WO2025055868A1 - Composé pour inhiber l'interaction protéine-protéine de cdk4/6 et de la cycline d - Google Patents

Composé pour inhiber l'interaction protéine-protéine de cdk4/6 et de la cycline d Download PDF

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WO2025055868A1
WO2025055868A1 PCT/CN2024/117829 CN2024117829W WO2025055868A1 WO 2025055868 A1 WO2025055868 A1 WO 2025055868A1 CN 2024117829 W CN2024117829 W CN 2024117829W WO 2025055868 A1 WO2025055868 A1 WO 2025055868A1
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formula
compound
membered
independently
substituted
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Chinese (zh)
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张肖男
何径舟
方晓敏
张善卓
黄越阳
王紫壹
居斌
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Hangzhou Acin Biotechnology Co Ltd
Sanomics Ai Co Ltd
Beijing Baidu Netcom Science and Technology Co Ltd
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Hangzhou Acin Biotechnology Co Ltd
Sanomics Ai Co Ltd
Beijing Baidu Netcom Science and Technology Co Ltd
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Priority to CN202480005168.3A priority Critical patent/CN120418255A/zh
Publication of WO2025055868A1 publication Critical patent/WO2025055868A1/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
    • 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
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine 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
    • C07D403/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present application relates to novel compounds, pharmaceutical compositions comprising the compounds of the present application, a combination, use of the compounds of the present application in the preparation of drugs for diseases that benefit or can be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D, and methods for treating diseases by using the compounds of the present application.
  • CDK4/6 Cyclin-dependent kinase 4/6
  • CCND cyclin D
  • Rb retinoblastoma protein
  • CDK4/6-CCND-Rb pathway is abnormally active in many tumor cells such as breast cancer, renal cancer, pancreatic cancer, liver cancer, brain tumors, and hematological tumors. Therefore, CDK4/6 is one of the ideal targets for the treatment of various tumors.
  • CDK4/6 inhibitors target the ATP (adenosine triphosphate) catalytic pocket of CDK4/6, such as Palbociclib, Rbociclib and Abemaciclib, etc. These drugs all have varying degrees of drug resistance and clinical side effects. Therefore, it is urgent to find new compounds that target the CDK4/6-CCND-Rb pathway.
  • ATP adenosine triphosphate
  • the present application provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or (VI), or an enantiomer, diastereomer, racemate, solvate, isotope derivative or pharmaceutically acceptable salt thereof,
  • Ar 1 , Ar 3 , Ar 4 and Ar 7 are each independently an unsubstituted or substituted 5-6-membered aryl or 3-8-membered heteroaryl;
  • Ar 2 , Ar 6 and U 2 are each independently an 8-10 membered bicyclic heterocycle
  • the R 1 is each independently hydrogen or C 0-3 alkylhydroxyl
  • the R 2 are each independently hydrogen or C 1-6 alkyl
  • R 3 is hydrogen, C 2-6 alkenyl or C 2-6 alkynyl
  • R 4 is unsubstituted or substituted C 3-8 cycloalkyl
  • Said X1 is N or C
  • the U 1 is -X 2 -(CH 2 ) n -C(O)-M 1 ;
  • the X 2 and X 3 are each independently S or O;
  • the M 1 is -N(R 5 )(R 6 );
  • the U4 is The R7 and R8 together with the connected C form a 3-6 membered saturated ring, wherein the 3-6 membered saturated ring contains one or more heteroatoms selected from N, O or S;
  • n 1 or 2.
  • the compounds of the present application inhibit the formation of the CDK4/6-CCND complex by inhibiting the protein-protein interaction between CDK4 and CCND and/or the protein-protein interaction between CDK6 and CCND, thereby inhibiting the activity of CDK4/6, thereby inhibiting the CDK4/6-CCND-Rb pathway, and the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) have good anti-cancer activity.
  • the mechanism of action of the compounds of the present application is different from that of the CDK4/6 inhibitors that have been marketed, and has reduced drug resistance and clinical side effects.
  • the present application provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI), or an enantiomer, diastereomer, racemate, solvate, isotope derivative or pharmaceutically acceptable salt thereof, for use in the preparation of a drug for a disease that benefits or can be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D.
  • the present application provides a pharmaceutical composition, which comprises a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) as described in the present application, or an enantiomer, diastereomer, racemate, solvate, isotope derivative or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the present application provides a combination comprising a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) as described herein, or an enantiomer, diastereomer, racemate, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.
  • the present application provides a method for treating a disease that benefits or can be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D, the method comprising administering to a subject in need of such treatment a therapeutically effective dose of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) as described herein, or an enantiomer, diastereomer, racemate, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, or the aforementioned combination.
  • Figure 1 shows the fluorescence signal diagram of protein-protein interaction between CDK4/6 and CCND1 in Example 1. Specifically, VN155-CDK4+VC155-CCND1, VN155-CDK6+VC155-CCND1 and their control Fluorescence signal diagram of VN155-CDK4+VC155-mCherry and VN155-CDK6+VC155-mCherry, where the green signal represents the interaction between the corresponding proteins.
  • FIG2 is a bar graph showing the protein-protein interaction between CDK4/6 and CCND1 blocked by Compounds 1 to 6 in Example 1.
