WO2021047677A1 - Inhibiteur de l'irak4 kinase et sa préparation et son utilisation - Google Patents

Inhibiteur de l'irak4 kinase et sa préparation et son utilisation Download PDF

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WO2021047677A1
WO2021047677A1 PCT/CN2020/115143 CN2020115143W WO2021047677A1 WO 2021047677 A1 WO2021047677 A1 WO 2021047677A1 CN 2020115143 W CN2020115143 W CN 2020115143W WO 2021047677 A1 WO2021047677 A1 WO 2021047677A1
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alkyl
substituted
unsubstituted
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compound
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段文虎
丁健
陈运
谢华
张惠斌
周金培
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中国科学院上海药物研究所
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a compound with IRAK4 kinase inhibitory activity and its preparation and application.
  • Interleukin-1 receptor-associated kinase 4 is a serine/threonine kinase directly located in the interleukin-1 (IL-1) receptor family (IL-1, IL-18 and IL-33) Receptors) and Toll-like receptors (TLRs, except TLR3) downstream are the key signal nodes for the transduction of innate immunity.
  • IL-1 family receptors and TLRs recruit the primary response gene 88 (MyD88) for myeloid differentiation of the scaffold adaptor protein through the conserved Toll/IL receptor (TIR) domain.
  • MyD88 primary response gene 88
  • MyD88 in turn uses the homotypic interaction of the death domain to recruit IRAK4, thereby activating downstream signaling pathways such as NF- ⁇ B and AP-1.
  • IRAK4 has a dual role of kinase and backbone. It mediates downstream signaling pathways by forming a larger signaling complex with MyD88 and IRAK1—myd bodies.
  • IRAK4 is constitutively activated, and in HEK293 cells expressing IL-1 receptor, human THP1 monocytes or primary human macrophages stimulated by Pam3CSK4, IL-1 stimulation does not significantly increase its intrinsic activity on Pellino1 .
  • IRAK4 In plasmacytoid dendritic cells with inactivated IRAK4 kinase, TLR7 and TLR9-mediated IFN- ⁇ / ⁇ production is eliminated. Obviously, the kinase activity of IRAK4 is not only necessary for TLRs (2, 4, 5, 7 and 9) to induce the production of pro-inflammatory cytokines and chemokines, but also for the induction of IFN- ⁇ / ⁇ mediated by TLR7 and TLR9. of. Although IRAK4 occupies an extremely important position in innate immunity, studies have shown that the TIR-MyD88-IRAK4 signaling pathway is essential for the protective immunity of a small number of purulent bacteria, but it is redundant for the host defenses of most natural infections.
  • rheumatoid arthritis characteristic anti-acidification antibody immune complex
  • SLE systemic lupus erythematosus
  • TLR TLRs
  • the activation of TLR can promote the differentiation of B cells into antibody-producing plasma cells, which can be used to activate the adaptive immune system.
  • Genetically modified mice with IRAK4 deletion or kinase-inactivated IRAK4 expression showed a certain degree of impaired immune response, such as the impaired induction of TNF ⁇ and IL-6 when induced by bacterial lipopolysaccharide (LPS).
  • mice are also resistant to experimentally induced arthritis, atherosclerosis, and MOG-induced encephalomyelitis.
  • IRAK4 kinase-inactivated mice have also been shown to be resistant to the development of Alzheimer's disease, a process thought to be due to reduced IL-1 production and signal transduction.
  • small molecule inhibitors of IRAK4 have been used to inhibit TLR-induced inflammatory signal transduction in vitro and in vivo.
  • Studies have shown that IRAK4 inhibitors can reduce gout-like inflammation in a uric acid-induced peritonitis model, ischemia-induced inflammation in 5/6 nephrectomy rats, and a mouse model of lupus erythematosus. Therefore, IRAK4 is considered to be an important pharmacological target for the treatment of chronic inflammatory diseases.
  • B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) 29% of cases have the mutation of MyD88 Leucine 265 to proline (L265P), which is the most important in ABC DLBCL Of activating mutations, in which IRAK4 assumes most of the functions of MYD88.
