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WO2020177657A1 - Composé chimique ayant une activité de dégradation de btk - Google Patents

Composé chimique ayant une activité de dégradation de btk Download PDF

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Publication number
WO2020177657A1
WO2020177657A1 PCT/CN2020/077404 CN2020077404W WO2020177657A1 WO 2020177657 A1 WO2020177657 A1 WO 2020177657A1 CN 2020077404 W CN2020077404 W CN 2020077404W WO 2020177657 A1 WO2020177657 A1 WO 2020177657A1
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Prior art keywords
compound
missing
pharmaceutically acceptable
integer
btk
Prior art date
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Ceased
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PCT/CN2020/077404
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English (en)
Chinese (zh)
Inventor
舒永志
林军
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Shanghai Meizer Pharmaceuticals Co Ltd
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Shanghai Meizer Pharmaceuticals Co Ltd
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Filing date
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Priority claimed from CN201910161658.3A external-priority patent/CN111662294A/zh
Application filed by Shanghai Meizer Pharmaceuticals Co Ltd filed Critical Shanghai Meizer Pharmaceuticals Co Ltd
Priority to CN202080018195.6A priority Critical patent/CN113490669B/zh
Publication of WO2020177657A1 publication Critical patent/WO2020177657A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a class of compounds with the activity of degrading tyrosine protein kinase Btk, and preparation and application thereof.
  • Btk (Bruton's tyrosine kinase) is a member of the Tec family of non-receptor tyrosine kinases. It is a gene necessary for cell differentiation and proliferation. It is also used in B-cell lymphoma and acute lymphoblastic leukemia (ALL ) And plasmacytoma. Btk is a key component of the B cell receptor (BCR) signaling pathway, and is a good site for targeted treatment of diseases such as B cell lymphoma.
  • BCR B cell receptor
  • Btk is a key regulator of B cell development, activation, signal transduction and survival, and is involved in the regulation of angiogenesis, cell proliferation and apoptosis, and cell movement.
  • Btk is also involved in many other hematopoietic cell signal pathways, for example, involved in the signal pathway mediated by Toll-like receptors and cytokine receptors in macrophages, and involved in the signal transduction of IgE receptors in mast cells.
  • Btk signaling pathway is the current non-Hodgkin lymphoma (NHL), especially chronic lymphocytic leukemia (CLL), B cell lymphoma and autoimmune diseases (rheumatoid arthritis, psoriasis, etc.) New hot spots in clinical treatment research (Deng Rong, Zhao Lizhi. Research progress of Btk inhibitors. Pharmaceutical Research, 2014, 33(6): 359-372.).
  • NDL non-Hodgkin lymphoma
  • CLL chronic lymphocytic leukemia
  • B cell lymphoma rheumatoid arthritis, psoriasis, etc.
  • the purpose of the present invention is to provide a compound capable of inhibiting and degrading Btk, and its preparation and application.
  • a is an integer between 0-30.
  • A is missing, or A is O(CH 2 ) h , where h is an integer between 0 and 5, such as h is 1, 2, 3, 4, or 5.
  • Z is missing, or Z is O(CH 2 ) h , where h is an integer between 0 and 5, such as h is 1, 2, 3, 4, or 5.
  • W 2 is missing, or W 2 is NH.
  • B is O.
  • a is an integer between 2 and 30; preferably, a is an integer between 4 and 20; more preferably, a is an integer between 5 and 10; most preferably, a is An integer between 6 and 8; for example, a is 3, 4, 5, 6, 7, 8, 9, or 10.
  • the X is CH 2 .
  • the compound of the present invention does not include the specific compound disclosed in patent document CN109422752A and/or WO2019042445A1.
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition and a method of administration thereof.
  • the composition contains the compound described in the first aspect, its isomers, prodrugs, pharmaceutically acceptable salts, and pharmaceutically acceptable salts. Acceptable carrier.
  • the pharmaceutical composition also contains another one or more anti-tumor agents.
  • the pharmaceutical composition is used to inhibit the activity of Bruton's tyrosine protein kinase (Btk) or reduce the level of Bruton's tyrosine protein kinase (Btk).
  • the pharmaceutical composition is used to treat diseases related to Bruton's tyrosine protein kinase (Btk) activity or expression.
  • Btk Bruton's tyrosine protein kinase
  • the third aspect of the present invention provides a use of the compound according to the first aspect of the present invention for:
  • the diseases include tumors and autoimmune diseases; preferably, the tumors include non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), B-cell lymphoma, etc.;
  • the autoimmune diseases include rheumatoid arthritis, psoriasis and the like.
