Cyclobutyl, aza cyclopentacyclobutyl, azetidinolocyclobutyl, azetidinolocyclopentyl, azetidinolocyclopentyl, azetidinolocyclopentyl, azetidine azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl Azetidinyl, azetidinyl azepanyl, azetidinyl azepanyl, azetidinyl azepanyl, azetidinyl azepine Cyclohexyl, azepanyl azepanyl, azepanyl azepanyl, piperazinocyclopropyl, piperazinocyclobutyl, piperazinocyclopentyl, piperazinocyclohexyl , piperazinospirocyclopropyl, piperazonaazetidinyl, piperazonaazeticyclopentyl, piperazonaazeticyclohexyl, 3,8-diazabicyclo[3.2.1]octyl Alkyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 2- Azabicyclo[2.2.1]heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1] Heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-azabicyclo[3.3.1]nonyl, 3,7-diazabicyclo[3.3.1]nonane group, the B 1 is optionally substituted by 1 to 8 R b ;
在一些实施方案中，B1选自 所述B1任选被1至8个Rb取代；In some embodiments, B1 is selected from The B 1 is optionally substituted by 1 to 8 R b ;
在一些实施方案中，选自 左侧与环A连接；In some embodiments, Selected from The left side is connected to ring A;
在一些实施方案中，选自 左侧与环C连接；In some embodiments, Selected from The left side is connected to ring C;
在一些实施方案中，X选自-N(Rx)S(＝O)2-、-S(＝O)2N(Rx)-、 左侧与环C连接；In some embodiments, X is selected from -N( Rx )S(=O) 2- , -S(=O) 2N ( Rx )-, The left side is connected to ring C;
在一些实施方案中，X选自-NHS(＝O)2-，左侧与环C连接；In some embodiments, X is selected from -NHS(=O) 2- , connected to ring C on the left;
在一些实施方案中，K选自5元杂芳基，所述K被1至3个Rk1、1个Rk2取代；In some embodiments, K is selected from 5-membered heteroaryl, and K is substituted by 1 to 3 R k1 , 1 R k2 ;
在一些实施方案中，K选自 In some embodiments, K is selected from
在一些实施方案中，Rx选自H、C1-6烷基或C3-6环烷基；In some embodiments, Rx is selected from H, C 1-6 alkyl, or C 3-6 cycloalkyl;
在一些实施方案中，Rx选自H；In some embodiments, Rx is selected from H;
在一些实施方案中，Rn选自H、C1-6烷基、-C1-4亚烷基-C3-6环烷基，所述的烷基、亚烷基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基的取代基所取代；In some embodiments, Rn is selected from H, C 1-6 alkyl, -C 1-4 alkylene-C 3-6 cycloalkyl, and the alkyl, alkylene or cycloalkyl is any Selected from 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C Substituted with 1-6 alkyl and C 1-6 alkoxy substituents;
在一些实施方案中，Rn选自H、C1-4烷基；In some embodiments, Rn is selected from H, C 1-4 alkyl;
在一些实施方案中，Rn选自H、甲基、乙基；In some embodiments, Rn is selected from H, methyl, ethyl;
在一些实施方案中，Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳 环基或4至10元杂环基的取代基所取代；In some embodiments, R a , R b , R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 1-6 alkoxy group, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10-membered heterocyclic ring, the -CH 2 -, alkyl group, alkene group base, alkynyl, alkoxy, carbocyclic or heterocyclic ring optionally substituted by 1 to 4 C 1-6 alkyl groups selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen, Hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbon Substituted by a substituent of a cyclic group or a 4 to 10-membered heterocyclyl group;
或者任意的Rb与Rc直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
或者任意的Rb与Ra直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
在一些实施方案中，Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；In some embodiments, R a , R b , R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne base, C 1-4 alkoxy group, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl group, alkene group base, alkynyl, alkoxy, carbocyclic or heterocyclic ring optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen, Hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocycle Substituted by the substituent of the base;
或者任意的Rb与Rc直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
或者任意的Rb与Ra直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
在一些实施方案中，任意的Rb与Rc直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；In some embodiments, any R b and R c are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 R a1 ;
在一些实施方案中，任意的Rb与Ra直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；In some embodiments, any R b and R a are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 R a1 ;
在一些实施方案中，Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基或C3-6环烷基，所述的烷基、炔基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R a , R b , and R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen group or C 3-6 cycloalkyl group, the alkyl group, alkynyl group, alkoxy group or cycloalkyl group is optionally substituted by 1 to 4 selected from halogen, OH, cyano group, NH 2 , C 1-4 Alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C Substituted with 3-6 cycloalkyl substituents;
在一些实施方案中，Ra、Rb、Rc各自独立的选自氘、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R a , R b , R c are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, Butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, Propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally Substituted by 1 to 4 substituents selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl ;
在一些实施方案中，Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代，所述的烷基、炔基、烷氧基、碳环基或杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；In some embodiments, R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3 -10 carbocyclyl or 4 to 10 membered heterocyclyl substituents substituted, the alkyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 2-6 Substituted by alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents;
在一些实施方案中，Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基，所述的烷基、炔基、烷氧基、碳环基或杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；In some embodiments, R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3 -6 carbocyclyl or 4 to 7-membered heterocyclyl, the alkyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1 -Substituted with a substituent of -4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
在一些实施方案中，Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基或C3-6环烷基，所述的烷基、炔基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, each R a1 is independently selected from halogen, OH, cyano, NH 2 , =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, or C 3 -6 cycloalkyl, the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted by the substituent of the base;
在一些实施方案中，Ra1各自独立的选自F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、 环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R a1 is each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propyl Alkynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclohexyl Butyl, cyclopentyl, and cyclohexyl are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, Substituted with C 3-6 cycloalkyl substituent;
在一些实施方案中，Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-O-C3-6环烷基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环、-S(＝O)2R1、-S(＝O)2NR1R2、-C(＝O)NR1R2、C(＝O)NR1S(＝O)2R3、-C(＝O)R1，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、碳环或杂环任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；In some embodiments, R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -OC 3-6 cycloalkyl, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q - 4 to 10 membered heterocycle, -S(＝O) 2 R 1 , -S(＝O) 2 NR 1 R 2 , -C(＝O)NR 1 R 2 , C(＝O)NR 1 S(＝ O) 2 R 3 , -C(=O)R 1 , the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic groups are any Selected from 1 to 4 selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, Substituted by cyano-substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents;
在一些实施方案中，Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C3-6环烷基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环、-S(＝O)2R1、-S(＝O)2NR1R2、-C(＝O)NR1R2、C(＝O)NR1S(＝O)2R3、-C(＝O)R1，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、碳环或杂环任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；In some embodiments, R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -OC 3-6 cycloalkyl, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q - 4 to 7-membered heterocycle, -S(＝O) 2 R 1 , -S(＝O) 2 NR 1 R 2 , -C(＝O)NR 1 R 2 , C(＝O)NR 1 S(＝ O) 2 R 3 , -C(=O)R 1 , the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic groups are any Selected from 1 to 4 selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, Substituted by cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl substituents;
在一些实施方案中，Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-4烷基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C3-6环烷基、C3-6环烷基、-CH2-C3-6环烷基、-S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2C1-4烷基、-S(＝O)2-C3-6环烷基、-S(＝O)2NHC1-4烷基、-C(＝O)C1-4烷基、-C(＝O)-C3-6环烷基、-C(＝O)NHC1-4烷基，所述的-CH2-、烷基、炔基、烷氧基、烷硫基、环烷基任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkynyl, C 1- 4 alkoxy group, C 1-4 alkylthio group, -OC 3-6 cycloalkyl group, C 3-6 cycloalkyl group, -CH 2 -C 3-6 cycloalkyl group, -S(=O) 2 NH 2. -C(=O)NH 2 , -S(=O) 2 C 1-4 alkyl, -S(=O) 2 -C 3-6 cycloalkyl, -S(=O) 2 NHC 1 -4 alkyl, -C(=O)C 1-4 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)NHC 1-4 alkyl, the - CH 2 -, alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl optionally 1 to 4 selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-4 alkyl base, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3 -6 substituted by cycloalkyl substituent;
在一些实施方案中，Rk1a选自COOH、S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2-甲基、-S(＝O)2-乙基、-S(＝O)2NH-甲基、-S(＝O)2NH-乙基、-C(＝O)-甲基、-C(＝O)-乙基、-C(＝O)NH-甲基、-C(＝O)NH-乙基，所述的甲基或乙基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R k1a is selected from COOH, S(=O) 2 NH 2 , -C(=O)NH 2 , -S(=O) 2 -methyl, -S(=O) 2 -ethyl base, -S(=O) 2 NH-methyl, -S(=O) 2 NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(= O)NH-methyl, -C(=O)NH-ethyl, the methyl or ethyl group is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl Substituted with substituents of base, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
在一些实施方案中，Rk1a选自COOH；In some embodiments, Rkla is selected from COOH;
在一些实施方案中，Rk1b选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propyne base, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene group, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , substituted by hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
在一些实施方案中，Rk1b选自甲基、乙基、丙基、异丙基、环丙基、-CH2-环丙基；In some embodiments, R k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl;
在一些实施方案中，Rk1c选自氘、CD3、H、甲基、乙基、丙基、异丙基、丁基、环丙基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, Rk1c is selected from deuterium, CD3 , H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl Propyl, butyl, and cyclopropyl are optionally selected from 1 to 4 deuterium, CD 3 , halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2- Substituted with 4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
在一些实施方案中，Rk1c选自甲基、乙基、丙基、异丙基、 -CH2-CF3、-CH2-环丙基、环丙基；In some embodiments, R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
在一些实施方案中，Rd各自独立的选自F、Cl、Br、I、氰基、OH、NO2、COOH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、-S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2-甲基、-S(＝O)2-乙基、-S(＝O)2NH-甲基、-S(＝O)2NH-乙基、-C(＝O)-甲基、-C(＝O)-乙基、-C(＝O)NH-甲基、-C(＝O)NH-乙基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R d is each independently selected from F, Cl, Br, I, cyano, OH, NO 2 , COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl , ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O) 2 NH 2 , -C(=O)NH 2 , -S(=O) 2 -methyl, -S(=O) 2 -ethyl, -S(=O) 2 NH-methyl, -S(=O) 2 NH-ethyl, -C( =O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, the methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally replaced by 1 to Substituted by 4 substituents selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
在一些实施方案中，R1、R2、R3各自独立的选自H、C1-6烷基、C3-10碳环基或4至10元杂环基，所述的烷基、碳环基或者杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；In some embodiments, R 1 , R 2 , and R 3 are each independently selected from H, C 1-6 alkyl, C 3-10 carbocyclyl, or 4 to 10-membered heterocyclyl, and the alkyl, The carbocyclyl or heterocyclic group is optionally substituted by 1 to 4 carbon atoms selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and hydroxyl-substituted C 1-6 Substituted by alkyl, cyano-substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents;
在一些实施方案中，R1、R2、R3各自独立的选自H、C1-4烷基、C3-6碳环或4至7元杂环，所述的烷基、碳环或者杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；In some embodiments, R 1 , R 2 , and R 3 are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclic ring, or 4 to 7-membered heterocyclic ring, and the alkyl group, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano Substituted with substituents of C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
在一些实施方案中，Z选自-CH(Rz1)CH2-S-Rz2或-CH(Rz1)CH2-Se-Rz2；In some embodiments, Z is selected from -CH(R z1 )CH 2 -SR z2 or -CH(R z1 )CH 2 -Se-R z2 ;
在一些实施方案中，Rz1选自-C1-4亚烷基-Z1-Rz3；In some embodiments, R z1 is selected from -C 1-4alkylene -Z 1 -R z3 ;
在一些实施方案中，Rz1选自-CH2CH2-Z1-Rz3；In some embodiments, R z1 is selected from -CH 2 CH 2 -Z 1 -R z3 ;
在一些实施方案中，Z1选自4至12元杂环基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；In some embodiments, Z1 is selected from 4 to 12 membered heterocyclyl, and Z1 is optionally selected from 1 to 4 Rz1a or optionally 1 selected from -OP(=O)(OH) 2 or Substituted with -CH 2 OP(=O)(OH) 2 substituent;
在一些实施方案中，Z1选自4至7元含氮杂单环、5至10含氮并环杂环基、5至11元含氮螺环杂环基、5至11元含氮桥环杂环基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；In some embodiments, Z1 is selected from the group consisting of 4 to 7-membered nitrogen-containing heteromonocycle, 5-10-membered nitrogen-containing paracyclic heterocyclyl, 5-11-membered nitrogen-containing spirocyclic heterocyclyl, 5-11-membered nitrogen-containing bridge Cyclic heterocyclyl, the Z 1 is optionally replaced by 1 to 4 R z1a or optionally 1 selected from -OP(=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 Substituted by substituents;
在一些实施方案中，Z1选自氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环己烯基、氮杂环庚基、氮杂环丁基螺环丙基、氮杂环戊基螺环丙基、氮杂环己基螺环丙基、氮杂环丁基螺环丁基、氮杂环戊基螺环丁基、氮杂环己基螺环丁基、氮杂环丁基螺环戊基、氮杂环戊基螺环戊基、氮杂环己基螺环戊基、氮杂环丁基螺环己基、氮杂环戊基螺环己基、氮杂环己基螺环己基、氮杂环丁基并环丙基、氮杂环戊基并环丙基、氮杂环己基并环丙基、氮杂环丁基并环丁基、氮杂环戊基并环丁基、氮杂环己基并环丁基、氮杂环丁基并环戊基、氮杂环戊基并环戊基、氮杂环己基并环戊基、氮杂环丁基并环己基、氮杂环戊基并环己基、氮杂环己基并环己基、3-氮杂双环[3.2.1]辛烷基、8-氮杂双环[3.2.1]辛烷基、2-氮杂双环[2.2.1]庚烷基、5-氮杂双环[2.2.1]庚烷基、3-氮杂双环[3.1.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.3.1]壬烷基、3-氧杂-7-氮杂双环[3.3.1]壬烷基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；In some embodiments, Z 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, Azetidinylspirocyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidine cyclobutylspirocyclopentyl, azetidinylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl Cyclohexyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidinylcyclobutyl, azetidinylcyclobutyl base, azetidinolocyclobutyl, azetidinolocyclopentyl, azetidinolocyclopentyl, azetidinolocyclopentyl, azetidinolocyclohexyl, nitrogen Heterocyclopentacyclohexyl, azacyclohexylcyclohexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[ 2.2.1]heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-Azabicyclo[3.3.1]nonyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, the Z 1 is optionally replaced by 1 to 4 R z1a or optionally Substituted with 1 substituent selected from -OP(=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 ;
在一些实施方案中，Z1选自 所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；In some embodiments, Z1 is selected from The Z 1 is optionally substituted by 1 to 4 R z1a or optionally by 1 substituent selected from -OP(=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 ;
在一些实施方案中，Rk2、Rz2各自独立的选自C6-10芳基或5至10元杂芳基，所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；In some embodiments, R k2 and R z2 are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, and the R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 optionally substituted by 1 to 4 R z2a ;
在一些实施方案中，Rk2、Rz2各自独立的选自苯基、苯并C4-6碳环基、苯并5至6元杂环基、5至6元杂芳基、9至10元杂芳基，所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；In some embodiments, R k2 and R z2 are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 9 to 10 Metaheteroaryl, the R k2 is optionally substituted by 1 to 4 R k2a , the R z2 is optionally substituted by 1 to 4 R z2a ;
在一些实施方案中，Rk2、Rz2各自独立的选自苯基、吡啶、 所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；In some embodiments, R k2 and R z2 are each independently selected from phenyl, pyridine, The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
在一些实施方案中，Rz1a、Rk2a、Rz2a各自独立的选自卤素、氰基、OH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；In some embodiments, R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy group, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10 membered heterocyclic ring, the -CH 2 -, alkyl group, alkenyl group, alkynyl group, The alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1 groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-6 alkyl group, and hydroxyl group. -6 alkyl, cyano substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents replace;
在一些实施方案中，Rz1a、Rk2a、Rz2a各自独立的选自卤素、氰基、OH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；In some embodiments, R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy group, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl group, alkenyl group, alkynyl group, The alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1 groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-4 alkyl group, and hydroxyl group. -4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7 membered heterocyclyl substituents replace;
在一些实施方案中，Rz1a、Rk2a、Rz2a各自独立的选自F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基，所述甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R z1a , R k2a , R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl , tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl optionally 1 to 4 selected from halogen, OH Substituted with substituents of , cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
在一些实施方案中，Rz1a、Rk2a、Rz2a各自独立的选自F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、 In some embodiments, R z1a , R k2a , R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl , tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
在一些实施方案中，Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2、-OP(＝O)(OH)(OC1-6烷基)、-CH2OP(＝O)(OH)(OC1-6烷基)、-OP(＝O)(OC1-6烷基)2、-CH2OP(＝O)(OC1-6 烷基)2；In some embodiments, R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 , -OP(=O)(OH )(OC 1-6 alkyl), -CH 2 OP(=O)(OH)(OC 1-6 alkyl), -OP(=O)(OC 1-6 alkyl) 2 , -CH 2 OP (＝O)(OC 1-6 alkyl) 2 ;
在一些实施方案中，Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2；In some embodiments, R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 ;
在一些实施方案中，q各自独立的选自0、1、2、3或4；In some embodiments, each q is independently selected from 0, 1, 2, 3, or 4;
在一些实施方案中，q各自独立的选自0、1、2；In some embodiments, q is each independently selected from 0, 1, and 2;
在一些实施方案中，p1、p2、p3各自独立的0、1、2或3；In some embodiments, p1, p2, and p3 are each independently 0, 1, 2, or 3;
在一些实施方案中，选自 In some embodiments, Selected from
任意地，casually,
1)当B选自时，B被1至8个Rb取代；1) When B is selected from When, B is replaced by 1 to 8 R b ;
或2)当B选自未取代的并且Z1选自通过氮原子与亚烷基连接的4至7元单环杂环基时，Z1被1至4个Rz1a取代；or 2) when B is selected from unsubstituted And when Z 1 is selected from a 4 to 7-membered monocyclic heterocyclyl group connected to an alkylene group through a nitrogen atom, Z 1 is substituted by 1 to 4 R z1a ;
所述通式(I)化合物任选被1至20个氘取代。The compounds of general formula (I) are optionally substituted by 1 to 20 deuteriums.
作为本发明的第一种实施方案，下述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a first embodiment of the present invention, the compound represented by the following general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
环A、环C、环D各自独立的选自C6-10芳基或5至10元杂芳基，所述环A任选被1至4个Ra取代，所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代；Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, the ring A is optionally substituted by 1 to 4 R a , and the ring C is optionally substituted by 1 to 4 R c substitutes, and the ring D is optionally substituted with 1 to 4 R d ;
B选自-B1-、-N(Rn)-B1-、-B1-N(Rn)-；B is selected from -B 1 -, -N(R n )-B 1 -, -B 1 -N(R n )-;
B1选自4至12元杂环基，所述杂环基任选被1至10个Rb取代；B 1 is selected from 4 to 12 membered heterocyclyl groups, which are optionally substituted by 1 to 10 R b ;
X选自-N(Rx)S(＝O)2-、-S(＝O)2N(Rx)-、左侧与环C连接；X is selected from -N(R x )S(=O) 2 -, -S(=O) 2 N(R x )-, The left side is connected to ring C;
K选自5元杂芳基，所述K被1至3个Rk1、1个Rk2取代；K is selected from a 5-membered heteroaryl group, and the K is substituted by 1 to 3 R k1 and 1 R k2 ;
Rx选自H、C1-6烷基或C3-6环烷基；R x is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl;
Rn选自H、C1-6烷基、-C1-4亚烷基-C3-6环烷基，所述的烷基、亚烷基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基的取代基所取代；R n is selected from H, C 1-6 alkyl, -C 1-4 alkylene-C 3-6 cycloalkyl, and the alkyl, alkylene or cycloalkyl is optionally substituted by 1 to 4 Selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, Substituted with C 1-6 alkoxy substituents;
Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R a , R b , and R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Alkoxy group, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkyl The oxygen group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1-6 alkyl groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-6 alkyl group, and hydroxyl group. Substituted by 6 alkyl, cyano substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents ;
或者任意的Rb与Rc直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
或者任意的Rb与Ra直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代，所述的烷基、炔基、烷氧基、碳环基或杂环基任选 被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or Substituted with substituents of 4 to 10 membered heterocyclic groups, the alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic groups are optional C 1 substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano Substituted with a substituent of -6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10-membered heterocyclyl;
Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-O-C3-6环烷基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环、-S(＝O)2R1、-S(＝O)2NR1R2、-C(＝O)NR1R2、C(＝O)NR1S(＝O)2R3、-C(＝O)R1，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、碳环或杂环任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy group, C 1-6 alkylthio group, -OC 3-6 cycloalkyl group, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10-membered heterocyclic ring , -S(＝O) 2 R 1 , -S(＝O) 2 NR 1 R 2 , -C(＝O)NR 1 R 2 , C(＝O)NR 1 S(＝O) 2 R 3 , -C(=O)R 1 , the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 Selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1 Substituted with a substituent of -6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10-membered heterocyclyl;
R1、R2、R3各自独立的选自H、C1-6烷基、C3-10碳环基或4至10元杂环基，所述的烷基、碳环基或者杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R 1 , R 2 , and R 3 are each independently selected from H, C 1-6 alkyl, C 3-10 carbocyclyl, or 4 to 10-membered heterocyclyl. The alkyl, carbocyclyl, or heterocyclic The group is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano Substituted with substituents of C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl;
Z选自-CH(Rz1)CH2-S-Rz2或-CH(Rz1)CH2-Se-Rz2；Z is selected from -CH(R z1 )CH 2 -SR z2 or -CH(R z1 )CH 2 -Se-R z2 ;
Rz1选自-C1-4亚烷基-Z1-Rz3；R z1 is selected from -C 1-4 alkylene -Z 1 -R z3 ;
Z1选自4至12元杂环基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from 4 to 12-membered heterocyclyl, and Z 1 is optionally selected from 1 to 4 R z1a or optionally 1 selected from -OP(=O)(OH) 2 or -CH 2 OP(= Substituted with O)(OH) 2 substituent;
Rk2、Rz2各自独立的选自C6-10芳基或5至10元杂芳基，所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；R k2 and R z2 are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, the R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a substitution;
Rz1a、Rk2a、Rz2a各自独立的选自卤素、氰基、OH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, - (CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10 membered heterocyclic ring, the -CH 2 -, alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano Substituted with substituents of C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl;
Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2、-OP(＝O)(OH)(OC1-6烷基)、-CH2OP(＝O)(OH)(OC1-6烷基)、-OP(＝O)(OC1-6烷基)2、-CH2OP(＝O)(OC1-6烷基)2；R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 , -OP(=O)(OH)(OC 1-6 Alkyl), -CH 2 OP(=O)(OH)(OC 1-6 alkyl), -OP(=O)(OC 1-6 alkyl) 2 , -CH 2 OP(=O)(OC 1-6 alkyl) 2 ;
q各自独立的选自0、1、2、3或4；q is independently selected from 0, 1, 2, 3 or 4;
条件是，requirement is,
1)当B选自时，B被1至8个Rb取代；1) When B is selected from When, B is replaced by 1 to 8 R b ;
或2)当B选自未取代的并且Z1选自通过氮原子与亚烷基连接的4至7元单环杂环基时，Z1被1至4个Rz1a取代；or 2) when B is selected from unsubstituted And when Z 1 is selected from a 4 to 7-membered monocyclic heterocyclyl group connected to an alkylene group through a nitrogen atom, Z 1 is substituted by 1 to 4 R z1a ;
所述通式(I)化合物任选被1至20个氘取代。The compounds of general formula (I) are optionally substituted by 1 to 20 deuteriums.
作为本发明的第二种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
环A、环C、环D各自独立的选自苯基、苯并C4-6碳环基、苯并5至6元杂环基、5至6元杂芳基、9至10元杂芳基，所述环A任选被1至4个Ra取代，所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代； Ring A, ring C, and ring D are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and 9- to 10-membered heteroaryl base, the ring A is optionally substituted by 1 to 4 R a , the ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
B1选自4至7元含氮单环杂环基、5至10元含氮并环杂环基、5至11元含氮螺环杂环基、5至11元含氮桥环杂环基，所述B1任选被1至8个Rb取代；B 1 is selected from the group consisting of 4 to 7-membered nitrogen-containing monocyclic heterocyclyl, 5- to 10-membered nitrogen-containing paracyclic heterocyclyl, 5- to 11-membered nitrogen-containing spirocyclic heterocyclyl, and 5- to 11-membered nitrogen-containing bridged heterocyclic ring. group, the B 1 is optionally substituted by 1 to 8 R b ;
Rn选自H、C1-4烷基；R n is selected from H, C 1-4 alkyl;
X选自-NHS(＝O)2-，左侧与环C连接；X is selected from -NHS(=O) 2 -, and the left side is connected to ring C;
Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R a , R b , and R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy group, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkyl The oxygen group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-4 alkyl group, and hydroxyl group. Substituted by 4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7 membered heterocyclyl substituents ;
或者任意的Rb与Rc直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
或者任意的Rb与Ra直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基，所述的烷基、炔基、烷氧基、碳环基或杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclic group, the alkyl group, alkynyl group, alkoxy group, carbocyclyl group or heterocyclic group is optionally substituted by 1 to 4 members selected from halogen, OH, cyano group, NH 2 , C 1- 4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, Substituted with a substituent of C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C3-6环烷基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环、-S(＝O)2R1、-S(＝O)2NR1R2、-C(＝O)NR1R2、C(＝O)NR1S(＝O)2R3、-C(＝O)R1，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、碳环或杂环任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy group, C 1-4 alkylthio group, -OC 3-6 cycloalkyl group, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring , -S(＝O) 2 R 1 , -S(＝O) 2 NR 1 R 2 , -C(＝O)NR 1 R 2 , C(＝O)NR 1 S(＝O) 2 R 3 , -C(=O)R 1 , the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 Selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1 Substituted with a substituent of -4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
R1、R2、R3各自独立的选自H、C1-4烷基、C3-6碳环或4至7元杂环，所述的烷基、碳环或者杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R 1 , R 2 , and R 3 are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclic ring or 4 to 7-membered heterocyclic ring. The alkyl group, carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1- Substituted with a substituent of 4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
Z1选自4至7元含氮杂单环、5至10含氮并环杂环基、5至11元含氮螺环杂环基、5至11元含氮桥环杂环基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from the group consisting of 4 to 7 membered nitrogen-containing heteromonocyclic groups, 5 to 10 membered nitrogen-containing paracyclic heterocyclic groups, 5 to 11 membered nitrogen-containing spirocyclic heterocyclic groups, and 5 to 11 membered nitrogen-containing bridged cyclic heterocyclic groups, so The Z 1 is optionally substituted by 1 to 4 R z1a or optionally by 1 substituent selected from -OP(=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 ;
Rk2、Rz2各自独立的选自苯基、苯并C4-6碳环基、苯并5至6元杂环基、5至6元杂芳基、9至10元杂芳基，所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；R k2 and R z2 are each independently selected from phenyl, benzo C 4-6 carbocyclic group, benzo 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, and 9- to 10-membered heteroaryl group, so The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
Rz1a、Rk2a、Rz2a各自独立的选自卤素、氰基、OH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, - (CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano Substituted with substituents of C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2；R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 ;
q各自独立的选自0、1、2；q is independently selected from 0, 1, and 2;
其余基团定义与第一种实施方案相同。 The remaining group definitions are the same as in the first embodiment.
作为本发明的第三种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
B1选自氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环己烯基、氮杂环庚基、氮杂环丁基螺环丙基、氮杂环戊基螺环丙基、氮杂环己基螺环丙基、氮杂环丁基螺环丁基、氮杂环戊基螺环丁基、氮杂环己基螺环丁基、氮杂环丁基螺环戊基、氮杂环戊基螺环戊基、氮杂环己基螺环戊基、氮杂环丁基螺环己基、氮杂环戊基螺环己基、氮杂环己基螺环己基、氮杂环丁基螺氮杂环丁基、氮杂环戊基螺氮杂环丁基、氮杂环己基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环戊基螺氮杂环戊基、氮杂环己基螺氮杂环戊基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环己基螺氮杂环己基、哌嗪螺环丙基、哌嗪螺环丁基、哌嗪螺环戊基、哌嗪螺环己基、哌嗪螺氮杂环丙基、哌嗪螺氮杂环丁基、哌嗪螺氮杂环戊基、哌嗪螺氮杂环己基、氮杂环丁基并环丙基、氮杂环戊基并环丙基、氮杂环己基并环丙基、氮杂环丁基并环丁基、氮杂环戊基并环丁基、氮杂环己基并环丁基、氮杂环丁基并环戊基、氮杂环戊基并环戊基、氮杂环己基并环戊基、氮杂环丁基并环己基、氮杂环戊基并环己基、氮杂环己基并环己基、氮杂环丁基并氮杂环丁基、氮杂环戊基并氮杂环丁基、氮杂环己基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环戊基并氮杂环戊基、氮杂环己基并氮杂环戊基、氮杂环丁基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环己基并氮杂环己基、哌嗪并环丙基、哌嗪并环丁基、哌嗪并环戊基、哌嗪并环己基、哌嗪螺并杂环丙基、哌嗪并氮杂环丁基、哌嗪并氮杂环戊基、哌嗪并氮杂环己基、3,8-二氮杂双环[3.2.1]辛烷基、3-氮杂双环[3.2.1]辛烷基、8-氮杂双环[3.2.1]辛烷基、2,5-二氮杂双环[2.2.1]庚烷基、2-氮杂双环[2.2.1]庚烷基、5-氮杂双环[2.2.1]庚烷基、3-氮杂双环[3.1.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、3,6-二氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.3.1]壬烷基、3,7-二氮杂双环[3.3.1]壬烷基，所述B1任选被1至8个Rb取代；B 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, azetidinylspiro Cyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl base, azetipentylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidine Butylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiro Azetipentyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl Piperazinespirocyclopropyl, piperazinespirocyclobutyl, piperazinespirocyclopentyl, piperazinespirocyclohexyl, piperazinespiroazetipropyl, piperazinespiroazetidinyl, piperazinespiroazetidine Pentyl, piperazinespiroazepanyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidinylcyclobutyl, Azetidylacyclobutyl, azetidylacyclobutyl, azetidylacyclobutyl, azetidylacyclopentyl, azetidylacyclopentyl, azepine cyclobutyl-cyclohexyl, azeti-cyclohexyl, azeti-cyclohexyl, azeti-cyclohexyl, azeti-cyclohexyl, azeti- Cyclohexyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl Azepanyl, azepanyl azepanyl, azepanyl azepanyl, piperazinocyclopropyl, piperazinocyclobutyl, piperazinocyclopentyl, piperazino Cyclohexyl, piperazinospirocyclopropyl, piperazonaazetidinyl, piperazonaazeticyclopentyl, piperazonaazeticyclohexyl, 3,8-diazabicyclo [3.2.1 ]octyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1. 1]Heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-azabicyclo[3.3.1]nonyl, 3,7-diazabicyclo[3.3.1] Nonyl, the B 1 is optionally substituted by 1 to 8 R b ;
Z1选自氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环己烯基、氮杂环庚基、氮杂环丁基螺环丙基、氮杂环戊基螺环丙基、氮杂环己基螺环丙基、氮杂环丁基螺环丁基、氮杂环戊基螺环丁基、氮杂环己基螺环丁基、氮杂环丁基螺环戊基、氮杂环戊基螺环戊基、氮杂环己基螺环戊基、氮杂环丁基螺环己基、氮杂环戊基螺环己基、氮杂环己基螺环己基、氮杂环丁基并环丙基、氮杂环戊基并环丙基、氮杂环己基并环丙基、氮杂环丁基并环丁基、氮杂环戊基并环丁基、氮杂环己基并环丁基、氮杂环丁基并环戊基、氮杂环戊基并环戊基、氮杂环己基并环戊基、氮杂环丁基并环己基、氮杂环戊基并环己基、氮杂环己基并环己基、3-氮杂双环[3.2.1]辛烷基、8-氮杂双环[3.2.1]辛烷基、2-氮杂双环[2.2.1]庚烷基、5-氮杂双环[2.2.1]庚烷基、3-氮杂双环[3.1.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.3.1]壬烷基、3-氧杂-7-氮杂双环[3.3.1]壬烷基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, azetidinylspiro Cyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl base, azetipentylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidine Butyl-cyclopropyl, azeti-cyclopropyl, azeti-cyclopropyl, azeti-cyclobutyl, azeti-cyclobutyl, aze-cyclohexyl cyclobutyl, azetidinylcyclohexyl, azetidinylcyclopentyl, azetidinylcyclohexyl, azetidinylcyclohexyl, azetidinylcyclopentyl Hexyl, azacyclohexylcyclohexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.1]heptane base, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[ 3.3.1]nonyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, the Z 1 is optionally replaced by 1 to 4 R z1a or optionally 1 is selected from -OP Substituted with (=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 substituents;
Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基或C3-6环烷基，所述的烷基、炔基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R a , R b , and R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy or C 3- 6 cycloalkyl, the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted by substituents;
Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基或C3-6环烷基，所述的烷基、炔基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧 基、C3-6环烷基的取代基所取代；R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy or C 3-6 cycloalkyl, The alkyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-4 alkyl selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, and halogen. group, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy Substituted with substituents of C 3-6 cycloalkyl group;
Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-4烷基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C3-6环烷基、C3-6环烷基、-CH2-C3-6环烷基、-S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2C1-4烷基、-S(＝O)2-C3-6环烷基、-S(＝O)2NHC1-4烷基、-C(＝O)C1-4烷基、-C(＝O)-C3-6环烷基、-C(＝O)NHC1-4烷基，所述的-CH2-、烷基、炔基、烷氧基、烷硫基、环烷基任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio group, -OC 3-6 cycloalkyl group, C 3-6 cycloalkyl group, -CH 2 -C 3-6 cycloalkyl group, -S(=O) 2 NH 2 , -C(= O)NH 2 , -S(=O) 2 C 1-4 alkyl, -S(=O) 2 -C 3-6 cycloalkyl, -S(=O) 2 NHC 1-4 alkyl, - C(=O)C 1-4 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)NHC 1-4 alkyl, the -CH 2 -, alkyl , alkynyl, alkoxy, alkylthio, cycloalkyl optionally substituted by 1 to 4 C selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted by substituents;
其余基团定义与本发明第一、第二种实施方案相同。The definitions of the remaining groups are the same as those in the first and second embodiments of the present invention.
作为本发明的第四种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
B选自-B1-、-N(CH3)-B1-、-B1-N(CH3)-；B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
B1选自 所述B1任选被1至8个Rb取代；B 1 selected from The B 1 is optionally substituted by 1 to 8 R b ;
环A选自 所述环A任选被1至4个Ra取代；Ring A is selected from The ring A is optionally substituted by 1 to 4 Ra ;
环C、环D各自独立的选自 所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代；Ring C and Ring D are each independently selected from The ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
或者选自 左侧与环A连接；or Selected from The left side is connected to ring A;
或者选自 左侧与环C连接；or Selected from The left side is connected to ring C;
Ra、Rb、Rc各自独立的选自氘、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R a , R b , R c are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl , ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally selected from 1 to 4 Substituted by halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
Ra1各自独立的选自F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、 乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R a1 is each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, Ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, Butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally selected from 1 to 4 halogen , OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
Rd各自独立的选自F、Cl、Br、I、氰基、OH、NO2、COOH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、-S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2-甲基、-S(＝O)2-乙基、-S(＝O)2NH-甲基、-S(＝O)2NH-乙基、-C(＝O)-甲基、-C(＝O)-乙基、-C(＝O)NH-甲基、-C(＝O)NH-乙基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R d is each independently selected from F, Cl, Br, I, cyano, OH, NO 2 , COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propyne base, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O) 2 NH 2 , -C(=O)NH 2 , -S(=O ) 2 -methyl, -S(=O) 2 -ethyl, -S(=O) 2 NH-methyl, -S(=O) 2 NH-ethyl, -C(=O)-methyl , -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, the methyl, ethyl, propyl, isopropyl, butyl base, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally 1 to 4 selected from halogen, Substituted with substituents of OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
Rz1选自-CH2CH2-Z1-Rz3；R z1 is selected from -CH 2 CH 2 -Z 1 -R z3 ;
Z1选自 所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 R z1a or optionally by 1 substituent selected from -OP(=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 ;
Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2；R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 ;
K选自 K is selected from
Rk1a选自COOH、S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2-甲基、-S(＝O)2-乙基、-S(＝O)2NH-甲基、-S(＝O)2NH-乙基、-C(＝O)-甲基、-C(＝O)-乙基、-C(＝O)NH-甲基、-C(＝O)NH-乙基，所述的甲基或乙基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R k1a is selected from COOH, S(=O) 2 NH 2 , -C(=O)NH 2 , -S(=O) 2 -methyl, -S(=O) 2 -ethyl, -S(= O) 2 NH-methyl, -S(=O) 2 NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl , -C(=O)NH-ethyl, the methyl or ethyl group is optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 Substituted by alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
Rk1b选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, Methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, Propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, and cyclopentyl are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C Substituted with substituents of 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
Rk1c选自氘、CD3、H、甲基、乙基、丙基、异丙基、丁基、环丙基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R k1c is selected from deuterium, CD 3 , H, methyl, ethyl, propyl, isopropyl, butyl, and cyclopropyl, and the methyl, ethyl, propyl, isopropyl, butyl, The cyclopropyl group is optionally selected from 1 to 4 deuterium, CD 3 , halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1 Substituted with -4 alkoxy and C 3-6 cycloalkyl substituents;
Rk2、Rz2各自独立的选自苯基、吡啶、 所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；R k2 and R z2 are each independently selected from phenyl, pyridine, The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
Rz1a、Rk2a、Rz2a各自独立的选自F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基，所述甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R z1a , R k2a , and R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene base, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl base, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
p1、p2、p3各自独立的0、1、2或3；p1, p2 and p3 are each independently 0, 1, 2 or 3;
其余基团定义与本发明第一、第二种或者第三种实施方案相同。The definitions of the remaining groups are the same as those in the first, second or third embodiment of the present invention.
作为本发明的第五种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Rk1a选自COOH；R k1a is selected from COOH;
Rk1c选自甲基、乙基、丙基、异丙基、-CH2-CF3、-CH2-环丙基、环丙基；R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
Rk1b选自甲基、乙基、丙基、异丙基、环丙基、-CH2-环丙基；R k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl;
Rz1a、Rk2a、Rz2a各自独立的选自F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、 R z1a , R k2a , and R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene base, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
选自 Selected from
其余基团定义与本发明第一、第二、三或四种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any one of the first, second, third or four embodiments of the present invention.
作为本发明的第六种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中通式(I)所示化合物选自通式(II-a)所示化合物，
As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein The compound represented by formula (I) is selected from the compounds represented by general formula (II-a),
B选自-B1-、-N(CH3)-B1-、-B1-N(CH3)-；B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
B1选自 所述B1任选被1至8个Rb取代；B 1 selected from The B 1 is optionally substituted by 1 to 8 R b ;
Rb各自独立的选自氘、F；R b are each independently selected from deuterium and F;
或者选自 or Selected from
Z1选自 所述Z1任选被1至4个F取代；Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 F;
Rk1c选自甲基、乙基、丙基、异丙基、-CH2-CF3、-CH2-环丙基、环丙基；R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
Rk2a选自F、Cl、甲基、乙基、环丙基； Rk2a is selected from F, Cl, methyl, ethyl, and cyclopropyl;
Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2。R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 .
作为本发明的第七种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中通式(I)所示化合物选自通式(III-a)或(III-b)所示化合物，

