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WO2021057867A1 - Classe d'inhibiteur de cdk à base d'arsine organique, son procédé de préparation et application associée - Google Patents

Classe d'inhibiteur de cdk à base d'arsine organique, son procédé de préparation et application associée Download PDF

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WO2021057867A1
WO2021057867A1 PCT/CN2020/117550 CN2020117550W WO2021057867A1 WO 2021057867 A1 WO2021057867 A1 WO 2021057867A1 CN 2020117550 W CN2020117550 W CN 2020117550W WO 2021057867 A1 WO2021057867 A1 WO 2021057867A1
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compound
substituted
unsubstituted
cancer
zsq
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Chinese (zh)
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谭立
李盈
周少青
庄光磊
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/66—Arsenic compounds
    • C07F9/70—Organo-arsenic compounds
    • C07F9/80—Heterocyclic compounds
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/66—Arsenic compounds
    • C07F9/70—Organo-arsenic compounds
    • C07F9/74—Aromatic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/66—Arsenic compounds
    • C07F9/70—Organo-arsenic compounds
    • C07F9/74—Aromatic compounds
    • C07F9/76—Aromatic compounds containing hydroxyl groups

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a type of cell cycle dependent kinase (CDK) inhibitor based on organic arsine, and a preparation method and application thereof.
  • CDK cell cycle dependent kinase
  • THZ1 can effectively inhibit the activation of RNA polymerase II at low concentrations, thereby inhibiting the transcription initiation of superregulators in cancer cells, and finally effectively inhibiting the growth of cancer cells, and in T cells
  • Acute lymphocytic leukemia (T-ALL), small cell lung cancer (SCLC), neuroblastoma, triple-negative breast cancer and other tumor models have shown good curative effects.
  • T-ALL Acute lymphocytic leukemia
  • SCLC small cell lung cancer
  • neuroblastoma triple-negative breast cancer and other tumor models have shown good curative effects.
  • THZ1 has significant off-target effects, and its pharmacokinetic properties are not ideal.
  • Gray et al. developed a highly specific CDK12/13 inhibitor THZ531 based on THZ1.
  • the latter can specifically induce apoptosis in some tumor cells, but still has pharmacokinetic shortcomings. Including such as low bioavailability, short half-life and so on.
  • Syros has improved on the basis of THZ1 to obtain a more specific SY-1365, which is currently in the first phase of clinical trials for the treatment of solid tumors.
  • the limitation of pharmacokinetic properties makes SY-1365 be administered by intravenous injection.
  • CDK inhibitors with high selectivity, high safety, and/or better pharmacokinetic properties.
  • the purpose of the present invention is to provide a CDK inhibitor with high selectivity, high safety, and/or better pharmacokinetic properties.
  • the inhibitor of the present invention is a type of CDK inhibitor based on organic arsine.
  • the first aspect of the present invention provides a compound of formula I, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate or solvate;
  • X 1 and X 2 are each independently selected from the following group: none, O, S, NR 8 , CH 2 ;
  • R 8 is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl;
  • R 1 and R 2 are each independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, -CO-Rd, where Rd is substituted or unsubstituted Substituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl; or R 1 , R 2 and adjacent X 1 , X 2 and As together form a substituted or unsubstituted 4- to 8-membered heterocyclic ring ,
  • the heterocyclic ring contains one As heteroatom and 0-3 heteroatoms selected from N, O and S;
  • R 3 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl;
  • n 1 is 0, 1, 2, 3 or 4;
  • Each R 4 is independently selected from: H, D, OH, amino, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 Alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl;
  • L 1 , L 2 and L 3 are each independently selected from the following group: none, -(Z)m-; and L 1 and L 2 are not all at the same time; wherein, each Z is independently selected from: C1-C6 alkylene Base, -NR 6 -, -NR 6 -R 7 -, -O-, -CO-, m is 1, 2, 3 or 4;
  • Each R 6 is independently selected from the following group: H, substituted or unsubstituted C1-C4 alkyl;
  • R 7 is a substituted or unsubstituted C1-C8 alkylene group
  • A is selected from the following group: unsubstituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3 -10 membered heterocycloalkyl;
  • B is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl;
  • C is selected from the following group: H, OH, -N(Ra)Rb, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C10 ring Alkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl;
  • Ra and Rb are each independently selected from the following group: H, substituted or unsubstituted C1-C4 alkyl; or Ra, Rb and the nitrogen atom connected to them together form a substituted or unsubstituted having at least one (such as 1, 2, 3) 3-10 membered heterocycloalkyl group consisting of N heteroatoms and 0-2 heteroatoms selected from O and S.
  • the substituted substitution refers to having one or more substituents selected from group A: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl , -OH, -N(Ra)Rb.
  • R 1 and R 2 jointly form a substituted or unsubstituted -(CH 2 )n 2 -structure; wherein, n 2 is 1, 2, or 3.
  • Position 2, 3 or 4 preferably 3 position.
  • the compound of formula I has the structure shown in I-a:
  • each of R 1 , R 2 , R 3 , R 4 , n 1 , L 1 , L 2 , L 3 , A, B, and C is independently shown in Table 1.
  • the corresponding groups in the specific compound are independently shown in Table 1.
  • any one of R 1 , R 2 , R 3 , R 4 , n 1 , L 1 , L 2 , L 3 , A, B, and C is shown in Table 1 respectively The corresponding group in the specific compound.
  • A is a substituted or unsubstituted divalent group selected from the group consisting of cyclohexyl, piperidinyl and phenyl.
  • B is a substituted or unsubstituted divalent group selected from the following group:
  • C is a substituted or unsubstituted group selected from the group consisting of phenyl, piperidinyl,
  • L 1 is absent or L 1 is C1-C3 alkylene (such as methylene) or -N(CH 3 )CH 2 -.
  • L 2 is -NH- or -NHCH 2 -.
  • L 3 does not exist or L 3 is -NH-.
  • R 4 is -OCH 3 , -OCH 2 CH 2 -Rc, wherein Rc is selected from the group consisting of -N(CH 3 ) 2 and
  • the compound of formula I is selected from the following table:
  • a pharmaceutical composition including;
  • the pharmaceutical composition further comprises one or more anticancer agents and/or immunosuppressive agents, preferably, the anticancer agent and/or immunosuppressive agent is selected from the following group: PARP1/ 2 Inhibitors, chemotherapy drugs that induce DNA damage in cancer cells, DNA alkylation chemotherapy drugs, DNA or RNA synthesis inhibitors, EGFR, ALK or FGFR tyrosine receptor kinase inhibitors, KRAS, MEK or ERK tumor signaling pathways Inhibitors, tumor immunotherapy drugs (such as PD-1 antibody, PD-L 1 antibody, etc.).