  • Nimbus's compounds ND-2110 and ND-2158 have outstanding anti-tumor effects in the xenograft OCI-Ly10 mouse model. They also have a good combined effect with the BTK inhibitor ibrutinib and the BCL-2 inhibitor ABT-199.
  • pancreatic ductal carcinoma does not exceed 6%.
  • p-IRAK4-negative tumor patients pIRAK4-positive PDAC patients have a higher chance of recurrence after surgery and a worse prognosis.
  • shRNA and CRISPR/Cas9n technology the researchers found that after inhibiting IRAK4, gemcitabine and 5-fluorouracil can kill pancreatic ductal cancer cells more effectively.
  • IRAK1/4 can drive the production of inflammatory cytokines and chemokines, allowing cancer-related fibroblasts (CAFs) to metastasize, invade and proliferate.
  • CAFs cancer-related fibroblasts
  • BALF bronchoalveolar infusion fluid
  • the object of the present invention is to provide a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers, its pharmaceutically acceptable salts, its prodrugs, Hydrate or solvate and preparation method and use thereof.
  • the first aspect of the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers, its pharmaceutically acceptable salts, its prodrugs, and its hydration Substance or solvate:
  • X, Y, Z, or W are independently selected from CH or N; and when X, Y, Z or W is CH, the H atom may be substituted by a substituent selected from the following group: halogen, C1-C3 alkane Group, C2-C6 acyl, C1-C3 alkoxy, trifluoromethoxy, trifluoroethoxy;
  • Ring A is a 3-8 membered saturated heterocyclic ring (including monocyclic, fused ring or spiro ring) containing 1-2 heteroatoms selected from N, O and S, and the saturated heterocyclic ring is optionally substituted by one or more A halogen, oxo, carboxyl, cyano, hydroxyl, substituted or unsubstituted 5-6 membered heterocycle, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl substituted, so
  • the substitution refers to substitution by one or more halogen, C1-C3 alkyl or hydroxy;
  • R 1 is selected from -NR 2 R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-11 membered saturated or partially saturated heterocyclic group, the substituents represented by R a;
  • R 2 and R 3 are each independently selected from hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, -(C0-C3 alkyl)-6-10 membered aromatic Group, -(C0-C3 alkyl)-5-10 membered heteroaryl group, -(C0-C3 alkyl)-saturated or partially saturated 4-10 membered heterocyclic group, said substitution refers to halogen, hydroxy, amino , Cyano or amide substitution;
  • R 2 and R 3 may form with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring optionally substituted with one or more substituents R a;
  • R 5 and R 6 are each independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted 4-6 membered heterocyclic ring, and the substituted Refers to substituted by one or more C1-C3 alkyl, hydroxyl, halogen, carboxylic acid, C2-C6 carboxylic acid ester.
  • R 2 and R 3 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring, and the heterocyclic ring is optionally substituted by one or more R b ;
  • R 1 is a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, and the aryl group or heteroaryl group is optionally substituted by one or Multiple R c substitutions;
  • R 1 is a substituted or unsubstituted 5-6 membered aromatic heterocyclic ring, and the aromatic heterocyclic ring is optionally substituted by one or more R c .
  • the ring A is a substituted or unsubstituted group selected from the following group:
  • each p is 1, 2 or 3 independently.
  • the R 1 is selected from the following group: -NR 2 R 3 , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5- 10-membered heteroaryl group, substituted or unsubstituted 3-6 membered saturated or partially saturated heterocyclic group, substituted or unsubstituted (3-6 membered saturated or partially saturated heterocyclic group) and 5-6 membered heteroaryl group.
  • ring A is selected from the following group:
  • R 4 is selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, and the substitution refers to substitution by one or more halogens.
  • the compound is selected from the compounds shown in Table 1.
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the following components:
  • the pharmaceutical composition also includes one or more active substances selected from the group consisting of immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, vinblastine compounds, paclitaxel, DNA Injury agents, Bcl-2 inhibitors, BTK inhibitors, JAK inhibitors, Hsp90 inhibitors, ALK inhibitors, FLT3 inhibitors, PI3K inhibitors and SYK inhibitors.