As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein The compound represented by formula (I) is selected from the compounds represented by general formula (III-a) or (III-b),

Rk1c选自甲基、乙基、丙基、异丙基、-CH2-CF3、-CH2-环丙基、环丙基；R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
Z1选自 所述Z1任选被1至4个F取代；Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 F;
Rk2a选自F、Cl、甲基、乙基、环丙基； Rk2a is selected from F, Cl, methyl, ethyl, and cyclopropyl;
Rz3选自-OH、-OP(＝O)(OH)2。R z3 is selected from -OH, -OP(=O)(OH) 2 .
本发明涉及如下所示的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1所示结构之一；The present invention relates to the compound shown below or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one;
表E-1












































Table E-1












































本发明涉及一种药物组合物，包括任意上述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，优选地，药物组合物中包含1-1500mg权前述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。The present invention relates to a pharmaceutical composition, including any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutically acceptable carriers, Preferably, the pharmaceutical composition contains 1-1500 mg of the aforementioned compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal.
本发明涉及一种药物组合物，包括治疗有效量的本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.
在一些实施方案中，本发明的药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如抑制Bcl-2或Bcl-xL相关疾病如肿瘤或眼部疾病)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望的改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、 70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg。"Effective amount" or "therapeutically effective amount" as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or disorder being treated (e.g., inhibiting Bcl-2 or Bcl- One or more symptoms of an xL-related disease such as a tumor or eye disease). In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg , 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90 -400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg , 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250 -300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.
在一些实施方案中，该药物组合物包括但不限于1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选抑制Bcl-2或Bcl-xL相关疾病(如肿瘤或眼部疾病)。A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable The therapeutically effective amount of the salt or co-crystal is preferably 1-1500 mg, and the disease preferably inhibits Bcl-2 or Bcl-xL related diseases (such as tumors or eye diseases).
一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以1-1000mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、80mg/天、100mg/天、125mg/天、150mg/天、160mg/天、200mg/天、300mg/天、320mg/天、400mg/天、480mg/天、600mg/天、640mg/天、800mg/天、1000mg/天。A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose. In some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量与上述药物组合物中其量相同。The present invention relates to a kit, which may include a composition in a single dose or multiple dose form. The kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical The amount of the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as that in the above pharmaceutical composition. The amount is the same.
本发明涉及任意上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与Bcl-2或Bcl-xL活性或表达量相关疾病的药物中的应用，优选地，所述疾病选自肿瘤或眼部疾病。The present invention relates to any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals for use in the preparation of treatments with Bcl-2 or Bcl-xL activity or Application in medicines for diseases related to expression levels. Preferably, the diseases are selected from tumors or eye diseases.
本发明涉及上述的药物组合物在用于制备治疗与Bcl-2或Bcl-xL活性或表达量相关疾病的药物中的应用，优选地，所述疾病选自肿瘤或眼部疾病，更优选地，所述疾病选自视网膜病变相关眼部疾病。The present invention relates to the application of the above pharmaceutical composition in the preparation of drugs for the treatment of diseases related to the activity or expression of Bcl-2 or Bcl-xL. Preferably, the disease is selected from tumors or eye diseases, more preferably , the disease is selected from retinopathy-related eye diseases.
本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。The amounts of the compounds of the invention or of their stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case converted to the free base form.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“卤素”是指F、Cl、Br或I。"Halogen" means F, Cl, Br or I.
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，为1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。"Halo-substituted" means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted" is simply referred to as "halogenated."
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
“杂烷基”指取代的或者未取代的烷基中的1个或多个(包括但不限于2、3、4、5或6个)碳原子被杂原子(包括但不限于N、O或S)替换。非限制性实施例包括-X(CH2)v-X(CH2)v-X(CH2)v-H(v为1至5的整数，X各自独立地选自键或杂原子，杂原子包括但不限于N、O或S，且至少有1个X选自杂原子，且杂原子中的N或S可被氧化成各种氧化态)。杂烷基可以是一价、二价、三价或四价。"Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replacement. Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )vH (v is an integer from 1 to 5, each , O or S, and at least 1 X is selected from heteroatoms, and N or S in the heteroatoms can be oxidized to various oxidation states). Heteroalkyl groups may be monovalent, divalent, trivalent or tetravalent.
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.
“亚杂烷基”是指取代的或者未取代的亚烷基中的1个或多个(包括但不限于2、3、4、5或6个)碳原子被杂原子(包括但不限于N、O或S)替换。非限制性实施例包括-X(CH2)v-X(CH2)v-X(CH2)v-，v为1至5的整数，X各自独立地选自键、N、O或S，且至少有1个X选自N、O或S。"Heteroalkylene" refers to a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) substitution. Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )v-, v is an integer from 1 to 5, 1 X is selected from N, O or S.
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；本文中出现的烯基，其定义与本定义一致。烯基可以是一价、二价、三价或四价。 "Alkenyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl base, 1-nonenyl, 3-nonenyl, 1-decene, 4-decene, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group appearing in this article has the same definition as this definition. Alkenyl groups may be monovalent, divalent, trivalent or tetravalent.
“炔基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，包括但不限于在主链包括2至10个碳原子、2至6个碳原子、2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。"Alkynyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1- Octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent .
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。"Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、 “碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O或S的杂原子，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, and containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of the heterocyclyl group Sexually substituted N and S can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabis Cycl[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl alkyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选 自N、O或S(＝O)n的杂原子。非限制性实施例包括： “螺环”或“螺环基”可以是一价、二价、三价或四价。"Spirocyclic" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Choice can contain 0 to 5 choices Heteroatom from N, O or S(=O) n . Non-limiting examples include: "Spiro" or "spiryl" may be monovalent, divalent, trivalent or tetravalent.
“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括： “并环”或“并环基”可以是一价、二价、三价或四价。"Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not Limited to selected from N, S (=O) n or O, n is 0, 1 or 2). The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "And ring" or "and ring group" can be monovalent, divalent, trivalent or tetravalent.
“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，桥环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括 立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane, adamantane. The "bridging ring" or "bridging ring base" may be monovalent, divalent, trivalent or tetravalent.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。本文中出现的“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”，其定义与螺环一致。"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms. "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing in this article have the same definition as spirocycle.
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。本文中出现的“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”，其定义与并环一致。"Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms. The definition of "carbocyclic ring", "carbocyclic ring group", "carbocyclic ring group" or "carbocyclic ring group" appearing in this article is consistent with that of carbocyclic ring.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。 本文中出现的“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”，其定义与桥环一致。"Carbon bridged ring", "bridged carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged carbocyclic ring group", "bridged carbocyclic ring group" or "carbon bridged ring group" appearing in this article are consistent with those of the bridged ring.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，本文中出现的杂环基、“单环杂环基”或“杂单环基”，其定义与杂环一致。"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to the "heterocyclyl" or "heterocycle" of a monocyclic system. The heterocyclyl, "monocyclic heterocycle" appearing in this article "Basic" or "heteromonocyclyl", its definition is consistent with heterocyclic.
“杂并环”、“杂并环基”“并环杂环基”或“杂并环基”是指含有杂原子的“并环”。本文中出现的杂并环、“杂并环基”“并环杂环基”或“杂并环基”，其定义与并环一致。"Heterocyclic ring", "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring radical" refers to a "heterocyclic ring" containing heteroatoms. The definitions of heterocyclic ring, "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring group" appearing in this article are consistent with those of the heterocyclic ring group.
“杂螺环”、“杂螺环基”、“螺环杂环基”或“杂螺环基”是指含有杂原子的“螺环”。本文中出现的杂螺环、“杂螺环基”、“螺环杂环基”或“杂螺环基”，其定义与螺环一致。"Heterospirocycle", "heterospirocyclyl", "spirocycloheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing heteroatoms. Heterospirocycle, "heterospirocyclyl", "spirocycloheterocyclyl" or "heterospirocyclyl" appearing in this article have the same definition as spirocycle.
“杂桥环”、“杂桥环基”、“桥环杂环基”或“杂桥环基”是指含有杂原子的“桥环”。本文中出现的杂桥环、“杂桥环基”、“桥环杂环基”或“杂桥环基”，其定义与桥环一致。"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "heterobridged cyclyl" refers to a "bridged ring" containing heteroatoms. The definition of hetero-bridged ring, "hetero-bridged cyclyl", "bridged-ring heterocyclyl" or "hetero-bridged cyclyl" appearing in this article is consistent with that of bridged ring.
“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aryl ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (= O)n, n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
“5元环并5元杂芳环”是指5并5元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了吡咯并吡咯环、吡唑并吡咯环、吡唑并吡唑环、吡咯并呋喃环、吡唑并呋喃环、吡咯并噻吩环、吡唑并噻吩环。"5-membered 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring. At least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, Pyrazolothiophene ring.
“5并6元杂芳环”是指5并6元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了苯并5元杂芳基、6元杂芳环并5元杂芳环。"5-6-membered heteroaromatic ring" refers to a 5-6-membered fused heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷 基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基，Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。"Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged cyclic group, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m - C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , -(CH 2 ) m S(=O) n R a , -(CH 2 ) m -ene Base -R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n is 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from the group including H, hydroxyl, amino, carbonyl, alkyl base, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option, R b and R c can form a five- or six-membered cycloalkyl or heterocycle group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged cyclic group, spirocyclic group or paracyclic group.
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。"Containing 1 to 5 heteroatoms selected from O, S, and N" means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.
“1至X个选自…的取代基所取代”是指被1、2、3….X个选自…的取代基所取代，X选自1至10之间的任意整数。如“1至X个选自…的取代基所取代”是指被1、2、3或4个选自…的取代基所取代。如“1至5个取代基所取代”是指被1、2、3、4或5个取代基所取代。如“杂桥环任选被1至4个选自F的取代基所取代”是指杂桥环任选被1、2、3或4个选自F的取代基所取代。"Substituted by 1 to X substituents selected from..." means substituted by 1, 2, 3... For example, “substituted by 1 to X substituents selected from…” means substituted by 1, 2, 3 or 4 substituents selected from…. For example, "substituted with 1 to 5 substituents" means substituted with 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from F.
X-Y元的环(3≤X＜Y，Y选自4至12之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。X-Y element rings (3≤X<Y, Y is selected from any integer between 4 and 12) include X, X+1, X+2, X+3, X+4….Y element rings. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings, and "5-10-membered heterocyclic ring" refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
“任选”或“任选地”或“任意地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" or "arbitrarily" means that the subsequently described event or circumstance may but does not necessarily occur, and the description includes instances where the event or circumstance does or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation. "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"Co-crystal" refers to a crystal formed by combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure states of API and CCF are both Solids, and there are fixed stoichiometric ratios between the components. A eutectic is a multicomponent crystal that includes both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed between a neutral solid and a salt or solvate.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。"Tautomers" refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需 的药物或者抑制剂的浓度。"IC 50 " is the amount required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.) the concentration of the drug or inhibitor.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited to these.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;
为了完成本发明的目的，根据本邻域技术人员已知的有机合成技术，从市售的化学品和/或化学文献中描述的化合物开始，制备本文所述反应中使用的化合物“商业上可用的化学品”是从标准的商业来源获得的，包括上海阿拉丁生化科技股份有限公司，上海麦克林生化科技有限公司，Sigma-Aldrich，阿法埃莎(中国)化学有限公司，梯希爱(上海)化成工业发展有限公司，安耐吉化学，上海泰坦科技股份有限公司，科龙化工，百灵威科技有限公司等。For the purposes of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Chemicals" were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXia ( Shanghai) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
THF：四氢呋喃；DMF：N,N-二甲基甲酰胺；DIPEA：N,N-二异丙基乙胺；HATU：CAS148893-10-1。THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS148893-10-1.
实施例1：化合物1的合成
Example 1: Synthesis of Compound 1
第一步：1a的合成Step 1: Synthesis of 1a
将2-氧代-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(5.0g，20.89mmol)溶于30mL甲醇中，氮气保护，0℃分批次加入硼氢化钠(1.19g，31.34mmol)，继续反应1小时。加20mL水，加入30mL乙酸乙酯萃取2次，无水硫酸钠干燥，减压浓缩，得到1a(4.5g，收率：89.26％)。Dissolve 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (5.0g, 20.89mmol) in 30mL methanol, under nitrogen protection, add sodium borohydride (1.19) in batches at 0°C g, 31.34mmol), continue the reaction for 1 hour. Add 20 mL of water, add 30 mL of ethyl acetate, extract twice, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1a (4.5 g, yield: 89.26%).
LCMS m/z＝186.1[M-55]+ LCMS m/z＝186.1[M-55] +
第二步：1b的合成Step 2: Synthesis of 1b
将1a(4.0g，16.57mmol)溶于50mL四氢呋喃，氮气保护，0℃分批加入氢化钠(1.0g，41.42mmol)，继续搅拌30分钟，在加入溴化苄(5.67g，33.14mmol)，室温搅拌过夜。加水淬灭反应，用50mL乙酸乙酯萃取2次，无水硫酸钠干燥，减压浓缩，柱层析得到1b(4.6g，收率：83.76％)。Dissolve 1a (4.0g, 16.57mmol) in 50mL tetrahydrofuran, under nitrogen protection, add sodium hydride (1.0g, 41.42mmol) in batches at 0°C, continue stirring for 30 minutes, then add benzyl bromide (5.67g, 33.14mmol), Stir at room temperature overnight. The reaction was quenched by adding water, extracted twice with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 1b (4.6 g, yield: 83.76%).
LCMS m/z＝332.2[M+H]+ LCMS m/z＝332.2[M+H] +
第三步：1c的合成Step 3: Synthesis of 1c
将1b(1.8g，5.43mmol)溶于20mL乙腈中，加入4mL 4N的盐酸二氧六环溶液，室温反应2小时。减压浓缩，加入碳酸氢钠水溶液5mL调节pH＝8左右，用二氯甲烷萃取5次，合并有机相，减压浓缩，得到1c(1.0g，收率：79.61％)。Dissolve 1b (1.8g, 5.43mmol) in 20mL acetonitrile, add 4mL 4N dioxane hydrochloride solution, and react at room temperature for 2 hours. Concentrate under reduced pressure, add 5 mL of sodium bicarbonate aqueous solution to adjust the pH to about 8, extract 5 times with dichloromethane, combine the organic phases, and concentrate under reduced pressure to obtain 1c (1.0 g, yield: 79.61%).
LCMS m/z＝232.2[M+H]+ LCMS m/z＝232.2[M+H] +
第四步：1d的合成Step 4: Synthesis of 1d
将中间体A(1.3g，4.4mmol)溶于20mL二氯甲烷中，加入1c(1.1g，4.84mmol)，氮气保护下冰水浴降温后加入三乙胺(1.78g，17.6mmol)，0℃搅拌30分钟,加入三乙酰氧基硼氢化钠(1.4g，6.6mmol)，室温搅拌过夜。加入30mL纯化水，分液，水相用50mL二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，滤液减压浓缩得到粗品，柱层析得到1d(1.45g，收率：64.52％)。Dissolve intermediate A (1.3g, 4.4mmol) in 20mL dichloromethane, add 1c (1.1g, 4.84mmol), cool in an ice-water bath under nitrogen protection, then add triethylamine (1.78g, 17.6mmol), 0°C Stir for 30 minutes, add sodium triacetoxyborohydride (1.4g, 6.6mmol), and stir at room temperature overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with 50 mL of methylene chloride, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain the crude product, which is then column chromatographed to obtain 1d (1.45 g, yield: 64.52% ).
LCMS m/z＝511.3[M+H]+ LCMS m/z＝511.3[M+H] +
第五步：1e的合成Step 5: Synthesis of 1e
1d(0.5g，0.98mmol)溶于5mL二氯甲烷，氮气保护，-78℃滴加三溴化硼(2mL，2mmol)，室温搅拌2小时。低温下加入碳酸氢钠水溶液淬灭反应，调pH＝8左右，用二氯甲烷萃取2次，无水硫酸钠干燥，减压浓缩，得到1e(40mg，收率：12.74％)。1d (0.5g, 0.98mmol) was dissolved in 5mL of dichloromethane, protected by nitrogen, and boron tribromide (2mL, 2mmol) was added dropwise at -78°C, and stirred at room temperature for 2 hours. Add sodium bicarbonate aqueous solution at low temperature to quench the reaction, adjust the pH to about 8, extract twice with dichloromethane, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1e (40 mg, yield: 12.74%).
LCMS m/z＝321.4[M+H]+ LCMS m/z＝321.4[M+H] +
第六步：化合物1的合成Step 6: Synthesis of Compound 1
中间体B(33mg，0.04mmol)溶于2mL N,N-二甲基甲酰胺,加入1e(19mg，0.059mmol),N,N-二异丙基乙胺(16mg，0.12mmol),室温搅拌2小时。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次，无水硫酸钠干燥，过滤后，减压浓缩，柱层析得到产品，再经过反相柱层析得到化合物1的三氟乙酸盐(10mg，收率：22.33％)。Intermediate B (33 mg, 0.04 mmol) was dissolved in 2 mL N, N-dimethylformamide, 1e (19 mg, 0.059 mmol), N, N-diisopropylethylamine (16 mg, 0.12 mmol) were added, and stirred at room temperature 2 hours. Add 30 mL of ethyl acetate, wash twice with water (20 mL Trifluoroacetate salt of compound 1 (10 mg, yield: 22.33%).
LCMS m/z＝560.3[M/2+H]+ LCMS m/z＝560.3[M/2+H] +
实施例3：化合物3的合成
Example 3: Synthesis of Compound 3
第一步：3a的合成 Step 1: Synthesis of 3a
(3S,4R)-3-氟-4-羟基哌啶-1-羧酸叔丁酯(1.0g，4.56mmol)溶于5mL二氯甲烷，加入5mL三氟乙酸，室温搅拌2小时。减压浓缩得到3a(0.54g，收率：99.4％)。(3S,4R)-3-Fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.0g, 4.56mmol) was dissolved in 5mL of methylene chloride, 5mL of trifluoroacetic acid was added, and stirred at room temperature for 2 hours. Concentrate under reduced pressure to obtain 3a (0.54g, yield: 99.4%).
LCMS m/z＝120.2[M+H]+ LCMS m/z＝120.2[M+H] +
第二步：3b的合成Step 2: Synthesis of 3b
将中间体A(0.45g，1.52mmol)溶于20mL二氯甲烷中，加入3a(0.18g，1.52mmol)，氮气保护下，冰水浴降温后，加入三乙胺(0.62g，6.08mmol)，0℃搅拌30分钟，加入三乙酰氧基硼氢化钠(0.48g，2.28mmol)，室温搅拌过夜。加入30mL纯化水，分液，水相用50mL二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，柱层析得到3b(0.5g，收率：82.54％)。Dissolve intermediate A (0.45g, 1.52mmol) in 20mL dichloromethane, add 3a (0.18g, 1.52mmol), under nitrogen protection, cool down in an ice-water bath, add triethylamine (0.62g, 6.08mmol), Stir at 0°C for 30 minutes, add sodium triacetoxyborohydride (0.48g, 2.28mmol), and stir at room temperature overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with 50 mL of methylene chloride, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is then column chromatographed to obtain 3b (0.5 g, yield: 82.54%).
LCMS m/z＝399.3[M+H]+ LCMS m/z＝399.3[M+H] +
第三步：化合物3c的合成Step 3: Synthesis of Compound 3c
3b(0.1g，0.25mmol)溶于2mL二氯甲烷，加入0.5mL三氟乙酸，室温搅拌2小时。减压浓缩得到3c(0.070g，收率：93.83％)。Dissolve 3b (0.1g, 0.25mmol) in 2mL of methylene chloride, add 0.5mL of trifluoroacetic acid, and stir at room temperature for 2 hours. Concentrate under reduced pressure to obtain 3c (0.070g, yield: 93.83%).
LCMS m/z＝299.2[M+H]+ LCMS m/z＝299.2[M+H] +
第四步：化合物3的合成Step 4: Synthesis of Compound 3
中间体B(30mg，0.037mmol)溶于2mL N,N-二甲基甲酰胺,加入3c(17mg，0.055mmol),N,N-二异丙基乙胺(14mg，0.11mmol),室温搅拌2小时。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次,无水硫酸钠干燥，过滤后，减压浓缩，柱层析得到产品，经反相柱层析得到化合物3的三氟乙酸盐(22mg，收率：54.17％)。Intermediate B (30 mg, 0.037 mmol) was dissolved in 2 mL of N,N-dimethylformamide, 3c (17 mg, 0.055 mmol), N, N-diisopropylethylamine (14 mg, 0.11 mmol) were added, and stirred at room temperature 2 hours. Add 30 mL of ethyl acetate, wash twice with water (20 mL The trifluoroacetate salt of 3 (22 mg, yield: 54.17%).
LCMS m/z＝549.6[M/2+H]+ LCMS m/z＝549.6[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.28(d,1H),8.19(s,1H),8.00(dd,1H),7.93(d,1H),7.86(d,1H),7.83–7.76(m,3H),7.64–7.30(s,11H),6.80–6.73(m,1H),5.35–5.15(m,1H),4.83–4.68(m,1H),4.66–4.48(m,8H),4.47–4.31(m,1H),4.13–3.99(m,2H),3.93–3.83(m,1H),3.66–3.42(m,3H),3.36–3.21(m,3H),3.02(s,3H),2.71–2.51(m,2H),2.47–2.26(m,2H),1.73(d,3H),1.35(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.28(d,1H),8.19(s,1H),8.00(dd,1H),7.93(d,1H),7.86(d,1H),7.83–7.76 (m,3H),7.64–7.30(s,11H),6.80–6.73(m,1H),5.35–5.15(m,1H),4.83–4.68(m,1H),4.66–4.48(m,8H) ,4.47–4.31(m,1H),4.13–3.99(m,2H),3.93–3.83(m,1H),3.66–3.42(m,3H),3.36–3.21(m,3H),3.02(s, 3H),2.71–2.51(m,2H),2.47–2.26(m,2H),1.73(d,3H),1.35(d,3H).
实施例4：化合物4的合成
Example 4: Synthesis of Compound 4
第一步：4a的合成 Step One: Synthesis of 4a
(3R,4S)-3-氟-4-羟基哌啶-1-羧酸叔丁酯(1.2g，5.47mmol)溶于5mL二氯甲烷，加入5mL三氟乙酸，室温搅拌2小时。减压浓缩得到化合物4a(0.65g，收率：99.74％)。(3R,4S)-3-Fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.2g, 5.47mmol) was dissolved in 5mL of methylene chloride, 5mL of trifluoroacetic acid was added, and stirred at room temperature for 2 hours. Concentrate under reduced pressure to obtain compound 4a (0.65g, yield: 99.74%).
LCMS m/z＝120.2[M+H]+ LCMS m/z＝120.2[M+H] +
第二步：化合物4b的合成Step 2: Synthesis of Compound 4b
将中间体A(0.45g，1.52mmol)溶于20mL二氯甲烷中，加入3a(0.18g，1.52mmol)，氮气保护下，冰水浴加入三乙胺(0.62g，6.08mmol)，0℃搅拌30分钟；加入三乙酰氧基硼氢化钠(0.48g，2.28mmol)，室温搅拌过夜。加入30mL纯化水，分液，水相用50mL二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，柱层析得到4b(0.5g，收率：82.54％)。Dissolve intermediate A (0.45g, 1.52mmol) in 20mL dichloromethane, add 3a (0.18g, 1.52mmol), add triethylamine (0.62g, 6.08mmol) in an ice-water bath under nitrogen protection, and stir at 0°C. 30 minutes; add sodium triacetoxyborohydride (0.48g, 2.28mmol), and stir at room temperature overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with 50 mL of methylene chloride, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is then column chromatographed to obtain 4b (0.5 g, yield: 82.54%).
LCMS m/z＝399.3[M+H]+ LCMS m/z＝399.3[M+H] +
第三步：化合物4c的合成Step 3: Synthesis of Compound 4c
4b(0.1g，0.25mmol)溶于2mL二氯甲烷，加入0.5mL三氟乙酸，室温搅拌2小时。减压浓缩得到化合物4c(0.070g，收率：93.83％)。4b (0.1g, 0.25mmol) was dissolved in 2mL dichloromethane, 0.5mL trifluoroacetic acid was added, and stirred at room temperature for 2 hours. Concentrate under reduced pressure to obtain compound 4c (0.070g, yield: 93.83%).
LCMS m/z＝299.2[M+H]+ LCMS m/z＝299.2[M+H] +
第四步：化合物4的合成Step 4: Synthesis of Compound 4
中间体B(50mg，0.061mmol)溶于2mL N,N-二甲基甲酰胺,加入4c(27mg，0.091mmol),N,N-二异丙基乙胺(24mg，0.18mmol),室温搅拌2小时。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次,无水硫酸钠干燥，过滤后，减压浓缩，柱层析得到产品，经反相柱层析得到化合物4的三氟乙酸盐(20mg，收率：29.87％)。Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL N,N-dimethylformamide, 4c (27 mg, 0.091 mmol), N, N-diisopropylethylamine (24 mg, 0.18 mmol) were added, and stirred at room temperature 2 hours. Add 30 mL of ethyl acetate, wash twice with water (20 mL The trifluoroacetate salt of 4 (20 mg, yield: 29.87%).
LCMS m/z＝549.8[M/2+H]+ LCMS m/z＝549.8[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.26(s,1H),8.18(s,1H),7.98(dd,1H),7.91(d,1H),7.84(d,1H),7.81–7.73(m,3H),7.62–7.29(m,11H),6.80–6.69(m,1H),5.32–5.12(m,1H),4.81–4.65(m,1H),4.63–4.46(m,8H),4.45–4.30(m,1H),4.10–3.97(m,2H),3.95–3.79(m,1H),3.69–3.41(m,3H),3.38–3.21(m,3H),3.00(s,3H),2.71–2.49(m,2H),2.45–2.24(m,2H),1.71(d,3H),1.33(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.26(s,1H),8.18(s,1H),7.98(dd,1H),7.91(d,1H),7.84(d,1H),7.81–7.73 (m,3H),7.62–7.29(m,11H),6.80–6.69(m,1H),5.32–5.12(m,1H),4.81–4.65(m,1H),4.63–4.46(m,8H) ,4.45–4.30(m,1H),4.10–3.97(m,2H),3.95–3.79(m,1H),3.69–3.41(m,3H),3.38–3.21(m,3H),3.00(s, 3H),2.71–2.49(m,2H),2.45–2.24(m,2H),1.71(d,3H),1.33(d,3H).
实施例5：化合物5的合成
Example 5: Synthesis of Compound 5
第一步：5B的合成Step One: Synthesis of 5B
将5A(1.0g，1.91mmol)、5A-1(530mg，2.29mmol)、碘化亚铜(36mg，0.19mmol)、[(2,6-二甲苯基)氨基](氧)乙酸(110mg，0.57mmol)和碳酸钾(790mg，5.73mmol)溶于20mL二甲基亚砜中，130℃封管反应12小时。加入水，乙酸乙酯萃取反应，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得5B(651mg，50.48％)。5A (1.0g, 1.91mmol), 5A-1 (530mg, 2.29mmol), copper iodide (36mg, 0.19mmol), [(2,6-dimethylphenyl)amino](oxy)acetic acid (110mg, 0.57mmol) and potassium carbonate (790mg, 5.73mmol) were dissolved in 20mL dimethyl sulfoxide, and the tube was sealed at 130°C for 12 hours. Water was added, the reaction was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5B (651 mg, 50.48%).
第二步：5C的合成Step 2: Synthesis of 5C
将5B(610mg，0.90mmol)溶于10mL乙醇和2mL水中，加入铁粉(250mg，4.5mmol)和氯化铵(240mg，4.5mmol)，90℃反应12小时。冷却至室温，过滤，减压浓缩，经柱层析纯化得5C(435mg，74.9％)。Dissolve 5B (610 mg, 0.90 mmol) in 10 mL ethanol and 2 mL water, add iron powder (250 mg, 4.5 mmol) and ammonium chloride (240 mg, 4.5 mmol), and react at 90°C for 12 hours. Cool to room temperature, filter, concentrate under reduced pressure, and purify through column chromatography to obtain 5C (435 mg, 74.9%).
LCMS m/z＝645.2[M+H]+ LCMS m/z＝645.2[M+H] +
第三步：5D的合成Step 3: 5D synthesis
将5C-1(350mg，1.06mmol)溶于5mL二氯甲烷中，0℃加入吡啶(170mg，2.13mmol)，搅拌1分钟，缓慢加入5C(460mg，0.71mmol),室温搅拌2小时。加入水，乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，柱层析纯化获得5D(410mg，61.73％)。Dissolve 5C-1 (350 mg, 1.06 mmol) in 5 mL of dichloromethane, add pyridine (170 mg, 2.13 mmol) at 0°C, stir for 1 minute, slowly add 5C (460 mg, 0.71 mmol), and stir at room temperature for 2 hours. Water was added, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 5D (410 mg, 61.73%).