  • CDK4/6 inhibitors Most of the targets of the CDK4/6 inhibitors currently on the market target the ATP catalytic pocket of CDK4/6, such as Palbociclib, Rbociclib and Abemaciclib, etc. These drugs have shown varying degrees of drug resistance and clinical side effects.
  • the compounds of the present application can inhibit the activity of CDK4/6 by inhibiting the formation of the CDK4/6-CCND complex, thereby inhibiting the CDK4/6-CCND-Rb pathway and having good anti-cancer activity.
  • the mechanism of action of the compounds of the present application is different from that of the CDK4/6 inhibitors that have been on the market, and drug resistance and clinical side effects are reduced to varying degrees.
  • the present application provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI), or an enantiomer, diastereomer, racemate, solvate, isotopic derivative or pharmaceutically acceptable salt thereof,
  • Ar 1 , Ar 3 , Ar 4 and Ar 7 are each independently an unsubstituted or substituted 5-6-membered aryl or 3-8-membered heteroaryl;
  • Ar 2 , Ar 6 and U 2 are each independently an 8-10 membered bicyclic heterocycle
  • the U 3 is -N(Ar 5 ) 2
  • the Ar 5 are each independently an unsubstituted or substituted 5-6-membered aryl or 3-8-membered heteroaryl;
  • the R 1 is each independently hydrogen or C 0-3 alkylhydroxyl
  • the R 2 are each independently hydrogen or C 1-6 alkyl
  • R 3 is hydrogen, C 2-6 alkenyl or C 2-6 alkynyl
  • R 4 is unsubstituted or substituted C 3-8 cycloalkyl
  • Said X1 is N or C
  • the U 1 is -X 2 -(CH 2 ) n -C(O)-M 1 ;
  • the X 2 and X 3 are each independently S or O;
  • the M 1 is -N(R 5 )(R 6 );
  • the U4 is The R7 and R8 together with the connected C form a 3-6 membered saturated ring, wherein the 3-6 membered saturated ring contains one or more heteroatoms selected from N, O or S;
  • the R9 and R10 together with the connected C form a 5-6 membered aryl or 5-6 membered heteroaryl;
  • n and t are each independently 1, 2 or 3;
  • n 1 or 2.
  • the term “plurality” or “multiplicity” refers to two or two, as well as more than two or two.
  • aryl refers to a hydrocarbon group containing one or more aromatic rings, for example, the aryl group is a monocyclic, bicyclic or tricyclic aromatic group having 6 to 20 carbon atoms.
  • 5-6 membered aryl refers to a monocyclic aryl group having 5-6 carbon atoms.
  • Examples of 5-6 membered aryl groups include, but are not limited to, phenyl.
  • heteroaryl refers to an aromatic monocyclic or fused ring group containing one or more ring heteroatoms independently selected from N, O and S.
  • the heteroaryl group can be bonded via a carbon atom or a heteroatom.
  • the heteroaryl can be an aromatic monocyclic or fused ring group containing 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the terms "3-8 yuan heteroaryl” and “5-6 yuan heteroaryl” should be interpreted accordingly, specifically referring to a heteroaryl with 3-8 ring atoms and a heteroaryl with 5-6 ring atoms.
  • heteroaryl includes but is not limited to furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl.
  • bicyclic heterocycle refers to a bicyclic group with unsaturated groups containing one or more ring heteroatoms independently selected from N, O and S.
  • 8-10 membered bicyclic heterocycle should be interpreted accordingly.
  • Embodiments of 8-10 membered bicyclic heterocycles include, but are not limited to, 5-membered ring fused 5-membered rings, 5-membered ring fused 6-membered rings or 6-membered ring fused 6-membered rings.
  • the fused 5-membered ring or 6-membered ring is independently an aromatic monocycle containing ring heteroatoms, an aromatic monocycle not containing ring heteroatoms, a non-aromatic monocycle containing ring heteroatoms or a non-aromatic monocycle not containing ring heteroatoms.
  • C 1-6 alkyl refers to a straight or branched saturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having one to six carbon atoms, and connected to the rest of the molecule by a single bond.
  • the terms “C 1-5 alkyl”, “C 1-4 alkyl”, “C 1-3 alkyl”, “C 1-2 alkyl” should be interpreted accordingly.
  • Examples of C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, or 1,1-dimethylethyl (tert-butyl).
  • C 0-3 alkylhydroxyl refers to a C 1-3 alkyl group as defined above in which one of the hydrogen atoms is replaced by -OH, or -OH when C is 0.
  • Examples of C 0-3 alkylhydroxyl include, but are not limited to, hydroxyl, hydroxymethyl, 2-hydroxyethyl, eth-1-ol, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like.
  • C 2-6 alkenyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having two to six carbon atoms, and connected to the rest of the molecule by a single bond.
  • the terms “C 2-5 alkenyl”, “C 2-4 alkenyl”, “C 2-3 alkenyl” should be interpreted accordingly.
  • Examples of C 2-6 alkenyl include, but are not limited to, vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-4-enyl, and pent-1,4-dienyl.
  • C 2-6 alkynyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having two to six carbon atoms, and connected to the remainder of the molecule by a single bond.
  • the terms "C 2-5 alkynyl”, “C 2-4 alkynyl”, “C 2-3 alkynyl” should be interpreted accordingly.
  • Examples of C 2-6 alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and pent-1,4-diynyl.