  • active substances selected from the group consisting of immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, vinblastine compounds, paclitaxel, DNA Injury agents, Bcl-2 inhibitors, BTK inhibitors, JAK inhibitors, Hsp90 inhibitors, ALK inhibitors, FLT3 inhibitors, PI3K inhibitors and SYK inhibitors.
  • the third aspect of the present invention provides a compound of the first aspect of the present invention, its stereoisomers, geometric isomers, tautomers, its pharmaceutically acceptable salts, its prodrugs, and its
  • the use of the hydrate or solvate or the pharmaceutical composition according to the second aspect of the present invention is used for a use selected from the following group:
  • the drug is also used to inhibit a protein kinase selected from the group consisting of FLT3, RET, VEGFR, ErbB2, or a combination thereof.
  • the IRAK4-mediated disease is selected from the group consisting of cancer, autoimmune disease, inflammatory disease and thromboembolic disease.
  • the cancer is selected from the group consisting of diffuse large B-cell lymphoma, multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, acute myeloid leukemia, chronic lymphocytic leukemia , Small lymphocytic lymphoma, pancreatic ductal carcinoma.
  • the autoimmune disease and inflammatory disease are selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, systemic erythema Lupus, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and intestinal stress syndrome.
  • the present inventors provided a novel IRAK4 inhibitor compound. Compared with the prior art IRAK4 inhibitor, the compound has significantly improved activity, so it can be used for the preparation of prevention and/ Or treat cancer, inflammatory diseases and autoimmune diseases and other related diseases mediated by IRAK4. Based on the above findings, the inventor completed the present invention.
  • heterocyclyl is a cyclic group having 1, 2, 3, 4, or 5 heteroatoms selected from the group consisting of O, N, or S.
  • the alkyl group is preferably an aliphatic alkyl group, which can be a linear alkyl group, a branched chain alkyl group, a spiro cycloalkyl group, a bridged cycloalkyl group, an alkenyl alkyl group, an alkynyl alkyl group, a cycloalkyl group, Cycloalkenyl, cycloalkynyl, alkoxyalkyl, alkoxyacylalkyl, cycloalkylalkyl, including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, tert-butyl, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, allyl, propargyl, cyclobutenyl, cyclohexenyl; in the form of "
  • the alkenyl group is preferably a vinyl group, a propenyl group, a butenyl group, a styryl group, a phenylpropenyl group, or a similar group.
  • the cycloalkyl group may be a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which includes 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably cycloalkyl Contains 3 to 6 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, etc.
  • polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • the heterocyclic group refers to a saturated or partially saturated monocyclic or polycyclic cyclic substituent, including 4 to 10-membered heterocyclic groups, and the heterocyclic group is one or more heteroatoms (nitrogen, (Oxygen, sulfur) saturated or unsaturated monocyclic, fused ring, spiro ring, fused ring, bridged ring, etc.
  • heterocyclic group described herein includes, but is not limited to, a group selected from the group consisting of morpholine ring, piperidine ring, piperazine ring, N-alkyl or acyl substituted piperazine ring, homopiperazine ring , N-alkyl or acyl substituted homopiperazine ring, pyrrole, tetrahydropyrrole, 7H-purine, etc.
  • the aryl group refers to a 6 to 10-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, and the group has a conjugated ⁇ -electron system, such as phenyl and Naphthyl.
  • the aryl ring may be condensed with a heterocyclic group, a heteroaryl group or a cycloalkyl ring.
  • Non-limiting examples include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, and benzopyridine. Azole, quinoline, benzindole, benzodihydrofuran.
  • the heteroaryl group refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl group can be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring.
  • the structural formula described in the present invention is intended to include all tautomers, optical isomers and stereoisomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers).
  • Conformers For example, R and S configurations containing asymmetric centers, (Z), (E) isomers and (Z), (E) conformers of double bonds. Therefore, individual stereochemical isomers, tautomers or enantiomers, diastereomers or geometric isomers or conformational isomers or mixtures of tautomers of the compounds of the present invention All belong to the scope of the present invention.
  • tautomers means that structural isomers with different energies can exceed the low energy barrier to convert into each other.
  • proton tautomers ie, proton transfer
  • interconversion through proton transfer such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
  • Valence tautomers include interconversion through some bond-forming electron recombination.