LCMS m/z＝935.4[M+H]+ LCMS m/z＝935.4[M+H] +
第四步：5F的合成Step 4: Synthesis of 5F
将5D(80mg，0.086mmol)和5E(48mg，0.13mmol)溶于3mLN,N-二甲基甲酰胺中，缓慢加入N,N-二异丙基乙胺(33mg，0.26mmol)，室温搅拌2小时。加水，乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，柱层析纯化得5F(75mg，67.81％)。Dissolve 5D (80 mg, 0.086 mmol) and 5E (48 mg, 0.13 mmol) in 3 mL N, N-dimethylformamide, slowly add N, N-diisopropylethylamine (33 mg, 0.26 mmol), and stir at room temperature. 2 hours. Add water, extract with ethyl acetate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify by column chromatography to obtain 5F (75 mg, 67.81%).
LCMS m/z＝1285.4[M+H]+ LCMS m/z＝1285.4[M+H] +
第五步：化合物5的合成Step 5: Synthesis of Compound 5
将5F(75mg，0.086mmol)溶于5mL二氯甲烷中，-78℃加入三溴化硼的二氯甲烷溶液(1mL， 10％v/v)，室温反应1小时。减压浓缩，残余物经柱层析分离纯化得化合物5(20mg，31.19％)。Dissolve 5F (75 mg, 0.086 mmol) in 5 mL dichloromethane, and add boron tribromide dichloromethane solution (1 mL, 10% v/v), react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain compound 5 (20 mg, 31.19%).
LCMS m/z＝1105.3[M+H]+ LCMS m/z＝1105.3[M+H] +
实施例7：化合物7的合成
Example 7: Synthesis of Compound 7
第一步：7B的合成Step One: Synthesis of 7B
将7A(5.0g，22.19mmol)溶于30mL甲醇中，氮气保护，0℃分批次加入硼氢化钠(1.26g，33.29mmol)，0℃反应1小时。加20mL水淬灭反应，加入30mL乙酸乙酯萃取2次，无水硫酸钠干燥，过滤后减压浓缩，得7B(4.5g，收率：89.22％)。Dissolve 7A (5.0g, 22.19mmol) in 30mL methanol under nitrogen protection, add sodium borohydride (1.26g, 33.29mmol) in batches at 0°C, and react at 0°C for 1 hour. Add 20 mL of water to quench the reaction, add 30 mL of ethyl acetate to extract twice, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain 7B (4.5 g, yield: 89.22%).
Ms m/z(ESI):228.3[M+H]+ Ms m/z(ESI):228.3[M+H] +
第二步：7C的合成Step 2: Synthesis of 7C
将7B(1.8g，7.92mmol)溶于20mL乙腈中，加入4mL 4N的盐酸二氧六环溶液，室温反应2小时。减压浓缩，加入碳酸氢钠水溶液5ml调节pH＝8左右，用二氯甲烷萃取5次，合并有机相，减压浓缩，得到7C(1.0g，收率：99.28％)。Dissolve 7B (1.8g, 7.92mmol) in 20mL acetonitrile, add 4mL 4N dioxane hydrochloride solution, and react at room temperature for 2 hours. Concentrate under reduced pressure, add 5 ml of sodium bicarbonate aqueous solution to adjust the pH to about 8, extract 5 times with dichloromethane, combine the organic phases, and concentrate under reduced pressure to obtain 7C (1.0 g, yield: 99.28%).
Ms m/z(ESI):128.2[M+H]+ Ms m/z(ESI):128.2[M+H] +
第三步：7D的合成Step 3: 7D synthesis
将(R)-(4-氧代-1-(苯硫基)丁-2-基)氨基甲酸叔丁酯(1.3g，4.4mmol)溶于20mL二氯甲烷中，加入7C(0.84g，6.6mmol)，氮气保护下，冰水浴降温后，加入三乙胺(1.34g，13.2mmol)，控制0℃左右搅拌30分钟，加入三乙酰氧基硼氢化钠(1.87g，8.8mmol)，室温搅拌过夜。加入30mL纯化水，分液，水相用50mL二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，柱层析得到7D(1.45g，收率：81.05％)。Dissolve (R)-(4-oxo-1-(phenylthio)but-2-yl)carbamic acid tert-butyl ester (1.3g, 4.4mmol) in 20mL dichloromethane, add 7C (0.84g, 6.6mmol), under nitrogen protection, after cooling in an ice-water bath, add triethylamine (1.34g, 13.2mmol), stir at about 0°C for 30 minutes, add sodium triacetoxyborohydride (1.87g, 8.8mmol), and stir at room temperature Stir overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with 50 mL of methylene chloride, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product, which is then column chromatographed to obtain 7D (1.45 g, yield: 81.05%).
Ms m/z(ESI):407.3[M+H]+ Ms m/z(ESI):407.3[M+H] +
第四步：7E的合成Step 4: Synthesis of 7E
将7D(1g，2.46mmol)溶于10mL DCM中，加入3mL 4N的盐酸二氧六环溶液，室温反应2小时，减压浓缩得到7E(500mg，收率：66.32％)。Dissolve 7D (1g, 2.46mmol) in 10mL DCM, add 3mL 4N dioxane hydrochloride solution, react at room temperature for 2 hours, and concentrate under reduced pressure to obtain 7E (500mg, yield: 66.32%).
第五步：化合物7的合成Step 5: Synthesis of Compound 7
中间体B(50mg，0.061mmol)溶于2mL N,N-二甲基甲酰胺,加入7E(28mg，0.091mmol),N,N-二异丙基乙胺(24mg，0.18mmol),室温搅拌2小时。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次,无水硫酸钠干燥，过滤后减压浓缩，柱层析得到产品，再经反相 柱层析得到化合物7的三氟乙酸盐(10mg，收率：14.83％)。Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL of N,N-dimethylformamide, 7E (28 mg, 0.091 mmol), N, N-diisopropylethylamine (24 mg, 0.18 mmol) were added, and stirred at room temperature. 2 hours. Add 30 mL of ethyl acetate, wash twice with water (20 mL Column chromatography gave the trifluoroacetate salt of compound 7 (10 mg, yield: 14.83%).
Ms m/z(ESI):1105.4[M+H]+ Ms m/z(ESI):1105.4[M+H] +
实施例8：化合物8的合成
Example 8: Synthesis of Compound 8
第一步：化合物8B的合成Step One: Synthesis of Compound 8B
将化合物8A(0.4g，1.82mmol)溶于20mL乙腈中，加入4N的盐酸二氧六环溶液2mL，室温搅拌反应2h。减压浓缩除去溶剂，加入碳酸氢钠水溶液5mL调节pH＝8，用二氯甲烷(20mL×5)萃取5次，合并有机相，减压浓缩得到8B(0.21g，收率：96.85％)。Compound 8A (0.4g, 1.82mmol) was dissolved in 20mL acetonitrile, 2mL of 4N dioxane hydrochloride solution was added, and the reaction was stirred at room temperature for 2h. Concentrate under reduced pressure to remove the solvent, add 5 mL of sodium bicarbonate aqueous solution to adjust pH=8, extract 5 times with dichloromethane (20 mL×5), combine the organic phases, and concentrate under reduced pressure to obtain 8B (0.21 g, yield: 96.85%).
Ms m/z(ESI):120.1[M+H]+ Ms m/z(ESI):120.1[M+H] +
第二步：化合物8C的合成Step 2: Synthesis of Compound 8C
将中间体A(0.21g，0.71mmol)溶于20mL二氯甲烷中，加入化合物8B(0.13g，1.06mmol)，氮气保护下，0℃下加入三乙胺(0.39g，2.13mmol)，0℃下搅拌30分钟。加入三乙酰氧基硼氢化钠(0.3g，1.42mmol)，升至室温反应过夜。加入30mL纯化水，分液，水相用(25mL×2)的二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，滤液减压浓缩后残余物用硅胶色谱柱柱层析后得到8C(0.22g，收率：77.75％)。Intermediate A (0.21g, 0.71mmol) was dissolved in 20 mL of methylene chloride, compound 8B (0.13g, 1.06mmol) was added, and triethylamine (0.39g, 2.13mmol) was added under nitrogen protection at 0°C. Stir for 30 minutes at ℃. Sodium triacetoxyborohydride (0.3g, 1.42mmol) was added, and the mixture was raised to room temperature and allowed to react overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with (25 mL 8C (0.22g, yield: 77.75%).
Ms m/z(ESI):343.2[M+H-56]+ Ms m/z(ESI):343.2[M+H-56] +
第三步：化合物8D的合成Step 3: Synthesis of Compound 8D
将8C(1g，2.51mmol)溶于10mL二氯甲烷中，加入4N的盐酸二氧六环溶液3mL，室温反应2h。减压浓缩除去溶剂，得到8D的盐酸盐，无需纯化直接下一步(500mg，收率：66.75％)。Dissolve 8C (1g, 2.51mmol) in 10mL of methylene chloride, add 3mL of 4N dioxane hydrochloride solution, and react at room temperature for 2h. The solvent was concentrated under reduced pressure to obtain the hydrochloride of 8D, which was directed to the next step without purification (500 mg, yield: 66.75%).
第四步：化合物8的合成Step 4: Synthesis of Compound 8
将中间体B(50mg，0.061mmol)溶于2mL DMF中，加入化合物8D(27mg，0.09mmol),DIPEA(23mg，0.18mmol),室温下搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水20mL洗涤一次,无水硫酸钠干燥，减压浓缩后粗品经硅胶柱层析及反向柱层析纯化得化合物8(20mg，收率：29.87％)。Dissolve intermediate B (50 mg, 0.061 mmol) in 2 mL DMF, add compound 8D (27 mg, 0.09 mmol), DIPEA (23 mg, 0.18 mmol), and stir at room temperature for 2 h. Add 30 mL of ethyl acetate, wash twice with water (20 mL × 2), wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 8. (20mg, yield: 29.87%).
Ms m/z(ESI):1097.4[M+H]+ Ms m/z(ESI):1097.4[M+H] +
1H NMR(400MHz,CF3COOD)δ8.27(s,1H),8.20(s,1H),8.03–7.96(m,1H),7.95–7.88(m,1H),7.87–7.74(m,4H),7.63–7.46(m,7H),7.44–7.35(m,4H),6.82–6.70(m,1H),5.11–4.95(m, 1H),4.81–4.69(m,1H),4.63–4.44(m,8H),4.13–3.98(m,2H),3.94–3.82(m,1H),3.78–3.61(m,2H),3.58–3.41(m,3H),3.33–3.23(m,2H),3.01(s,3H),2.69–2.44(m,2H),2.40–2.09(m,2H),1.71(d,3H),1.33(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.27(s,1H),8.20(s,1H),8.03–7.96(m,1H),7.95–7.88(m,1H),7.87–7.74(m, 4H),7.63–7.46(m,7H),7.44–7.35(m,4H),6.82–6.70(m,1H),5.11–4.95(m, 1H),4.81–4.69(m,1H),4.63–4.44(m,8H),4.13–3.98(m,2H),3.94–3.82(m,1H),3.78–3.61(m,2H),3.58– 3.41(m,3H),3.33–3.23(m,2H),3.01(s,3H),2.69–2.44(m,2H),2.40–2.09(m,2H),1.71(d,3H),1.33( d,3H).
实施例9：化合物9的合成
Example 9: Synthesis of Compound 9
第一步：化合物9B的合成Step One: Synthesis of Compound 9B
将化合物9A(0.7g，3.06mmol)溶于10mL乙腈中，加入4N的盐酸二氧六环溶液3mL，室温反应2h。减压浓缩除去溶剂，加入碳酸氢钠水溶液5mL调节pH＝8左右，用二氯甲烷(20mL×5)萃取5次，合并有机相，减压浓缩，得到9B(0.35g，收率：89.93％)。Compound 9A (0.7g, 3.06mmol) was dissolved in 10mL acetonitrile, 3mL of 4N dioxane hydrochloride solution was added, and the reaction was carried out at room temperature for 2h. Concentrate under reduced pressure to remove the solvent, add 5 mL of sodium bicarbonate aqueous solution to adjust the pH to about 8, extract 5 times with dichloromethane (20 mL × 5), combine the organic phases, and concentrate under reduced pressure to obtain 9B (0.35 g, yield: 89.93% ).
Ms m/z(ESI):128.2[M+H]+ Ms m/z(ESI):128.2[M+H] +
第二步：化合物9C的合成Step 2: Synthesis of Compound 9C
将中间体A溶于20mL二氯甲烷中，加入9B(0.19g，1.53mmol)，氮气保护下，0℃下加入三乙胺(0.31g，3.06mmol)，0℃搅拌30分钟。加入三乙酰氧基硼氢化钠(0.43g，2.04)，升至室温搅拌过夜。加入30mL纯化水，分液，水相用(25mL×2)的二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，滤液减压浓缩后残留物用硅胶色谱柱柱层析得到9C(0.3g，收率：72.34％)。Dissolve Intermediate A in 20 mL of methylene chloride, add 9B (0.19g, 1.53mmol), add triethylamine (0.31g, 3.06mmol) at 0°C under nitrogen protection, and stir at 0°C for 30 minutes. Add sodium triacetoxyborohydride (0.43g, 2.04), raise to room temperature and stir overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with (25 mL (0.3g, yield: 72.34%).
Ms m/z(ESI):351.2[M+H-56]+ Ms m/z(ESI):351.2[M+H-56] +
第三步：化合物9D的合成Step 3: Synthesis of Compound 9D
将化合物9C(0.3g，0.74mmol)溶于8mL二氯甲烷中，加入4N的盐酸二氧六环溶液3mL，室温反应2h。减压浓缩除去溶剂，得到9D的盐酸盐，无需纯化直接下一步(200mg，收率：88.19％)。Compound 9C (0.3g, 0.74mmol) was dissolved in 8mL of methylene chloride, 3mL of 4N dioxane hydrochloride solution was added, and the reaction was carried out at room temperature for 2h. The solvent was concentrated under reduced pressure to obtain the hydrochloride of 9D, which was directed to the next step without purification (200 mg, yield: 88.19%).
Ms m/z(ESI):306.2[M+H]+ Ms m/z(ESI):306.2[M+H] +
第四步：化合物9的合成Step 4: Synthesis of Compound 9
将中间体B(50mg，0.061mmol)溶解于3mL DMF中，加入化合物9D(28mg，0.091mmol),DIPEA(24mg，0.18mmol)，室温反应2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水20mL洗涤一次，无水硫酸钠干燥，减压浓缩后粗品经硅胶柱层析及反向柱层析纯化得化合物9(21mg，收率：31.13％)。Dissolve intermediate B (50 mg, 0.061 mmol) in 3 mL DMF, add compound 9D (28 mg, 0.091 mmol), DIPEA (24 mg, 0.18 mmol), and react at room temperature for 2 h. Add 30 mL of ethyl acetate, wash twice with water (20 mL × 2), wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 9. (21 mg, yield: 31.13%).
Ms m/z(ESI):1105.4[M+H]+ Ms m/z(ESI):1105.4[M+H] +
1H NMR(400MHz,CF3COOD)δ8.25(s,1H),8.21–8.16(m,1H),8.04–7.94(m,1H),7.93–7.87(m,1H),7.84–7.71(m,4H),7.62–7.44(m,7H),7.41–7.31(m,4H),6.85–6.69(m,1H),4.80–4.69(m,1H),4.64–4.42(m,8H),4.14–3.98(m,1H),3.91–3.65(m,1H),3.63–3.31(m,4H),3.30– 3.22(m,2H),2.99(s,3H),2.61–2.19(m,4H),1.70(d,3H),1.51–1.36(m,2H),1.32(d,3H),1.15–0.89(m,2H),0.87–0.68(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.25(s,1H),8.21–8.16(m,1H),8.04–7.94(m,1H),7.93–7.87(m,1H),7.84–7.71( m,4H),7.62–7.44(m,7H),7.41–7.31(m,4H),6.85–6.69(m,1H),4.80–4.69(m,1H),4.64–4.42(m,8H), 4.14–3.98(m,1H),3.91–3.65(m,1H),3.63–3.31(m,4H),3.30– 3.22(m,2H),2.99(s,3H),2.61–2.19(m,4H),1.70(d,3H),1.51–1.36(m,2H),1.32(d,3H),1.15–0.89( m,2H),0.87–0.68(m,2H).
实施例10：化合物10的合成
Example 10: Synthesis of Compound 10
第一步：化合物10B的合成Step One: Synthesis of Compound 10B
将化合物10A(1.0g，4.2mmol)溶于30mL甲醇中，氮气保护下，0℃下分批次加入硼氢化钠(0.32g，8.4mmol)，继续反应1h。加20mL水淬灭反应，并用乙酸乙酯(15mL×2)萃取2次，合并有机相，无水硫酸钠干燥，减压浓缩后残留物用硅胶色谱柱柱层析得到10B(0.75g，收率：73.99％)。Compound 10A (1.0g, 4.2mmol) was dissolved in 30mL methanol, and sodium borohydride (0.32g, 8.4mmol) was added in batches at 0°C under nitrogen protection, and the reaction was continued for 1 hour. Add 20 mL of water to quench the reaction, and extract twice with ethyl acetate (15 mL rate: 73.99%).
Ms m/z(ESI):242.3[M+H]+ Ms m/z(ESI):242.3[M+H] +
第二步：化合物10C的合成Step 2: Synthesis of Compound 10C
将化合物10B(0.75g，3.11mmol)溶于8mL乙腈中，加入4N的盐酸二氧六环溶液3mL，室温反应2h。减压浓缩除去溶剂，加入碳酸氢钠水溶液5mL调节pH＝8左右，用二氯甲烷(20mL×5)萃取5次，合并有机相，减压浓缩，得到10C(0.35g，收率：79.7％)。Compound 10B (0.75g, 3.11mmol) was dissolved in 8mL of acetonitrile, 3mL of 4N dioxane hydrochloride solution was added, and the reaction was carried out at room temperature for 2h. Concentrate under reduced pressure to remove the solvent, add 5 mL of sodium bicarbonate aqueous solution to adjust the pH to about 8, extract 5 times with dichloromethane (20 mL × 5), combine the organic phases, and concentrate under reduced pressure to obtain 10C (0.35 g, yield: 79.7% ).
Ms m/z(ESI):142.2[M+H]+ Ms m/z(ESI):142.2[M+H] +
第三步：化合物10D的合成Step 3: Synthesis of Compound 10D
将中间体A溶于20mL二氯甲烷中，加入化合物10C(0.22g，1.53mmol)，氮气保护下，0℃下加入三乙胺(0.31g，3.06mmol)，0℃下搅拌30min。将三乙酰氧基硼氢化钠(0.43g，2.04mmol)加至反应瓶中，升至室温搅拌过夜。加入30mL水稀释，分液，水相用(25mL×2)二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶色谱柱柱层析得到化合物10D(0.31g，收率：72.26％)。Dissolve Intermediate A in 20 mL of dichloromethane, add compound 10C (0.22g, 1.53mmol), add triethylamine (0.31g, 3.06mmol) at 0°C under nitrogen protection, and stir at 0°C for 30 min. Sodium triacetoxyborohydride (0.43g, 2.04mmol) was added to the reaction flask, and the mixture was raised to room temperature and stirred overnight. Add 30 mL of water to dilute, separate the layers, extract the aqueous phase twice with (25 mL Compound 10D (0.31g, yield: 72.26%).
Ms m/z(ESI):365.3[M+H-56]+ Ms m/z(ESI):365.3[M+H-56] +
第四步：化合物10E的合成Step 4: Synthesis of Compound 10E
将化合物10D(0.31g，0.76mmol)溶于8mL二氯甲烷中，加入4N的盐酸二氧六环溶液3mL，室温反应2h。减压浓缩除去溶剂，得到10E的盐酸盐，无需纯化直接下一步(200mg，收率：85.87％)。Compound 10D (0.31g, 0.76mmol) was dissolved in 8mL of methylene chloride, 3mL of 4N dioxane hydrochloride solution was added, and the reaction was carried out at room temperature for 2h. The solvent was concentrated under reduced pressure to obtain the hydrochloride of 10E, which was directed to the next step without purification (200 mg, yield: 85.87%).
Ms m/z(ESI):321.4[M+H]+ Ms m/z(ESI):321.4[M+H] +
第五步：化合物10的合成Step 5: Synthesis of Compound 10
将中间体B(50mg，0.061mmol)溶解于3mL DMF中,加入化合物10E(29mg，0.091mmol),DIPEA(23mg，0.18mmol),室温搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL x 2)， 用饱和食盐水20mL洗涤一次,无水硫酸钠干燥，过滤，滤液减压浓缩后粗品经硅胶柱层析及反向柱层析纯化得化合物10(18mg，收率：26.35％)。Dissolve intermediate B (50 mg, 0.061 mmol) in 3 mL DMF, add compound 10E (29 mg, 0.091 mmol), DIPEA (23 mg, 0.18 mmol), and stir at room temperature for 2 h. Add 30mL ethyl acetate, wash twice with water (20mL x 2), Wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 10 (18 mg, yield: 26.35%).
Ms m/z(ESI):1119.4[M+H]+ Ms m/z(ESI):1119.4[M+H] +
1H NMR(400MHz,CF3COOD)δ8.30–8.24(m,1H),8.19(s,1H),8.03–7.96(m,1H),7.95–7.89(m,1H),7.87–7.74(m,4H),7.63–7.53(m,4H),7.52–7.44(m,3H),7.43–7.34(m,4H),6.83–6.74(m,1H),4.82–4.70(m,1H),4.63–4.47(m,8H),4.47–4.27(m,2H),4.13–3.98(m,2H),3.95–3.75(m,2H),3.54–3.41(m,2H),3.33–3.23(m,2H),3.01(s,3H),2.45–2.34(m,1H),2.31–2.21(m,1H),2.20–2.01(m,4H),1.91–1.76(m,2H),1.72(d,3H),1.69–1.52(m,2H),1.33(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.30–8.24(m,1H),8.19(s,1H),8.03–7.96(m,1H),7.95–7.89(m,1H),7.87–7.74( m,4H),7.63–7.53(m,4H),7.52–7.44(m,3H),7.43–7.34(m,4H),6.83–6.74(m,1H),4.82–4.70(m,1H), 4.63–4.47(m,8H),4.47–4.27(m,2H),4.13–3.98(m,2H),3.95–3.75(m,2H),3.54–3.41(m,2H),3.33–3.23(m ,2H),3.01(s,3H),2.45–2.34(m,1H),2.31–2.21(m,1H),2.20–2.01(m,4H),1.91–1.76(m,2H),1.72(d ,3H),1.69–1.52(m,2H),1.33(d,3H).
实施例11：化合物11的合成
Example 11: Synthesis of Compound 11
第一步：化合物11B的合成Step One: Synthesis of Compound 11B
将(R)-1,1,1-三氟异丙胺盐酸盐(8.02g，70.95mmol)溶于10mL甲醇中，加入三乙胺调节pH＝7左右，再加入11A(3.0g，6.45mmol)和乙酸(4.26g，70.95mmol)，置于封管中100℃反应16h。将反应冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析得11B(2.64g，产率：70.9％)Dissolve (R)-1,1,1-trifluoroisopropylamine hydrochloride (8.02g, 70.95mmol) in 10mL methanol, add triethylamine to adjust the pH to about 7, then add 11A (3.0g, 6.45mmol) ) and acetic acid (4.26g, 70.95mmol) were placed in a sealed tube and reacted at 100°C for 16h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 11B (2.64g, yield: 70.9%)
第二步：化合物11C的合成Step 2: Synthesis of Compound 11C
将化合物11B(0.60g，1.04mmol)加入到10mL二甲亚砜中，依次加入1-(硝基苯基)哌嗪(0.65g，3.12mmol)、碘化亚铜(0.02g，0.1mmol)、2,6-二甲基苯基氨甲酰基甲酸(0.20g，1.04mmol)、碳酸钾(0.43g，3.12mmol)，氮气氛围下升温至130℃反应12h，将反应液冷却至室温，加入饱和氯化铵溶液淬灭反应，乙酸乙酯(10mL×5)萃取5次，合并有机相，无水硫酸镁干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析，得到11C(0.12g，产率：17.77％)。Compound 11B (0.60g, 1.04mmol) was added to 10mL of dimethyl sulfoxide, followed by 1-(nitrophenyl)piperazine (0.65g, 3.12mmol) and copper iodide (0.02g, 0.1mmol). , 2,6-dimethylphenylcarbamoylcarbamate (0.20g, 1.04mmol), potassium carbonate (0.43g, 3.12mmol), heated to 130°C for 12h reaction under nitrogen atmosphere, cooled the reaction solution to room temperature, and added The reaction was quenched with saturated ammonium chloride solution, extracted 5 times with ethyl acetate (10 mL (0.12g, yield: 17.77%).
第三步：化合物11D的合成Step 3: Synthesis of Compound 11D
将化合物11C(0.6g，0.85mmol)溶于20mL甲醇中，加入100mg 10％钯碳，氢气氛围下室温搅拌1h。将反应液用硅藻土过滤，滤液减压浓缩后得化合物11D(380mg，产率：76.68％)Compound 11C (0.6g, 0.85mmol) was dissolved in 20mL methanol, 100mg 10% palladium on carbon was added, and stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 11D (380 mg, yield: 76.68%)
Ms m/z(ESI):583.8[M+H]+ Ms m/z(ESI):583.8[M+H] +
第四步：化合物11E的合成Step 4: Synthesis of Compound 11E
将3-(三氟甲基磺酰基)-4-氟苯磺酰氯(300mg，0.51mmol)溶于10mL二氯甲烷中，氮气保护下0℃下加入吡啶(200mg，0.61mmol)，11D(200mg，2.55mmol)的二氯甲烷溶液10mL，加完后继续反应1h。减压浓缩，残余物用硅胶色谱柱柱层析得11E(310mg，产率：69.61％)。 Dissolve 3-(trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (300mg, 0.51mmol) in 10mL dichloromethane, add pyridine (200mg, 0.61mmol) at 0°C under nitrogen protection, 11D (200mg , 2.55 mmol) of dichloromethane solution 10 mL, continue the reaction for 1 hour after addition. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 11E (310 mg, yield: 69.61%).
Ms m/z(ESI):873.1[M+H]+ Ms m/z(ESI):873.1[M+H] +
第五步：化合物11的合成Step 5: Synthesis of Compound 11
将化合物11E(50mg，0.057mmol)溶于2mL DMF中,依次加入3c(26mg，0.086mmol),DIPEA(66mg，0.51mmol),加完后室温搅拌反应2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水30mL洗涤一次,有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后粗品经硅胶柱层析及反向柱层析纯化得化合物11(12mg，收率：6.13％)。Compound 11E (50 mg, 0.057 mmol) was dissolved in 2 mL DMF, and 3c (26 mg, 0.086 mmol) and DIPEA (66 mg, 0.51 mmol) were added in sequence. After the addition was completed, the reaction was stirred at room temperature for 2 h. Add 30 mL of ethyl acetate, wash twice with water (20 mL Compound 11 (12 mg, yield: 6.13%) was purified by chromatography.
Ms m/z(ESI):1151.3[M+H]+ Ms m/z(ESI):1151.3[M+H] +
1H NMR(400MHz,CF3COOD)δ8.34–8.21(m,1H),8.06–7.87(m,2H),7.86–7.74(m,3H),7.67–7.18(m,13H),6.83–6.72(m,1H),5.43–5.17(m,1H),5.13–4.78(m,1H),4.68–4.28(m,8H),4.16–4.01(m,2H),3.98–3.80(m,1H),3.73–3.42(m,3H),3.42–3.23(m,3H),3.20–2.87(m,2H),2.77–2.28(m,4H),2.11–1.78(m,3H),1.59–1.36(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.34–8.21(m,1H),8.06–7.87(m,2H),7.86–7.74(m,3H),7.67–7.18(m,13H),6.83– 6.72(m,1H),5.43–5.17(m,1H),5.13–4.78(m,1H),4.68–4.28(m,8H),4.16–4.01(m,2H),3.98–3.80(m,1H ),3.73–3.42(m,3H),3.42–3.23(m,3H),3.20–2.87(m,2H),2.77–2.28(m,4H),2.11–1.78(m,3H),1.59–1.36 (m,2H).
实施例12：化合物12的合成
Example 12: Synthesis of Compound 12
第一步：化合物12a的合成Step One: Synthesis of Compound 12a
将原料N-叔丁氧羰基-去甲托品酮(1.0g，4.44mmol)溶于15mL甲醇中，氮气氛围下，0℃下分批次加入硼氢化钠(0.25g，6.66mmol)，继续反应1h。加20mL水淬灭反应，加入乙酸乙酯(15mL×2)萃取2次，无水硫酸钠干燥，减压浓缩，得到12a(0.95g，收率：94.13％)。Dissolve the raw material N-tert-butoxycarbonyl-nortropinone (1.0g, 4.44mmol) in 15mL methanol, add sodium borohydride (0.25g, 6.66mmol) in batches at 0°C under a nitrogen atmosphere, and continue Reaction 1h. Add 20 mL of water to quench the reaction, add ethyl acetate (15 mL × 2) for extraction twice, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 12a (0.95 g, yield: 94.13%).
Ms m/z(ESI):172.2[M+H-56]+ Ms m/z(ESI):172.2[M+H-56] +
第二步：化合物12b的合成Step 2: Synthesis of Compound 12b
将化合物12a(0.95g，4.18mmol)溶于10mL乙腈中，加入3mL 4N的盐酸二氧六环溶液，室温反应2h。减压浓缩得到化合物12b，白色固体(0.5g，收率：94.05％)。Compound 12a (0.95g, 4.18mmol) was dissolved in 10mL acetonitrile, 3mL 4N dioxane hydrochloride solution was added, and the reaction was carried out at room temperature for 2h. Concentrate under reduced pressure to obtain compound 12b as a white solid (0.5 g, yield: 94.05%).
Ms m/z(ESI):128.2[M+H]+ Ms m/z(ESI):128.2[M+H] +
第三步：化合物12c的合成Step 3: Synthesis of Compound 12c
将中间体A(0.5g，1.69mmol)溶于20mL二氯甲烷中，加入化合物12b(0.32g，2.54mmol)，氮气氛围下，0℃加入三乙胺(0.68g，6.76mmol)，保持0℃搅拌30min；将三乙酰氧基硼氢化钠(0.54g，2.54mmol)加至反应瓶中，升至室温搅拌过夜。加入30mL纯化水，分液，水相用二氯甲烷(25mL×2)萃取两次，合并有机相，无水硫酸钠干燥，滤液减压浓缩后残余物经硅胶色谱柱柱层析得到12c，无色油状物(0.4g，收率：58.21％)。Dissolve intermediate A (0.5g, 1.69mmol) in 20mL dichloromethane, add compound 12b (0.32g, 2.54mmol), add triethylamine (0.68g, 6.76mmol) under nitrogen atmosphere at 0°C, and keep 0 Stir at ℃ for 30 minutes; add sodium triacetoxyborohydride (0.54g, 2.54mmol) into the reaction bottle, raise to room temperature and stir overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with dichloromethane (25 mL Colorless oil (0.4g, yield: 58.21%).
Ms m/z(ESI):407.5[M+H]+ Ms m/z(ESI):407.5[M+H] +
第四步：化合物12d的合成 Step 4: Synthesis of Compound 12d
将化合物12c(40mg，0.098mmol)溶于5mL乙腈中，加入1mL 4N的盐酸二氧六环溶液，室温反应2h。减压浓缩得到12d的盐酸盐(28mg，产率：93.23％)Compound 12c (40 mg, 0.098 mmol) was dissolved in 5 mL acetonitrile, 1 mL 4N dioxane hydrochloride solution was added, and the reaction was carried out at room temperature for 2 h. Concentrate under reduced pressure to obtain 12d hydrochloride (28 mg, yield: 93.23%)
Ms m/z(ESI):307.3[M+H]+ Ms m/z(ESI):307.3[M+H] +
第五步：化合物12的合成Step 5: Synthesis of Compound 12
将中间体B(50mg，0.061mmol)溶于2mL DMF中，加入12d(28mg，0.091mmol),DIPEA(24mg，0.18mmol)，室温搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水20mL洗涤一次,无水硫酸钠干燥，减压浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物12的三氟乙酸盐(25mg，收率：37.06％)。Dissolve intermediate B (50 mg, 0.061 mmol) in 2 mL DMF, add 12d (28 mg, 0.091 mmol), DIPEA (24 mg, 0.18 mmol), and stir at room temperature for 2 h. Add 30 mL of ethyl acetate, wash twice with water (20 mL × 2), wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 12. trifluoroacetate (25 mg, yield: 37.06%).
Ms m/z(ESI):553.5[M/2+H]+ Ms m/z(ESI):553.5[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.27(s,1H),8.19(s,1H),8.04–7.97(m,1H),7.95–7.88(m,1H),7.88–7.75(m,4H),7.63–7.53(m,4H),7.52–7.32(m,7H),6.86–6.74(m,1H),4.84–4.70(m,1H),4.67–4.42(m,9H),4.33–4.16(m,2H),4.15–3.98(m,1H),3.41–3.19(m,4H),3.01(s,3H),2.68–2.18(m,10H),1.73(d,3H),1.34(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.27(s,1H),8.19(s,1H),8.04–7.97(m,1H),7.95–7.88(m,1H),7.88–7.75(m, 4H),7.63–7.53(m,4H),7.52–7.32(m,7H),6.86–6.74(m,1H),4.84–4.70(m,1H),4.67–4.42(m,9H),4.33– 4.16(m,2H),4.15–3.98(m,1H),3.41–3.19(m,4H),3.01(s,3H),2.68–2.18(m,10H),1.73(d,3H),1.34( d,3H).
实施例13：化合物13的合成
Example 13: Synthesis of Compound 13
第一步：化合物13a的合成Step One: Synthesis of Compound 13a
将原料(3S,4R)-3-氟-4-羟基哌啶-1-羧酸叔丁酯(1.0g，4.56mmol)溶于5mL二氯甲烷，加入5mL三氟乙酸，室温搅拌2h。减压浓缩除去溶剂，得到13a的三氟乙酸盐(0.54g，收率：99.4％)。Dissolve the raw material (3S, 4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.0g, 4.56mmol) in 5mL of methylene chloride, add 5mL of trifluoroacetic acid, and stir at room temperature for 2h. The solvent was concentrated under reduced pressure to obtain the trifluoroacetate salt of 13a (0.54 g, yield: 99.4%).
Ms m/z(ESI):120.2[M+H]Ms m/z(ESI):120.2[M+H]
第二步：化合物13b的合成Step 2: Synthesis of Compound 13b
将中间体A溶于20mL二氯甲烷中，加入化合物13a(0.18g，1.52mmol)，氮气氛围下，0℃下加入三乙胺(0.62g，6.08mmol)，控制0℃左右搅拌30min。加入三乙酰氧基硼氢化钠(0.48g，2.28mmol)，室温反应过夜。加入30mL纯化水，分液，水相用二氯甲烷(25mL×2)萃取两次，合并有机相，无水硫酸钠干燥，滤液减压浓缩残余物经硅胶色谱柱柱层析得到13b(0.4g，收率：66.03％)。Dissolve Intermediate A in 20 mL of methylene chloride, add compound 13a (0.18g, 1.52mmol), add triethylamine (0.62g, 6.08mmol) at 0°C under a nitrogen atmosphere, and stir at about 0°C for 30 minutes. Sodium triacetoxyborohydride (0.48g, 2.28mmol) was added and the reaction was carried out at room temperature overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with dichloromethane (25 mL g, yield: 66.03%).
Ms m/z(ESI):399.3[M+H]+ Ms m/z(ESI):399.3[M+H] +
第三步：化合物13c的合成Step 3: Synthesis of Compound 13c
将化合物13b(0.1g，0.25mmol)溶于2mL二氯甲烷，加入2mL盐酸二氧六环，室温搅拌2h。减压浓缩得到13c的盐酸盐(0.056g，收率：75.06％)。 Compound 13b (0.1g, 0.25mmol) was dissolved in 2mL of methylene chloride, 2mL of dioxane hydrochloride was added, and the mixture was stirred at room temperature for 2h. Concentrate under reduced pressure to obtain the hydrochloride salt of 13c (0.056g, yield: 75.06%).
Ms m/z(ESI):299.2[M+H]+ Ms m/z(ESI):299.2[M+H] +
第四步：化合物13的合成Step 4: Synthesis of Compound 13
将中间体B(50mg，0.061mmol)溶于2mL DMF，加入化合物13c的盐酸盐(27mg，0.091mmol)，DIPEA(24mg，0.18mmol)，室温搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水20mL洗涤一次,无水硫酸钠干燥，减压浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物13的三氟乙酸盐(23mg，收率：34.35％)。Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL DMF, the hydrochloride of compound 13c (27 mg, 0.091 mmol) and DIPEA (24 mg, 0.18 mmol) were added, and stirred at room temperature for 2 h. Add 30 mL of ethyl acetate, wash twice with water (20 mL × 2), wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 13. of trifluoroacetate (23 mg, yield: 34.35%).
Ms m/z(ESI):549.3[M/2+H]+ Ms m/z(ESI):549.3[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.24(s,1H),8.16(s,1H),8.00–7.93(m,1H),7.92–7.86(m,1H),7.84–7.79(m,1H),7.79–7.71(m,3H),7.59–7.50(m,4H),7.49–7.42(m,3H),7.41–7.31(m,4H),6.76–6.69(m,1H),5.09–4.92(m,1H),4.80–4.66(m,1H),4.59–4.40(m,8H),4.07–3.95(m,1H),3.88–3.76(m,1H),3.72–3.38(m,5H),3.33–3.20(m,2H),2.98(s,3H),2.69–2.44(m,2H),2.38–2.21(m,2H),2.04–1.95(m,1H),1.69(d,3H),1.30(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.24(s,1H),8.16(s,1H),8.00–7.93(m,1H),7.92–7.86(m,1H),7.84–7.79(m, 1H),7.79–7.71(m,3H),7.59–7.50(m,4H),7.49–7.42(m,3H),7.41–7.31(m,4H),6.76–6.69(m,1H),5.09– 4.92(m,1H),4.80–4.66(m,1H),4.59–4.40(m,8H),4.07–3.95(m,1H),3.88–3.76(m,1H),3.72–3.38(m,5H ),3.33–3.20(m,2H),2.98(s,3H),2.69–2.44(m,2H),2.38–2.21(m,2H),2.04–1.95(m,1H),1.69(d,3H ),1.30(d,3H).
实施例14：化合物14的合成
Example 14: Synthesis of Compound 14
第一步：化合物14a的合成Step One: Synthesis of Compound 14a
将原料(S)-1,1,1-三氟异丙胺盐酸盐(1.5g，10.00mmol)溶于10mL甲醇中，加入三乙胺调pH＝7左右，再加入11A(1.0g，2.00mmol)和乙酸(1.32g，22mmol)，置于封管100℃反应过夜。将反应冷却至室温，减压浓缩后残余物柱层析得14a(0.62g，产率：53.74％)。Dissolve raw material (S)-1,1,1-trifluoroisopropylamine hydrochloride (1.5g, 10.00mmol) in 10mL methanol, add triethylamine to adjust pH=7, then add 11A (1.0g, 2.00 mmol) and acetic acid (1.32g, 22mmol), placed in a sealed tube at 100°C to react overnight. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain 14a (0.62 g, yield: 53.74%).