  • the anticancer agent and/or immunosuppressive agent is selected from the following group: PARP1/ 2 Inhibitors, chemotherapy drugs that induce DNA damage in cancer cells, DNA alkylation chemotherapy drugs, DNA or RNA synthesis inhibitors, EGFR, ALK or FGFR tyrosine receptor kinase inhibitors, KRAS, MEK or ERK tumor signaling pathways Inhibitors, tumor immunotherapy drugs (such as PD-1 antibody, PD
  • the pharmaceutical composition further contains one or more anti-cancer agents and/or immunosuppressive agents, preferably, the anti-cancer agent and/or immunosuppressive agent is selected from the following group: Ola Pani, lukapanib, niraparib, methotrexate, capecitabine, gemcitabine, deoxyfluridine, pemetrexed disodium, pazopanib, imatinib, Erot Tinib, Lapatinib, Gefitinib, Vandetanib, Herceptin, Bevacizumab, Rituximab, Trastuzumab, Paclitaxel, Vinorelbine, Docetaxel, Doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, triptorelin, flustatin Amine, leuprolide, anastrozole, ifo
  • the third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate or solvate Or the use of the pharmaceutical composition as described in the second aspect of the present invention to prepare a pharmaceutical composition for the treatment and/or prevention of diseases or disorders related to the activity or expression of CDK12 and/or CDK13.
  • the disease or condition is cancer.
  • the cancer is selected from the group consisting of T-cell acute lymphoblastic leukemia (T-ALL), small cell lung cancer (SCLC), neuroblastoma, non-small cell lung cancer (NSCLC), colon cancer , Acute Myeloid Leukemia (AML), Chronic Lymphatic Leukemia (CLL), Non-Hodgkin Lymphoma (NHL), Multiple Myeloma, Ovarian Cancer, Ewing's Sarcoma, Skin Cancer, Prostate Cancer, Liver Cancer , Pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, brain tumor, squamous cell carcinoma, peritoneal cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, esophageal adenocarcinoma, esophageal squamous cell Carcinoma, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal strom
  • the cancer is a kinase high-expressing cancer selected from the group consisting of CDK12, CDK13, KRAS, or a combination thereof.
  • the cancer is non-CDK7 high-expressing type.
  • the fourth aspect of the present invention provides a method for preparing the compound of formula I as described in the first aspect of the present invention, which comprises the steps:
  • Z is selected from: halogen, -OMs, -OTs, -OTf, -OAc or -OAr;
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , A, B, C, and n1 are as described in the first aspect of the present invention.
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , A, B, C, and n 1 are as described in the first aspect of the present invention.
  • the sixth aspect of the present invention provides an intermediate compound having a structural formula selected from: A1, A2, A3 or A4:
  • Z is selected from: H, halogen, -OMs, -OTs, -OTf, -OAc or -OAr;
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , A, B, C, and n1 are as described in the first aspect of the present invention.
  • the seventh aspect of the present invention provides a use of A1, A2, A3 or A4 compound for preparing compound I.
  • the eighth aspect of the present invention provides a CDK12 and/or CDK13 inhibitor, including:
  • the ninth aspect of the present invention provides a method for selectively inhibiting cell cycle-dependent kinases in vitro, which includes the steps:
  • the cell cycle-dependent kinase is combined with the compound of formula I as described in the first aspect of the present invention, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate or solvate or as the present invention
  • the pharmaceutical composition of the second aspect of the invention is contacted to selectively inhibit the cell cycle-dependent kinase.
  • the method is non-therapeutic and non-diagnostic.
  • the cell cycle-dependent kinase CDK is selected from the following group: CDK12, CDK13, or a combination thereof, preferably, CDK12 and CDK13.
  • the "selectively inhibit” refers to the inhibitory activity E1 of the compound on the targeted CDK (such as CDK12 and/or CDK13) and the non-targeted kinase (such as CDK7 or selected from the table).
  • the ratio of inhibitory activity E2 (E1/E2) of 4 other non-targeted kinases) is ⁇ 2, preferably ⁇ 5, more preferably ⁇ 10.
  • the reciprocal inhibitory activity of the EC 50 E is the reciprocal inhibitory activity of the EC 50 E.
  • the tenth aspect of the present invention provides a method for inhibiting the growth or proliferation of tumor cells in vitro, which comprises the steps of:
  • the method is non-therapeutic and non-diagnostic.
  • Figure 1 shows the effect of representative compounds on the phosphorylation of Ser2 and Ser5 of Pol II in H3122 (A) or A549 (B) cells.
  • Figure 2 shows the competitive effects of representative compounds such as ZSQ5-38, ZSQ8-36, etc. on the covalent binding of THZ1-biotin to CDK7 or 12 in H3122 cells at a concentration of 1 ⁇ M.
  • Figure 3 shows the effect of representative compounds such as ZSQ8-36 and ZSQ14-66 on CDK7 or 12 catalyzed Pol II CTD Ser5 phosphorylation at different concentrations.
  • Figure 4 shows the concentration-time curves of representative compounds ZSQ5-38 and ZSQ8-36 in plasma, as well as pharmacokinetic parameters.
  • Figure 5 shows the inhibitory effects of representative compounds ZSQ5-38 and ZSQ8-36 on the growth and proliferation of various cancer cell lines at low concentrations.
  • Figure 6 shows the inhibitory effects of representative compounds ZSQ14-60 and ZSQ17-22 on the growth and proliferation of various cancer cell lines at low concentrations.
  • Figure 7 shows the inhibitory effect of representative compound ZSQ8-36 on the growth of subcutaneous tumors in SW1573 (A) and H460 (B) nude mice.
  • the compound of the present invention is an organic arsine-based cell cycle-dependent kinase inhibitor shown in formula I.
  • the organic arsine group (moiety) is the part that covalently interacts with the active site of CDK12/13 Therefore, it can provide excellent inhibitory activity and better specificity.
  • Experimental results show that the compound of the present invention has unexpected excellent specificity for targeting CDK12/13, and has high safety and few toxic and side effects.
  • the compound of the present invention also has excellent pharmacokinetic properties, a long half-life, and is suitable for preparation of medicines. The present invention has been completed on this basis.
  • alkyl by itself or as part of another substituent refers to a straight or branched hydrocarbon group having the specified number of carbon atoms (e.g., C1-C8 alkyl, C1-C6 or C1-C3 alkane Group, where C1-8 or C1-C8 represents 1-8 carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. .
  • alkenyl refers to an unsaturated alkyl group having one or more double bonds.