  • cycloalkyl refers to a monocyclic or bicyclic saturated hydrocarbon group consisting only of carbon and hydrogen atoms and connected to the rest of the molecule by a single bond.
  • C 3-8 cycloalkyl should be interpreted accordingly and may specifically refer to a cycloalkyl group having 3-8 carbon atoms. Examples of C 3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • unsubstituted or substituted means that the group or ring may be unsubstituted, or the group or ring may be substituted with one or more substituents as defined herein.
  • halogen refers to bromine, chlorine, fluorine or iodine.
  • saturated ring refers to a ring in which all the ring bonds involved in the ring formation are saturated bonds.
  • 5-6 membered saturated ring refers to a saturated ring having 5-6 carbon atoms
  • 3-6 membered saturated ring, the 3-6 membered saturated ring containing one or more heteroatoms of N, O or S refers to a 3, 4, 5 or 6 membered saturated carbon ring and one or more carbon atom ring members can be independently replaced by a heteroatom selected from N, O or S.
  • fused refers to two ring elements that are connected by sharing two ring atoms.
  • Ar 1 is phenyl substituted with a C 1-6 alkyl group.
  • Ar 3 is a 5-6 membered heteroaryl substituted by halogen.
  • Ar 4 is phenyl substituted by halogen.
  • Ar 5 and Ar 7 are each independently phenyl or a 5-6-membered heteroaryl.
  • the Ar 2 is an 8-membered bicyclic heterocycle.
  • the 8-membered bicyclic heterocycle contains one or more N atoms.
  • the Ar 6 is a 9-membered bicyclic heterocycle.
  • the 9-membered bicyclic heterocycle contains one or more N atoms.
  • the U 2 is a 9-membered bicyclic heterocycle.
  • the 9-membered bicyclic heterocycle contains one or more N atoms.
  • the R 1 is each independently C 0-3 alkylhydroxyl.
  • the R 2 are each independently C 1-3 alkyl.
  • said R 3 is C 2-6 alkynyl.
  • said R 4 is unsubstituted C 3-8 cycloalkyl.
  • X1 is N.
  • X2 is S and X3 is O.
  • said R 5 and R 6 together with the N to which they are attached form a 10-membered bicyclic heterocyclic ring.
  • the R 7 and R 8 together with the attached C form a 5-membered saturated ring.
  • the 5-membered saturated ring contains one or more O atoms.
  • the R 9 and R 10 together with the attached C form a phenyl group or a 6-membered heteroaryl group.
  • the R 11 and R 12 together with the attached N and C form a 5-membered saturated ring.
  • the compound of formula (I) is in,
  • Ar 1 is an unsubstituted or substituted 5-6-membered aryl or 3-8-membered heteroaryl;
  • Ar 2 is an 8-10-membered bicyclic heterocycle.
  • Ar 2 is an 8-membered bicyclic heterocycle, a 9-membered bicyclic heterocycle, or a 10-membered bicyclic heterocycle.
  • Ar 2 is an 8-membered bicyclic heterocycle, and the 8-membered bicyclic heterocycle contains one or more N atoms.
  • Ar 2 is a 5-membered ring fused to a 5-membered ring. In some embodiments, Ar 2 is a 5-membered unsaturated heterocyclic ring fused to a 5-membered saturated carbocyclic ring. In some embodiments, Ar 2 is a 5-membered unsaturated heterocyclic ring fused to a 5-membered saturated carbocyclic ring, and Ar 2 contains two N atoms.
  • Ar 2 is or In some embodiments, in the compound of formula (I), Ar 2 is
  • the compound of formula (I) has the structure of formula (I-1):
  • Ar 1 is an unsubstituted or substituted 5-6-membered aryl group or 3-8-membered heteroaryl group.
  • Ar 1 is unsubstituted phenyl or phenyl substituted by C 1-6 alkyl. In some embodiments, in the compounds of formula (I) or (I-1), Ar 1 is phenyl substituted by C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl , C 1-2 alkyl or methyl.
  • Ar 1 is a phenyl substituted with a methyl group. In some embodiments, Ar 1 is a phenyl substituted with 1, 2, 3, 4 or 5 methyl groups. In some embodiments, the methyl substitution may be ortho-, meta- or para-substituted relative to the connecting bond.
  • the compound of formula (I) or formula (I-1) is selected from
  • the compound of formula (II) is:
  • each of the R 1 is independently a C 0-3 alkyl hydroxyl group. In some embodiments, in the compound of formula (II), each of the R 1 is independently a hydroxyl group, a hydroxymethyl group, a 2-hydroxy In some embodiments, in the compound of formula (II), R 1 is hydroxyl.
  • each of the R 2 is independently a C 1-6 alkyl. In some embodiments, in the compound of formula (II), each of the R 2 is independently a C 1-5 alkyl, a C 1-4 alkyl, a C 1-3 alkyl, a C 1-2 alkyl or a methyl.
  • R 3 is C 2-6 alkenyl. In some embodiments, in the compound of formula (II), R 3 is C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 alkenyl or vinyl.
  • R 3 is C 2-6 alkynyl. In some embodiments, in the compound of formula (II), R 3 is C 2-5 alkynyl, C 2-4 alkynyl, C 2-3 alkynyl or ethynyl.
  • the R 1 is hydroxyl; the R 2 is methyl; and the R 3 is ethynyl.