1H NMR(400MHz,CDCl3)δ7.30(dd,2H),7.25–7.16(m,6H),7.01–6.93(m,3H),6.92–6.88(m,2H),5.05(d,2H),4.63(dt,1H),2.74(s,3H),1.72(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.30(dd,2H),7.25–7.16(m,6H),7.01–6.93(m,3H),6.92–6.88(m,2H),5.05(d,2H ),4.63(dt,1H),2.74(s,3H),1.72(d,3H).
第二步：化合物14b的合成Step 2: Synthesis of Compound 14b
将化合物14a(0.60g，1.04mmol)加入到10mL二甲亚砜中，依次加入1-(硝基苯基)哌嗪(0.65g，3.12mmol)、碘化亚铜(0.02g，0.1mmol)、2,6-二甲基苯基氨甲酰基甲酸(0.20g，1.04mmol)、碳酸钾(0.43g，3.12mmol)，氮气氛围下加热至130℃反应12h。冷却至室温，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(10mL×5)，合并有机相洗涤，无水硫酸镁干燥，粗品经硅胶柱层析分离纯化，得14b(0.12g，产率：17.77％)。Compound 14a (0.60g, 1.04mmol) was added to 10mL of dimethyl sulfoxide, followed by 1-(nitrophenyl)piperazine (0.65g, 3.12mmol) and copper iodide (0.02g, 0.1mmol). , 2,6-dimethylphenylcarbamoylcarbamate (0.20g, 1.04mmol), potassium carbonate (0.43g, 3.12mmol), heated to 130°C under nitrogen atmosphere and reacted for 12h. Cool to room temperature, add saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate (10 mL Yield: 17.77%).
1H NMR(400MHz,CDCl3)δ8.14(d,2H),7.17(dd,3H),7.13–6.94(m,5H),6.94–6.88(m,2H),6.83(d,2H),6.70(dd,1H),6.60(d,2H),5.08(s,2H),4.67(dt,1H),3.46–3.39(m,4H),3.12–3.03(m,4H),2.73(s,3H),1.73(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.14(d,2H),7.17(dd,3H),7.13–6.94(m,5H),6.94–6.88(m,2H),6.83(d,2H), 6.70(dd,1H),6.60(d,2H),5.08(s,2H),4.67(dt,1H),3.46–3.39(m,4H),3.12–3.03(m,4H),2.73(s, 3H),1.73(d,3H).
第三步：化合物14c的合成 Step 3: Synthesis of Compound 14c
将化合物14b(0.12g，0.17mmol)溶于20mL甲醇中，加入50mg 10％钯碳，氢气氛围下室温搅拌1h。过滤，滤液直接浓缩得化合物14c，灰色固体(90mg，产率：90.8％)Compound 14b (0.12g, 0.17mmol) was dissolved in 20mL methanol, 50mg 10% palladium on carbon was added, and stirred at room temperature for 1 hour under a hydrogen atmosphere. Filter, and the filtrate is directly concentrated to obtain compound 14c, a gray solid (90 mg, yield: 90.8%)
Ms m/z(ESI):583.8[M+H]+ Ms m/z(ESI):583.8[M+H] +
第四步：化合物14d的合成Step 4: Synthesis of Compound 14d
将3-(三氟甲基磺酰基)-4-氟苯磺酰氯(20mg，0.061mmol)溶于20mL二氯甲烷,氮气氛围下，0℃加入吡啶(20mg，0.26mmol)，再加入化合物14c(30mg，0.051mmol)的二氯甲烷溶液10mL，加完后继续反应1h。直接减压浓缩后残余物经硅胶色谱柱柱层析得14d(27mg，产率：60.62％)。Dissolve 3-(trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (20mg, 0.061mmol) in 20mL dichloromethane, add pyridine (20mg, 0.26mmol) at 0°C under nitrogen atmosphere, and then add compound 14c (30 mg, 0.051 mmol) in dichloromethane solution 10 mL, continue the reaction for 1 hour after adding. After direct concentration under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 14d (27 mg, yield: 60.62%).
Ms m/z(ESI):873.1[M+H]+ Ms m/z(ESI):873.1[M+H] +
第五步：化合物14的合成Step 5: Synthesis of Compound 14
将化合物14d(50mg，0.057mmol)溶于2mL DMF，加入化合物4c(34mg，0.11mmol),DIPEA(37mg，0.29mmol),室温搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水20mL洗涤一次,无水硫酸钠干燥，减压浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物14(12mg，产率：18.28％)Dissolve compound 14d (50 mg, 0.057 mmol) in 2 mL DMF, add compound 4c (34 mg, 0.11 mmol), DIPEA (37 mg, 0.29 mmol), and stir at room temperature for 2 h. Add 30 mL of ethyl acetate, wash twice with water (20 mL × 2), wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 14. (12mg, yield: 18.28%)
Ms m/z(ESI):549.8[M/2+H]+ Ms m/z(ESI):549.8[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.25(s,1H),7.97(d,1H),7.88–7.72(m,3H),7.60–7.29(m,13H),7.26–7.15(m,1H),6.76–6.69(m,1H),5.23(d,1H),4.90(dd,1H),4.56–4.32(m,8H),4.02(s,2H),3.94–3.85(m,1H),3.46(s,3H),3.29–2.95(m,5H),2.69–2.52(m,2H),2.44–2.28(m,2H),2.02(d,1H),1.92(dd,2H),1.43(dd,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.25(s,1H),7.97(d,1H),7.88–7.72(m,3H),7.60–7.29(m,13H),7.26–7.15(m, 1H),6.76–6.69(m,1H),5.23(d,1H),4.90(dd,1H),4.56–4.32(m,8H),4.02(s,2H),3.94–3.85(m,1H) ,3.46(s,3H),3.29–2.95(m,5H),2.69–2.52(m,2H),2.44–2.28(m,2H),2.02(d,1H),1.92(dd,2H),1.43 (dd,2H).
实施例15：化合物15的合成
Example 15: Synthesis of Compound 15
将原料14d(50mg，0.057mmol)溶于2mL DMF中，加入7E(26mg，0.085mmol),DIPEA(37mg，0.29mmol),室温搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水10mL洗涤一次,无水硫酸钠干燥，减压浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物15(12mg，产率：18.15％)Dissolve raw material 14d (50 mg, 0.057 mmol) in 2 mL DMF, add 7E (26 mg, 0.085 mmol), DIPEA (37 mg, 0.29 mmol), and stir at room temperature for 2 hours. Add 30 mL of ethyl acetate, wash twice with water (20 mL × 2), wash once with 10 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography and reverse column chromatography to obtain compound 15. (12mg, yield: 18.15%)
Ms m/z(ESI):580.3[M/2+H]+ Ms m/z(ESI):580.3[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.20(s,1H),7.97–7.87(m,1H),7.77–7.65(m,2H),7.61–7.26(m,13H),7.25–7.03(m,2H),6.73–6.60(m,1H),4.95–4.78(m,1H),4.73–4.63(m,1H),4.53–4.07(m,8H),4.02–3.88(m,1H),3.84–3.57(m,2H),3.48–3.14(m,7H),3.03–2.72(m,3H),2.66–2.40(m,2H),2.35–2.11(m,3H),2.09–1.71(m,5H). 1 H NMR (400MHz, CF 3 COOD) δ8.20(s,1H),7.97–7.87(m,1H),7.77–7.65(m,2H),7.61–7.26(m,13H),7.25–7.03( m,2H),6.73–6.60(m,1H),4.95–4.78(m,1H),4.73–4.63(m,1H),4.53–4.07(m,8H),4.02–3.88(m,1H), 3.84–3.57(m,2H),3.48–3.14(m,7H),3.03–2.72(m,3H),2.66–2.40(m,2H),2.35–2.11(m,3H),2.09–1.71(m ,5H).
实施例17：化合物17的合成
Example 17: Synthesis of Compound 17
第一步：化合物17a的合成Step One: Synthesis of Compound 17a
将原料1-环丙基乙胺盐酸盐(1.46g，12.00mmol)溶于20mL甲醇中，加入三乙胺调pH＝7左右，再加入11A(2.0g，4.00mmol)和乙酸(2.4g，40mmol)，封管100℃反应过夜。冷却至室温，反应液浓缩，残余物经硅胶色谱柱柱层析分离纯化得化合物17a(1.2g，产率：56.65％)。Dissolve the raw material 1-cyclopropylethylamine hydrochloride (1.46g, 12.00mmol) in 20mL methanol, add triethylamine to adjust the pH to about 7, then add 11A (2.0g, 4.00mmol) and acetic acid (2.4g , 40 mmol), seal the tube and react at 100°C overnight. After cooling to room temperature, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography to obtain compound 17a (1.2 g, yield: 56.65%).
1H NMR(400MHz,CDCl3)δ7.27–7.19(m,6H),7.19–7.14(m,1H),7.09–6.93(m,4H),6.94–6.87(m,2H),5.06(s,2H),3.33–3.22(m,1H),2.75(s,3H),1.49(d,3H),0.96(dd,1H),0.65–0.55(m,1H),0.45(dd,1H),0.10(dd,1H),0.02(d,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.27–7.19(m,6H),7.19–7.14(m,1H),7.09–6.93(m,4H),6.94–6.87(m,2H),5.06(s ,2H),3.33–3.22(m,1H),2.75(s,3H),1.49(d,3H),0.96(dd,1H),0.65–0.55(m,1H),0.45(dd,1H), 0.10(dd,1H),0.02(d,1H).
第二步：化合物17b的合成Step 2: Synthesis of Compound 17b
将化合物17a(1.0g，1.82mmol)加入到10mL二甲亚砜中，依次加入1-(硝基苯基)哌嗪(0.75g，3.64mmol)、碘化亚铜(0.035g，0.18mmol)、2,6-二甲基苯基氨甲酰基甲酸(0.35g，1.82mmol)、碳酸钾(0.75g，5.46mmol)，氮气氛围下加热至130℃反应12h，冷却至室温，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(10mL×5)，合并有机相洗涤，无水硫酸镁干燥，粗品经硅胶柱层析分离纯化，得17b(0.63g，产率：51.27％)。Compound 17a (1.0g, 1.82mmol) was added to 10mL dimethyl sulfoxide, followed by 1-(nitrophenyl)piperazine (0.75g, 3.64mmol) and copper iodide (0.035g, 0.18mmol). , 2,6-dimethylphenylcarbamoylcarbamate (0.35g, 1.82mmol), potassium carbonate (0.75g, 5.46mmol), heated to 130°C for 12h reaction under nitrogen atmosphere, cooled to room temperature, and added saturated chlorine The reaction was quenched with ammonium solution, extracted with ethyl acetate (10 mL × 5), the organic phases were combined, washed, and dried over anhydrous magnesium sulfate. The crude product was separated and purified by silica gel column chromatography to obtain 17b (0.63 g, yield: 51.27%).
第三步：化合物17c的合成Step 3: Synthesis of Compound 17c
将原料17b(0.63g，0.93mmol)溶于20mL甲醇中，加入50mg10％钯碳，氢气氛围下室温反应1h。过滤，滤液直接浓缩得化合物17c。灰色固体(0.42g，产率：81.36％)Dissolve raw material 17b (0.63g, 0.93mmol) in 20mL of methanol, add 50mg of 10% palladium on carbon, and react at room temperature for 1 hour in a hydrogen atmosphere. Filter, and the filtrate is directly concentrated to obtain compound 17c. Gray solid (0.42g, yield: 81.36%)
Ms m/z(ESI):555.2[M+H]+ Ms m/z(ESI):555.2[M+H] +
第四步：化合物17d的合成Step 4: Synthesis of compound 17d
将原料3-(三氟甲基磺酰基)-4-氟苯磺酰氯(0.3g，0.91mmol)溶于20mL二氯甲烷,氮气氛围下，0℃加入吡啶(0.3g，3.8mmol)，再加17c(0.42g，0.76mmol)的二氯甲烷溶液10mL，加完后继续反应1h。减压浓缩后残余物柱层析分离纯化得17d。黄色固体(0.27g，产率：42.03％)。Dissolve the raw material 3-(trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (0.3g, 0.91mmol) in 20mL dichloromethane, add pyridine (0.3g, 3.8mmol) at 0°C under a nitrogen atmosphere, and then Add 10 mL of dichloromethane solution of 17c (0.42 g, 0.76 mmol), and continue the reaction for 1 hour after the addition. After concentration under reduced pressure, the residue was separated and purified by column chromatography to obtain 17d. Yellow solid (0.27g, yield: 42.03%).
Ms m/z(ESI):845.7[M+H]+ Ms m/z(ESI):845.7[M+H] +
第四步：化合物17的合成Step 4: Synthesis of Compound 17
原料17d(50mg，0.059mmol)溶于2mL DMF，加入7E(27mg，0.087mmol),DIPEA(38mg，0.29mmol),室温搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水10mL洗涤一次,无水硫酸钠干燥，浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物17(14mg，产率：20.97％)Raw material 17d (50 mg, 0.059 mmol) was dissolved in 2 mL DMF, 7E (27 mg, 0.087 mmol), DIPEA (38 mg, 0.29 mmol) were added, and stirred at room temperature for 2 hours. Add 30 mL of ethyl acetate, wash twice with water (20 mL , yield: 20.97%)
Ms m/z(ESI):566.3[M/2+H]+ Ms m/z(ESI):566.3[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.20(s,1H),8.14(s,1H),7.95–7.90(m,1H),7.89–7.84(m,1H),7.82–7.68(m,4H),7.58–7.47(m,4H),7.46–7.39(m,3H),7.38–7.29(m,4H),6.75–6.63(d,1H),4.70–4.36(m,8H),4.17–3.90(m,2H),3.84–3.60(m,3H),3.45–3.14(m,8H),3.04–2.89(m,3H),2.57–2.45(m,1H),2.32–2.14(m,3H),2.12–1.92(m,2H),1.74–1.66(m,1H),1.48–1.31(m,3H),1.03–0.63(m,2H),0.55–0.13(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.20(s,1H),8.14(s,1H),7.95–7.90(m,1H),7.89–7.84(m,1H),7.82–7.68(m, 4H),7.58–7.47(m,4H),7.46–7.39(m,3H),7.38–7.29(m,4H),6.75–6.63(d,1H),4.70–4.36(m,8H),4.17– 3.90(m,2H),3.84–3.60(m,3H),3.45–3.14(m,8H),3.04–2.89(m,3H),2.57–2.45(m,1H),2.32–2.14(m,3H ),2.12–1.92(m,2H),1.74–1.66(m,1H),1.48–1.31(m,3H),1.03–0.63(m,2H),0.55–0.13(m,2H).
化合物18：化合物18的合成
Compound 18: Synthesis of Compound 18
原料17d(50mg，0.059mmol)溶于2mL DMF，加入4c(19mg，0.064mmol),DIPEA(38mg，0.29mmol),室温搅拌2h。加入30mL乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水10mL洗涤一次,无水硫酸钠干燥，浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物18(13mg，产率：19.61％)Raw material 17d (50mg, 0.059mmol) was dissolved in 2mL DMF, 4c (19mg, 0.064mmol) and DIPEA (38mg, 0.29mmol) were added, and stirred at room temperature for 2h. Add 30 mL of ethyl acetate, wash twice with water (20 mL , yield: 19.61%)
Ms m/z(ESI):1123.5[M+H]+ Ms m/z(ESI):1123.5[M+H] +
1H NMR(400MHz,CF3COOD)δ8.24–8.19(m,1H),8.16–8.10(m,1H),7.96–7.91(m,1H),7.89–7.84(m,1H),7.82–7.67(m,4H),7.57–7.47(m,4H),7.46–7.38(m,3H),7.38–7.29(m,4H),6.74–6.69(d,1H),5.26–5.10(m,1H),4.57–4.26(m,8H),4.04–3.92(m,2H),3.89–3.63(m,2H),3.61–3.35(m,4H),3.27–3.18(m,2H),2.96–2.89(m,3H),2.67–2.47(m,2H),2.40–2.21(m,2H),2.03–1.63(m,3H),1.44–1.31(m,2H),1.03–0.65(m,2H),0.53–0.13(m,2H). 1 H NMR (400MHz, CF 3 COOD) δ8.24–8.19(m,1H),8.16–8.10(m,1H),7.96–7.91(m,1H),7.89–7.84(m,1H),7.82– 7.67(m,4H),7.57–7.47(m,4H),7.46–7.38(m,3H),7.38–7.29(m,4H),6.74–6.69(d,1H),5.26–5.10(m,1H ),4.57–4.26(m,8H),4.04–3.92(m,2H),3.89–3.63(m,2H),3.61–3.35(m,4H),3.27–3.18(m,2H),2.96–2.89 (m,3H),2.67–2.47(m,2H),2.40–2.21(m,2H),2.03–1.63(m,3H),1.44–1.31(m,2H),1.03–0.65(m,2H) ,0.53–0.13(m,2H).
实施例19：化合物19的制备
Example 19: Preparation of Compound 19
将原料11E(50mg，0.057mmol)溶于2ml DMF,加入7E(26mg，0.086mmol),DIPEA(22mg，0.17mmol),室温搅拌2h。加入30ml乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次,无水硫酸钠干燥，减压浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物19(14mg，21.18％)。Dissolve raw material 11E (50mg, 0.057mmol) in 2ml DMF, add 7E (26mg, 0.086mmol), DIPEA (22mg, 0.17mmol), and stir at room temperature for 2h. Add 30 ml of ethyl acetate, wash twice with water (20 mL 14mg, 21.18%).
Ms m/z(ESI):1159.3[M+H]+ Ms m/z(ESI):1159.3[M+H] +
实施例20：化合物20的制备
Example 20: Preparation of Compound 20
第一步：化合物20B的制备Step One: Preparation of Compound 20B
将20A(5.0g，46.24mmol)置于封管中，用100mL N,N-二甲基甲酰胺溶解，加入DIPEA(9g，50.86mmol)和3,4-二氟硝基苯(4.05g，50.86mmol)。体系氮气保护下加热至120℃过夜，向体系中加入300mL乙酸乙酯稀释，然后用150mL水洗有机相三次，150mL饱和食盐水洗一次，有机相干燥旋干，残余物经过柱层析纯化，即得到化合物20B(3.0g,产率：36.5％)。Place 20A (5.0g, 46.24mmol) in a sealed tube, dissolve it in 100mL N,N-dimethylformamide, add DIPEA (9g, 50.86mmol) and 3,4-difluoronitrobenzene (4.05g, 50.86mmol). The system was heated to 120°C overnight under nitrogen protection, and 300 mL of ethyl acetate was added to the system to dilute it, then the organic phase was washed three times with 150 mL of water and once with 150 mL of saturated brine, the organic phase was dried and spin-dried, and the residue was purified by column chromatography to obtain Compound 20B (3.0 g, yield: 36.5%).
LCMS m/z＝356.2[M+H]+ LCMS m/z＝356.2[M+H] +
第二步：化合物20C的制备Step 2: Preparation of compound 20C
将中间体20B(3.0g，8.45mmol)溶解于30mL超干的N,N-二甲基甲酰胺中，体系氮气保护置于冰浴下20min，然后加入60％氢化钠(375mg，9.3mmol)，加完后体系自动升至室温反应3h。将反应液直接倒入100mL的冰水中，加入200mL乙酸乙酯稀释，有机相用100mL水洗有机相三次，100mL饱和食盐水洗一次，有机相干燥旋干，残余物经过柱层析纯化，即得到化合物20C(2.8g，产率：99％)Intermediate 20B (3.0g, 8.45mmol) was dissolved in 30mL of ultra-dry N,N-dimethylformamide. The system was placed in an ice bath under nitrogen protection for 20min, and then 60% sodium hydride (375mg, 9.3mmol) was added. , after the addition, the system automatically rose to room temperature and reacted for 3 hours. Pour the reaction solution directly into 100 mL of ice water, add 200 mL of ethyl acetate to dilute, wash the organic phase three times with 100 mL of water and once with 100 mL of saturated brine, dry the organic phase and spin dry, and the residue is purified by column chromatography to obtain the compound. 20C (2.8g, yield: 99%)
LCMS m/z＝336.2[M+H]+ LCMS m/z＝336.2[M+H] +
第三步：化合物20D的制备Step 3: Preparation of Compound 20D
氮气保护下，将中间体20C(0.8g,2.4mmol)溶于20mL乙腈中，然后加入5mL盐酸1,4-二氧六环溶液，随后体系自动升至室温下反应1h，减压浓缩除去溶剂得到产品20D的盐酸盐(720mg粗品)，直接用于下一步反应。Under nitrogen protection, dissolve intermediate 20C (0.8g, 2.4mmol) in 20mL acetonitrile, then add 5mL hydrochloric acid 1,4-dioxane solution, and then the system automatically rises to room temperature for reaction for 1h, and is concentrated under reduced pressure to remove the solvent. The hydrochloride salt of product 20D (720 mg crude product) was obtained, which was directly used in the next reaction.
LCMS m/z＝236.1[M+H]+ LCMS m/z＝236.1[M+H] +
第四步：20E的制备Step 4: Preparation of 20E
将化合物5A(800mg，1.53mmol)、20D(720mg，3.06mmol)、碘化亚铜(170mg，0.92mmol)、[(2,6-二甲苯基)氨基](氧)乙酸(570mg，3.06mmol)和碳酸钾(630mg，4.59mmol)溶解于15mL的DMSO中，在130℃下封管中反应10小时。加入一定量的水淬灭反应，EA萃取反应，饱和氯化钠洗涤，无水硫酸钠干燥，柱层析纯化即得化合物20E(320mg，29.15％)。Compound 5A (800mg, 1.53mmol), 20D (720mg, 3.06mmol), copper iodide (170mg, 0.92mmol), [(2,6-dimethylphenyl)amino](oxy)acetic acid (570mg, 3.06mmol) ) and potassium carbonate (630 mg, 4.59 mmol) were dissolved in 15 mL of DMSO, and the reaction was carried out in a sealed tube at 130°C for 10 hours. A certain amount of water was added to quench the reaction, the reaction was extracted with EA, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, and purified by column chromatography to obtain compound 20E (320 mg, 29.15%).
Ms m/z(ESI):677.2[M+H]Ms m/z(ESI):677.2[M+H]
第五步：20F的制备Step 5: Preparation of 20F
将化合物20E(300mg，0.44mmol)溶解于10mL的甲醇和10mL乙酸乙酯中，然后加入10％ 钯炭(50mg，0.47mmol)，在室温下搅拌反应1小时。硅藻土过滤，收集滤液，减压浓缩，即得化合物20F(200mg，81.59％)。Compound 20E (300 mg, 0.44 mmol) was dissolved in 10 mL of methanol and 10 mL of ethyl acetate, and then 10% Palladium on carbon (50 mg, 0.47 mmol) was stirred and reacted at room temperature for 1 hour. Filter through diatomaceous earth, collect the filtrate, and concentrate under reduced pressure to obtain compound 20F (200 mg, 81.59%).
LCMS m/z＝557.2[M+H]+ LCMS m/z＝557.2[M+H] +
第三步：20G的制备Step 3: Preparation of 20G
将化合物5C-1(129mg，0.40mmol)溶解于5mL的二氯甲烷中，然后在0℃下加入吡啶(85mg，1.08mmol)，搅拌10分钟再缓慢加入20F(200mg，0.36mmol)，整个体系在室温下搅拌2小时。加入一定量的水淬灭反应，乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥，柱层析纯化得产物20G(180mg，59.01％)。Dissolve compound 5C-1 (129 mg, 0.40 mmol) in 5 mL of dichloromethane, then add pyridine (85 mg, 1.08 mmol) at 0°C, stir for 10 minutes, and then slowly add 20F (200 mg, 0.36 mmol), and the entire system Stir at room temperature for 2 hours. A certain amount of water was added to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain product 20G (180 mg, 59.01%).
LCMS m/z＝847.1[M+H]+ LCMS m/z＝847.1[M+H] +
第四步：化合物20的制备Step 4: Preparation of Compound 20
将20G(80mg，0.094mmol)溶于5ml DMF,加入10E(45.19mg，0.14mmol),DIPEA(36.45mg，0.28mmol),室温搅拌2h。加入30ml乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次,无水硫酸钠干燥，减压浓缩，粗品经硅胶柱层析及反向柱层析纯化得化合物20(15mg，13.9％)。Dissolve 20G (80mg, 0.094mmol) in 5ml DMF, add 10E (45.19mg, 0.14mmol), DIPEA (36.45mg, 0.28mmol), and stir at room temperature for 2h. Add 30 ml of ethyl acetate, wash twice with water (20 mL 15 mg, 13.9%).
Ms m/z(ESI):1147.3[M+H]+ Ms m/z(ESI):1147.3[M+H] +
实施例21：化合物21的制备
Example 21: Preparation of Compound 21
第一步：21C的制备Step One: Preparation of 21C
将原料21A(2.2g，6.12mmol)溶于20mL无水乙醇中，依次加入化合物4-环丙基苯甲醛21B(0.98g，6.73mmol)、三乙胺(1.55g，15.3mmol)、3-乙基-5-(2-羟乙基)-4-甲基噻唑溴化物(0.77g，3.06mmol)，通入氮气，体系升温至75℃，搅拌6h，反应体系降至室温，浓缩，用乙酸乙酯稀释，洗涤有机相，无水硫酸镁干燥，过滤浓缩，残余物经柱层析得产品21C(1.8g，收率：58.2％)Dissolve raw material 21A (2.2g, 6.12mmol) in 20mL of absolute ethanol, and add compound 4-cyclopropylbenzaldehyde 21B (0.98g, 6.73mmol), triethylamine (1.55g, 15.3mmol), 3- Ethyl-5-(2-hydroxyethyl)-4-methylthiazole bromide (0.77g, 3.06mmol), add nitrogen, heat the system to 75°C, stir for 6 hours, cool the reaction system to room temperature, concentrate, and use Dilute with ethyl acetate, wash the organic phase, dry over anhydrous magnesium sulfate, filter and concentrate, and the residue is subjected to column chromatography to obtain product 21C (1.8g, yield: 58.2%)
第二步：21D的制备Step 2: Preparation of 21D
将原料(S)-1,1,1-三氟异丙胺盐酸盐(1.6g，10.68mmol)溶于10mL甲醇中，加入三乙胺调pH＝7左右，再加入21C(1.8g，3.5 6mmol)和乙酸(2.14g，35.6mmol)，100℃封管反应过夜。浓缩，残余物直接柱层析得产品得目标产物21D(0.73g，产率：72％)。Dissolve raw material (S)-1,1,1-trifluoroisopropylamine hydrochloride (1.6g, 10.68mmol) in 10mL methanol, add triethylamine to adjust pH=7, then add 21C (1.8g, 3.5 6mmol) and acetic acid (2.14g, 35.6mmol), seal the tube at 100°C overnight. After concentration, the residue was directly column chromatographed to obtain the target product 21D (0.73g, yield: 72%).
1H NMR(400MHz,CDCl3)δ7.23(dd,4H),7.20–7.15(m,1H),7.03–6.94(m,5H),6.94–6.86(m,3H),5.06(s,2H),4.73–4.69(m,1H),2.73(s,3H),1.89–1.83(m,1H),1.69(d,3H),1.02–0.94(m,2H),0.74–0.64(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.23(dd,4H),7.20–7.15(m,1H),7.03–6.94(m,5H),6.94–6.86(m,3H),5.06(s,2H ),4.73–4.69(m,1H),2.73(s,3H),1.89–1.83(m,1H),1.69(d,3H),1.02–0.94(m,2H),0.74–0.64(m,2H ).
第三步：21E的制备 Step 3: Preparation of 21E
将原料21D(0.6g，1.03mmol)溶于10mL二氧六环和2mL水的混合溶剂中，依次加入N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(0.48g，1.54mmol)，碳酸铯(0.67g，2.06mmol)，Pd(dppf)Cl2二氯甲烷络合物(0.084g，0.10mmol)，氮气置换后加热至100℃反应2h，直接减压浓缩，残余物经柱层析得产品21E(0.55g，收率78％)。Dissolve raw material 21D (0.6g, 1.03mmol) in a mixed solvent of 10mL dioxane and 2mL water, and add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester in sequence (0.48g, 1.54mmol), cesium carbonate (0.67g, 2.06mmol), Pd(dppf)Cl 2 dichloromethane complex (0.084g, 0.10mmol), heated to 100°C for 2 hours after nitrogen replacement, directly reduced The mixture was concentrated under pressure, and the residue was subjected to column chromatography to obtain product 21E (0.55 g, yield 78%).
第四步：21F的制备Step 4: Preparation of 21F
将原料21E(0.55g，0.80mmol)溶于5mL二氯甲烷中，加入2mL 4N盐酸-二氧六环溶液，室温反应2h，减压浓缩，得21F的盐酸盐(0.45g，收率：96％)。Dissolve raw material 21E (0.55g, 0.80mmol) in 5mL of methylene chloride, add 2mL of 4N hydrochloric acid-dioxane solution, react at room temperature for 2h, and concentrate under reduced pressure to obtain 21F hydrochloride (0.45g, yield: 96%).
LCMS m/z＝585.3[M+H]+ LCMS m/z＝585.3[M+H] +
第五步：21G的制备Step 5: Preparation of 21G
将原料21F的盐酸盐(0.45g，0.77mmol)溶于5mL DMF，依次加入对氟硝基苯(0.16g，1.16mmol)，碳酸钾(0.21g，0.54mmol)氮气氛围下，加热至50℃反应16h。加入20mL乙酸乙酯，用水洗3次(20mL×3)，30mL食盐水洗涤一次，无水硫酸钠干燥，减压浓缩，残余物经柱层析得21G(0.53g，收率：97％)。Dissolve the hydrochloride of raw material 21F (0.45g, 0.77mmol) in 5mL DMF, add p-fluoronitrobenzene (0.16g, 1.16mmol) and potassium carbonate (0.21g, 0.54mmol) in sequence under nitrogen atmosphere, and heat to 50 ℃ reaction for 16h. Add 20 mL of ethyl acetate, wash three times with water (20 mL .
第六步：21H的制备Step 6: Preparation of 21H
将原料21G(0.53g，0.75mmol)溶于10mL甲醇中，加入50mg 10％钯碳，置换氢气氛围后室温反应2h，过滤，滤液浓缩的得21H(0.31g，收率：70％)，直接用于下一步。Dissolve raw material 21G (0.53g, 0.75mmol) in 10mL methanol, add 50mg 10% palladium on carbon, replace the hydrogen atmosphere and react at room temperature for 2 hours, filter, and concentrate the filtrate to obtain 21H (0.31g, yield: 70%), directly for the next step.
Ms m/z(ESI):588.3[M+H]+ Ms m/z(ESI):588.3[M+H] +
第七步：21I的制备Step 7: Preparation of 21I
原料化合物5C-1(0.21g，0.64mmol)溶于20mL二氯甲烷,氮气保护，降温至0℃加入吡啶(0.21g，2.65mmol)，在加21H(0.31g，0.53mmol)的二氯甲烷溶液10mL，加完后继续反应1h。直接减压浓缩，残余物经柱层析得产品21I(0.15g，产率：32％)。The raw material compound 5C-1 (0.21g, 0.64mmol) was dissolved in 20mL of methylene chloride, protected by nitrogen, cooled to 0°C, added pyridine (0.21g, 2.65mmol), and then added 21H (0.31g, 0.53mmol) in methylene chloride. 10 mL of solution was added and the reaction was continued for 1 hour. Directly concentrate under reduced pressure, and the residue is subjected to column chromatography to obtain product 21I (0.15g, yield: 32%).
Ms m/z(ESI):878.1[M+H]+ Ms m/z(ESI):878.1[M+H] +
第八步：化合物21的制备Step 8: Preparation of compound 21
将原料21I(60mg，0.071mmol)溶于2mL DMF，依次加入10E(34mg，0.11mmol),DIPEA(46mg，0.36mmol),室温搅拌2h。加入30ml乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次,无水硫酸钠干燥，减压浓缩，柱层析得到粗产品，粗品经硅胶柱层析及反向柱层析纯化得化合物(23mg，收率：27.5％)。Dissolve raw material 21I (60mg, 0.071mmol) in 2mL DMF, add 10E (34mg, 0.11mmol) and DIPEA (46mg, 0.36mmol) in sequence, and stir at room temperature for 2h. Add 30 ml of ethyl acetate, wash twice with water (20 mL The compound was purified by chromatography (23 mg, yield: 27.5%).
Ms m/z(ESI):1178.4[M+H]+ Ms m/z(ESI):1178.4[M+H] +
实施例22：化合物22的合成
Example 22: Synthesis of Compound 22
第一步：22A的合成Step One: Synthesis of 22A
在氮气氛围下，将5A(1.0g，1.91mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(885mg， 2.86mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯(II)(138mg，0.19mmol)、碳酸铯(1.24g，3.82mmol)溶于20mL1,4-二氧六环和4mL水中，100℃反应3小时。加入水稀释，乙酸乙酯(25mL×3)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得22A(1.1g，91.84％)。Under a nitrogen atmosphere, 5A (1.0g, 1.91mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (885mg, 2.86mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (138mg, 0.19mmol), cesium carbonate (1.24g, 3.82mmol) were dissolved in 20mL of 1,4-dioxy Six rings and 4 mL of water were reacted at 100°C for 3 hours. Add water to dilute, extract with ethyl acetate (25mL .
第二步：22B的合成Step 2: Synthesis of 22B
将22A(1.1g，1.76mmol)溶于10mL二氯甲烷和5mL 4N的盐酸1,4-二氧六环溶液中，室温搅拌2小时。减压浓缩得22B的盐酸盐(800mg，86.66％)。Dissolve 22A (1.1g, 1.76mmol) in 10mL dichloromethane and 5mL 4N 1,4-dioxane hydrochloric acid solution, and stir at room temperature for 2 hours. Concentrate under reduced pressure to obtain 22B hydrochloride (800 mg, 86.66%).
LCMS m/z＝525.3[M+H]+ LCMS m/z＝525.3[M+H] +
第三步：22C的合成Step 3: Synthesis of 22C
将22B的盐酸盐(524mg，1.00mmol)溶于15mL N,N-二甲基甲酰胺中，碳酸钾(276mg，2.00mmol)，对氟硝基苯(211mg，1.50mmol)，升温至80℃搅拌2小时。加入水稀释，乙酸乙酯(25mL×3)萃取，无水硫酸钠干燥，过滤后减压浓缩，残余物经柱层析纯化得22C(350mg，56.86％)。Dissolve 22B hydrochloride (524mg, 1.00mmol) in 15mL N,N-dimethylformamide, potassium carbonate (276mg, 2.00mmol), p-fluoronitrobenzene (211mg, 1.50mmol), and heat to 80 °C and stir for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 22C (350 mg, 56.86%).
LCMS m/z＝646.4[M+H]+ LCMS m/z＝646.4[M+H] +
第四步：22D的合成Step 4: 22D synthesis
将22C(350mg，0.54mmol)溶于10mL甲醇中，加入10％Pd/C(350mg)，氢气置换保护，室温搅拌2小时。过滤后，减压浓缩得22D(200mg，69.93％)。Dissolve 22C (350 mg, 0.54 mmol) in 10 mL methanol, add 10% Pd/C (350 mg), replace with hydrogen for protection, and stir at room temperature for 2 hours. After filtration, it was concentrated under reduced pressure to obtain 22D (200 mg, 69.93%).
LCMS m/z＝528.3[M+H]+ LCMS m/z＝528.3[M+H] +
第五步：化合物22E的合成Step 5: Synthesis of Compound 22E
将5C-1(105mg，0.318mmol)溶于5mL二氯甲烷中，0℃加入吡啶(51mg，0.639mmol)，搅拌1分钟，缓慢加入22D(121mg，0.23mmol),室温搅拌2小时。加入水稀释，乙酸乙酯(25mL×3)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，残余物经柱层析纯化得22E(80mg，42.64％)。Dissolve 5C-1 (105 mg, 0.318 mmol) in 5 mL of dichloromethane, add pyridine (51 mg, 0.639 mmol) at 0°C, stir for 1 minute, slowly add 22D (121 mg, 0.23 mmol), and stir at room temperature for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 22E (80 mg, 42.64%).
LCMS m/z＝818.2[M+H]+ LCMS m/z＝818.2[M+H] +
第六步：化合物22的合成Step 6: Synthesis of Compound 22
将22E(80mg，0.098mmol)和10E(48mg，0.15mmol)溶于3mL N,N-二甲基甲酰胺中，缓慢加入N,N-二异丙基乙胺(33mg，0.26mmol)，室温搅拌2小时。加入水稀释，乙酸乙酯(25mL×2)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，柱层析纯化得化合物22(10mg，9.13％)。Dissolve 22E (80mg, 0.098mmol) and 10E (48mg, 0.15mmol) in 3mL N,N-dimethylformamide, slowly add N,N-diisopropylethylamine (33mg, 0.26mmol), room temperature Stir for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×2), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify by column chromatography to obtain compound 22 (10 mg, 9.13%).
LCMS m/z＝1118.4[M+H]+ LCMS m/z＝1118.4[M+H] +
1H NMR(400MHz,CF3COOD)δ8.23–8.11(m,1H),7.94(dd,1H),7.72–7.62(m,2H),7.57(s,1H),7.54–7.23(m,14H),6.74(d,1H),4.71–4.60(m,1H),4.41–4.22(m,2H),4.08–3.71(m,8H),3.51–3.34(m,2H),3.29–3.17(m,2H),3.16–3.04(m,1H),2.90(s,3H),2.46–2.26(m,5H),2.25–1.72(m,8H),1.69–1.47(m,4H),1.26(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.23–8.11(m,1H),7.94(dd,1H),7.72–7.62(m,2H),7.57(s,1H),7.54–7.23(m, 14H),6.74(d,1H),4.71–4.60(m,1H),4.41–4.22(m,2H),4.08–3.71(m,8H),3.51–3.34(m,2H),3.29–3.17( m,2H),3.16–3.04(m,1H),2.90(s,3H),2.46–2.26(m,5H),2.25–1.72(m,8H),1.69–1.47(m,4H),1.26( d,3H).
实施例23：化合物23的制备
Example 23: Preparation of Compound 23
第一步：化合物23C的制备Step One: Preparation of Compound 23C