  • alkynyl refers to an unsaturated alkyl group having one or more triple bonds.
  • unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1, 4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologues and isomers.
  • cycloalkyl refers to having the specified number of ring atoms (e.g., C 3 -C 10 , C4-C7 or C5-C6 cycloalkyl) and is fully saturated or has no Hydrocarbon ring with more than one double bond.
  • Cycloalkyl also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like.
  • heterocycloalkyl refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Ammonium.
  • the heterocycloalkyl group can be a monocyclic, bicyclic or polycyclic ring system.
  • heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, Piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc.
  • the heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom (such as O, N, S).
  • a ring carbon or a heteroatom such as O, N, S.
  • a heteroatom such as O, N, S.
  • cycloalkylalkyl and heterocycloalkylalkyl it is meant that the cycloalkyl or heterocycloalkyl group is connected to the rest of the molecule through an alkyl or alkylene linker.
  • cyclobutylmethyl- is a cyclobutyl ring attached to the methylene linker of the rest of the molecule.
  • alkylene by itself or as part of another substituent refers to a divalent group derived from an alkane, such as -CH 2 CH 2 CH 2 CH 2 -.
  • Alkyl groups (or alkylene groups) generally have 1 to 24 carbon atoms, of which those groups having 10 or fewer carbon atoms (such as 1, 2, 3, 4, 5, or 6) are preferred in the present invention.
  • “Lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, usually having 4 or fewer carbon atoms.
  • alkenylene or “alkynylene” refers to an unsaturated form of "alkylene” having a double bond or a triple bond, respectively.
  • alkoxy or “alkyloxy”, “alkylamino” or “alkylamino” and “alkylthio” or “alkylthio” (or thioalkoxy ) Is used in its conventional sense to refer to those alkyl groups attached to the rest of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • the alkyl group can be the same or different, and can also be combined with each other.
  • the nitrogen atoms connected to the alkyl group combine to form a 3-7 membered ring.
  • halo or halogen (Hal) by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl or polyhaloalkyl.
  • C 1-4 haloalkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.
  • aryl means a polyunsaturated (usually aromatic) hydrocarbon group, which may be a single ring or multiple rings (up to three rings) fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, which can be a single ring or multiple rings fused together or covalently linked ( Bicyclic, at most tricyclic) wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized.
  • Aryl and heteroaryl groups can be connected to other parts of the molecule through any ring atom (such as the ortho, meta, and para positions of the substituent), and heteroaryl groups can be connected to the rest of the molecule through heteroatoms.
  • aryl groups include phenyl, naphthyl, and biphenyl
  • heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, Quinoxalinyl, quinazolinyl, cinnoline, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzotriazinyl Isoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyrid
  • heteroatom is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).
  • the bond from the substituent (usually the R group) to the center of the aromatic ring will be understood to mean a bond that provides a connection at any available vertex of the aromatic ring.
  • the description also includes links to rings fused to aromatic rings.
  • a bond drawn to the center of the indolebenzene moiety will represent a bond connected to any available vertex of the six- or five-membered ring portion of the indole.
  • each chiral carbon atom may optionally be R configuration or S configuration, or a mixture of R configuration and S configuration.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (for example, separated enantiomers) Body) should be included in the scope of the present invention.
  • the compounds provided herein have a defined stereochemistry (represented by R or S, or indicated by a dashed or wedge-shaped bond)
  • those skilled in the art will understand that those compounds are substantially free of other isomers (e.g., at least 80% , 90%, 95%, 98%, 99% and up to 100% free of other isomers).
  • the term “comprising”, “comprising” or “including” means that various ingredients can be used together in the mixture or composition of the present invention. Therefore, the terms “mainly consisting of” and “consisting of” are included in the term “containing”.
  • the term "pharmaceutically acceptable” ingredient refers to a substance that is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, a substance that has a reasonable benefit/risk ratio.
  • the term "therapeutically effective dose” refers to any amount of the drug as described below, when used alone or in combination with another therapeutic agent, the amount of the drug can promote the regression of the disease, which is manifested as disease symptoms Reduce the severity of the disease, increase the frequency and duration of the asymptomatic period, or prevent the disorder or disability caused by the disease.
  • the "therapeutically effective dose” of the drug of the present invention also includes the “preventively effective dose”.
  • the “preventively effective dose” is any amount of the drug as described below, when the amount of the drug is administered alone or in combination with another therapeutic agent When a subject is at risk of developing a disease or suffering from recurrence of the disease, the occurrence or recurrence of the disease can be suppressed.
  • pharmaceutically acceptable salt refers to a salt formed by a compound of the present invention and an acid or base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • a preferred class of salts are the salts of the compounds of this invention with bases.
  • Suitable bases for salt formation include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, and piperazine.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate
  • organic bases such as ammonia, triethylamine, diethylamine, and piperazine.
  • Some compounds in the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the solvates of the present invention include stoichiometric solvates such as hydrates, etc., as well as compounds containing variable amounts of water formed when they are prepared by a low-pressure sublimation drying method.
  • the invention also includes all suitable isotopic variants of the compounds of the invention.
  • Isotopic variants of the compounds of the present invention are defined as those in which at least one atom is replaced by an atom having the same atomic number but having an atomic mass different from the atomic mass commonly found in nature.
  • isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, and 17 respectively. O, 18 O, 35 S, 18 F and 36 Cl.
  • isotopic variants of the present invention for example, those in which radioisotopes (such as 3 H or 14 C) are incorporated, are used in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred because they are easy to prepare and detect.
  • substitution with isotopes e.g., deuterium, ie, 2 H
  • Isotopic variants of the compounds of the present invention can generally be prepared by conventional operations, for example, by using suitable reagents for appropriate isotopic variants, by an exemplary method or the preparation described in the experimental section below.
  • treating refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded vertebral mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • ZSQ-5-38 can be used interchangeably with “ZSQ5-38” and “ZSQ538” to indicate a compound of ZSQ-5-38, and similar numbering rules are the same.
  • a compound of the present invention refers to a compound of formula I, or a stereoisomer or tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof;
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , A, B, C, and n1 are as described in the first aspect of the present invention.
  • the present invention provides methods for preparing compounds of formula I.
  • the compounds of the present invention can be prepared by a variety of synthetic operations. Exemplary methods for preparing these compounds may include (but are not limited to) the following procedures.
  • the compound of formula I of the present invention can be completed by the exemplary methods described in the following schemes and examples, as well as related publications used by those skilled in the art.
  • Step i Protect the arsenous acid functional group of A1 in an ester or amide manner, and ethanedithiol, ethylene glycol, etc. can be used as a protective reagent.