  • 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, including the steps:
  • a compound of formula III is reacted with a compound of formula II to obtain a compound of formula I, where M 1 is a leaving group such as a hydroxyl group, a halogen, or a sulfonate or W 1 -M1 is an aldehyde or ketone;
  • M 1 is a leaving group such as a hydroxyl group, a halogen, or a sulfonate or W 1 -M1 is an aldehyde or ketone;
  • the method further includes the steps:
  • the inventor prepared a class of compounds with the structure shown in Formula I, and found that it has Bruton's tyrosine protein kinase (Btk) inhibitory and degradation activity.
  • the compound has an inhibitory effect on Bruton's tyrosine protein kinase (Btk) at a very low concentration, and the inhibitory activity is quite excellent, so it can be used for treatment and Bruton's tyrosine protein kinase (Btk). Sex or expression related diseases such as tumors.
  • the present invention has been completed on this basis.
  • the present invention discloses a new class of compounds and their use to inhibit and degrade Bruton's tyrosine protein kinase (Btk). These compounds can inhibit and degrade Btk, and can be used to treat tumors or autoimmune diseases.
  • Btk Bruton's tyrosine protein kinase
  • C 1-8 hydrocarbon group refers to a functional group containing only two types of atoms, carbon and hydrogen, in which the number of carbon atoms is 1-8.
  • Hydrocarbyl can be regarded as the free radical left after the corresponding hydrocarbon loses one hydrogen atom, which can be alkyl, cycloalkyl, alkenyl or alkynyl, etc.; its structure can be linear, branched or cyclic; It is aliphatic or aromatic.
  • C 1-6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , Tert-butyl, or similar groups.
  • alkoxy as used herein includes O-alkyl, where “alkyl” is as defined above.
  • halo as used in the present invention includes fluoro, chloro, bromo or iodo unless otherwise indicated.
  • the compounds of the present invention may contain double bonds. When containing such double bonds, the compounds of the present invention exist in cis, trans or mixtures thereof.
  • the halogen described herein includes fluorine, chlorine, bromine and iodine.
  • alkyl group and the alkyl portion of the alkoxy group referred to herein can be linear, branched or cyclic.
  • cycloalkyl refers to a functional group containing both carbon and hydrogen atoms. Including cycloalkyl, cycloalkenyl (containing at least one carbon-carbon double bond) and aryl. They can be single ring, double ring and multiple ring. They can be spiro rings or fused rings.
  • heterocyclic hydrocarbon group refers to a functional group containing carbon, hydrogen and at least one heteroatom other than carbon and hydrogen. Including heterocycloalkyl, heterocycloalkenyl (containing at least one carbon-carbon double bond) and heteroaryl.
  • One or more ring-forming atoms in the ring are heteroatoms.
  • the heteroatoms can be O, N, and S atoms, and various combinations thereof. They can be single ring, double ring and multiple ring. They can be spiro rings or fused rings.
  • substituted includes but is not limited to fluorine, chlorine, bromine, cyano, hydroxyl, amino, C 1-6 hydrocarbyloxy, C 1-6 halogenated hydrocarbyl, C 1-6 acyl, C 1 -6 Sulfonyl.
  • hydrocarbyloxy refers to an O-hydrocarbyl group, where the “hydrocarbyl group” is as defined above.
  • amino group refers to N (H or hydrocarbyl 1) (H or hydrocarbyl 2), where "hydrocarbyl” is as defined above.
  • 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” ingredients refers to substances that are suitable for humans and/or animals without excessive side effects (such as toxicity, irritation, and allergic reactions), that is, substances that have a reasonable benefit/risk ratio.
  • the term "effective amount" refers to the amount of a therapeutic agent that treats, alleviates, or prevents the target disease or condition, or shows a detectable therapeutic or preventive effect.
  • the precise effective amount for a subject depends on the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experiments can be used to determine the effective amount, which can be judged by clinicians.
  • substituted means that one or more hydrogen atoms on the group are substituted by a substituent selected from the following group: halogen, unsubstituted or halogenated C 1-6 alkyl, Unsubstituted or halogenated C 2-6 acyl, unsubstituted or halogenated C 1-6 alkyl-hydroxy.
  • each chiral carbon atom may optionally be R configuration or S configuration, or a mixture of R configuration and S configuration.