氮气保护下，将化合物23A(1.5g，3.26mmol)、23B(1.21g，6.52mmol)、碘化亚铜(370mg，1.96mmol)、[(2,6-二甲苯基)氨基](氧)乙酸(1.26g，6.52mmol)和碳酸钾(2.25g，16.3mmol)溶解于20mL的DMSO中，在130℃下耐压瓶中反应10小时。加水淬灭反应，EA萃取(30mL×2)，饱和氯化钠洗涤，无水硫酸钠干燥，柱层析纯化即得化合物23C(1.1g，59.6％)。Under nitrogen protection, compound 23A (1.5g, 3.26mmol), 23B (1.21g, 6.52mmol), copper iodide (370mg, 1.96mmol), [(2,6-xylyl)amino] (oxygen) Acetic acid (1.26g, 6.52mmol) and potassium carbonate (2.25g, 16.3mmol) were dissolved in 20 mL of DMSO and reacted in a pressure-resistant bottle at 130°C for 10 hours. The reaction was quenched by adding water, extracted with EA (30 mL×2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 23C (1.1 g, 59.6%).
Ms m/z(ESI):566.1[M+H]+ Ms m/z(ESI):566.1[M+H] +
第二步：化合物23D的制备Step 2: Preparation of Compound 23D
氮气保护下，将中间体23C(1.1g,1.94mmol)溶于20mL乙腈中，冰浴下缓慢加入加入5mL盐酸1,4-二氧六环溶液，升至室温反应1h，减压浓缩除去溶剂得到产品23D的盐酸盐(880mg粗品)，直接用于下一步反应。Under nitrogen protection, dissolve intermediate 23C (1.1g, 1.94mmol) in 20mL acetonitrile, slowly add 5mL of 1,4-dioxane hydrochloric acid solution under an ice bath, raise to room temperature, react for 1 hour, and concentrate under reduced pressure to remove the solvent. The hydrochloride salt of product 23D (880 mg crude product) was obtained, which was directly used in the next reaction.
LCMS m/z＝466.1[M+H]+LCMS m/z＝466.1[M+H]+
第三步：化合物23E的制备Step 3: Preparation of Compound 23E
将中间体23D的盐酸盐(0.3g,0.64mmol)和对氟硝基苯(0.11g,0.77mmol)溶于20mL DMF中，然后加入碳酸铯(0.83g,2.56mmol)，升至80℃反应12h，加水淬灭反应，EA萃取(5mL×2)，饱和氯化钠洗涤，无水硫酸钠干燥，柱层析纯化即得化合物23E(0.31g，82.5％)。Dissolve the hydrochloride of intermediate 23D (0.3g, 0.64mmol) and p-fluoronitrobenzene (0.11g, 0.77mmol) in 20mL DMF, then add cesium carbonate (0.83g, 2.56mmol) and raise to 80°C React for 12 hours, add water to quench the reaction, extract with EA (5mL×2), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain compound 23E (0.31g, 82.5%).
LCMS m/z＝587.2[M+H]+ LCMS m/z＝587.2[M+H] +
第四步：化合物23F的制备Step 4: Preparation of Compound 23F
将化合物23E(300mg，0.51mmol)溶解于10mL的甲醇和2mL水中，加入氯化铵(140mg，2.56mmol)和铁粉(150mg，2.63mmol)，升至80℃反应反应3小时，冷却至室温，直接加入硅胶拌样，减压浓缩，柱层析纯化即得化合物23F(200mg，70.9％)。Dissolve compound 23E (300 mg, 0.51 mmol) in 10 mL of methanol and 2 mL of water, add ammonium chloride (140 mg, 2.56 mmol) and iron powder (150 mg, 2.63 mmol), raise the temperature to 80°C and react for 3 hours, then cool to room temperature. , directly add silica gel to mix the sample, concentrate under reduced pressure, and purify by column chromatography to obtain compound 23F (200 mg, 70.9%).
LCMS m/z＝557.3[M+H]+ LCMS m/z＝557.3[M+H] +
第五步：化合物23G的制备Step 5: Preparation of compound 23G
将化合物5C-1(140mg，0.43mmol)溶解于5mL的二氯甲烷中，0℃下加入吡啶(85mg，1.08mmol)，搅拌10分钟，再缓慢加入23F(200mg，0.36mmol),室温搅拌2小时。加水淬灭反应，EA萃取(5mL×2)，饱和氯化钠洗涤，无水硫酸钠干燥，柱层析纯化获得23G(180mg，59.01％)。Dissolve compound 5C-1 (140 mg, 0.43 mmol) in 5 mL of dichloromethane, add pyridine (85 mg, 1.08 mmol) at 0°C, stir for 10 minutes, then slowly add 23F (200 mg, 0.36 mmol), and stir at room temperature for 2 Hour. The reaction was quenched by adding water, extracted with EA (5 mL×2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 23G (180 mg, 59.01%).
LCMS m/z＝847.3[M+H]+ LCMS m/z＝847.3[M+H] +
第六步：化合物23H的制备Step 6: Preparation of compound 23H
将23G(180mg，0.21mmol)溶于5ml DMF，加入中间体B(71mg，0.25mmol),DIPEA(81mg，0.63mmol)，室温搅拌2h。加入30ml乙酸乙酯，用水洗涤2次(20mL×2)，用饱和食盐水洗涤一次,无水硫酸钠干燥，减压浓缩，柱层析纯化得产物23H(150mg，64.48％)。Dissolve 23G (180 mg, 0.21 mmol) in 5 ml DMF, add intermediate B (71 mg, 0.25 mmol), DIPEA (81 mg, 0.63 mmol), and stir at room temperature for 2 h. Add 30 ml of ethyl acetate, wash twice with water (20 mL × 2), wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain the product 23H (150 mg, 64.48%).
LCMS m/z＝1107.2[M+H]+ LCMS m/z＝1107.2[M+H] +
第七步：化合物23的制备Step 7: Preparation of compound 23
将23H(100mg，0.09mmol)溶解于10mL的甲醇和2mL水中，加入氢氧化钠(18mg，0.45mmol)，在室温下搅拌反应12小时。用稀盐酸调节pH＝4左右，加入水稀释，乙酸乙酯(25mL×2)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品经硅胶柱层析及反向柱层析(流动相A：0.5％的NH4HCO3水溶液，流动相B：乙腈，A的10％至40％的B溶液梯度洗脱)纯化得化合物23(43mg，44.25％)。23H (100 mg, 0.09 mmol) was dissolved in 10 mL of methanol and 2 mL of water, sodium hydroxide (18 mg, 0.45 mmol) was added, and the reaction was stirred at room temperature for 12 hours. Adjust pH=4 with dilute hydrochloric acid, add water to dilute, extract with ethyl acetate (25mL×2), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, the crude product is subjected to silica gel column chromatography and reverse reverse flow Compound 23 (43 mg, 44.25%) was purified by column chromatography (mobile phase A: 0.5% aqueous NH 4 HCO 3 solution, mobile phase B: acetonitrile, gradient elution of 10% to 40% A in B solution).
LCMS m/z＝1080.2[M+H]+ LCMS m/z＝1080.2[M+H] +
实施例24：化合物24的合成
Example 24: Synthesis of Compound 24
将22E(60mg，0.076mmol)和中间体24A(21mg，0.076mmol)溶于3mL DMF中，缓慢加入DIPEA(49mg，0.38mmol)，室温搅拌2小时。加入水稀释，乙酸乙酯(25mL×2)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品经硅胶柱层析及反向柱层析(流动相A：0.5％的NH4HCO3水溶液，流动相B：乙腈，A的10％至40％的B溶液梯度洗脱)纯化得化合物24(23mg，28.05％)。Dissolve 22E (60 mg, 0.076 mmol) and intermediate 24A (21 mg, 0.076 mmol) in 3 mL DMF, slowly add DIPEA (49 mg, 0.38 mmol), and stir at room temperature for 2 hours. Add water to dilute, extract with ethyl acetate (25mL×2), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5 % NH 4 HCO 3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% to 40% A in B solution) to obtain compound 24 (23 mg, 28.05%).
LCMS m/z(ESI):540.0[M/2+H]+ LCMS m/z(ESI):540.0[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.29(s,1H),8.08–7.98(m,1H),7.80–7.71(m,2H),7.70–7.62(m,1H),7.62–7.51(m,9H),7.47–7.30(m,5H),6.86–6.77(m,1H),4.80–4.68(m,1H),4.51–4.27(m,1H),4.21–3.99(m,3H),3.97–3.82(m,3H),3.75–3.62(m,1H),3.62–3.39(m,3H),3.38–3.13(m,4H),2.99(s,3H),2.70-2.57(m,1H),2.55–2.12(m,9H),1.74(d,3H),1.35(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.29(s,1H),8.08–7.98(m,1H),7.80–7.71(m,2H),7.70–7.62(m,1H),7.62–7.51( m,9H),7.47–7.30(m,5H),6.86–6.77(m,1H),4.80–4.68(m,1H),4.51–4.27(m,1H),4.21–3.99(m,3H), 3.97–3.82(m,3H),3.75–3.62(m,1H),3.62–3.39(m,3H),3.38–3.13(m,4H),2.99(s,3H),2.70-2.57(m,1H ),2.55–2.12(m,9H),1.74(d,3H),1.35(d,3H).
实施例25：化合物25的合成
Example 25: Synthesis of Compound 25
第一步：25A的合成Step One: Synthesis of 25A
将氘代异丙胺盐酸盐0.65g，10.00mmol)溶于10mL甲醇中，加入三乙胺调pH＝7左右，加 入2-乙酰基-3-(3-溴苯基)-4-(4-氯苯基)-4-氧代丁酸苄酯(1.0g，2.00mmol)和乙酸(1.2g，20mmol)，耐压瓶100℃反应过夜。反应液浓缩，残余物柱层析分离纯化得25A(0.3g，产率：28.36％)。Dissolve 0.65g of deuterated isopropylamine hydrochloride, 10.00mmol) in 10mL of methanol, add triethylamine to adjust pH = about 7, add Add 2-acetyl-3-(3-bromophenyl)-4-(4-chlorophenyl)-4-oxobutyric acid benzyl ester (1.0g, 2.00mmol) and acetic acid (1.2g, 20mmol), The pressure-resistant bottle was reacted at 100°C overnight. The reaction solution was concentrated, and the residue was separated and purified by column chromatography to obtain 25A (0.3 g, yield: 28.36%).
第二步：25B的合成Step 2: Synthesis of 25B
在氮气氛围下，将25A(0.32g，0.61mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(0.28mg，0.92mmol)、Pd(dppf)Cl2(50mg，0.061mmol)、碳酸铯(0.4g，1.22mmol)溶于20mL1,4-二氧六环和4mL水中，100℃反应3小时。加入水稀释，乙酸乙酯(25mL×3)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得25B(0.30g，77.91％)。Under a nitrogen atmosphere, 25A (0.32g, 0.61mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.28mg, 0.92mmol), Pd (dppf) Cl 2 (50 mg, 0.061 mmol) and cesium carbonate (0.4 g, 1.22 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water, and reacted at 100°C for 3 hours. Add water to dilute, extract with ethyl acetate (25 mL .
第二步：25C的合成Step 2: Synthesis of 25C
将25B(0.3g，0.48mmol)溶于5mL二氯甲烷和2mL 4N的盐酸1,4-二氧六环溶液中，室温搅拌2小时。减压浓缩得25C的盐酸盐(0.23g，90.22％)。Dissolve 25B (0.3g, 0.48mmol) in 5mL of dichloromethane and 2mL of 4N 1,4-dioxane hydrochloric acid solution, and stir at room temperature for 2 hours. Concentrate under reduced pressure to obtain 25C hydrochloride (0.23g, 90.22%).
LCMS m/z＝531.7[M+H]+ LCMS m/z＝531.7[M+H] +
第三步：25D的合成Step 3: 25D synthesis
将25C的盐酸盐(0.155g，0.29mmol)溶于15mL N,N-二甲基甲酰胺中，碳酸铯(0.19g，0.59mmol)，对氟硝基苯(0.061g，0.43mmol)，50℃搅拌2小时。加入水稀释，乙酸乙酯(25mL×3)萃取，无水硫酸钠干燥，过滤后减压浓缩，残余物经柱层析纯化得25D(0.145g，76.66％)。Dissolve 25C hydrochloride (0.155g, 0.29mmol) in 15mL N,N-dimethylformamide, cesium carbonate (0.19g, 0.59mmol), p-fluoronitrobenzene (0.061g, 0.43mmol), Stir at 50°C for 2 hours. Add water to dilute, extract with ethyl acetate (25mL×3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 25D (0.145g, 76.66%).
第四步：25E的合成Step 4: Synthesis of 25E
将25D(145mg，0.22mmol)溶于10mL甲醇中，加入10％Pd/C(50mg)，氢气置换保护，室温搅拌2小时。过滤后，减压浓缩得25E(108mg，91.91％)。Dissolve 25D (145 mg, 0.22 mmol) in 10 mL methanol, add 10% Pd/C (50 mg), replace with hydrogen for protection, and stir at room temperature for 2 hours. After filtration, it was concentrated under reduced pressure to obtain 25E (108 mg, 91.91%).
LCMS m/z＝534.6[M+H]+ LCMS m/z＝534.6[M+H] +
第五步：化合物25F的合成Step 5: Synthesis of Compound 25F
将5C-1(98mg，0.30mmol)溶于5mL二氯甲烷中，0℃加入吡啶(48mg，0.60mmol)，搅拌1分钟，缓慢加入25E(108mg，0.20mmol),室温搅拌2小时。加入水稀释，乙酸乙酯(25mL×3)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，残余物经柱层析纯化得25F(70mg，42.46％)。Dissolve 5C-1 (98 mg, 0.30 mmol) in 5 mL of dichloromethane, add pyridine (48 mg, 0.60 mmol) at 0°C, stir for 1 minute, slowly add 25E (108 mg, 0.20 mmol), and stir at room temperature for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 25F (70 mg, 42.46%).
LCMS m/z＝818.2[M+H]+ LCMS m/z＝818.2[M+H] +
第六步：化合物25的合成Step 6: Synthesis of Compound 25
将25F(38mg，0.046mmol)和中间体24A(39mg，0.14mmol)溶于3mL DMF中，缓慢加入DIPEA(30mg，0.23mmol)，室温搅拌2小时。加入水稀释，乙酸乙酯(25mL×2)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品经硅胶柱层析及反向柱层析(流动相A：0.5％的NH4HCO3水溶液，流动相B：乙腈，A的10％至40％的B溶液梯度洗脱)纯化得化合物25(16mg，32.06％)。Dissolve 25F (38 mg, 0.046 mmol) and intermediate 24A (39 mg, 0.14 mmol) in 3 mL DMF, slowly add DIPEA (30 mg, 0.23 mmol), and stir at room temperature for 2 hours. Add water to dilute, extract with ethyl acetate (25mL×2), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5 % NH 4 HCO 3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% to 40% A in B solution) to obtain compound 25 (16 mg, 32.06%).
LC-Ms m/z(ESI):542.8[M/2+H]+ LC-Ms m/z(ESI):542.8[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.28(s,1H),8.06–7.97(m,1H),7.84–7.71(m,2H),7.71–7.63(m,2H),7.62–7.47(m,9H),7.47–7.35(m,4H),6.87–6.75(m,1H),4.76–4.52(m,1H),4.16–3.99(m,3H),3.98–3.81(m,3H),3.76–3.39(m,4H),3.38–3.13(m,4H),3.01–2.95(m,3H),2.71-2.58(m,1H),2.57–2.29(m,8H),2.28–2.14(m,1H). 1 H NMR (400MHz, CF 3 COOD) δ8.28(s,1H),8.06–7.97(m,1H),7.84–7.71(m,2H),7.71–7.63(m,2H),7.62–7.47( m,9H),7.47–7.35(m,4H),6.87–6.75(m,1H),4.76–4.52(m,1H),4.16–3.99(m,3H),3.98–3.81(m,3H), 3.76–3.39(m,4H),3.38–3.13(m,4H),3.01–2.95(m,3H),2.71-2.58(m,1H),2.57–2.29(m,8H),2.28–2.14(m ,1H).
实施例26：化合物26的合成
Example 26: Synthesis of Compound 26
第一步：26A的合成Step One: Synthesis of 26A
将原料N-Boc-哌嗪-d8(0.6g，3.09mmol)，4-氟硝基苯(0.65g，4.63mmol)碳酸铯(2.03g，6.24mmol)溶于15mL DMF中，加热至50℃反应16h。加入20mL乙酸乙酯，用水洗3次(20mL×3)，30mL食盐水洗涤一次，无水硫酸钠干燥，减压浓缩，柱层析得产品26A(0.78g，收率：80.04％)。Dissolve the raw materials N-Boc-piperazine-d 8 (0.6g, 3.09mmol), 4-fluoronitrobenzene (0.65g, 4.63mmol) and cesium carbonate (2.03g, 6.24mmol) in 15mL DMF, and heat to 50 ℃ reaction for 16h. Add 20 mL of ethyl acetate, wash three times with water (20 mL × 3), wash once with 30 mL of saline, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain product 26A (0.78 g, yield: 80.04%).
第二步：26B的合成Step 2: Synthesis of 26B
将原料26A(0.57g，1.81mmol)溶于5mL二氯甲烷，加入2mL 4N盐酸二氧六环溶液，室温搅拌2h，减压浓缩，残留物溶于30mL二氯甲烷，用碳酸氢钠水溶液调pH＝8左右，有机相用无水硫酸钠干燥，减压浓缩得产品26B(0.36g，收率：92.39％)。Dissolve raw material 26A (0.57g, 1.81mmol) in 5mL dichloromethane, add 2mL 4N dioxane hydrochloride solution, stir at room temperature for 2h, concentrate under reduced pressure, dissolve the residue in 30mL dichloromethane, and adjust with sodium bicarbonate aqueous solution pH=about 8, the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain product 26B (0.36g, yield: 92.39%).
第三步：26C的合成Step 3: Synthesis of 26C
将5A(0.60g，1.15mmol)溶于10mL二甲亚砜，依次加入26B(0.36g，1.7mmol)、碘化亚铜(0.020g，0.11mmol)、2,6-二甲基苯基氨甲酰基甲酸(0.22g，1.15mmol)、碳酸钾(0.48g，3.45mmol)，氮气氛围下130℃反应12h。降至室温，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(10mL×5)，合并有机相洗涤，无水硫酸镁干燥，粗品经硅胶柱层析分离纯化，得26C(0.2g，产率：26.46％)。Dissolve 5A (0.60g, 1.15mmol) in 10mL dimethyl sulfoxide, then add 26B (0.36g, 1.7mmol), copper iodide (0.020g, 0.11mmol), and 2,6-dimethylphenylamino Formylformic acid (0.22g, 1.15mmol) and potassium carbonate (0.48g, 3.45mmol) were reacted at 130°C for 12h under nitrogen atmosphere. Cool to room temperature, add saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate (10 mL Yield: 26.46%).
第四步：26D的合成Step 4: 26D synthesis
将26C(0.20g，0.30mmol)溶于10mL甲醇中，加入50mg 10％钯碳，氢气氛围室温反应1h，过滤，滤液直接浓缩得26D(0.112mg，产率：69.51％)Dissolve 26C (0.20g, 0.30mmol) in 10mL methanol, add 50mg 10% palladium on carbon, react at room temperature in a hydrogen atmosphere for 1 hour, filter, and the filtrate is directly concentrated to obtain 26D (0.112mg, yield: 69.51%)
LC-Ms m/z(ESI):537.8[M+H]+ LC-Ms m/z(ESI):537.8[M+H] +
第五步：26E的合成Step 5: Synthesis of 26E
将3-(三氟甲基磺酰基)-4-氟苯磺酰氯(78mg，0.24mmol)溶于20mL二氯甲烷,氮气氛围下，0℃加入吡啶(79mg，1.0mmol)，再加26D(110mg，0.20mmol)的二氯甲烷溶液10mL，加完后继续反应1h。减压浓缩残余物柱层析分离纯化得26E(64mg，产率：38.68％)。Dissolve 3-(trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (78mg, 0.24mmol) in 20mL dichloromethane, add pyridine (79mg, 1.0mmol) at 0°C under nitrogen atmosphere, and add 26D ( 110 mg, 0.20 mmol) in 10 mL of methylene chloride solution. After addition, continue the reaction for 1 hour. The residue was concentrated under reduced pressure and separated and purified by column chromatography to obtain 26E (64 mg, yield: 38.68%).
第六步：化合物26的合成Step 6: Synthesis of Compound 26
将26E(55mg，0.066mmol)溶于2mL DMF，加入中间体24A(56mg，0.20mmol)，DIPEA(43mg，0.33mmol)，室温搅拌2h。加入30mL乙酸乙酯，有机层用水洗涤2次(20mL×2)，用饱和食盐水10mL洗涤一次,无水硫酸钠干燥，浓缩，粗品经硅胶柱层析及反向柱层析(流动相A：0.5％的NH4HCO3水溶液，流动相B：乙腈，A的10％至40％的B溶液梯度洗脱)纯化得化合物26(13mg，18.11％)。 Dissolve 26E (55 mg, 0.066 mmol) in 2 mL DMF, add intermediate 24A (56 mg, 0.20 mmol) and DIPEA (43 mg, 0.33 mmol), and stir at room temperature for 2 h. Add 30 mL of ethyl acetate, wash the organic layer twice with water (20 mL : 0.5% NH 4 HCO 3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% to 40% A of B solution) to obtain compound 26 (13 mg, 18.11%).
LC-Ms m/z(ESI):544.3[M/2+H]+ LC-Ms m/z(ESI):544.3[M/2+H] +
1H NMR(400MHz,CF3COOD)δ8.33–8.28(m,1H),8.25–8.19(m,1H),8.06–8.00(m,1H),7.97–7.92(m,1H),7.90–7.86(m,1H),7.85–7.78(m,3H),7.65–7.49(m,7H),7.48–7.37(m,4H),6.84–6.76(m,1H),4.85–4.73(m,1H),4.63–4.27(m,1H),4.12–4.02(m,1H),3.96–3.82(m,1H),3.73–3.61(m,1H),3.59–3.39(m,3H),3.37–3.16(m,3H),3.04(s,3H),2.71–2.58(m,1H),2.57–2.46(m,1H),2.41–2.29(m,3H),2.28–2.15(m,1H),1.75(d,3H),1.37(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.33–8.28(m,1H),8.25–8.19(m,1H),8.06–8.00(m,1H),7.97–7.92(m,1H),7.90– 7.86(m,1H),7.85–7.78(m,3H),7.65–7.49(m,7H),7.48–7.37(m,4H),6.84–6.76(m,1H),4.85–4.73(m,1H ),4.63–4.27(m,1H),4.12–4.02(m,1H),3.96–3.82(m,1H),3.73–3.61(m,1H),3.59–3.39(m,3H),3.37–3.16 (m,3H),3.04(s,3H),2.71–2.58(m,1H),2.57–2.46(m,1H),2.41–2.29(m,3H),2.28–2.15(m,1H),1.75 (d,3H),1.37(d,3H).
实施例27：化合物27的合成
Example 27: Synthesis of Compound 27
第一步：化合物27B的合成Step One: Synthesis of Compound 27B
将27A(5g，49.43mmol)溶于50mL THF和5mL水中，缓慢加入碳酸钠(15.72g，148.23mmol)，在冰浴下缓慢加入氯甲酸-9-芴基甲酯(15.35g，59.34mmol)，升温至室温搅拌2小时。加入水稀释，乙酸乙酯(25mL×3)萃取，无水硫酸钠干燥，过滤后减压浓缩，残余物经柱层析纯化得27B(11.2g，70.06％)。Dissolve 27A (5g, 49.43mmol) in 50mL THF and 5mL water, slowly add sodium carbonate (15.72g, 148.23mmol), and slowly add 9-fluorenylmethyl chloroformate (15.35g, 59.34mmol) under an ice bath. , warmed to room temperature and stirred for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 27B (11.2 g, 70.06%).
LCMS m/z＝324.2[M+H]+ LCMS m/z＝324.2[M+H] +
第二步：化合物27C的合成Step 2: Synthesis of compound 27C
将27B(5g，15.47mmol)溶于15mL吡啶，缓慢加入四溴化碳(10.26g，30.94mmol)，置换氮气3次，搅拌30分钟，在冰浴下缓慢加入三甲氧基磷(4.03g，32.49mmol)，升温至室温搅拌2小时。加入水稀释，乙酸乙酯(25mL×3)萃取，无水硫酸钠干燥，过滤后减压浓缩，残余物经柱层析纯化得27C(4.5g，67.43％)。Dissolve 27B (5g, 15.47mmol) in 15mL pyridine, slowly add carbon tetrabromide (10.26g, 30.94mmol), replace nitrogen three times, stir for 30 minutes, slowly add trimethoxyphosphorus (4.03g, 32.49mmol), heated to room temperature and stirred for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain 27C (4.5 g, 67.43%).
LCMS m/z＝432.2[M+H]+ LCMS m/z＝432.2[M+H] +
第三步：化合物27D的合成Step 3: Synthesis of Compound 27D
将27C(4.5g，1.61mmol)溶解在50mL THF和5mL水中，加入氢氧化锂(4.5g，1.61mmol)。常温反应12h，过滤收集滤液，减压浓缩得27D粗品(0.78g)，无需进一步纯化直接进行下一步。Dissolve 27C (4.5g, 1.61mmol) in 50mL THF and 5mL water, and add lithium hydroxide (4.5g, 1.61mmol). React at room temperature for 12 hours, collect the filtrate by filtration, and concentrate under reduced pressure to obtain 27D crude product (0.78g). Go to the next step without further purification.
LCMS m/z＝210.1[M+H]+ LCMS m/z＝210.1[M+H] +
第四步：化合物27E的合成Step 4: Synthesis of Compound 27E
将中间体A(0.5g，1.69mmol)溶于10mL N,N-二甲基乙酰胺中，加入27D(0.42g，2.01mmol)和乙酸(0.1g，1.69mmol)，氮气保护下，搅拌30分钟，加入三乙酰氧基硼氢化钠(0.72g，3.40mmol)，室温搅拌过夜。加入30mL纯化水，分液，水相用50mL二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，柱层析得到27E(0.61g，收率：73.88％)。 Dissolve intermediate A (0.5g, 1.69mmol) in 10mL N,N-dimethylacetamide, add 27D (0.42g, 2.01mmol) and acetic acid (0.1g, 1.69mmol), and stir for 30 under nitrogen protection. minutes, add sodium triacetoxyborohydride (0.72g, 3.40mmol), and stir at room temperature overnight. Add 30 mL of purified water, separate the layers, extract the aqueous phase twice with 50 mL of methylene chloride, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is then column chromatographed to obtain 27E (0.61 g, yield: 73.88%).
LCMS m/z＝489.3[M+H]+ LCMS m/z＝489.3[M+H] +
第五步：化合物27F的合成Step 5: Synthesis of Compound 27F
将化合物27E(0.3g，0.61mmol)溶解在DCM(10mL)中，然后加入TMSI(0.73g，3.66mmol)。常温下反应2h，除去溶剂得27F粗品(0.21g),无需进一步纯化，直接用于下一步反应。Compound 27E (0.3 g, 0.61 mmol) was dissolved in DCM (10 mL), then TMSI (0.73 g, 3.66 mmol) was added. React at room temperature for 2 hours, remove the solvent, and obtain 27F crude product (0.21g), which can be directly used in the next step of reaction without further purification.
LCMS m/z＝361.2[M+H]+ LCMS m/z＝361.2[M+H] +
第六步：化合物27的合成Step 6: Synthesis of Compound 27
27F粗品(110mg，0.31mmol)溶于2mL DMF中，加入22E(250mg，0.31mmol),DIPEA(120mg，0.93mmol),室温搅拌2小时。减压浓缩，加入乙腈析出固体，过滤收集固体，经制备HPLC分离纯化得到化合物27的三氟乙酸盐(80mg，收率：22.27％)。Dissolve crude 27F (110 mg, 0.31 mmol) in 2 mL DMF, add 22E (250 mg, 0.31 mmol), DIPEA (120 mg, 0.93 mmol), and stir at room temperature for 2 hours. Concentrate under reduced pressure, add acetonitrile to precipitate a solid, collect the solid by filtration, and obtain the trifluoroacetate salt of compound 27 (80 mg, yield: 22.27%) by preparative HPLC separation and purification.
HPLC制备方法：仪器:SHIMADZU LC-20AP；制备柱:C18；流动相:A为0.1％TFA水溶液；B为乙腈；HPLC preparation method: Instrument: SHIMADZU LC-20AP; Preparation column: C18; Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile;
洗脱方法:B的32％至62％的A溶液，梯度洗脱15分钟；流速:25mL/min；柱温:室温；检测波长:220nm；Elution method: 32% to 62% A solution of B, gradient elution for 15 minutes; flow rate: 25mL/min; column temperature: room temperature; detection wavelength: 220nm;
LCMS m/z＝1158.2[M+H]+ LCMS m/z＝1158.2[M+H] +
1H NMR(400MHz,CF3COOD)δ8.34–8.27(m,1H),8.07–8.00(m,1H),7.82–7.72(m,2H),7.69–7.64(m,1H),7.64–7.35(m,14H),6.86–6.77(m,1H),5.18–4.86(m,1H),4.82–4.69(m,1H),4.14–4.01(m,3H),4.00–3.85(m,3H),3.80–3.68(m,1H),3.63–3.42(m,3H),3.40–3.15(m,4H),3.00(s,3H),2.74–2.22(m,10H),1.76(d,3H),1.36(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.34–8.27(m,1H),8.07–8.00(m,1H),7.82–7.72(m,2H),7.69–7.64(m,1H),7.64– 7.35(m,14H),6.86–6.77(m,1H),5.18–4.86(m,1H),4.82–4.69(m,1H),4.14–4.01(m,3H),4.00–3.85(m,3H ),3.80–3.68(m,1H),3.63–3.42(m,3H),3.40–3.15(m,4H),3.00(s,3H),2.74–2.22(m,10H),1.76(d,3H ),1.36(d,3H).
实施例28：化合物28的制备
Example 28: Preparation of Compound 28
第一步：28B的制备Step One: Preparation of 28B
氮气保护下，将原料28A(0.5g，2.07mmol)和四溴甲烷(1.37g，4.14mmol)溶于5mL吡啶中，在冰浴中冷却并缓慢滴加亚磷酸三甲酯(541mg，4.35mmol)立即形成沉淀物，然后缓慢形成黄色，在0℃下继续搅拌30分钟。然后在室温下1.5小时，反应液倒进水里面，加入1N稀盐酸调pH＝7左右，然后加入乙酸乙酯15mL萃取两次，有机层用1N稀盐酸洗涤两次，用Na2SO4干燥，过滤，浓缩，经柱层析得到28B(0.6g，收率：83％)。Under nitrogen protection, dissolve raw material 28A (0.5g, 2.07mmol) and tetrabromomethane (1.37g, 4.14mmol) in 5mL of pyridine, cool in an ice bath and slowly add trimethyl phosphite (541mg, 4.35mmol) dropwise. A precipitate formed immediately, then slowly formed a yellow color, and stirring was continued for 30 minutes at 0°C. Then, at room temperature for 1.5 hours, pour the reaction solution into water, add 1N dilute hydrochloric acid to adjust the pH to about 7, then add 15 mL of ethyl acetate to extract twice, wash the organic layer twice with 1N dilute hydrochloric acid, and dry with Na 2 SO 4 , filtered, concentrated, and obtained 28B (0.6g, yield: 83%) through column chromatography.
LCMS m/z＝350.2[M+H]+ LCMS m/z＝350.2[M+H] +
第二步：28C的制备Step 2: Preparation of 28C
氮气保护下，将中间体28B(84mg,0.241mmol)溶于3mL二氯甲烷中，然后加入21mL 三氟乙酸，随后体系室温下反应1h，减压浓缩除去溶剂，得到粗产物28C(89mg)未经进一步纯化，直接用于下一步反应。Under nitrogen protection, dissolve intermediate 28B (84 mg, 0.241 mmol) in 3 mL of methylene chloride, and then add 21 mL trifluoroacetic acid, and then the system was reacted at room temperature for 1 h, and the solvent was concentrated under reduced pressure to obtain crude product 28C (89 mg) without further purification, which was directly used in the next reaction.
LCMS m/z＝250.2[M+H]+ LCMS m/z＝250.2[M+H] +
第三步：28D的制备Step 3: Preparation of 28D
氮气保护下，将中间体28D粗品(89mg,0.241mmol)溶于3mL超干1.2-二氯乙烷和3mL超干甲醇的混合溶剂中，然后分别加入醋酸钠(79mg，0.964mmol)、醋酸(0.1mL)和分子筛(50mg)，于室温下搅拌15min，然后加入中间体A(107mg，0.362mmol)，随后体系室温下反应1h。加入三乙酰氧基硼氢化钠(153mg，0.723mmol)，室温搅拌过夜。减压浓缩除去溶剂，经柱层析得到产物28D(124mg，两步收率：97％)。Under nitrogen protection, the crude intermediate 28D (89 mg, 0.241 mmol) was dissolved in a mixed solvent of 3 mL ultra-dry 1.2-dichloroethane and 3 mL ultra-dry methanol, and then sodium acetate (79 mg, 0.964 mmol) and acetic acid ( 0.1mL) and Molecular sieve (50 mg), stirred at room temperature for 15 min, then added intermediate A (107 mg, 0.362 mmol), and then the system reacted at room temperature for 1 h. Sodium triacetoxyborohydride (153 mg, 0.723 mmol) was added and stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and product 28D (124 mg, two-step yield: 97%) was obtained through column chromatography.
LCMS m/z＝529.2[M+H]+ LCMS m/z＝529.2[M+H] +
第四步：28E的制备Step 4: Preparation of 28E
氮气保护下，将中间体28D(124mg,0.235mmol)溶于5mL超干二氯甲烷中，然后缓慢滴加三甲基碘硅烷(0.2mL，1.41mmol)，室温搅拌2h，浓缩，残余物加二氯甲烷10mL溶解，再次浓缩，重复两次后，得到粗产品28E(210mg)，粗产品直接用于下一步反应。Under nitrogen protection, intermediate 28D (124 mg, 0.235 mmol) was dissolved in 5 mL of ultra-dry dichloromethane, then trimethyliodosilane (0.2 mL, 1.41 mmol) was slowly added dropwise, stirred at room temperature for 2 h, concentrated, and the residue was added Dissolve 10 mL of dichloromethane, concentrate again, and repeat twice to obtain crude product 28E (210 mg), which is directly used in the next step of the reaction.
LCMS m/z＝401.2[M+H]+ LCMS m/z＝401.2[M+H] +
第五步：化合物28的制备Step 5: Preparation of compound 28
氮气保护下，将中间体28E(210mg,0.235mmol)溶于5mL超干的DMF中，然后依次加入N,N-二异丙基乙胺(155mg，1.2mmol)和中间体22E(160mg，0.2mmol)，室温搅拌过夜，减压浓缩，经制备HPLC分离纯化得到化合物28的三氟乙酸盐(20mg，收率：8.5％)。Under nitrogen protection, dissolve intermediate 28E (210 mg, 0.235 mmol) in 5 mL of ultra-dry DMF, then add N, N-diisopropylethylamine (155 mg, 1.2 mmol) and intermediate 22E (160 mg, 0.2 mmol), stirred at room temperature overnight, concentrated under reduced pressure, and separated and purified by preparative HPLC to obtain the trifluoroacetate salt of compound 28 (20 mg, yield: 8.5%).
HPLC制备方法：HPLC preparation method:
仪器:SHIMADZU LC-20AP；Instrument: SHIMADZU LC-20AP;
制备柱:C18；Preparative column: C18;
流动相:A为0.1％TFA水溶液；B为乙腈；Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile;
洗脱方法:B的48％至68％的A溶液，梯度洗脱15分钟；Elution method: 48% to 68% A solution of B, gradient elution for 15 minutes;
流速:25mL/min；Flow rate: 25mL/min;
柱温:室温；Column temperature: room temperature;
检测波长:220nm；Detection wavelength: 220nm;
LCMS m/z＝1199.3[M+H]+ LCMS m/z＝1199.3[M+H] +
1H NMR(400MHz,CF3COOD)δ8.37–8.27(m,1H),8.10–7.96(m,1H),7.85–7.72(m,2H),7.69–7.30(m,15H),6.89–6.77(m,1H),4.85–4.66(m,2H),4.48–4.32(m,2H),4.17–3.77(m,7H),3.61–3.45(m,2H),3.39–3.28(m,2H),3.27–3.14(m,1H),2.99(s,3H),2.56–2.33(m,5H),2.31–2.11(m,3H),2.10–1.84(m,6H),1.75(d,3H),1.35(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.37–8.27(m,1H),8.10–7.96(m,1H),7.85–7.72(m,2H),7.69–7.30(m,15H),6.89– 6.77(m,1H),4.85–4.66(m,2H),4.48–4.32(m,2H),4.17–3.77(m,7H),3.61–3.45(m,2H),3.39–3.28(m,2H ),3.27–3.14(m,1H),2.99(s,3H),2.56–2.33(m,5H),2.31–2.11(m,3H),2.10–1.84(m,6H),1.75(d,3H ),1.35(d,3H).
实施例29：化合物29的制备
Example 29: Preparation of Compound 29
氮气保护下，将中间体27F(250mg crude,0.55mmol)溶于10mL超干的DMF中，依次加入N,N-二异丙基乙胺(356mg，2.76mmol)和中间体26E(377mg，0.46mmol)，室温反应过夜，减压除去多余的溶剂，经制备HPLC分离纯化得到化合物29的三氟乙酸盐(97mg，收率：8.5％)。Under nitrogen protection, dissolve intermediate 27F (250mg crude, 0.55mmol) in 10mL of ultra-dry DMF, and add N,N-diisopropylethylamine (356mg, 2.76mmol) and intermediate 26E (377mg, 0.46 mmol), react at room temperature overnight, remove excess solvent under reduced pressure, and obtain the trifluoroacetate salt of compound 29 (97 mg, yield: 8.5%) through preparative HPLC separation and purification.
HPLC制备方法：仪器:SHIMADZU LC-20AP；制备柱:C18；流动相:A为0.1％TFA水溶液；B为乙腈；洗脱方法:B的25％至60％的A溶液，梯度洗脱15分钟；流速:25mL/min；柱温:室温；检测波长:220nm；HPLC preparation method: Instrument: SHIMADZU LC-20AP; Preparation column: C18; Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile; Elution method: 25% to 60% A solution of B, gradient elution for 15 minutes ;Flow rate: 25mL/min; Column temperature: room temperature; Detection wavelength: 220nm;
LCMS m/z＝1167.3[M+H]+ LCMS m/z＝1167.3[M+H] +
1H NMR(400MHz,CF3COOD)δ8.33–8.28(m,1H),8.25–8.19(m,1H),8.07–8.00(m,1H),7.99–7.92(m,1H),7.91–7.78(m,4H),7.70–7.33(m,11H),6.84–6.75(m,1H),5.17–4.87(m,1H),4.85–4.72(m,1H),4.13–4.01(m,1H),3.99–3.85(m,1H),3.79–3.66(m,1H),3.61–3.24(m,6H),3.04(s,3H),2.71–2.46(m,3H),2.43–2.23(m,3H),1.76(d,3H),1.37(d,3H). 1 H NMR (400MHz, CF 3 COOD) δ8.33–8.28(m,1H),8.25–8.19(m,1H),8.07–8.00(m,1H),7.99–7.92(m,1H),7.91– 7.78(m,4H),7.70–7.33(m,11H),6.84–6.75(m,1H),5.17–4.87(m,1H),4.85–4.72(m,1H),4.13–4.01(m,1H ),3.99–3.85(m,1H),3.79–3.66(m,1H),3.61–3.24(m,6H),3.04(s,3H),2.71–2.46(m,3H),2.43–2.23(m ,3H),1.76(d,3H),1.37(d,3H).
根据上述实施例的合成方法，制备如下化合物：