  • Step ii Introduce the R 3 substituent into the amine group of A2 by S N 2 substitution reaction, using R3-halogen, and react under basic conditions (such as sodium hydride).
  • Step iii The introduction of the L1 group by the acylation reaction of the phenyl ring amino group of A3 can be catalyzed by (but not limited to) phosphorus oxychloride reagent.
  • Step iv Connect the A functional group site of A5 with L 1 of A4 through acylation reaction, urea reaction or SN 2 substitution.
  • the compound of the present invention has excellent inhibitory activity on cell cycle dependent kinase (CDK), the compound of the present invention and its pharmaceutically acceptable salts, hydrates or solvates, and drugs containing the compound of the present invention as the main active ingredient
  • CDK cell cycle dependent kinase
  • the composition can be used to treat, prevent and alleviate diseases or disorders related to the activity or expression of CDK.
  • the compounds of the present invention can be used to treat cancer.
  • Representative cancers include (but are not limited to): T-cell acute lymphoblastic leukemia (T-ALL), small cell lung cancer (SCLC), neuroblastoma, non-small cell lung cancer (NSCLC), colon cancer, acute myeloid Leukemia (AML), Chronic Lymphatic Leukemia (CLL), Non-Hodgkin Lymphoma (NHL), Multiple Myeloma, Ovarian Cancer, Ewing's Sarcoma, Skin Cancer, Prostate Cancer, Liver Cancer, Pancreatic Cancer, Gastric cancer, esophageal cancer, bladder cancer, brain tumor, squamous cell carcinoma, peritoneal cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, in situ Cancer, lymphoma, neurofibroma, thyroid cancer, bone cancer, brain cancer, colon cancer, test
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-500 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • anticancer agents for example, PARP1/2 inhibitors (Olaparid, Rucaparib, or Niraparib, etc.), chemotherapy drugs that induce DNA damage in cancer cells (cis Platinum, carboplatin or oxaliplatin, etc.), DNA alkylating chemotherapy drugs (nimustine, etc.), DNA or RNA synthesis inhibitors (gemcitabine, etc.), tyrosine receptor kinases such as EGFR, ALK or FGFR Inhibitors, tumor signal pathway inhibitors such as KRAS, MEK or ERK, tumor immunotherapy drugs (PD-1 antibody, PD-L 1 antibody, etc.); in some embodiments, the compound of the present invention is jointly administered to a cancer subject And other traditional cancer treatments, such as radiotherapy or surgery. Radiotherapy is well known in the art and includes X-ray therapy, such as gamma radiation, and radiopharmaceutical therapy.
  • the CDK inhibitors of the present invention are used in the same or separate formulations with other agents that are part of a combination treatment regimen, or used sequentially with the other agents.
  • the general range of the therapeutically effective dose of the compound of formula I or the composition of the compound of formula I will be: about 1 to 2000 mg/day, about 10 to about 1000 mg/day, about 10 to about 500 mg/day, about 10 to about 250 mg/day , About 10 to about 100 mg/day, or about 10 to about 50 mg/day.
  • the therapeutically effective dose will be given in one or more doses.
  • the specific dosage of the compound of the present invention for any specific patient will depend on various factors, such as the age, gender, weight, general health, diet, individual response, administration time, and treatment of the patient to be treated. The severity of the disease, the activity of the specific compound administered, the dosage form, the mode of application and the concomitant drugs.
  • the therapeutically effective amount for a given situation can be determined by routine experiments and is within the ability and judgment of the clinician or physician.
  • the compound or composition will be administered in multiple doses based on the individual condition of the patient and in a manner that allows delivery of a therapeutically effective amount.
  • the organic arsine group (moiety) is used as the part that covalently interacts with the active site of CDK12/13, thus providing excellent inhibitory activity and better specificity.
  • the inhibitory activity of CDK12 and 13 is better than existing inhibitors, and can effectively inhibit the growth and proliferation of cancer cells.
  • the combination of the compound of the present invention and CDK12, 13 is irreversible, and its pharmacological effect is longer and the curative effect is longer.
  • 4-Aminophenylarsonic acid (108.5g, 500mmol) was dissolved in 300ml ethanol, and the mixed solution was heated to reflux. Phenylhydrazine (92ml, 1mol) was added dropwise (over 1h). During the addition, a large amount of nitrogen was generated. When the nitrogen generation slowed down, continue to reflux and stir for 1.5h.
  • the mixed solution was concentrated by distillation under reduced pressure, sodium hydroxide solution (40g dissolved in 400ml water) and 400ml ether were added. Separate the liquids, add saturated ammonium chloride solution (400ml) to the aqueous phase and stir for 1h at 0°C, a large amount of white solids are precipitated. A white needle-like solid was obtained by filtration and dried under vacuum to obtain 40 g of product with a yield of 40%.
  • ZSQ-1-18 (40 g, 199 mmol) was dissolved in 200 ml of absolute ethanol and heated to reflux. Then, ethanedithiol (20ml, 240mmol) was added dropwise to the mixed solution within 30min, and heating and stirring were continued for 30min. Subsequently, the mixture was cooled in ice water and filtered to obtain a crude product, which was recrystallized from ethanol to obtain 42 g of a white solid with a yield of 81%.
  • methylmagnesium bromide (1M tetrahydrofuran solution, 100ml, 100mmol) was added dropwise to indole (11.7g, 100mmol) in THF (60ml) within 30 min.
  • the solution was continuously stirred at 0°C for 30 min.
  • 2,4,5-Trichloropyrimidine (5.73ml, 50mmol) was added dropwise to obtain a yellow solution.
  • the ice bath was removed, and the solution was stirred at room temperature for 1 h to obtain a red solution.
  • the mixed solution was heated to 60° C. and stirring was continued for 1.5 hours.
  • ZSQ-8-36 (123mg, 0.19mmol), mercury perchlorate trihydrate (71mg, 0.157mmol) were dissolved in 3ml DMSO, the mixed solution was stirred at room temperature for 10min, and it was immediately separated and purified by C18 reversed-phase column chromatography. It was eluted with H 2 O/CH 3 CN (1:4) to obtain 102 mg of yellow powder with a yield of 92%.
  • ZSQ-5-26 (202mg, 0.5mmol), ZSQ-5-57-2 (196mg, 0.5mmol) and p-toluenesulfonic acid monohydrate (285mg, 1.5mmol) were mixed and dissolved in 2ml of N-methylpyrrolidone.
  • the mixed solution was heated and stirred at 135°C for 2h.
  • the cooled solution was directly separated and purified by C18 reversed-phase column chromatography, and eluted with H 2 O/CH 3 CN (1:9) to obtain 86 mg of yellow powder with a yield of 22%.