  • the term "compound of the invention” refers to a compound represented by Formula I.
  • the term also includes various crystal forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula I.
  • the term "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.
  • the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt thereof;
  • a is an integer between 0-30.
  • the present invention has optimized the linker connection mode and structure in the compound through a large number of studies. The result shows that the linker’s connection position and structure have a great influence on the activity of the compound. It has Btk degradation activity, and has Btk degradation activity when in meta position.
  • studies have found that when a in the linker structure is 5 or more, the compound of the present invention not only significantly improves anti-tumor activity, but also exhibits a significant inhibitory effect on ibrutinib-resistant tumor cells, which is expected Less technical effect.
  • the compound package of the present invention can form pharmaceutically acceptable salts with inorganic acids, organic acids or bases.
  • the inorganic acid includes but is not limited to hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid;
  • the organic acid includes but not limited to methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzene Sulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, etc.;
  • the alkali includes but is not limited to inorganic Salts and amines.
  • pharmaceutically acceptable salts refers to those salts suitable for contact with tissues of humans and mammals without excessive toxicity, irritation, allergic reactions, etc. according to medical judgment. Pharmaceutically acceptable salts are well known in the art.
  • the present invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I.
  • Prodrugs include compounds in which the precursor molecule is covalently bound to the free carboxyl group of the compound of formula I through a carbonate bond, a carbamate bond, an amide bond, an alkyl ester bond, a phosphate bond, and a phosphoramidate bond. On the hydroxyl, amino or amine group.
  • the preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the preparation method of the compound of formula I includes the steps:
  • a compound of formula III is reacted with a compound of formula II to obtain a compound of formula I, where M 1 is a leaving group such as a hydroxyl group, a halogen, or a sulfonate or W 1 -M1 is an aldehyde or ketone;
  • M 1 is a leaving group such as a hydroxyl group, a halogen, or a sulfonate or W 1 -M1 is an aldehyde or ketone;
  • the method further includes the steps:
  • the compound of formula I can be used for one or more of the following purposes:
  • the disease related to the activity or expression of Bruton's tyrosine protein kinase is a tumor, preferably a tumor selected from the group consisting of non-small cell lung cancer, inflammatory muscle fiber Cell tumor and so on.
  • the compound of formula I of the present invention can be used to prepare a pharmaceutical composition, which comprises: (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable Carrier.
  • the effective amount refers to a therapeutically effective amount or an inhibitory effective amount.
  • the compound of formula I of the present invention can also be used in a method for inhibiting or degrading Bruton's tyrosine protein kinase (Btk).
  • Btk Bruton's tyrosine protein kinase
  • the inhibitory effective amount of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof when administered to the inhibitory object, is 0.001-500 nmol/L, preferably 0.01 -200nmol/L.
  • the present invention also provides a method for treating diseases related to the activity or expression of Bruton's tyrosine protein kinase (Btk), the method comprising: administering a therapeutically effective amount of a compound of formula I to a subject, Or the pharmaceutical composition containing the compound of formula I as an active ingredient.
  • Btk Bruton's tyrosine protein kinase
  • the compound of the present invention has excellent inhibitory activity on Bruton's tyrosine protein kinase (Btk), the compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates , And the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used to treat, prevent, and alleviate diseases related to Btk activity or expression. According to the prior art, the compounds of the present invention can be used to treat diseases including tumors.
  • Btk Bruton's tyrosine protein kinase
  • 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/agent, more preferably, 5-200 mg of the compound of the present invention/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 ), 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 emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • 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) humectant, 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 gly
  • 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 microcapsules 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 form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant.
  • 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.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
  • the daily administered dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • a Btk inhibitor with a novel structure and its preparation and application are provided.
  • the inhibitor can inhibit the activity of Btk at a very low concentration.
  • a pharmaceutical composition for treating diseases related to Btk enzyme activity is provided.
  • the present invention optimizes the linker connection mode and structure in the compound. It was unexpectedly found that the linker's connection position and structure have a great influence on the activity of the compound. For example, the two structural units connecting the piperidine ring are in the right It has no Btk degradation activity when it is in the position, but it has Btk degradation activity when it is in the meta position. In addition, studies have found that when a is 5 or more in the linker structure, the compound of the present invention not only significantly improves anti-tumor activity, but also exhibits a significant inhibitory effect on ibrutinib-resistant tumor cells, which is expected Less technical effect.