According to the synthetic methods of the above examples, the following compounds were prepared:

生物测试例Biological test examples
1、化合物对Bcl-xL/Bcl-2靶点亲和力评价(TR-FRET)1. Compound affinity evaluation for Bcl-xL/Bcl-2 target (TR-FRET)
化合物对Bcl-xL靶点亲和力评价(TR-FRET)Compound affinity evaluation for Bcl-xL target (TR-FRET)
在384稀释板中用DMSO(Sigma，D4540)对受试化合物分别进行3倍梯度稀释，受试化合物的最终起始浓度为10000nM。将稀释好的不同浓度化合物转移75nL到384反应板中,确保DMSO含量为0.5％。随后加5μL经稀释的3×Bcl-xL酶(BPS，50273)溶液到384反应板中，确保反应终浓度为5nM，1000rpm离心1min，25℃孵育10min。转移5μL/孔3×f-Bax底物(GenScript)溶液到384反应板中，确保反应终浓度为30nM，1000rpm离心1min。转移5μL 1×MAb-Anti-His-Tb(Cisbio，61HISTLA)试剂到384反应板中，1000rpm离心1min，25℃孵育60min。反应结束后，使用BMG酶标仪读取HTRF(Homogeneous Time-Resolved Fluorescence)信号。信号强度用于表征酶的活性程度。利用GraphPad非线性拟合公式(式1)计算IC50：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope)    式(1)The test compounds were diluted 3 times in a 384 dilution plate using DMSO (Sigma, D4540). The final starting concentration of the test compounds was 10000 nM. Transfer 75nL of diluted compounds of different concentrations to the 384 reaction plate, ensuring that the DMSO content is 0.5%. Then add 5 μL of diluted 3×Bcl-xL enzyme (BPS, 50273) solution to the 384 reaction plate to ensure the final reaction concentration is 5 nM, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min. Transfer 5 μL/well 3×f-Bax substrate (GenScript) solution to the 384 reaction plate, ensure the final concentration of the reaction is 30 nM, and centrifuge at 1000 rpm for 1 min. Transfer 5 μL of 1×MAb-Anti-His-Tb (Cisbio, 61HISTLA) reagent to the 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min. After the reaction, use a BMG microplate reader to read the HTRF (Homogeneous Time-Resolved Fluorescence) signal. Signal intensity is used to characterize the degree of enzyme activity. Calculate IC 50 using the GraphPad nonlinear fitting formula (Equation 1):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)×HillSlope) Formula (1)
X:化合物浓度log值      Y:抑制率(％inhibition)X: Log value of compound concentration Y: Inhibition rate (%inhibition)
化合物对Bcl-2靶点亲和力评价(TR-FRET)Compound affinity evaluation for Bcl-2 target (TR-FRET)
在384稀释板中用DMSO(Sigma，D4540)对阳性化合物(A-1210477)和受试化合物进行3倍梯度稀释，使得阳性化合物和受试化合物最终起始浓度分别为1000nM和10000nM。将稀释好的不同浓度化合物转移75nL至384反应板中,确保DMSO含量为0.5％。随后转移5μL/孔3×BCL-2酶(BPS，50272)溶液到384反应板中，确保反应终浓度为2nM，1000rpm离心1min，25℃孵育10min。转移5μL/孔3×Bio-tin-BIM(GenScript)底物溶液到384反应板中，确保反应终浓度为30nM，1000rpm离心1min。转移5μL/孔1×His-Tb(Cisbio，61HISTLA)&SA-d2(Cisbio，610SADLF)试剂到384反应板中，1000rpm离心1min，25℃孵育60min。使用BMG酶标仪读取HTRF(Homogeneous Time-Resolved Fluorescence)信号。信号强度用于表征激酶的活性程度。利用GraphPad非线性拟合公式(式1)计算IC50：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope)   式(2)The positive compound (A-1210477) and the test compound were serially diluted 3-fold with DMSO (Sigma, D4540) in a 384 dilution plate, so that the final starting concentrations of the positive compound and the test compound were 1000 nM and 10000 nM respectively. Transfer 75nL of diluted compounds of different concentrations to the 384 reaction plate, ensuring that the DMSO content is 0.5%. Then transfer 5 μL/well 3×BCL-2 enzyme (BPS, 50272) solution to the 384 reaction plate to ensure the final concentration of the reaction is 2 nM, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min. Transfer 5 μL/well 3×Bio-tin-BIM (GenScript) substrate solution to the 384 reaction plate, ensure the final concentration of the reaction is 30 nM, and centrifuge at 1000 rpm for 1 min. Transfer 5 μL/well 1×His-Tb (Cisbio, 61HISTLA) & SA-d2 (Cisbio, 610SADLF) reagent to the 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min. Use a BMG microplate reader to read the HTRF (Homogeneous Time-Resolved Fluorescence) signal. Signal intensity is used to characterize the degree of kinase activity. Calculate IC 50 using the GraphPad nonlinear fitting formula (Equation 1):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)×HillSlope) Formula (2)
X:化合物浓度log值     Y:抑制率(％inhibition)X: Log value of compound concentration Y: Inhibition rate (%inhibition)
生物测试结果见表1，表2：The biological test results are shown in Table 1 and Table 2:
表1化合物对Bcl-xL靶点亲和力的TR-FRET IC50