  • the combined organic phase is dried with anhydrous sodium sulfate, filtered and concentrate. It was separated and purified by silica gel column chromatography and eluted with PE/EA (2:1) to obtain 178 mg of white powder with a yield of 46%.
  • ZSQ-7-81 (1.25g, 10mmol) was dissolved in a sealed tube containing 30ml of dry ethanol, 20% sodium ethoxide solution (3.74g, 11mmol) was added, and the mixed solution was heated to reflux temperature and stirred for 22h. After the completion of the reaction, the reaction solution was concentrated, diluted with water (20ml), adjusted to pH 3 with a dilute hydrochloric acid solution, a large amount of solids precipitated, filtered and washed with water several times. A yellow powder was obtained, and 1.29 g of white powder was obtained after drying, and the yield was 66%.
  • the combined organic phase is dried with anhydrous sodium sulfate, filtered and concentrate. It was separated and purified by silica gel column chromatography, and eluted with DCM/EA (1:1) to obtain 162 mg of white powder with a yield of 49%.
  • the compound ZSQ-7-94 (200mg, 0.5mmol), ZSQ-8-1 (133mg, 0.55mmol), tris(dibenzylideneacetone) two palladium (23mg, 0.025mmol), 1,1'-binaphthalene -2,2'-bisdiphenylphosphine (47mg, 0.075mmol) and sodium tert-butoxide (58mg, 0.6mmol) were mixed in 2ml of toluene, heated to 95°C under nitrogen atmosphere and stirred for 16h. After the reaction is completed, wash with H 2 O (30ml ⁇ 3), extract with EA (40ml), and wash with saturated sodium chloride solution (30ml).
  • ZSQ-8-9 (66mg, 0.1mmol) mercury perchlorate trihydrate (36mg, 0.08mmol) was dissolved in 2ml DMSO, the mixed solution was stirred at room temperature for 10min, and immediately separated and purified by C18 reversed-phase column chromatography. H 2 O/CH 3 CN (1:5) was eluted to obtain 49.5 mg of yellow solid with a yield of 82%.
  • ZSQ-7-88 (318mg, 1.39mmol), DIPEA (0.46ml, 2.78mmol) and ZSQ-7-75 (544mg, 1.39mmol) were dissolved in 6ml of absolute ethanol, heated to 85°C and stirred overnight. After the completion of the reaction, the reaction solution was concentrated, washed with water (30ml ⁇ 2), extracted with EA (30ml), and washed with saturated sodium chloride solution (30ml). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography, eluted with PE/EA (5:1), to obtain 588 mg of brown solid, with a yield of 72%.
  • methylmagnesium bromide (1M tetrahydrofuran solution, 70ml, 70mmol) was added dropwise to indole (8.26g, 70mmol) in THF (50ml) within 30 min.
  • the solution was continuously stirred at 0°C for 30 min.
  • 2,4-Dichloro-5-iodopyrimidine (2.74 g, 35 mmol) was added dropwise to obtain a yellow solution.
  • the ice bath was removed, and the solution was stirred at room temperature for 1 h to obtain a red solution.
  • the mixed solution was heated to 60° C. and stirring was continued for 1.5 hours.
  • the mixture was cooled to room temperature, and acetic acid (70 ml) was added dropwise.
  • ZSQ-13-87 (105mg, 0.23mmol), DIPEA (0.11ml, 0.69mmol) and ZSQ-5-4 (91mg, 0.24mmol) were dissolved in 4ml of THF solution, and the mixed solution was stirred at room temperature 4h. Then it was washed with 2N dilute hydrochloric acid solution (20ml), and extracted with EA (3 ⁇ 30ml), and then washed with water (2 ⁇ 20ml). The organic phases were combined, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure, and separated and purified by silica gel column chromatography, eluted with DCM/EA (2:1), to obtain 75 mg of white powder with a yield of 43%.
  • ZSQ-13-88 (75mg, 0.1mmol) and anhydrous potassium carbonate (41mg, 0.3mmol) were dissolved in a mixed solution of 2ml of anhydrous methanol and 2ml of anhydrous THF, and placed at room temperature to mix and stir for 4h. After the reaction was completed, the pH was adjusted to weakly acidic with TFA, and the reaction solution was directly separated and purified by C18 reversed-phase column chromatography, eluted with H 2 O/CH 3 CN (1:6), to obtain 52 mg of yellow powder with a yield of 85%.
  • ZSQ-14-10 (93mg, 0.20mmol), DIPEA (0.10ml, 0.60mmol) and ZSQ-5-4 (88mg, 0.21mmol) were dissolved in 2ml of THF solution, and the mixed solution was stirred at room temperature 4h. Then it was washed with 2N dilute hydrochloric acid solution (20ml), and extracted with EA (3 ⁇ 30ml), and then washed with water (2 ⁇ 20ml). The organic phases were combined, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure, and separated and purified by silica gel column chromatography, eluted with DCM/EA (3:1), to obtain 95 mg of yellow solid with a yield of 59%.
  • ZSQ-15-1 (4.88g, 43mmol) was dissolved in a sealed tube containing 80ml of dry ethanol, 20% sodium ethoxide solution (16g, 47.5mmol) was added, the mixed solution was heated to reflux temperature and stirred for 22h. After the completion of the reaction, the reaction solution was concentrated, diluted with water (50ml), and adjusted to pH 3 with a dilute hydrochloric acid solution. A large amount of solid precipitated out, filtered and washed with water several times. A yellow powder is obtained, and 2.98 g of white powder is obtained after drying.
  • the compound ZSQ-15-74 (416mg, 1.0mmol), 2-piperidine ethanol (165mg, 1.0mmol), tris(dibenzylideneacetone) two palladium (46mg, 0.05mmol), 1,1'-binaphthyl -2,2'-bisdiphenylphosphine (93mg, 0.15mmol) and sodium tert-butoxide (106mg, 1.1mmol) were mixed in 3ml of toluene, heated to 95°C under nitrogen atmosphere and stirred for 16h. After the reaction is completed, wash with H 2 O (30ml ⁇ 3), extract with EA (40ml), and wash with saturated sodium chloride solution (30ml).
  • ZSQ-15-97 (115mg, 0.4mmol), potassium carbonate (138mg, 1.0mmol), potassium iodide (33mg, 0.2mmol) and ZSQ-5-4 (228mg, 0.6mmol) were dissolved in 1.5ml CH 3 CN/1.5ml DMF solution, the mixed solution was stirred at room temperature for 4h. Then it was acidified with TFA, separated and purified by C18 reversed-phase column chromatography, and eluted with H 2 O/CH 3 CN (1:9) to obtain 153 mg of pink solid with a yield of 65%.