  • the compound of formula (II) is selected from:
  • the compound of formula (III) is:
  • Ar 3 is an unsubstituted or substituted 5-6-membered aryl or 3-8-membered heteroaryl
  • R 2 is independently hydrogen or C 1-6 alkyl
  • R 4 is an unsubstituted or substituted C 3-8 cycloalkyl
  • X 1 is N or C.
  • Ar 3 is an unsubstituted 5-6 membered heteroaryl or a substituted 5-6 membered heteroaryl. In some embodiments, in the compound of formula (III), Ar 3 is a substituted 5-6 membered heteroaryl. In some embodiments, in the compound of formula (III), Ar 3 is a 5-6 membered heteroaryl substituted by halogen. In some embodiments, in the compound of formula (III), Ar 3 is a pyridyl, pyrazolyl, imidazolyl, pyrrolyl, pyridazinyl, pyrimidinyl or pyrazinyl substituted by halogen. In some embodiments, in the compound of formula (III), Ar 3 is a pyridyl substituted by halogen.
  • Ar 3 is In some embodiments, in the compound of formula (III), Ar 3 is
  • each of the R2 is independently C1-6 alkyl. In some embodiments, in the compound of formula (III), each of the R2 is independently C1-5 alkyl, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl or methyl. In some embodiments, in the compound of formula (III), each of the R2 is methyl.
  • X 1 is N.
  • the compound of formula (III) has the structure of formula (III-1):
  • said R 4 is unsubstituted or substituted C 3-8 cycloalkyl.
  • the R 4 is an unsubstituted C 3-8 cycloalkyl or a C 3-8 cycloalkyl substituted by a C 1-6 alkyl. In some embodiments, in the compound of formula (III), the R 4 is an unsubstituted C 3-8 cycloalkyl. In some embodiments, in the compound of formula (III), the R 4 is a cyclopropyl.
  • Ar 3 is The R2 is methyl; the R4 is cyclopropyl; and the X1 is N.
  • the compound of formula (III) is selected from:
  • the compound of formula (IV) is:
  • Ar 4 is an unsubstituted or substituted 5-6 membered aryl or 3-8 membered heteroaryl;
  • U 1 is -X 2 -(CH 2 ) n -C(O)-M 1 ;
  • M 1 is -N(R 5 )(R 6 ), R 5 and R 6 together with the N to which they are connected form an 8-10 membered bicyclic heterocycle;
  • R 2 is hydrogen or C 1-6 alkyl;
  • X 2 and X 3 are each independently S or O; and n is 1, 2 or 3.
  • Ar 4 is unsubstituted phenyl or substituted phenyl. In some embodiments, in the compound of formula (IV), Ar 4 is phenyl substituted by halogen or C 1-6 alkyl.
  • Ar 4 is phenyl substituted by halogen.
  • the halogen is F.
  • the F substitution can be ortho-, meta- or para- substitution relative to the connecting bond.
  • the R 5 and R 6 form an 8, 9 or 10-membered bicyclic heterocycle together with the N to which they are attached. In some embodiments, in the compound of formula (IV), the R 5 and R 6 form a 10-membered bicyclic heterocycle together with the N to which they are attached. In some embodiments, in the compound of formula (IV), the R 5 and R 6 form a 6-membered ring fused 6-membered ring together with the N to which they are attached. In some embodiments, the R 5 and R 6 form a 6-membered aromatic ring fused 6-membered saturated heterocycle together with the N to which they are attached.
  • the R 5 and R 6 form a phenyl-fused hexahydropyridyl, a phenyl-fused hexahydropyridazinyl, a phenyl-fused hexahydropyrimidinyl or a phenyl-fused hexahydropyrazinyl together with the N to which they are attached.
  • each of the R2 is independently C1-6 alkyl. In some embodiments, in the compound of formula (III), each of the R2 is independently C1-5 alkyl, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl or methyl. In some embodiments, in the compound of formula (III), each of the R2 is methyl.
  • n 1
  • R 2 is methyl; n is 1.
  • said X2 is S, and said X3 is O.
  • Ar 4 is phenyl substituted by halogen; R 5 and R 6 together with the attached N form a phenyl-fused hexahydropyridinyl; R 2 is methyl; n is 1; X 2 is S; and X 3 is O.
  • the compound of formula (IV) is selected from:
  • the compound of formula (V) is:
  • Ar 6 and U 2 are each independently an 8-10 membered bicyclic heterocyclic ring; U 3 is -N(Ar 5 ) 2 , and Ar 5 is each independently an unsubstituted or substituted 5-6 membered aryl or 3-8 membered heteroaryl.
  • Ar 6 is an 8-, 9- or 10-membered bicyclic heterocycle. In some embodiments, in the compound of formula (V), Ar 6 is a 9-membered bicyclic heterocycle, and the 9-membered bicyclic heterocycle contains one or more N atoms. In some embodiments, in the compound of formula (V), Ar 6 is a 6-membered ring fused to a 5-membered ring, and the 6-membered ring fused to the 5-membered ring contains 1, 2, 3 or 4 nitrogen atoms.
  • Ar 6 is a 6-membered aromatic ring fused to a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring contains 1, 2, 3 or 4 nitrogen atoms.
  • Ar 6 is a phenyl-fused imidazolyl, a phenyl-fused pyrazolyl, a phenyl-fused pyrrolyl, a phenyl-fused triazolyl or a phenyl-fused tetrazolyl.