注：A≤20nMTable 1 TR-FRET IC 50 of compound affinity for Bcl-xL target site


Note: A≤20nM
表2化合物对Bcl-xL/Bcl-2靶点亲和力的TR-FRET IC50
Table 2 TR-FRET IC 50 of compounds for Bcl-xL/Bcl-2 target affinity
结论：本发明化合物，例如实施例化合物，对Bcl-xL靶点具有较高的结合能力。相对于Bcl-2靶点，本发明化合物对Bcl-xL靶点具有高的选择性，与对照化合物1、对照化合物2的三氟乙酸盐相比较，本发明化合物具有更优的选择性。特别是化合物25对Bcl-xL的靶点亲和力是对Bcl-2靶点亲和力的1207倍，化合物22对Bcl-xL的靶点亲和力是对Bcl-2靶点亲和力的893倍，化合物21、24、27的三氟乙酸盐、28的三氟乙酸盐对Bcl-xL的靶点亲和力均超过对Bcl-2靶点亲和力的295倍。Conclusion: The compounds of the present invention, such as the example compounds, have high binding ability to the Bcl-xL target. Relative to the Bcl-2 target, the compound of the present invention has high selectivity for the Bcl-xL target. Compared with the trifluoroacetate salt of Compound 1 and Compound 2, the compound of the present invention has better selectivity. In particular, the target affinity of compound 25 for the Bcl-xL target is 1207 times that of the Bcl-2 target. The target affinity of compound 22 for Bcl-xL is 893 times that of the Bcl-2 target. Compounds 21 and 24 The affinity of 27 trifluoroacetate and 28 trifluoroacetate to the Bcl-xL target was 295 times higher than the affinity to the Bcl-2 target.
对照化合物1结构：
Structure of reference compound 1:
对照化合物2：
Control compound 2:
2.抗衰老检测试验2. Anti-aging test
实验方法：人源成纤维原生细胞系WI-38细胞来源于ATCC(货号：CCL-75)，培养于EMEM+10％FBS+1％双抗培养基，37℃，5％CO2孵箱中。当细胞处于指数增长期时，收集细胞，计数，种板于10cm2皿，待细胞贴壁后，用200nM的丝裂霉素C(MMC，厂家：Absin，货号：47029279)处理细胞48h，构建细胞衰老模型，同时设置DMSO处理细胞组作为溶媒对照，确保DMSO终浓度为0.1％以下。将经MMC/DMSO处理的细胞消化，离心，重悬，按照5000个/孔(MMC)和1000个/孔(DMSO)的密度铺入384孔板中培养5天，随后加入配制好的不同浓度的化合物孵育48h，随后进行SA-β-gal染色，染色步骤如下：Experimental method: Human fibroblast primary cell line WI-38 cells are derived from ATCC (Product No.: CCL-75), cultured in EMEM+10% FBS+1% double antibody medium, 37°C, 5% CO 2 incubator . When the cells are in the exponential growth phase, collect the cells, count them, and plate them on a 10cm2 dish. After the cells adhere to the wall, treat the cells with 200nM mitomycin C (MMC, manufacturer: Absin, product number: 47029279) for 48 hours, and construct In the cell senescence model, a DMSO-treated cell group was also set as a vehicle control to ensure that the final concentration of DMSO was less than 0.1%. The cells treated with MMC/DMSO were digested, centrifuged, resuspended, and plated into a 384-well plate at a density of 5000 cells/well (MMC) and 1000 cells/well (DMSO) for 5 days, and then the prepared different concentrations were added. The compound was incubated for 48h, followed by SA-β-gal staining. The staining steps were as follows:
a)弃去培养基，用1×PBS清洗细胞2次，除去全部洗涤液；a) Discard the culture medium, wash the cells twice with 1×PBS, and remove all washing fluid;
b)用4％多聚甲醛固定液固定细胞，15μL/孔，室温固定15分钟；b) Fix cells with 4% paraformaldehyde fixative, 15 μL/well, at room temperature for 15 minutes;
c)每孔用50μL 1×PBS冲洗细胞3次；c) Wash the cells 3 times with 50μL 1×PBS in each well;
d)按照试剂盒(厂家：sigma，货号：CS0030)要求配置SA-β-gal染色液；d) Configure SA-β-gal staining solution according to the requirements of the kit (manufacturer: sigma, product number: CS0030);
e)每孔加入10μL染色液，密封板，于37℃孵育3-6h,或者过夜(根据实际染色情况定)；e) Add 10 μL of staining solution to each well, seal the plate, and incubate at 37°C for 3-6 hours, or overnight (depending on the actual staining situation);
f)用1×PBS冲洗细胞两次，并用DAPI(1:400，厂家：Thermo；货号:62248)和F-actin(厂家：Invitrogen，货号：A12380)室温染色1h；f) Wash the cells twice with 1×PBS and stain with DAPI (1:400, manufacturer: Thermo; Catalog No.: 62248) and F-actin (Manufacturer: Invitrogen, Catalog No.: A12380) at room temperature for 1 hour;
g)用CQ1(厂家:YOKOGAWA，货号：1042288)拍照分析；g) Use CQ1 (manufacturer: YOKOGAWA, product number: 1042288) to take pictures and analyze;
数据处理：每个样本共统计2000个细胞中SA-β-gal+的细胞百分比，并记为SA％，并按照式(1)计算化合物组相对溶媒对照的SA-β-gal+百分比(Cpd％)，使用GraphPad Prism软件作图，绘制量-效关系曲线并使用四参数分析方法计算IC50值。Data processing: Count the cell percentage of SA-β-gal+ in 2000 cells for each sample, and record it as SA%, and calculate the SA-β-gal+ percentage (Cpd%) of the compound group relative to the vehicle control according to formula (1) , use GraphPad Prism software to draw graphs, draw dose-effect relationship curves and use four-parameter analysis methods to calculate IC 50 values.
Cpd％＝(SA％给药/SA％溶媒对照)*100％式(1)Cpd%=(SA% administration/SA% vehicle control)*100% Formula (1)
表3化合物对SA-β-gal染色的WI-38衰老细胞IC50
Table 3 IC 50 of compounds on SA-β-gal stained WI-38 senescent cells
结论：本发明化合物，例如实施例化合物，特别是化合物22，对丝裂霉素C诱导的SA-β-半乳糖苷酶染色的WI-38衰老细胞具有较好的抑制活性。Conclusion: The compounds of the present invention, such as the example compounds, especially compound 22, have good inhibitory activity against mitomycin C-induced SA-β-galactosidase-stained WI-38 senescent cells.
衰老细胞选择性杀伤试验方案Senescent cell selective killing test protocol
实验方法：人源成纤维原生细胞系WI-38细胞来源于ATCC(货号：CCL-75)，培养于EMEM+10％FBS+1％双抗培养基，37℃，5％CO2孵箱中。当细胞处于指数增长期时，收集细胞，计数，种板于10cm2皿，待细胞贴壁后，用200nM的丝裂霉素C(MMC，厂家：Absin，货号：47029279)处理细胞48h，构建细胞衰老模型，同时设置DMSO处理细胞组作为溶媒对照，确保DMSO终 浓度为0.1％以下。将经MMC/DMSO处理的细胞消化，离心，重悬，按照5000个/孔(MMC处理)和1000个/孔(DMSO处理)的密度铺入384孔板中，并加入配制好的不同浓度的化合物共孵育，化合物处理7天后，对于MMC处理的一块板中的“衰老”细胞以及作为对照的另一块板中的非“衰老”细胞，用CellTiter-Glo(厂家：Promega,货号：18002030)测定ATP水平，以此作为细胞活性的替代指标，判断化合物对衰老细胞的选择性杀伤作用。Experimental method: Human fibroblast primary cell line WI-38 cells are derived from ATCC (Product No.: CCL-75), cultured in EMEM+10% FBS+1% double antibody medium, 37°C, 5% CO 2 incubator . When the cells are in the exponential growth phase, collect the cells, count them, and plate them on a 10cm2 dish. After the cells adhere to the wall, treat the cells with 200nM mitomycin C (MMC, manufacturer: Absin, product number: 47029279) for 48 hours, and construct In the cell senescence model, a DMSO-treated cell group was also set up as a vehicle control to ensure that the DMSO The concentration is 0.1% or less. Digest the cells treated with MMC/DMSO, centrifuge, resuspend, and spread them into a 384-well plate at a density of 5000 cells/well (MMC treatment) and 1000 cells/well (DMSO treatment), and add prepared different concentrations of The compounds were co-incubated. After 7 days of compound treatment, the "senescent" cells in one plate treated with MMC and the non-"senescent" cells in another plate as a control were measured with CellTiter-Glo (Manufacturer: Promega, Cat. No.: 18002030) ATP levels are used as a surrogate indicator of cell activity to determine the selective killing effect of compounds on senescent cells.
CTG检测步骤如下：The CTG detection steps are as follows:
a)将CTG试剂平衡至室温，1:1混匀。a) Equilibrate CTG reagent to room temperature and mix 1:1.
b)向实验板中1:1加入试剂，震荡混匀。在Evision仪器上检测。b) Add reagents to the experimental plate at a ratio of 1:1 and shake to mix. Tested on Evision instrument.
数据处理：发光读数使用GraphPad Prism 8.0软件根据式(1)和式(2)分别计算化合物抑制细胞增殖的IC50值和最大抑制率。T给药为化合物孵育7天后信号读值，T溶媒为溶媒对照孵育7天后细胞信号读值。
Growth％＝(T给药/T溶媒×100)％     式(1)Data processing: Luminescence readings use GraphPad Prism 8.0 software to calculate the IC 50 value and maximum inhibition rate of compounds inhibiting cell proliferation according to formula (1) and formula (2) respectively. T administration is the signal reading after 7 days of incubation with the compound, and T vehicle is the cell signal reading after 7 days of incubation with the vehicle control.
Growth% = (T administration /T vehicle × 100)% Formula (1)
Max inhibition％计算：按照式(1)处理，计算在化合物最高浓度下的抑制率。
Max inhibition％＝(100-Growth)％     式(2)Calculation of Max inhibition%: According to formula (1), calculate the inhibition rate at the highest concentration of the compound.
Max inhibition%=(100-Growth)% Formula (2)
结论：本发明化合物对丝裂霉素C诱导的WI-38衰老细胞有较好的抑制活性。Conclusion: The compound of the present invention has good inhibitory activity on WI-38 senescent cells induced by mitomycin C.
3.CYP450酶抑制测试3.CYP450 enzyme inhibition test
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的2种同工酶(CYP2C9、CYP2D6)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型CYP2C9和CYP2D6的抑制潜能。The purpose of this study is to use an in vitro test system to evaluate the effect of the test substance on the activity of two isoenzymes (CYP2C9 and CYP2D6) of human liver microsomal cytochrome P450 (CYP). The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, By processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC 50 value, and evaluate the effect of the test substance on each Inhibitory potential of CYP enzyme isoforms CYP2C9 and CYP2D6.
表4化合物的CYP450酶抑制测试结果
Table 4 CYP450 enzyme inhibition test results of compounds
结论：本发明化合物，例如实施例化合物，特别是化合物22、24、26对CYP2C9和CYP2D6抑制弱于对照化合物1，由CYP2C9和CYP2D6代谢引发的药物相互作用风险更低。本发明化合物对CYP酶各亚型均无明显的抑制作用。Conclusion: The compounds of the present invention, such as the example compounds, especially compounds 22, 24, and 26, inhibit CYP2C9 and CYP2D6 weaker than the control compound 1, and the risk of drug interactions caused by the metabolism of CYP2C9 and CYP2D6 is lower. The compound of the present invention has no obvious inhibitory effect on each subtype of CYP enzyme.
4、化合物对MOLT-4细胞增殖抑制活性研究4. Study on the inhibitory activity of compounds on MOLT-4 cell proliferation
MOLT-4细胞是人急性淋巴母细胞白血病细胞系。购自ATCC，培养条件：RPMI-1640+10％FBS+1％双抗，培养于37℃，5％CO2孵箱中。细胞铺板于96孔板，5×103个/孔。铺板后，加入不同浓度化合物，于37℃，5％CO2孵箱中继续培养72小时。培养结束后，加入细胞活力检测试剂(Promega，G7573)，混匀2分钟，室温孵育10分钟，应用多功能酶标仪(BMG，PHERAstar FSX)检测发光信号。发光读数使用GraphPad Prism 8.0软件根据式(1)和式(2)分别计算化 合物抑制细胞增殖的IC50值和最大抑制率。其中T给药为化合物孵育72小时后细胞信号读值，T溶 媒为溶媒对照孵育72小时后细胞信号读值。
Growth％＝T给药/T溶媒×100    式(1)MOLT-4 cells are a human acute lymphoblastic leukemia cell line. Purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator. Cells were plated in a 96-well plate at 5 × 10 3 cells/well. After plating, compounds of different concentrations were added and cultured for 72 hours in a 37°C, 5% CO 2 incubator. After the culture, add cell viability detection reagent (Promega, G7573), mix for 2 minutes, incubate at room temperature for 10 minutes, and use a multifunctional microplate reader (BMG, PHERAstar FSX) to detect the luminescence signal. Luminescence readings were calculated using GraphPad Prism 8.0 software according to equations (1) and (2). IC 50 value and maximum inhibition rate of the compound inhibiting cell proliferation. Among them, T administration is the cell signal reading value after 72 hours of incubation with the compound, and T vehicle is the cell signal reading value after 72 hours of incubation with the vehicle control.
Growth%=T administration /T vehicle ×100 Formula (1)
Max inhibition％计算：按照式(2)处理，计算在化合物最高浓度下的抑制率。
Max inhibition％＝100％-Growth％   式(2)Calculation of Max inhibition%: According to formula (2), calculate the inhibition rate at the highest concentration of the compound.
Max inhibition%=100%-Growth% Formula (2)
结论：本发明化合物，特别是实施例化合物，对MOLT-4细胞有较好的增殖抑制活性。Conclusion: The compounds of the present invention, especially the compounds of the examples, have good proliferation inhibitory activity on MOLT-4 cells.
5、化合物对NCI-H446细胞增殖抑制活性研究5. Study on the inhibitory activity of compounds on NCI-H446 cell proliferation
NCI-H446细胞(人小细胞肺癌细胞系)购自ATCC，培养条件：RPMI-1640+10％FBS+1％双抗，培养于37℃，5％CO2孵箱中。细胞铺板于96孔板，种板密度为1×103个/孔。第2天向孔板中加入不同浓度化合物(化合物起始浓度10μM，5倍稀释，9个浓度梯度)，于37℃，5％CO2孵箱中继续培养72h。培养结束后，加入细胞活力检测试剂(Promega，G7573)，混匀2分钟，室温孵育10分钟，应用多功能酶标仪(BMG，PHERAstar FSX)检测发光信号。发光读数使用GraphPad Prism 8.0软件根据式(1)和式(2)分别计算化合物抑制细胞增殖的IC50值和最大抑制率。其中T给药为化合物孵育72小时后细胞信号读值，T溶媒为溶媒对照孵育72小时后细胞信号读值。
Growth％＝(T给药/T溶媒×100)％    式(1)NCI-H446 cells (human small cell lung cancer cell line) were purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator. Cells were plated in a 96-well plate at a density of 1 × 10 3 cells/well. On the second day, compounds of different concentrations (compound starting concentration 10 μM, 5-fold dilution, 9 concentration gradients) were added to the well plate, and the culture was continued for 72 h in a 37°C, 5% CO 2 incubator. After the culture, add cell viability detection reagent (Promega, G7573), mix for 2 minutes, incubate at room temperature for 10 minutes, and use a multifunctional microplate reader (BMG, PHERAstar FSX) to detect the luminescence signal. Luminescence readings use GraphPad Prism 8.0 software to calculate the IC 50 value and maximum inhibition rate of compounds inhibiting cell proliferation according to formula (1) and formula (2), respectively. Among them, T administration is the cell signal reading value after 72 hours of incubation with the compound, and T vehicle is the cell signal reading value after 72 hours of incubation with the vehicle control.
Growth% = (T administration /T vehicle × 100)% Formula (1)
Max inhibition％计算：按照式(1)处理，计算在化合物最高浓度下的抑制率。
Max inhibition％＝100％-Growth％   式(2)Calculation of Max inhibition%: According to formula (1), calculate the inhibition rate at the highest concentration of the compound.
Max inhibition%=100%-Growth% Formula (2)
结论：本发明化合物，特别是实施例化合物，对NCI-H446细胞有较好的增殖抑制活性。Conclusion: The compounds of the present invention, especially the compounds of the examples, have good proliferation inhibitory activity on NCI-H446 cells.
6、化合物对Kasumi-1细胞增殖抑制活性研究6. Study on the inhibitory activity of compounds on Kasumi-1 cell proliferation
Kasumi-1细胞(人急性原粒细胞白血病细胞系)，购自ATCC，培养条件：RPMI-1640+20％FBS+1％双抗，培养于37℃，5％CO2孵箱中。细胞铺板于96孔板，种板密度为1.2×104个/孔。铺板后加入不同浓度化合物(化合物起始浓度10μM，5倍稀释，9个浓度梯度)，于37℃，5％CO2孵箱中继续培养72h。培养结束后，加入细胞活力检测试剂(Promega，G7573)，混匀2分钟，室温孵育10分钟，应用多功能酶标仪(BMG，PHERAstar FSX)检测发光信号。发光读数使用GraphPad Prism 8.0软件根据式(1)和式(2)分别计算化合物抑制细胞增殖的IC50值和最大抑制率。其中T给药为化合物孵育72小时后细胞信号读值，T溶媒为溶媒对照孵育72小时后细胞信号读值。
Growth％＝(T给药/T溶媒×100)％    式(1)Kasumi-1 cells (human acute myelocytic leukemia cell line) were purchased from ATCC, culture conditions: RPMI-1640+20% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator. Cells were plated in a 96-well plate with a seed plate density of 1.2×10 4 cells/well. After plating, compounds of different concentrations (compound starting concentration 10 μM, 5-fold dilution, 9 concentration gradients) were added, and the culture was continued for 72 h in a 37°C, 5% CO 2 incubator. After the culture, add cell viability detection reagent (Promega, G7573), mix for 2 minutes, incubate at room temperature for 10 minutes, and use a multifunctional microplate reader (BMG, PHERAstar FSX) to detect the luminescence signal. Luminescence readings use GraphPad Prism 8.0 software to calculate the IC 50 value and maximum inhibition rate of compounds inhibiting cell proliferation according to formula (1) and formula (2), respectively. Among them, T administration is the cell signal reading after 72 hours of incubation with the compound, and T vehicle is the cell signal reading after 72 hours of incubation with the vehicle control.
Growth% = (T administration /T vehicle × 100)% Formula (1)
Max inhibition％计算：按照式(1)处理，计算在化合物最高浓度下的抑制率。
Max inhibition％＝100％-Growth％    式(2)Calculation of Max inhibition%: According to formula (1), calculate the inhibition rate at the highest concentration of the compound.
Max inhibition%=100%-Growth% Formula (2)
结论：本发明化合物，特别是实施例化合物，对Kasumi-1细胞有较好的增殖抑制活性。Conclusion: The compounds of the present invention, especially the compounds of the examples, have good proliferation inhibitory activity on Kasumi-1 cells.
以下药代动力学测试中，含有磷酸酯的化合物(前药)需同时对受试物本身以及其对应水解的化合物(原药)做定量分析。例如化合物27，需同时检测化合物27和其对应的原药化合物24。In the following pharmacokinetic tests, compounds containing phosphate esters (prodrugs) require quantitative analysis of both the test substance itself and its corresponding hydrolyzed compound (original drug). For example, compound 27 needs to be detected simultaneously with its corresponding original drug compound 24.
7、小鼠药代动力学测试7. Mouse pharmacokinetic test
1.1试验动物：雄性C57Mice小鼠，20～25g，3-6只/化合物。购于成都达硕实验动物有限公司。1.1 Test animals: male C57Mice mice, 20~25g, 3-6/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
1.2试验设计：试验当天，小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。1.2 Experimental design: On the day of the experiment, mice were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
表5.给药信息
Table 5. Dosing information
注：静脉给药溶媒:5％DMSO+95％(3％Tween 80 in PBS)Note: Intravenous administration vehicle: 5% DMSO+95% (3% Tween 80 in PBS)
于给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析，如受试化合物为前药分子，则同时对样品进行前药和原药的定量分析。Before and after administration, 0.06 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, and 24h. Before analysis and detection, all samples were stored at -80°C, and LC-MS/MS was used to quantitatively analyze the samples. If the test compound is a prodrug molecule, quantitative analysis of the prodrug and original drug was performed on the sample at the same time.
结论：本发明化合物，特别是实施例化合物，经静脉给药，在小鼠体内，原药有较好的暴露量，例如化合物27、28、29水解后原药分别为24、22、26，具有较好的暴露量。Conclusion: When the compounds of the present invention, especially the compounds of the examples, are administered intravenously, the original drug has a good exposure in mice. For example, after hydrolysis of compounds 27, 28, and 29, the original drugs are 24, 22, and 26, respectively. Have better exposure.
8、大鼠药代动力学测试8. Rat pharmacokinetic test
1.1试验动物：雄性SD大鼠，220g左右，6～8周龄，3-6只/化合物。购于成都达硕实验动物有限公司。1.1 Test animals: male SD rats, about 220g, 6 to 8 weeks old, 3-6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
1.2试验设计：试验当天，大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。1.2 Experimental design: On the day of the experiment, rats were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
表6.给药信息

注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；或5％DMSO+95％(3％Tween 80in PBS)
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水)Table 6. Dosing information

Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; or 5% DMSO+95% (3% Tween 80in PBS)
(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline)
于给药前及给药后异氟烷麻醉经眼眶取血0.15ml，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为：0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析，如受试化合物为前药分子，则同时对样品进行前药和原药的定量分析。Before and after administration, 0.15 ml of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, and 24h. Before analysis and detection, all samples were stored at -80°C, and LC-MS/MS was used to quantitatively analyze the samples. If the test compound is a prodrug molecule, quantitative analysis of the prodrug and original drug was performed on the sample at the same time.
结论：本发明化合物，特别是实施例化合物，经静脉给药，在大鼠体内，原药有较好的暴露量。例如化合物27、28、29水解后原药分别为24、22、26，具有较好的暴露量。Conclusion: When the compounds of the present invention, especially the example compounds, are administered intravenously, the original drug has a good exposure in rats. For example, after hydrolysis of compounds 27, 28, and 29, the original drugs are 24, 22, and 26 respectively, which have better exposure.
9、比格犬药代动力学测试9. Beagle dog pharmacokinetics test
试验动物：雄性比格犬，8～11kg左右，3-6只/化合物，购于北京玛斯生物技术有限公司。Experimental animals: male beagles, about 8-11kg, 3-6/compound, purchased from Beijing Mas Biotechnology Co., Ltd.
试验方法：试验当天，比格犬按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。按照表1给药。Test method: On the day of the test, the beagle dogs were randomly divided into groups according to their weight. No food or water for 12 to 14 hours one day before administration, and food 4 hours after administration. Dosage according to Table 1.
表7.给药信息


注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；或5％DMSO+95％(3％Tween 80in PBS)
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水)Table 7. Dosing information


Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; or 5% DMSO+95% (3% Tween 80in PBS)
(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline)
于给药前及给药后通过颈静脉或四肢静脉取血1ml，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24,48,72h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析，如受试化合物为前药分子，则同时对样品进行前药和原药的定量分析。Before and after administration, take 1 ml of blood from the jugular vein or limb veins and place it in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h. Before analysis and detection, all samples were stored at -80°C, and LC-MS/MS was used to quantitatively analyze the samples. If the test compound is a prodrug molecule, quantitative analysis of the prodrug and original drug was performed on the sample at the same time.
结论：本发明化合物，特别是实施例化合物，经静脉给药，在比格犬体内，原药有较好的暴露量。例如化合物27、28、29水解后原药分别为24、22、26，具有较好的暴露量。Conclusion: When the compounds of the present invention, especially the compounds of the examples, are administered intravenously, the original drug has a good exposure in the body of beagle dogs. For example, after hydrolysis of compounds 27, 28, and 29, the original drugs are 24, 22, and 26 respectively, which have better exposure.
10、猴药代动力学测试10. Monkey pharmacokinetic test
试验动物：雄性食蟹猴，3～5kg，3～6年龄，3-6只/化合物。购于苏州西山生物技术有限公司。Test animals: male cynomolgus monkey, 3-5kg, 3-6 years old, 3-6 animals/compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
试验方法：试验当天，猴按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to body weight. No food and water for 14 to 18 hours one day before administration, and food 4 hours after administration.
表8.给药信息

注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；或5％DMSO+95％(3％Tween 80in PBS)
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水)Table 8. Dosing information

Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; or 5% DMSO+95% (3% Tween 80in PBS)
(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline)
于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5min,15min,30min,1,2,4,6,8,10,12,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析，如受试化合物为前药分子，则同时对样品进行前药和原药的定量分析。Before and after administration, 1.0 mL of blood was taken from the veins of the limbs and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5min, 15min, 30min, 1, 2, 4, 6, 8, 10, 12, and 24h. Before analysis and detection, all samples were stored at -80°C, and LC-MS/MS was used to quantitatively analyze the samples. If the test compound is a prodrug molecule, quantitative analysis of the prodrug and original drug was performed on the sample at the same time.
结论：本发明化合物，特别是实施例化合物，经静脉给药，在猴体内，原药有较好的暴露量。例如化合物27、28、29水解后原药分别为24、22、26，具有较好的暴露量。Conclusion: When the compounds of the present invention, especially the compounds of the examples, are administered intravenously, the original drug has a good exposure in monkeys. For example, after hydrolysis of compounds 27, 28, and 29, the original drugs are 24, 22, and 26 respectively, which have better exposure.
11、肝微粒体稳定性测试11. Liver microsome stability test
本实验采用人、犬、大鼠和小鼠五种属肝微粒体作为体外模型来评价受试物的代谢稳定性。This experiment uses five types of hepatic microsomes from humans, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substance.
在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC-MS/ The MS method detects the concentration of the test substance in the sample, and calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the liver microsome intrinsic clearance rate CL int (mic) and the liver intrinsic clearance rate CL int(Liver) .
结论：本发明化合物，特别是实施例化合物，有较好的肝微粒体稳定性。 Conclusion: The compounds of the present invention, especially the compounds in the examples, have good liver microsome stability.