  • the compound ZSQ-14-35 (2.29 g, 10 mmol) was dissolved in 20 ml of methanol, Pd/C (200 mg) was added, and the mixture was stirred at room temperature for 12 h under a hydrogen atmosphere. After the reaction was completed, it was filtered through celite and washed with DCM. The filtrate was concentrated and drained by an oil pump to obtain 1.99 g of white solid with a yield of 99%.
  • ZSQ-14-58 (82mg, 0.2mmol), DIPEA (0.13ml, 0.8mmol) and ZSQ-5-4 (76mg, 0.2mmol) were dissolved in 3ml of THF solution, and the mixed solution was stirred at room temperature 4h. Then it was washed with 2N dilute hydrochloric acid solution (20ml), and extracted with EA (3 ⁇ 30ml), and then washed with water (2 ⁇ 20ml). The organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure, separated and purified by silica gel column chromatography, eluted with DCM/EA (3:1), to obtain 79 mg of yellow solid with a yield of 56%.
  • ZSQ-16-8 (24.7 g, 100 mmol) was dissolved in 100 ml methanol and heated to reflux. Then, ethanedithiol (10ml, 120mmol) was added dropwise to the mixed solution within 30min, and heating and stirring were continued for 30min. Subsequently, the mixed solution was concentrated, separated and purified by silica gel column chromatography, and eluted with PE/EA (10:1) to obtain a crude yellow solid product. It was dissolved in THF, and then separated and purified by C18 reversed-phase column chromatography, eluted with H 2 O/CH 3 CN (8:1), to obtain 9 g of a yellow solid product with a yield of 29.5%.
  • the adopted biological test protocol is: the effect of the compound on the cell growth activity of the acute lymphoblastic leukemia cell line Jurkat and the non-small cell lung cancer cell line H3122.
  • Jurkat cells blood cancer, suspension type
  • H3122 cells solid tumor, adherent type
  • Method Culture Jurkat or H3122 cells in vitro and grow to logarithmic growth phase. Collect the cells, centrifuge at 1000 rpm for 5 min, discard the supernatant, and adjust the cell concentration to 2.5 ⁇ 10 5 /mL (Jurkat) or 1.5 ⁇ 10 5 /mL (H3122). ), inoculate the cells into a 384-well plate, 40 ⁇ l per well.
  • the adopted biological test protocol is: the effect of the compound on the growth activity of various non-small cell lung cancer cell lines.
  • the cell viability was calculated by detecting the chemiluminescence value, thereby obtaining the biological activity of the compound to inhibit the growth of cancer cells, and comparing it with the reported CDK inhibitors THZ1 and THZ531.
  • Method Culture various non-small cell lung cancer cells in vitro, after they grow to logarithmic growth phase, digest and collect the cells, centrifuge at 1000 rpm for 5 minutes, discard the supernatant, adjust the cell concentration to 1.5 ⁇ 10 5 /mL, and inoculate the cells to 384 wells In the plate, 40 ⁇ l per well. Add 5 ⁇ L each of compounds of different concentrations or DMSO to the corresponding wells, place in a cell incubator (37°C, 5% CO 2 ) and incubate for 72 hours, add 15 ⁇ l Cell Titer-Glo solution to each well, incubate at room temperature for 30 minutes, and detect chemiluminescence Value (luminescence) to measure the level of intracellular ATP. Take the unstimulated DMSO control well as 100% cell viability. Use Prism Graphpad statistical software to calculate the IC 50 value of the compound.
  • RNA polymerase II forms transcription complexes with transcription factors such as CDK7, 12, 13 and BRD4 through super enhancers to promote the high expression of oncogenes such as MYC and RUNX 1, thereby maintaining cancer Cell survival and proliferation.
  • CDK7, 12, and 13 are jointly responsible for the continuous phosphorylation of the Ser5 site in the Pol II C-terminal domain (CTD) repeat sequence to ensure the normal start of the Pol II transcription program; and CDK12, 13 It is responsible for the continuous phosphorylation of the Ser2 site in the Pol II CTD repeat sequence to ensure the correct progress of the transcription elongation process and the repair of DNA damage.
  • Figure 1 shows the effect of representative compounds on the phosphorylation of Ser2 and Ser5 of Pol II in H3122 (A) or A549 (B) cells.
  • the experimental results show:
  • Compounds such as ZSQ5-38, ZSQ8-36 and ZSQ9-75 can effectively inhibit the phosphorylation of Ser2 at a concentration of 1 ⁇ M, but not the phosphorylation of Ser5;
  • THZ1 inhibits phosphorylation at both sites at the same time.
  • Covalent inhibitors such as THZ1 or THZ531 can form covalent bonds with specific cysteine residues in the binding pocket of CDK7, 12, or 13, and then irreversibly bind to CDK7, 12, or 13.
  • the reported THZ1-biotin is a derivative of THZ1, and it can also form covalent bonds with CDK7, 12, and 13 in the cell lysate, and then CDK7, 12, and 13 can be combined with streptavidin beads. Enriched.
  • THZ1, THZ531 or ZSQ series of CDK inhibitors bind irreversibly to CDK7, 12 or 13, because the binding pocket is already occupied, THZ1-biotin can no longer bind to CDK7, 12 or 13. Therefore, based on the competitive enrichment experiment of THZ1-biotin and streptavidin microbeads, it is possible to accurately determine whether the CDK inhibitor binds irreversibly to CDK7, 12, or 13.
  • H3122 cells were cultured in vitro and grown to the logarithmic growth phase. The cells were digested and collected, centrifuged at 1000 rpm for 5 minutes, the supernatant was discarded, and the cell concentration was adjusted to 1 ⁇ 10 6 /mL.
  • a 12-well cell culture plate In a 12-well cell culture plate, add 1ml of cells to each well, add 100nL of DMSO solution (final concentration of 1 ⁇ M) of a representative drug with a concentration of 10mM to each well, control with THZ1, THZ531 or DMSO, and place it in a cell incubator (37°C, After culturing in 5% CO2) for 4 hours, wash twice with pre-cooled PBS solution, add 200 ⁇ L of NP40 cell lysate and protease inhibitor to the wells, and lyse for 30 minutes at 4°C.
  • Figure 2 shows the competitive effects of representative compounds such as ZSQ5-38, ZSQ8-36, etc. on the covalent binding of THZ1-biotin to CDK7 or 12 in H3122 cells at a concentration of 1 ⁇ M.