  • Ar 6 is a phenyl-fused triazolyl, optionally, Ar 6 is In some embodiments, Ar 6 can also be
  • the compound of formula (V) has the structure of formula (V-1);
  • U 2 is an 8-10 membered bicyclic heterocyclic ring
  • U 3 is -N(Ar 5 ) 2
  • Ar 5 is each independently an unsubstituted or substituted 5-6 membered aryl or 3-8 membered heteroaryl.
  • the Ar 5 is each independently unsubstituted phenyl or 5-6 membered heteroaryl, or substituted phenyl or 5-6 membered heteroaryl. In some embodiments, the Ar 5 is each independently unsubstituted phenyl, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl. In some embodiments, the Ar 5 is phenyl.
  • U 2 is an 8-, 9- or 10-membered bicyclic heterocycle. In some embodiments, in the compound of formula (V), U 2 is a 9-membered bicyclic heterocycle, and the 9-membered bicyclic heterocycle contains one or more N atoms. In some embodiments, in the compound of formula (V), U 2 is a 6-membered ring fused to a 5-membered ring, and the 6-membered ring fused to the 5-membered ring contains 1, 2, 3 or 4 nitrogen atoms.
  • U 2 is a 6-membered aromatic ring fused to a 5-membered heteroaromatic ring, and the 5-membered heteroaromatic ring contains 1, 2, 3 or 4 nitrogen atoms.
  • U 2 is a phenyl-fused imidazolyl, a phenyl-fused pyrazolyl, a phenyl-fused pyrrolyl, a phenyl-fused triazolyl or a phenyl-fused tetrazolyl.
  • U 2 is a phenyl-fused triazolyl, optionally, U 2 is In some embodiments, U2 can also be
  • the compound of formula (V) is selected from:
  • the compound of formula (VI) is:
  • Ar 7 is an unsubstituted or substituted 5-6 membered aryl or 3-8 membered heteroaryl
  • the U4 is The R7 and R8 together with the connected C form a 3-6 membered saturated ring, wherein the 3-6 membered saturated ring contains one or more heteroatoms selected from N, O or S;
  • the R9 and R10 together with the connected C form a 5-6 membered aryl or 5-6 membered heteroaryl;
  • t is 1, 2, or 3;
  • n 1 or 2.
  • Ar 7 is unsubstituted or substituted 5-6 membered aryl or 3-8 membered heteroaryl. In some embodiments, in the compound of formula (VI), Ar 7 is phenyl or 5-6 membered heteroaryl. In some embodiments, in the compound of formula (VI), Ar 7 is phenyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl.
  • t is 1, 2 or 3.
  • Ar 7 is phenyl; and t is 1.
  • the R 9 and R 10 together with the attached C form a 5-6 membered aryl or 5-6 membered heteroaryl. In some embodiments, in the compound of formula (VI), the R 9 and R 10 together with the attached C form a phenyl or 5-6 membered heteroaryl.
  • the R 9 and R 10 together with the attached C form a phenyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl.
  • the R 11 and R 12 together with the N and C to which they are attached form a 5-6 membered saturated ring. In some embodiments, in the compound of formula (VI), the R 11 and R 12 together with the N and C to which they are attached form a 5-membered saturated ring. In some embodiments, in the compound of formula (VI), the 5-membered saturated ring comprises 1 N atom, and optionally further comprises 1, 2 or 3 heteroatoms selected from N, O or S.
  • the R 9 and R 10 together with the attached C form a phenyl group; the R 11 and R 12 together with the attached N and C form a 5-membered saturated ring.
  • the compound of formula (VI) has the structure of formula (VI-1);
  • the U 4 is The R7 and R8 together with the connected C form a 3-6 membered saturated ring, the 3-6 membered saturated ring contains one or more heteroatoms selected from N, O or S, and m is 1 or 2.
  • R 7 and R 8 together with the C to which they are attached form a 3-6 membered saturated ring, and the 3-6 membered saturated ring contains one or more heteroatoms selected from N, O or S.
  • R 7 and R 8 together with the C to which they are attached form a 5-membered saturated ring, and the 5-membered saturated ring contains one or more heteroatoms selected from N, O or S.
  • R 7 and R 8 together with the C to which they are attached form a 5-membered saturated ring, and the 5-membered saturated ring contains one or more O atoms.
  • R 7 and R 8 together with the C to which they are attached form a 5-membered saturated ring, and the 5-membered saturated ring contains 1, 2, 3 or 4 O atoms.
  • R 7 and R 8 together with the C to which they are attached form a 5-membered saturated ring, and the 5-membered saturated ring contains 2 O atoms, optionally, the 5-membered saturated ring is selected from In some embodiments, the 5-membered saturated ring can also be selected from
  • m 1
  • the compound of formula (VI) is selected from
  • the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V) or (VI) of the present application may be in one of the following forms: possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, solvates, isotopic derivatives or pharmaceutically acceptable salts.
  • possible stereoisomers rotamers, atropisomers, tautomers or mixtures thereof, solvates, isotopic derivatives or pharmaceutically acceptable salts.
  • geometric (cis or trans) stereoisomers diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.
  • solvate refers to the association of one or more solvent molecules with the compound of the present application or its salt.
  • Solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, ethyl acetate or acetic acid, etc.