Claims (12)

  1. 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(I)所示的化合物，其中
    A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compounds represented by general formula (I), wherein
    环A、环C、环D各自独立的选自C6-10芳基或5至10元杂芳基，所述环A任选被1至4个Ra取代，所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代；Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, the ring A is optionally substituted by 1 to 4 R a , and the ring C is optionally substituted by 1 to 4 R c substitutes, and the ring D is optionally substituted with 1 to 4 R d ;
    B选自-B1-、-N(Rn)-B1-、-B1-N(Rn)-；B is selected from -B 1 -, -N(R n )-B 1 -, -B 1 -N(R n )-;
    B1选自4至12元杂环基，所述杂环基任选被1至10个Rb取代；B 1 is selected from 4 to 12 membered heterocyclyl groups, which are optionally substituted by 1 to 10 R b ;
    X选自-N(Rx)S(＝O)2-、-S(＝O)2N(Rx)-、 左侧与环C连接；X is selected from -N(R x )S(=O) 2 -, -S(=O) 2 N(R x )-, The left side is connected to ring C;
    K选自5元杂芳基，所述K被1至3个Rk1、1个Rk2取代；K is selected from a 5-membered heteroaryl group, and the K is substituted by 1 to 3 R k1 and 1 R k2 ;
    Rx选自H、C1-6烷基或C3-6环烷基；R x is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl;
    Rn选自H、C1-6烷基、-C1-4亚烷基-C3-6环烷基，所述的烷基、亚烷基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基的取代基所取代；R n is selected from H, C 1-6 alkyl, -C 1-4 alkylene-C 3-6 cycloalkyl, and the alkyl, alkylene or cycloalkyl is optionally substituted by 1 to 4 Selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, Substituted with C 1-6 alkoxy substituents;
    Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R a , R b , and R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Alkoxy group, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkyl The oxygen group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1-6 alkyl groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-6 alkyl group, and hydroxyl group. Substituted by 6 alkyl, cyano substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents ;
    或者任意的Rb与Rc直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
    或者任意的Rb与Ra直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
    Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代，所述的烷基、炔基、烷氧基、碳环基或杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or Substituted with 4 to 10 membered heterocyclic group substituents, the alkyl, alkynyl, alkoxy, carbocyclyl or heterocyclic group is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2. C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 2-6 alkynyl, C 1- Substituted with a substituent of 6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl;
    Rd、Rk1各自独立的选自氘、卤素、氰基、OH、NO2、COOH、CD3、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-O-C3-6环烷基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环、-S(＝O)2R1、-S(＝O)2NR1R2、-C(＝O)NR1R2、C(＝O)NR1S(＝O)2R3、-C(＝O)R1，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、碳环或杂环任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R d and R k1 are each independently selected from deuterium, halogen, cyano, OH, NO 2 , COOH, CD 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy group, C 1-6 alkylthio group, -OC 3-6 cycloalkyl group, -(CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10 membered heterocyclic ring , -S(＝O) 2 R 1 , -S(＝O) 2 NR 1 R 2 , -C(＝O)NR 1 R 2 , C(＝O)NR 1 S(＝O) 2 R 3 , -C(=O)R 1 , the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 Selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1 Substituted by -6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents;
    R1、R2、R3各自独立的选自H、C1-6烷基、C3-10碳环基或4至10元杂环基，所述的烷基、 碳环基或者杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R 1 , R 2 and R 3 are each independently selected from H, C 1-6 alkyl, C 3-10 carbocyclic group or 4 to 10 membered heterocyclic group, the alkyl group, The carbocyclyl or heterocyclic group is optionally substituted by 1 to 4 carbon atoms selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and hydroxyl-substituted C 1-6 Substituted by alkyl, cyano-substituted C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents;
    Z选自-CH(Rz1)CH2-S-Rz2或-CH(Rz1)CH2-Se-Rz2；Z is selected from -CH(R z1 )CH 2 -SR z2 or -CH(R z1 )CH 2 -Se-R z2 ;
    Rz1选自-C1-4亚烷基-Z1-Rz3；R z1 is selected from -C 1-4 alkylene -Z 1 -R z3 ;
    Z1选自4至12元杂环基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from 4 to 12-membered heterocyclyl, and Z 1 is optionally selected from 1 to 4 R z1a or optionally 1 selected from -OP(=O)(OH) 2 or -CH 2 OP(= Substituted with O)(OH) 2 substituent;
    Rk2、Rz2各自独立的选自C6-10芳基或5至10元杂芳基，所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；R k2 and R z2 are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, the R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a substitution;
    Rz1a、Rk2a、Rz2a各自独立的选自卤素、氰基、OH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-(CH2)q-C3-10碳环、-(CH2)q-4至10元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6炔基、C1-6烷氧基、C3-10碳环基或4至10元杂环基的取代基所取代；R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, - (CH 2 ) q -C 3-10 carbocyclic ring, -(CH 2 ) q -4 to 10 membered heterocyclic ring, the -CH 2 -, alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano Substituted with substituents of C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl;
    Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2、-OP(＝O)(OH)(OC1-6烷基)、-CH2OP(＝O)(OH)(OC1-6烷基)、-OP(＝O)(OC1-6烷基)2、-CH2OP(＝O)(OC1-6烷基)2；R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 , -OP(=O)(OH)(OC 1-6 Alkyl), -CH 2 OP(=O)(OH)(OC 1-6 alkyl), -OP(=O)(OC 1-6 alkyl) 2 , -CH 2 OP(=O)(OC 1-6 alkyl) 2 ;
    q各自独立的选自0、1、2、3或4；q is independently selected from 0, 1, 2, 3 or 4;
    条件是，1)当B选自时，B被1至8个Rb取代；The conditions are, 1) when B is selected from When, B is replaced by 1 to 8 R b ;
    或2)当B选自未取代的并且Z1选自通过氮原子与亚烷基连接的4至7元单环杂环基时，Z1被1至4个Rz1a取代；or 2) when B is selected from unsubstituted And when Z 1 is selected from a 4 to 7-membered monocyclic heterocyclyl group connected to an alkylene group through a nitrogen atom, Z 1 is substituted by 1 to 4 R z1a ;
    所述通式(I)化合物任选被1至20个氘取代。The compounds of general formula (I) are optionally substituted by 1 to 20 deuteriums.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
    环A、环C、环D各自独立的选自苯基、苯并C4-6碳环基、苯并5至6元杂环基、5至6元杂芳基、9至10元杂芳基，所述环A任选被1至4个Ra取代，所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代；Ring A, ring C, and ring D are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and 9- to 10-membered heteroaryl base, the ring A is optionally substituted by 1 to 4 R a , the ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
    B1选自4至7元含氮单环杂环基、5至10元含氮并环杂环基、5至11元含氮螺环杂环基、5至11元含氮桥环杂环基，所述B1任选被1至8个Rb取代；B 1 is selected from the group consisting of 4 to 7-membered nitrogen-containing monocyclic heterocyclyl, 5- to 10-membered nitrogen-containing paracyclic heterocyclyl, 5- to 11-membered nitrogen-containing spirocyclic heterocyclyl, and 5- to 11-membered nitrogen-containing bridged heterocyclic ring. group, the B 1 is optionally substituted by 1 to 8 R b ;
    Rn选自H、C1-4烷基；R n is selected from H, C 1-4 alkyl;
    X选自-NHS(＝O)2-，左侧与环C连接；X is selected from -NHS(=O) 2 -, and the left side is connected to ring C;
    Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R a , R b , and R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy group, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkyl The oxygen group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, OH, cyano group, NH 2 , C 1-6 alkyl group, halogen-substituted C 1-4 alkyl group, and hydroxyl group. Substituted by 4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7 membered heterocyclyl substituents ;
    或者任意的Rb与Rc直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代； Or any R b and R c are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
    或者任意的Rb与Ra直接连接形成4至7元杂环，所述的杂环任选被1至4个Ra1取代；Or any R b and R a are directly connected to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1 ;
    Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基，所述的烷基、炔基、烷氧基、碳环基或杂环基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclic group, the alkyl group, alkynyl group, alkoxy group, carbocyclyl group or heterocyclic group is optionally substituted by 1 to 4 members selected from halogen, OH, cyano group, NH 2 , C 1- 4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, Substituted with a substituent of C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
    Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C3-6环烷基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环、-S(＝O)2R1、-S(＝O)2NR1R2、-C(＝O)NR1R2、C(＝O)NR1S(＝O)2R3、-C(＝O)R1，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、碳环或杂环任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy group, C 1-4 alkylthio group, -OC 3-6 cycloalkyl group, -(CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring , -S(＝O) 2 R 1 , -S(＝O) 2 NR 1 R 2 , -C(＝O)NR 1 R 2 , C(＝O)NR 1 S(＝O) 2 R 3 , -C(=O)R 1 , the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 Selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1 Substituted with a substituent of -4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
    R1、R2、R3各自独立的选自H、C1-4烷基、C3-6碳环或4至7元杂环，所述的烷基、碳环或者杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R 1 , R 2 , and R 3 are each independently selected from H, C 1-4 alkyl, C 3-6 carbocyclic ring or 4 to 7-membered heterocyclic ring. The alkyl group, carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1- Substituted with a substituent of 4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
    Z1选自4至7元含氮杂单环、5至10含氮并环杂环基、5至11元含氮螺环杂环基、5至11元含氮桥环杂环基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from the group consisting of 4 to 7 membered nitrogen-containing heteromonocyclic groups, 5 to 10 membered nitrogen-containing paracyclic heterocyclic groups, 5 to 11 membered nitrogen-containing spirocyclic heterocyclic groups, and 5 to 11 membered nitrogen-containing bridged cyclic heterocyclic groups, so The Z 1 is optionally substituted by 1 to 4 R z1a or optionally by 1 substituent selected from -OP(=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 ;
    Rk2、Rz2各自独立的选自苯基、苯并C4-6碳环基、苯并5至6元杂环基、5至6元杂芳基、9至10元杂芳基，所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；R k2 and R z2 are each independently selected from phenyl, benzo C 4-6 carbocyclic group, benzo 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, and 9- to 10-membered heteroaryl group, so The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
    Rz1a、Rk2a、Rz2a各自独立的选自卤素、氰基、OH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-(CH2)q-C3-6碳环、-(CH2)q-4至7元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6碳环基或4至7元杂环基的取代基所取代；R z1a , R k2a , and R z2a are each independently selected from halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, - (CH 2 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -4 to 7-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring Or the heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano Substituted with substituents of C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4 to 7-membered heterocyclyl;
    Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2；R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 ;
    q各自独立的选自0、1、2。q is independently selected from 0, 1, and 2.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound according to claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
    B1选自氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环己烯基、氮杂环庚基、氮杂环丁基螺环丙基、氮杂环戊基螺环丙基、氮杂环己基螺环丙基、氮杂环丁基螺环丁基、氮杂环戊基螺环丁基、氮杂环己基螺环丁基、氮杂环丁基螺环戊基、氮杂环戊基螺环戊基、氮杂环己基螺环戊基、氮杂环丁基螺环己基、氮杂环戊基螺环己基、氮杂环己基螺环己基、氮杂环丁基螺氮杂环丁基、氮杂环戊基螺氮杂环丁基、氮杂环己基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环戊基螺氮杂环戊基、氮杂环己基螺氮杂环戊基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环己基螺氮杂环己基、哌嗪螺环丙基、哌嗪螺环丁基、哌嗪螺环戊基、哌嗪螺环己基、哌嗪螺氮杂环丙基、哌嗪螺氮杂环丁基、哌嗪螺氮杂环戊基、哌嗪螺氮杂环己基、氮杂环丁基并环丙基、氮杂环戊基并环丙基、氮杂环己基并环丙基、氮杂环丁基并环丁基、氮杂环戊基并环丁基、 氮杂环己基并环丁基、氮杂环丁基并环戊基、氮杂环戊基并环戊基、氮杂环己基并环戊基、氮杂环丁基并环己基、氮杂环戊基并环己基、氮杂环己基并环己基、氮杂环丁基并氮杂环丁基、氮杂环戊基并氮杂环丁基、氮杂环己基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环戊基并氮杂环戊基、氮杂环己基并氮杂环戊基、氮杂环丁基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环己基并氮杂环己基、哌嗪并环丙基、哌嗪并环丁基、哌嗪并环戊基、哌嗪并环己基、哌嗪螺并杂环丙基、哌嗪并氮杂环丁基、哌嗪并氮杂环戊基、哌嗪并氮杂环己基、3,8-二氮杂双环[3.2.1]辛烷基、3-氮杂双环[3.2.1]辛烷基、8-氮杂双环[3.2.1]辛烷基、2,5-二氮杂双环[2.2.1]庚烷基、2-氮杂双环[2.2.1]庚烷基、5-氮杂双环[2.2.1]庚烷基、3-氮杂双环[3.1.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、3,6-二氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.3.1]壬烷基、3,7-二氮杂双环[3.3.1]壬烷基，所述B1任选被1至8个Rb取代；B 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, azetidinylspiro Cyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl base, azetipentylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidine Butylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiro Azetipentyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl Piperazinespirocyclopropyl, piperazinespirocyclobutyl, piperazinespirocyclopentyl, piperazinespirocyclohexyl, piperazinespiroazetipropyl, piperazinespiroazetidinyl, piperazinespiroazetidine Pentyl, piperazinespiroazepanyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidinylcyclopropyl, azetidinylcyclobutyl, Azepanylcyclobutyl, Azetidinolocyclobutyl, azetidinolocyclopentyl, azetidinolocyclopentyl, azetidinolocyclopentyl, azetidinolocyclohexyl, azepine Pentyl cyclohexyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, azetidinyl azetidinyl, nitrogen Heterobutyl azepanyl, azetyl azetyl, azetyl azetyl, azetyl azetyl, azetyl Azacyclohexyl, azepanazacyclohexyl, piperazinocyclopropyl, piperazinocyclobutyl, piperazinocyclopentyl, piperazinocyclohexyl, piperazinospirocyclopropyl base, piperazonaazetidinyl, piperazonaazetipentyl, piperazonaazetihexyl, 3,8-diazabicyclo[3.2.1]octyl, 3-azabicyclo [3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1] Heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3,6- Diazabicyclo[3.1.1]heptyl, 3-azabicyclo[3.3.1]nonyl, 3,7-diazabicyclo[3.3.1]nonyl, the B 1 is optional Replaced by 1 to 8 R b ;
    Z1选自氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环己烯基、氮杂环庚基、氮杂环丁基螺环丙基、氮杂环戊基螺环丙基、氮杂环己基螺环丙基、氮杂环丁基螺环丁基、氮杂环戊基螺环丁基、氮杂环己基螺环丁基、氮杂环丁基螺环戊基、氮杂环戊基螺环戊基、氮杂环己基螺环戊基、氮杂环丁基螺环己基、氮杂环戊基螺环己基、氮杂环己基螺环己基、氮杂环丁基并环丙基、氮杂环戊基并环丙基、氮杂环己基并环丙基、氮杂环丁基并环丁基、氮杂环戊基并环丁基、氮杂环己基并环丁基、氮杂环丁基并环戊基、氮杂环戊基并环戊基、氮杂环己基并环戊基、氮杂环丁基并环己基、氮杂环戊基并环己基、氮杂环己基并环己基、3-氮杂双环[3.2.1]辛烷基、8-氮杂双环[3.2.1]辛烷基、2-氮杂双环[2.2.1]庚烷基、5-氮杂双环[2.2.1]庚烷基、3-氮杂双环[3.1.1]庚烷基、6-氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.3.1]壬烷基、3-氧杂-7-氮杂双环[3.3.1]壬烷基，所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from azetidinyl, azetipentyl, azehexyl, azehexenyl, azepanyl, azetidinylspirocyclopropyl, azetidinylspiro Cyclopropyl, azetidinylspirocyclopropyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl, azetidinylspirocyclobutyl base, azetipentylspirocyclopentyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidinylspirocyclohexyl, azetidine Butyl-cyclopropyl, azeti-cyclopropyl, azeti-cyclopropyl, azeti-cyclobutyl, azeti-cyclobutyl, aze-cyclohexyl cyclobutyl, azetidinylcyclohexyl, azetidinylcyclopentyl, azetidinylcyclohexyl, azetidinylcyclohexyl, azetidinylcyclopentyl Hexyl, azacyclohexylcyclohexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.1]heptane base, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[ 3.3.1]nonyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, the Z 1 is optionally replaced by 1 to 4 R z1a or optionally 1 is selected from -OP Substituted with (=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 substituents;
    Ra、Rb、Rc各自独立的选自氘、卤素、氰基、OH、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基或C3-6环烷基，所述的烷基、炔基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R a , R b , and R c are each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy or C 3- 6 cycloalkyl, the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted by substituents;
    Ra1各自独立的选自卤素、OH、氰基、NH2、＝O、C1-4烷基、C2-4炔基、C1-4烷氧基或C3-6环烷基，所述的烷基、炔基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R a1 is each independently selected from halogen, OH, cyano, NH 2 , =O, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy or C 3-6 cycloalkyl, The alkyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-4 alkyl selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, and halogen. Substituted with substituents such as hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, and C 3-6 cycloalkyl. ;
    Rd、Rk1各自独立的选自氘、CD3、卤素、氰基、OH、NO2、COOH、C1-4烷基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C3-6环烷基、C3-6环烷基、-CH2-C3-6环烷基、-S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2C1-4烷基、-S(＝O)2-C3-6环烷基、-S(＝O)2NHC1-4烷基、-C(＝O)C1-4烷基、-C(＝O)-C3-6环烷基、-C(＝O)NHC1-4烷基，所述的-CH2-、烷基、炔基、烷氧基、烷硫基、环烷基任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代。R d and R k1 are each independently selected from deuterium, CD 3 , halogen, cyano, OH, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio group, -OC 3-6 cycloalkyl group, C 3-6 cycloalkyl group, -CH 2 -C 3-6 cycloalkyl group, -S(=O) 2 NH 2 , -C(= O)NH 2 , -S(=O) 2 C 1-4 alkyl, -S(=O) 2 -C 3-6 cycloalkyl, -S(=O) 2 NHC 1-4 alkyl, - C(=O)C 1-4 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)NHC 1-4 alkyl, the -CH 2 -, alkyl , alkynyl, alkoxy, alkylthio, cycloalkyl optionally substituted by 1 to 4 C selected from deuterium, CD 3 , halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituted by substituents.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    B选自-B1-、-N(CH3)-B1-、-B1-N(CH3)-； B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
    B1选自 所述B1任选被1至8个Rb取代；B 1 selected from The B 1 is optionally substituted by 1 to 8 R b ;
    环A选自 所述环A任选被1至4个Ra取代；Ring A is selected from The ring A is optionally substituted by 1 to 4 Ra ;
    环C、环D各自独立的选自 所述环C任选被1至4个Rc取代，所述环D任选被1至4个Rd取代； Ring C and Ring D are each independently selected from The ring C is optionally substituted by 1 to 4 R c , and the ring D is optionally substituted by 1 to 4 R d ;
    或者选自 左侧与环A连接；or Selected from The left side is connected to ring A;
    或者选自 左侧与环C连接；or Selected from The left side is connected to ring C;
    Ra、Rb、Rc各自独立的选自氘、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R a , R b , R c are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl , ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally selected from 1 to 4 Substituted by halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
    Ra1各自独立的选自F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、 乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R a1 is each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, Ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, Butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally selected from 1 to 4 halogen , OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
    Rd各自独立的选自F、Cl、Br、I、氰基、OH、NO2、COOH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、-S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2-甲基、-S(＝O)2-乙基、-S(＝O)2NH-甲基、-S(＝O)2NH-乙基、-C(＝O)-甲基、-C(＝O)-乙基、-C(＝O)NH-甲基、-C(＝O)NH-乙基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R d is each independently selected from F, Cl, Br, I, cyano, OH, NO 2 , COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propyne base, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O) 2 NH 2 , -C(=O)NH 2 , -S(=O ) 2 -methyl, -S(=O) 2 -ethyl, -S(=O) 2 NH-methyl, -S(=O) 2 NH-ethyl, -C(=O)-methyl , -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, the methyl, ethyl, propyl, isopropyl, butyl base, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally 1 to 4 selected from halogen, Substituted with substituents of OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
    Rz1选自-CH2CH2-Z1-Rz3；R z1 is selected from -CH 2 CH 2 -Z 1 -R z3 ;
    Z1选自 所述Z1任选被1至4个Rz1a或任选被1个选自-OP(＝O)(OH)2或-CH2OP(＝O)(OH)2的取代基所取代；Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 R z1a or optionally by 1 substituent selected from -OP(=O)(OH) 2 or -CH 2 OP(=O)(OH) 2 ;
    Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2；R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 ;
    K选自 K is selected from
    Rk1a选自COOH、S(＝O)2NH2、-C(＝O)NH2、-S(＝O)2-甲基、-S(＝O)2-乙基、-S(＝O)2NH-甲基、-S(＝O)2NH-乙基、-C(＝O)-甲基、-C(＝O)-乙基、-C(＝O)NH-甲基、-C(＝O)NH-乙基，所述的甲基或乙基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R k1a is selected from COOH, S(=O) 2 NH 2 , -C(=O)NH 2 , -S(=O) 2 -methyl, -S(=O) 2 -ethyl, -S(= O) 2 NH-methyl, -S(=O) 2 NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl , -C(=O)NH-ethyl, the methyl or ethyl group is optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 Substituted by alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
    Rk1b选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, Methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, Propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, and cyclopentyl are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C Substituted with substituents of 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
    Rk1c选自氘、CD3、H、甲基、乙基、丙基、异丙基、丁基、环丙基，所述的甲基、乙基、丙基、异丙基、丁基、环丙基任选被1至4个选自氘、CD3、卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R k1c is selected from deuterium, CD 3 , H, methyl, ethyl, propyl, isopropyl, butyl, and cyclopropyl, and the methyl, ethyl, propyl, isopropyl, butyl, The cyclopropyl group is optionally selected from 1 to 4 deuterium, CD 3 , halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1 Substituted with -4 alkoxy and C 3-6 cycloalkyl substituents;
    Rk2、Rz2各自独立的选自苯基、吡啶、 所述Rk2任选被1至4个Rk2a取代，所述Rz2任选被1至4个Rz2a取代；R k2 and R z2 are each independently selected from phenyl, pyridine, The R k2 is optionally substituted by 1 to 4 R k2a , and the R z2 is optionally substituted by 1 to 4 R z2a ;
    Rz1a、Rk2a、Rz2a各自独立的选自F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基，所述甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基任选被1至4个选自卤素、OH、氰基、NH2、CF3、羟甲基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基的取代基所取代；R z1a , R k2a , and R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene base, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl base, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl optionally 1 to 4 selected from halogen, OH, cyano, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
    p1、p2、p3各自独立的0、1、2或3。p1, p2, and p3 are each independently 0, 1, 2, or 3.
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
    Rk1a选自COOH；R k1a is selected from COOH;
    Rk1c选自甲基、乙基、丙基、异丙基、-CH2-CF3、-CH2-环丙基、环丙基；R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
    Rk1b选自甲基、乙基、丙基、异丙基、环丙基、-CH2-环丙基；R k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl;
    Rz1a、Rk2a、Rz2a各自独立的选自F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、 R z1a , R k2a , and R z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, acetylene base, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    选自 Selected from
  6. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中通式(I)所示化合物选自通式(II-a)所示化合物，
    The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound represented by the general formula (I) is selected from the general formula The compound shown in (II-a),
    B选自-B1-、-N(CH3)-B1-、-B1-N(CH3)-；B is selected from -B 1 -, -N(CH 3 )-B 1 -, -B 1 -N(CH 3 )-;
    B1选自 所述B1任选被1至8个Rb取代；B 1 selected from The B 1 is optionally substituted by 1 to 8 R b ;
    Rb各自独立的选自氘、F；R b are each independently selected from deuterium and F;
    或者选自 or Selected from
    Z1选自 所述Z1任选被1至4个F取代；Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 F;
    Rk1c选自甲基、乙基、丙基、异丙基、-CH2-CF3、-CH2-环丙基、环丙基；R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
    Rk2a选自F、Cl、甲基、乙基、环丙基； Rk2a is selected from F, Cl, methyl, ethyl, and cyclopropyl;
    Rz3选自-OH、-CH2OH、-OP(＝O)(OH)2、-CH2OP(＝O)(OH)2。R z3 is selected from -OH, -CH 2 OH, -OP(=O)(OH) 2 , -CH 2 OP(=O)(OH) 2 .
  7. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中通式(I)所示化合物选自通式(III-a)或(III-b)所示化合物，

    The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound represented by the general formula (I) is selected from the general formula Compounds represented by (III-a) or (III-b),

    Rk1c选自甲基、乙基、丙基、异丙基、-CH2-CF3、-CH2-环丙基、环丙基；R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH 2 -CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
    Z1选自 所述Z1任选被1至4个F取代；Z 1 is selected from The Z 1 is optionally substituted by 1 to 4 F;
    Rk2a选自F、Cl、甲基、乙基、环丙基； Rk2a is selected from F, Cl, methyl, ethyl, and cyclopropyl;
    Rz3选自-OH、-OP(＝O)(OH)2。R z3 is selected from -OH, -OP(=O)(OH) 2 .
  8. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1所示结构之一。The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one.
  9. 一种药物组合物，包括权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，优选地，药物组合物中包含1-1500mg权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。A pharmaceutical composition comprising the compound of any one of claims 1 to 8 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical composition an acceptable carrier, preferably, the pharmaceutical composition contains 1-1500 mg of the compound of any one of claims 1-8 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or eutectics.
  10. 根据权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或权利要求9所述的组合物在用于制备治疗与Bcl-2或Bcl-xL活性或表达量相关疾病的药物中的应用。The compound according to any one of claims 1 to 8 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the composition according to claim 9 Application in the preparation of drugs for the treatment of diseases related to Bcl-2 or Bcl-xL activity or expression.
  11. 根据权利要求10所述的应用，其中，所述的疾病选自肿瘤或眼部疾病。The use according to claim 10, wherein the disease is selected from tumors or eye diseases.
  12. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或权利要求9所述的组合物，治疗有效量优选1-1500mg，所述的疾病优选Bcl-2或Bcl-xL活性或表达量相关疾病。 A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1 to 8 or its stereoisomer, deuterated product, solvate, or pro- Drug, metabolite, pharmaceutically acceptable salt or co-crystal or the composition of claim 9, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably a disease related to the activity or expression of Bcl-2 or Bcl-xL .
PCT/CN2023/117251 2022-09-06 2023-09-06 Compound for inhibiting bcl-2 or bcl-xl and use thereof in medicine WO2024051741A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
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CN103562202A (en) * 2011-01-25 2014-02-05 密执安大学评议会 BCL-2/BCL-XL inhibitors and therapeutic methods using the same
CN109152933A (en) * 2016-04-21 2019-01-04 生物风险投资有限责任公司 Induce the compound of degradation and application thereof of anti-apoptotic BCL-2 family protein
WO2019033122A1 (en) * 2017-08-11 2019-02-14 Unity Biotechnology, Inc. Treatment of lung diseases using pharmaceutical agents that eliminate senescent cells
CN110302205A (en) * 2013-01-16 2019-10-08 密歇根大学董事会 The medical usage and its pharmaceutical composition of BCL-2/Bcl-xL inhibitor
CN111372598A (en) * 2017-08-11 2020-07-03 联合生物科技公司 Treatment of ophthalmic conditions such as macular degeneration, glaucoma, and diabetic retinopathy with agents that eliminate aging cells

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Publication number Priority date Publication date Assignee Title
CN103562202A (en) * 2011-01-25 2014-02-05 密执安大学评议会 BCL-2/BCL-XL inhibitors and therapeutic methods using the same
CN110302205A (en) * 2013-01-16 2019-10-08 密歇根大学董事会 The medical usage and its pharmaceutical composition of BCL-2/Bcl-xL inhibitor
CN109152933A (en) * 2016-04-21 2019-01-04 生物风险投资有限责任公司 Induce the compound of degradation and application thereof of anti-apoptotic BCL-2 family protein
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