  • THZ1 also inhibits the covalent binding of THZ1-biotin to CDK7, 12 and 13; THZ531 has a slight inhibition on CDK7;
  • Compounds such as ZSQ5-38, ZSQ8-36, ZSQ9-75 and ZSQ17-22 can completely or almost completely inhibit the covalent binding of THZ1-biotin to CDK12 or 13 at a concentration of 1 ⁇ M, but hardly affect THZ1-biotin Covalently binding to CDK7, compared with THZ531, compounds such as ZSQ5-38, ZSQ8-36, ZSQ9-75 and ZSQ17-22 have a smaller effect on CDK7 and higher selectivity;
  • ZSQ compounds can inhibit the kinase activity of CDK12 and 13 in cancer cells with high efficiency, high specificity and irreversibility.
  • CDK7 and 12 proteins can catalyze the phosphorylation of Ser5 of Pol II CTD in vitro. Therefore, when the kinase activity of CDK7 or 12 is inhibited, the phosphorylation modification of Ser5 will be weakened or lost.
  • the gel was washed 5 times with RIPA buffer, and then washed 3 times with kinase buffer (50mM HEPES pH7.4, 50mM KCl, 10mM MgCl 2 ), and mixed with 100 ⁇ L kinase buffer for subsequent in vitro kinase reaction.
  • kinase buffer 50mM HEPES pH7.4, 50mM KCl, 10mM MgCl 2
  • 100 ⁇ L kinase buffer for subsequent in vitro kinase reaction Add 10 ⁇ L of gel mixture to each well, and incubate at 4°C overnight. Then add 1 ⁇ g of bacterial expression and purified GST-Pol II CTD protein and 100 ⁇ M ATP, shake reaction at 37°C for 1 hour, add 4% SDS loading buffer to terminate the reaction, cook at 95°C for 10 minutes, and identify by western-blot.
  • Figure 3 shows the effect of representative compounds such as ZSQ8-36 and ZSQ14-66 on CDK7 or 12 catalyzed Pol II CTD Ser5 phosphorylation at different concentrations.
  • THZ1 simultaneously inhibits the phosphorylation modification of CDK7 and 12 catalytic substrates
  • ZSQ14-66 significantly inhibited the phosphorylation of CDK7 and 12 catalytic substrates at a concentration of 250 nM, while ZSQ14-60 partially inhibited the phosphorylation of CDK7 catalytic substrates at a concentration of 500 nM.
  • the biological test protocol used is: the effect of the compound on the in vitro enzyme activity of the kinase group.
  • the representative compound can only inhibit the enzyme activity of a few kinases below 50% at a concentration of 1 ⁇ M; in contrast, the representative compound can completely inhibit the kinase activity of CDK12 at a concentration of 500 nM ( Activity Test Example 5).
  • THZ531 has an effect on RSK2.
  • Kinases such as STK16 have strong binding, and the compound of the present invention has basically no effect on the activity of these kinases. This suggests that the compound of the present invention has a different kinase selectivity from the existing CDK12/13 inhibitors. Has better selectivity and safety.
  • the drug metabolism was tested in vivo in mice, and the selectivity of the compound of the present invention to the kinase group was verified in vivo.
  • Figure 4 shows the concentration-time curves of representative compounds ZSQ5-38 and ZSQ8-36 in plasma, as well as pharmacokinetic parameters.
  • the representative compound ZSQ5-38 of the present invention has an inhibitory effect on the growth of lung cancer cell lines that depend on the growth of the KRAS gene or have KRAS activating point mutations.
  • Select H441, H460 and other kinds of cells respectively observe the number of cell clones by crystal violet staining method, and obtain the biological activity of the compound to inhibit the growth of cancer cells.
  • Method Culture various lung cancer cells in vitro, after they grow to logarithmic growth phase, digest and collect the cells, centrifuge at 1000 rpm for 5 minutes, discard the supernatant, adjust the cell concentration to 1.5 ⁇ 10 5 /mL, and inoculate the cells into a 12-well plate. 1ml per hole. Add 5 ⁇ L each of compounds of different concentrations or DMSO to the corresponding wells, place in a cell culture incubator (37°C, 5% CO 2 ) and culture for one week (change the medium once during the period), add 4% PFA solution to each well to fix 20 Then add 0.1% crystal violet solution to stain for 20 minutes, wash twice with PBS, scan and image, and use unstimulated DMSO control wells as 100% cell viability.
  • Figures 5 and 6 show that representative compounds ZSQ5-38 and ZSQ8-36 can completely or effectively inhibit the growth and proliferation of a variety of cell lines at a concentration of 1 ⁇ M, and can completely or effectively inhibit SW1573, H460, etc. at a concentration of 300nM.
  • ZSQ14-60 and ZSQ17-22 can completely inhibit the growth and proliferation of various cell lines at a concentration of 0.3 ⁇ M, and can completely or effectively inhibit the growth and proliferation of several cell lines such as HCC44 and H23 at a concentration of 300nM. Growth and proliferation.
  • the nude mouse tumor formation experiment is a method for studying tumors and their treatment in vivo, that is, injecting human tumor cells under the skin of nude mice to observe tumor growth and even the effect of anti-tumor drugs.
  • a blank dispensed solvent was used as a control, and the volume of subcutaneous tumors and the body weight of nude mice were monitored at the same time.
  • Lung cancer is currently the tumor type with the highest morbidity and mortality in the world, and the research of its targeted therapy has been receiving extensive attention.
  • the KRAS gene one of the lung cancer driver genes, is difficult to make drugs.
  • KRAS G12C inhibitors such as AMG510 and MRTX849 have been developed, there is no clinically marketed drug targeting KRAS mutations, so the treatment of KRAS mutation lung cancer It is still a hot spot in the field of tumor research today.
  • Method Use KRAS mutant lung cancer cells SW1573 and H460 to inject 1X10 6 cells/mouse into the right dorsal side of nude mice, observe the growth of the subcutaneous tumor every day, and prepare for administration when the tumor grows to a suitable size.
  • the test compound was dissolved in a dispensing solvent (10% NMP, 30% PEG400, 60% ultrapure water) on the same day to make a 10 mg/mL solution.
  • Nude mice injected with SW1573 and H460 cells were divided into administration group and blank group respectively.
  • the experimental group injected with SW1573 cells was administered intragastrically at 50 mg/kg each, and the experimental group injected with H460 cells was administered at 5 mg/kg each.
  • Intraperitoneal administration while the control group was given intraperitoneal or intraperitoneal injection of blank dispensed solvent, and the volume of subcutaneous tumor was monitored every other day.
  • Figure 7 shows the inhibitory effect of representative compound ZSQ8-36 on the growth of subcutaneous tumors in SW1573 (A) and H460 (B) nude mice.
