WO2024051741A1 - Composé pour inhiber bcl-2 ou bcl-xl et son utilisation en médecine - Google Patents

Composé pour inhiber bcl-2 ou bcl-xl et son utilisation en médecine 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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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/fr

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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 or sparfloxacin
    • 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.

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Abstract

La présente invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, une substance deutérée, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un co-cristal, et un intermédiaire de celui-ci, son procédé de préparation, et son utilisation dans la préparation d'un médicament pour le traitement de maladies associées à l'activité ou à la quantité d'expression de Bcl-2 ou Bcl-xL.
PCT/CN2023/117251 2022-09-06 2023-09-06 Composé pour inhiber bcl-2 ou bcl-xl et son utilisation en médecine WO2024051741A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103562202A (zh) * 2011-01-25 2014-02-05 密执安大学评议会 Bcl-2/bcl-xl抑制剂和使用它们的治疗方法
CN109152933A (zh) * 2016-04-21 2019-01-04 生物风险投资有限责任公司 诱导抗细胞凋亡bcl-2家族蛋白的降解的化合物及其用途
WO2019033122A1 (fr) * 2017-08-11 2019-02-14 Unity Biotechnology, Inc. Traitement de maladies pulmonaires à l'aide d'agents pharmaceutiques qui éliminent des cellules sénescentes
CN110302205A (zh) * 2013-01-16 2019-10-08 密歇根大学董事会 BCL-2/Bcl-xL抑制剂的医药用途及其药物组合物
CN111372598A (zh) * 2017-08-11 2020-07-03 联合生物科技公司 使用消除衰老细胞的药剂治疗诸如黄斑变性,青光眼,和糖尿病性视网膜病变等眼科状况

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103562202A (zh) * 2011-01-25 2014-02-05 密执安大学评议会 Bcl-2/bcl-xl抑制剂和使用它们的治疗方法
CN110302205A (zh) * 2013-01-16 2019-10-08 密歇根大学董事会 BCL-2/Bcl-xL抑制剂的医药用途及其药物组合物
CN109152933A (zh) * 2016-04-21 2019-01-04 生物风险投资有限责任公司 诱导抗细胞凋亡bcl-2家族蛋白的降解的化合物及其用途
WO2019033122A1 (fr) * 2017-08-11 2019-02-14 Unity Biotechnology, Inc. Traitement de maladies pulmonaires à l'aide d'agents pharmaceutiques qui éliminent des cellules sénescentes
CN111372598A (zh) * 2017-08-11 2020-07-03 联合生物科技公司 使用消除衰老细胞的药剂治疗诸如黄斑变性,青光眼,和糖尿病性视网膜病变等眼科状况

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