  • isotopic derivative refers to a structure depicted by a chemical formula given herein, in which one or more atoms are replaced by isotopic atoms having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the compounds of the present application include, for example, isotopes of hydrogen.
  • incorporation of certain isotopes, particularly deuterium (i.e., 2 H or D) can provide certain therapeutic advantages by providing higher metabolic stability, such as increasing half-life in vivo or reducing dosage requirements or improving therapeutic index or tolerability.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, chlorine, fluorine or iodine, such as 3 H, 11 C, 13 C, 14 C, 15 N , 18 F, 35 S, 36 Cl, 123 I, 124 I or 125 I , etc.
  • the present application includes compounds incorporated with one or more of the above isotopes, for example, including the incorporation of radioactive isotopes 3 H and/or 14 C, or also including the incorporation of non-radioactive isotopes 2 H and/or 13 C.
  • the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) of the present application may exist in a free form or in the form of a salt thereof.
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the compounds described herein and exhibits lower undesirable toxicological effects.
  • pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compounds in free acid or free base form with a suitable base or acid, respectively.
  • pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, etc.
  • the organic acid includes acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid or sulfosalicylic acid, etc.
  • pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.
  • the inorganic bases include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the organic bases include, for example, primary amines, secondary amines, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc.
  • the organic bases include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine, etc.
  • the present application provides a pharmaceutical composition, comprising a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) as described in the first aspect of the present application, or an enantiomer, diastereomer, racemate, solvate, isotope derivative or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the term "pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable raw material, component or carrier that imparts form or consistency to the pharmaceutical composition. When mixed, each carrier is compatible with the other ingredients of the pharmaceutical composition, thereby avoiding significantly reducing the efficacy of the compound of the present application when administered to a subject and avoiding interactions of drug ingredients that would result in pharmaceutically unacceptable.
  • the pharmaceutically acceptable carrier includes, but is not limited to, a diluent, a filler, a binder, a disintegrant, a lubricant, a glidant, a granulating agent, a coating agent, a wetting agent, a solvent, a co-solvent, a suspending agent, Emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants or buffers, etc.
  • a diluent a filler, a binder, a disintegrant, a lubricant, a glidant, a granulating agent, a coating agent, a wetting agent, a solvent, a co-solvent, a suspending agent, Emulsifiers, sweeteners, flavoring agents, taste masking agents, color
  • the compound of the present application and one or more of the pharmaceutically acceptable carriers are formulated into a dosage form suitable for administration to a subject via a desired route of administration.
  • the dosage form of the pharmaceutical composition includes but is not limited to tablets, capsules, caplets, pills, lozenges, powders, syrups, brews, suspensions, solutions, emulsions, transdermal patches, suppositories, inhalants, creams, ointments, lotions, pastes, sprays, injections or gels, etc.
  • the present application provides a combination, which comprises a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) described in the first aspect of the present application, or an enantiomer, diastereomer, racemate, solvate, isotope derivative or pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.
  • the therapeutically active agent includes, but is not limited to, other anticancer agents, antiallergic agents, antiemetics, or analgesics, etc.
  • other anticancer agents used with the compounds of the present invention can be selected based on the disease or condition being treated.
  • the other anticancer agents may include but are not limited to trastuzumab, pertuzumab, lapatinib, tamoxifen, everolimus, paclitaxel or sipatinib;
  • the other anticancer agents may include but are not limited to bleomycin, cisplatin or topotecan, etc.;
  • the other anticancer agents may include but are not limited to sorafenib, lenvatinib mesylate, fluorouracil or oxaliplatin, etc.;
  • the other anticancer agents may include but are not limited to flutamide, goserelin, docetaxel, cabazitaxel, mitoxantrone or estradiol nitrogen mustard, etc.; for the treatment of prostate cancer, the other anticancer agents may include but are not limited to flutamide, goserelin, do
  • the compounds of the present application can be used in combination with antiallergic agents.
  • the antiallergic agents include but are not limited to dexamethasone, beclomethasone, hydrocortisone, prednisone, prednisolone, diphenhydramine, cyproheptadine, salbutamol or terbutaline, etc.
  • the compound of the present application can be used in combination with an antiemetic for possible vomiting.
  • the antiemetic includes but is not limited to aprepitant, ondansetron, granisetron, lorazepam, dexamethasone, prochlorperazine or casopitant, etc.
  • the compound of the present application in order to relieve the pain of the subject, can be used in combination with an analgesic.
  • the analgesic includes but is not limited to morphine, oxycodone, fentanyl or oxymorphone hydrochloride, etc.
  • the present application provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) as described in the first aspect of the present application, or an enantiomer, diastereomer, racemate, solvate, isotope derivative or pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for a disease that benefits or can be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D.
  • disease refers to any change in the state of the body or some organs that interrupts or interferes with the performance of functions and/or causes symptoms (such as discomfort, dysfunction, adverse stress or even death) in the person suffering from the disease or those who come into contact with it.
  • treat refers to alleviating or ameliorating a disease or disorder (i.e., slowing or arresting the development of the disease or at least one clinical symptom); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder.
  • Cyclin D is an important member of the cyclin family that regulates the transition from the G1-S phase. Cyclin D has three subtypes, namely, cyclin D1 (CCND1), cyclin D2 (CCND2), and cyclin D3 (CCND3), and the three subtypes have similar expression results.