  • CDK7, 12 and 13 in the cell cycle-dependent kinase (CDK) family belong to this type of kinase target.
  • CDK cyclin dependent kinases family of kinases belong to more than a dozen members of the serine/threonine protein kinase family, some of which are involved in the key kinases of cell cycle regulation. According to the different functions of CDKs, they can be divided into two categories: CDK1, 2, 4, and 6 are involved in cell cycle regulation; CDK7-13 is involved in transcription regulation.
  • CDK7-cyclin H, CDK8-cyclin C, CDK9-cyclin T and CDK12/13-cyclin K all regulate the initiation or elongation of the transcription process by regulating the phosphorylation of RNA polymerase II to promote the subsequent
  • the super-enhancer expresses a variety of cancer-promoting genes (such as MYC, RUNX, etc.) to maintain the growth and survival of cancer cells.
  • CDK12 is an important component that regulates DNA damage and repair in cancer cells.
  • the inactivation of CDK12 can produce a synergistic effect with DNA damage repair inhibitors (such as the PARP inhibitor olaparib), and can also enhance the infiltration of immune cells in solid tumors. -Further promote the efficacy of tumor immunotherapy.
  • CDK13 is a homologous protein of CDK12, its structure is very similar to CDK12, only a few amino acid residues are different from CDK12, and its known function is equivalent to CDK12.
  • CDK7 is an important transcription factor that regulates the transcription initiation of cancer-promoting genes, and at the same time regulates the normal operation of the cell cycle. It is reported in the literature that inhibiting CDK7 may have an adverse effect on the differentiation of normal cells.
  • the present invention provides a compound of formula I that selectively inhibits CDK12 and/or 13, without inhibiting or weakly inhibiting CDK7.
  • the existing CDK7/12/13 triple inhibitor THZ1 not only inhibits these three CDKs, but also inhibits many other kinases, leading to toxic and side effects; the improved SY-1365 mainly inhibits CDK7, and has a negative effect on CDK12, 13.
  • the inhibitory effect of CDK12/13 is weak; CDK12/13 dual inhibitors that do not inhibit or basically do not inhibit CDK7 have a significantly better targeting selectivity than triple inhibitors (see Activity Test Example 6), and tumors of different genotypes are sensitive to it Sex is also different from CDK7 inhibitors.
  • the CDK inhibitor of the present invention is an optimized targeted inhibitor.
  • the organic arsine group (moiety) is the part that covalently interacts with the active site of CDK12/13, thus providing excellent Inhibitory activity and better specificity. From the experimental data, the present invention specifically binds to CDK12, CDK13 and other specific kinases, does not bind or basically does not bind to CDK7 or more than 300 other tested kinases, and, It has shown good selectivity among different cell lines, so it has far superior safety than existing arsine compounds.

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Abstract

L'invention concerne une classe d'inhibiteur de CDK à base d'arsine organique, son procédé de préparation et une application associée. L'invention concerne plus particulièrement un composé représenté par la formule (I), un stéréoisomère, un tautomère, un sel, un hydrate ou un solvate pharmaceutiquement acceptables de celui-ci. L'invention concerne également son procédé de préparation et une application associée. Chaque groupe dans la formule est tel que défini dans la description.
PCT/CN2020/117550 2019-09-27 2020-09-24 Classe d'inhibiteur de cdk à base d'arsine organique, son procédé de préparation et application associée Ceased WO2021057867A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115521290A (zh) * 2022-10-10 2022-12-27 四川大学华西医院 一种1，4-二取代吲哚类化合物的制备及其抗肿瘤应用
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025217307A1 (fr) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Procédés de prédiction de la réponse à un inhibiteur de ras(on) et polythérapies
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113801163B (zh) * 2020-06-17 2025-03-04 中国科学院上海有机化学研究所 一类基于有机砷的ii型丙酮酸激酶抑制剂及其制备方法和用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2772303A (en) * 1947-01-28 1956-11-27 Ernst A H Friedheim Therapeutic organometallic compounds containing antimony and sulfur
CN1589149A (zh) * 2001-09-24 2005-03-02 托斯克公司 减低毒性的顺铂制剂及其使用方法
WO2005034935A1 (fr) * 2003-10-10 2005-04-21 Assistance Publique - Hopitaux De Paris Utilisation de derives organoarsenies ou organostibiques pour leurs proprietes anticancereuses
CN1742100A (zh) * 2002-11-07 2006-03-01 单检索有限公司 对线粒体通透性转换的诱导
CN103756630A (zh) * 2014-01-09 2014-04-30 浙江新安化工集团股份有限公司 单组份防霉透明脱醇型硅酮密封胶及其制备方法
CN107814796A (zh) * 2017-10-16 2018-03-20 湖南大学 一种基于苯并呋咱的环境敏感染料及其制备方法和应用
CN109369724A (zh) * 2018-10-23 2019-02-22 兰州大学 一种有机砷化合物及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2772303A (en) * 1947-01-28 1956-11-27 Ernst A H Friedheim Therapeutic organometallic compounds containing antimony and sulfur
CN1589149A (zh) * 2001-09-24 2005-03-02 托斯克公司 减低毒性的顺铂制剂及其使用方法
CN1742100A (zh) * 2002-11-07 2006-03-01 单检索有限公司 对线粒体通透性转换的诱导
WO2005034935A1 (fr) * 2003-10-10 2005-04-21 Assistance Publique - Hopitaux De Paris Utilisation de derives organoarsenies ou organostibiques pour leurs proprietes anticancereuses
CN103756630A (zh) * 2014-01-09 2014-04-30 浙江新安化工集团股份有限公司 单组份防霉透明脱醇型硅酮密封胶及其制备方法
CN107814796A (zh) * 2017-10-16 2018-03-20 湖南大学 一种基于苯并呋咱的环境敏感染料及其制备方法和应用
CN109369724A (zh) * 2018-10-23 2019-02-22 兰州大学 一种有机砷化合物及其用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
W LEE LEWIS , H E BENT: "A study of 3, 4-diamino-phenylarsonic acid and some of its derivatives", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 48, 5 April 1926 (1926-04-05), pages 949 - 957, XP055795171 *
WALTER A JACOBS , MICHAEL HEIDELBERGER: "Aromatic arsenic compounds.V. N-substituted glycylarsanilic acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 41, 31 December 1919 (1919-12-31), pages 1809 - 1821, XP055795180 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115521290A (zh) * 2022-10-10 2022-12-27 四川大学华西医院 一种1，4-二取代吲哚类化合物的制备及其抗肿瘤应用
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025217307A1 (fr) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Procédés de prédiction de la réponse à un inhibiteur de ras(on) et polythérapies
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras

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