  • Example 8 Western blot detection of the activity of the compound to degrade Btk protein
  • Ramos cell line was cultured in an incubator at 37°C, 5% CO 2 and saturated humidity with RPMI1640 medium containing 10% serum.
  • Compound BTK degradation rate Compound BTK degradation rate 1 ++++ 11 ++++ 2 ++++ 20 ++++ 5 ++++ twenty one ++++ 6 ++++ 25 ++++ 8 ++++ 26 ++++ 10 ++++ Control Compound I -
  • control compound I The structure of the control compound I is as follows:
  • Example 9 CTG method to detect the inhibitory effect of compounds on the proliferation of DOHH2 cells (human B-cell lymphoma cells)
  • the inhibitory effect of the compound on the proliferation of DOHH2 cells was tested in vitro by the CTG method.
  • the cells were cultured in RPMI1640 medium with 10% serum. Inoculate a 96-well plate with 1 ⁇ 10 4 cells/well, and place it in a 37°C, 5% CO 2 incubator. The incubation time after adding the test compound (10 ⁇ M) was 72 hours. Then add an appropriate amount of CTG reagent, measure the luminescence value and calculate the inhibition rate.
  • Compound Inhibition rate Compound Inhibition rate 1 ++++ 3 ++++ 2 ++++ 5 ++++ 6 ++++ To To
  • Example 10 CTG method to detect the inhibitory effect of the compound on the proliferation of REC-1 and other tumor cells
  • CTG method was used to test the compound's proliferation inhibitory effects on REC-1 (human mantle cell tumor cells, available from ATCC) and TMD-8 (human diffuse large B lymphoma cells, available from ATCC).
  • the cells were cultured in RPMI1640 medium with 10% fetal bovine serum. Inoculate a 96-well plate with 1 ⁇ 10 4 cells/well, and place it in a 37°C, 5% CO 2 incubator. The incubation time after adding the test compound (10 ⁇ M) was 72 hours. Then add an appropriate amount of CTG reagent, measure the luminescence value, and calculate the inhibition rate.
  • TMD-8 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum FBS. The cells were placed in a 5% CO 2 incubator at 37°C.
  • the animals that are too large, too small, or have irregular tumor shapes are eliminated, 30 tumor-bearing mice with a tumor volume of 101.34 ⁇ 209.86 mm 3 are selected, and the animals are divided into 3 groups by random block method
  • the groups are the model group, the control compound 1 group, and the compound 6 group, with 10 mice in each group.
  • the day of grouping is recorded as Day 0, and the administration is started according to the animal body weight, and the dosage is 30 mg/kg.
  • the calculation formula is as follows:
  • Tumor inhibition rate (1-administration group tumor volume/model group tumor volume)*100%
  • control compound 1 The structure of control compound 1 is as follows:
  • Example 12 Western blot detection of the p-Btk inhibitory activity of the compound in the Btk-C481S mutant Hela cell line
  • BTK(Cys481Ser) drives ibrutinib resistance via ERK1/2 and protects BTK(wild-type) MYD88 -mutated cells by a paracrine mechanism.Blood.2018;131(18):2047-2059.), cultured in an incubator at 37°C, 5% CO 2 , and saturated humidity with DMEM high glucose medium containing 10% fetal bovine serum .
  • DMSO control group ibrutinib (100nM) group, compound 2 or 6 (100nM) administration group
  • collect cells after treatment for 24 hours add pre-cooled cell lysate, place on ice for 10 minutes, extract total cell protein, BCA Method to determine protein concentration and quantify.
  • compound 6 of the present invention has significant degradation activity on Btk-C481S mutant protein in Hela cells, and can significantly inhibit p-Btk, while ibrutinib cannot degrade Btk-C481S mutant protein, and can hardly inhibit p-Btk. Btk. It shows that the compound of the present invention can overcome ibrutinib resistance.

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Abstract

La présente invention concerne un composé chimique ayant une activité de dégradation de Btk. De façon spécifique, la présente invention concerne un composé chimique tel que représenté dans la formule I ; les définitions de chaque groupe sont telles que définies dans la description. Le composé chimique de la présente invention a une activité inhibitrice de Btk satisfaisante et peut dégrader la Btk ; il peut être utilisé pour préparer un médicament pour le traitement d'une maladie liée à l'activité de Btk. (I)
PCT/CN2020/077404 2019-03-02 2020-03-02 Composé chimique ayant une activité de dégradation de btk Ceased WO2020177657A1 (fr)

Priority Applications (1)

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