  • the compounds of formula (I), (II), (III), (IV), (V) or (VI) provided herein have an inhibitory activity IC50 of no more than 1000 ⁇ M, 800 ⁇ M, 600 ⁇ M, 500 ⁇ M, 400 ⁇ M, 300 ⁇ M, 200 ⁇ M, 100 ⁇ M, or 50 ⁇ M against CDK4/6 kinase.
  • the disease that can be treated or benefited by inhibiting the protein-protein interaction between CDK4/6 and cyclin D includes cancer.
  • the disease that can be treated or benefited by inhibiting the protein-protein interaction between CDK4/6 and cyclin D includes cancer.
  • the disease that benefits from or can be treated by protein-protein interaction of D is selected from breast cancer, glioma, liver cancer, prostate cancer, cervical cancer, lung cancer, leukemia, gastric cancer, ovarian cancer or colon cancer.
  • the compounds of formula (I), (II), (III), (IV), (V) or (VI) provided herein have a toxicity IC50 of no more than 1000 ⁇ M, 800 ⁇ M, 600 ⁇ M, 500 ⁇ M, 400 ⁇ M, 300 ⁇ M, 200 ⁇ M, 100 ⁇ M, or 50 ⁇ M to human breast cancer cells MCF-7.
  • the compounds of formula (I), (II), (III), (IV), (V) or (VI) provided herein have a toxicity IC50 of no more than 1000 ⁇ M, 800 ⁇ M, 600 ⁇ M, 500 ⁇ M, 400 ⁇ M, 300 ⁇ M, 200 ⁇ M, 100 ⁇ M, or 50 ⁇ M to human breast cancer cells HCC1937.
  • the toxicity IC50 of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) provided herein to cervical cancer cells HeLa is no more than 1000 ⁇ M, 800 ⁇ M, 600 ⁇ M, 500 ⁇ M, 400 ⁇ M, 300 ⁇ M, 200 ⁇ M, 100 ⁇ M, or 50 ⁇ M.
  • the disease that can benefit from or be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D includes breast cancer and/or cervical cancer.
  • the present application provides a method for treating a disease that benefits or can be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D, the method comprising administering to a subject in need of such treatment a therapeutically effective dose of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) as described in the first aspect of the present application, or an enantiomer, diastereomer, racemate, solvate, isotope derivative or pharmaceutically acceptable salt thereof.
  • the term "subject” refers to primates (e.g., humans), dogs, rabbits, guinea pigs, pigs, rats, and mice.
  • the subject is a primate.
  • the subject is a human.
  • a subject is "in need of” a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.
  • the term "therapeutically effective dose” refers to an amount that results in benefit or treatment of a disease compared to a corresponding subject not receiving the amount, but the amount is sufficiently low within the scope of reasonable medical judgment to avoid serious side effects.
  • the therapeutically effective dose of a compound will vary with the specific compound selected (e.g., taking into account the potency, efficacy and half-life of the compound); the route of administration selected; the disease to be treated; the severity of the disease to be treated; the age, size, weight and physical condition of the patient to be treated: the medical history of the patient to be treated; the duration of treatment; the nature of concurrent treatment; the desired therapeutic effect and other factors, but can still be determined by a person skilled in the art in a routine manner.
  • the disease that benefits or can be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D includes cancer.
  • the disease that benefits or can be treated by inhibiting the protein-protein interaction between CDK4/6 and cyclin D is selected from breast cancer, glioma, liver cancer, prostate cancer, cervical cancer, lung cancer, leukemia, gastric cancer, ovarian cancer or colon cancer.
  • Compound 1 purchased from Shanghai Taoshu Biotechnology Co., Ltd.
  • Compound 2 purchased from Shanghai Taoshu Biotechnology Co., Ltd.
  • Compound 3 purchased from Shanghai Taoshu Biotechnology Co., Ltd.
  • Compound 4 purchased from Shanghai Taoshu Biotechnology Co., Ltd.
  • Compound 5 purchased from Shanghai Taoshu Biotechnology Co., Ltd.
  • Compound 6 was purchased from Shanghai Taoshu Biotechnology Co., Ltd.
  • Example 1 Inhibition of protein-protein interaction between CDK4/6 and CCND
  • the protein-protein interaction experiment of inhibiting CDK4/6 and CCND was carried out based on bimolecular fluorescence complementation (BiFC) technology. The specific steps are as follows:
  • VN155-CDK4, VN155-CDK6 and VC155-CCND1 vectors were constructed and confirmed by sequencing.
  • HEK293T cells from Zhejiang University Laboratory plated in 24-well plates were co-transfected with VN155-CDK4+VC155-CCND1 and VN155-CDK6+VC155-CCND1 as well as the negative control plasmid VC155-mCherry (0.3 ⁇ g of each plasmid per well), and the fluorescence intensity of intracellular protein-protein interactions was detected by fluorescence microscopy (Olympus, IX73) after incubation for 18 hours.
  • HEK293T cells were plated in a 96-well plate, and 12 hours later, the cells were co-transfected with VN155-CDK4+VC155-CCND1 and VN155-CDK6+VC155-CCND1 (50 ng/well for each plasmid).
  • the compound of the present application was added at a final concentration of 10 ⁇ M, and the cells were cultured in a 37°C cell culture incubator for 18 hours.
  • the fluorescence signal representing the intracellular protein-protein interaction was detected by fluorescence microscopy (Olympus, IX73) (detection channel: FITC), and the fluorescence intensity of the cells was quantitatively measured using a high-content system (MD, IXM-C).
  • the co-transfected mCherry signal intensity was used as a reference signal to normalize the protein-protein interaction signal.
  • compounds 1 to 5 can block the interaction of CDK4/CCND1, and compounds 4-6 can block the interaction of CDK6/CCND1.
  • CDK4-CCND1-RB1CT (RB1 protein C-terminus, containing S795 site) and CDK6-CCND1-RB1CT were overexpressed respectively.
  • the cells were collected, and the phosphorylation level of RB1CT S795 was detected by western blotting (S795 antibody purchased from Abclonal), and the corresponding IC 50 value was calculated to indirectly measure the kinase inhibitory activity of the compound.
  • Enzyme inhibitory activity of the compound (IC 50 , unit: ⁇ M)
  • Compounds 1-6 have different degrees of inhibitory effects on CDK4 kinase, among which compounds 1 and compound 6 have excellent inhibitory activity on CDK4 kinase, and compound 5 has good inhibitory activity on CDK4 kinase.
  • Compounds 4-6 have good inhibitory effects on CDK6 kinase, among which compounds 5 and 6 have excellent inhibitory effects on CDK6 kinase.
  • Example 3 Experiment on inhibiting proliferation of various cancer cells
  • the CCK-8 method was used to test the inhibitory effect of the compounds of the present application on the proliferation of human breast cancer (MCF-7, HCC1937) cell lines and cervical cancer (HeLa) cell lines.
  • the specific method is as follows:
  • Compounds 1-6 showed good cytotoxicity to MCF-7 cells, HCC1937 cells and HeLa cells. Compound 6 showed excellent cytotoxicity to MCF-7 cells, and compound 1 showed excellent cytotoxicity to HCC1937 cells and HeLa cells.

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Abstract

La présente demande concerne un composé pour inhiber l'interaction protéine-protéine entre CDK4/6 et la cycline D. Le composé a le résultat représenté dans la formule (I), la formule (II), la formule (III), la formule (IV), la formule (V) ou la formule (VI), et a une utilisation dans la préparation de médicaments pour des maladies qui bénéficient ou peuvent être traitées par inhibition de l'interaction protéine-protéine entre CDK4/6 et la cycline D.
PCT/CN2024/117829 2023-09-13 2024-09-09 Composé pour inhiber l'interaction protéine-protéine de cdk4/6 et de la cycline d Pending WO2025055868A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143482A1 (fr) * 2022-01-29 2023-08-03 上海辉启生物医药科技有限公司 Composé ou sel de 2-aminopyrimidine, son procédé de préparation et son utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143482A1 (fr) * 2022-01-29 2023-08-03 上海辉启生物医药科技有限公司 Composé ou sel de 2-aminopyrimidine, son procédé de préparation et son utilisation

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AL-WAHAIBI LAMYA H., ABU-MELHA HANAA M., IBRAHIM DIAA A.: "Synthesis of Novel 1,2,4-Triazolyl Coumarin Derivatives as Potential Anticancer Agents", JOURNAL OF CHEMISTRY, vol. 2018, 14 October 2018 (2018-10-14), US , pages 1 - 8, XP093290910, ISSN: 2090-9063, DOI: 10.1155/2018/5201374 *
DATABASE REGISTRY 13 March 2002 (2002-03-13), ANONYMOUS: "1,3,5-Triazin-2-amine, 4,6-bis(1H-benzotriazol-1-yl)-N,N-diphenyl- ", XP093290904, retrieved from STN Database accession no. 400750-86-9 *
DATABASE REGISTRY 15 April 2010 (2010-04-15), ANONYMOUS: "1H-Pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione, 10-[[4-(1,4-dioxa-8-azaspiro[4.5]dec-8- ylcarbonyl)phenyl]methyl]-2,3- dihydro-", XP093290907, retrieved from STN Database accession no. 1219217-73-8 *
DATABASE REGISTRY 18 February 2011 (2011-02-18), ANONYMOUS: "C21 H28 O2", XP009562380, retrieved from STN Database accession no. 1263199-25-2 *
DATABASE REGISTRY 2 March 2012 (2012-03-02), ANONYMOUS: "Ethanone, 1-(3,4-dihydro-2(1H)-isoquinolinyl)-2-[[4-ethyl-5-[3-(4- methoxyphenyl)-1,2,4-oxadiazol-5-yl]-4H-1,2,4", XP093290901, retrieved from STN Database accession no. 1359537-65-7 *
DATABASE REGISTRY 28 November 2007 (2007-11-28), ANONYMOUS: "1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole, 6-(2-methylphenyl)-3-(1,4,5,6-tetrahydro-3-cyclopentapyrazolyl)- ", XP093290893, retrieved from STN Database accession no. 956085-26-0 *
DATABASE REGISTRY 8 July 2021 (2021-07-08), ANONYMOUS: "1H-Inden-1-one, 2-cyclopropyl-2,3-dihydro-5-[5-methyl-1-(3- pyridinyl)-1H- 1,2,3-triazol-4-yl]-", XP093290896, retrieved from STN Database accession no. 2650638-37-0 *

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