  • the pharmaceutically acceptable salts are not particularly limited, and preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates and aryl sulfonates;
  • the inorganic acid salts include hydrochlorides , Hydrobromide, nitrate, sulfate, phosphate, etc.;
  • the organic acid salt includes formate, acetate, propionate, benzoate, maleate, fumarate, succinate Acid salt, tartrate, citrate, etc.;
  • the alkyl sulfonate includes methane sulfonate, ethyl sulfonate, etc.;
  • the aryl sulfonate includes benzene sulfonate, p-toluene sulfonate Wait.
  • the pharmaceutically acceptable solvate of the compound represented by the general formula (I) is not particularly limited, and preferably includes: a compound represented by the general formula (I) and water, ethanol, isopropanol, diethyl ether, Solvates such as acetone.
  • the present invention provides a compound represented by formula (I), its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, its prodrug, its hydrate or solvate ,
  • each group has the same definition as above.
  • any one of X, Y, Z, W, ring A, and R 1 is the corresponding group in the specific compound described in Table 1.
  • the compound is preferably the compound prepared in the embodiment.
  • the compound is selected from the compounds listed in Table 1.
  • 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, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
  • a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • alkali metal salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium salt
  • ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
  • methylamine salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
  • prodrug includes a type of compound that itself can be biologically active or inactive, and when taken by a proper method, it undergoes metabolism or chemical reaction in the human body to transform into a class of compounds, or the compound is composed of Salt or solution.
  • the prodrugs include (but are not limited to) carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, and azo compounds of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
  • Compound 5 can be reduced under palladium-carbon/hydrogen or iron powder/ammonium chloride conditions to obtain compound 6;
  • Compound II-5 can be reduced under palladium carbon/hydrogen to obtain compound II-6;
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one selected from the group consisting of the compound represented by formula (I), its pharmaceutically acceptable salt, its prodrug, its hydrate and solvate Or multiple and optionally, pharmaceutically acceptable carriers, which can be used to treat diseases related to IRAK4 activity or expression level.
  • the pharmaceutical composition can be prepared into various forms according to different administration routes.
  • the compound of the present invention has excellent inhibitory activity against IRAK4, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and containing the compound of the present invention as the main active ingredient
  • the pharmaceutical composition can be used to treat, prevent and alleviate diseases related to IRAK4 activity or expression, for example, to prevent and/or treat diseases related to abnormal expression of IRAK4 signaling pathway.
  • the compounds of the present invention can be used to treat the following diseases: cancer, autoimmune diseases, inflammatory diseases and thromboembolic diseases.
  • the compounds can be used to treat the following diseases: diffuse large B-cell lymphoma , Multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, pancreatic ductal carcinoma, rheumatoid arthritis, osteoarthritis, adolescents Arthritis, chronic obstructive pulmonary disease, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis and intestinal stress syndrome.
  • diffuse large B-cell lymphoma Multiple myeloma
  • mantle cell lymphoma Waldenstrom's macroglobulinemia
  • acute myeloid leukemia chronic lymphocytic leukemia
  • small lymphocytic lymphoma pancreatic ductal carcinoma
  • rheumatoid arthritis osteo
  • 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 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 administration method 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, some 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 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.
  • 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.
  • the dosage is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • Methyl 2-(2,4-difluorophenyl)acetate (5g, 26.8mmol) was dissolved in anhydrous tetrahydrofuran (60mL), argon replacement protection, and methylmagnesium bromide solution (27mL) was added dropwise at -78°C 3M diethyl ether solution, 80.5mmol), after dripping, after 10 minutes, it was transferred to room temperature and reacted for 1 hour. TLC detected that the reaction was completed.
  • Methyl 2-(4-chloro-2-fluorophenyl)acetate (5.37g, 26.5mmol) was dissolved in anhydrous tetrahydrofuran (60mL), protected by argon replacement, and methylmagnesium bromide solution was added dropwise at -78°C (26.5mL 3M ether solution), after dripping, turn to room temperature after 15 minutes and react for 1 hour. TLC detects that the reaction is complete. Saturated ammonium chloride solution was added dropwise under ice bath to quench, ethyl acetate (200 mL) and water were extracted, the ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 1 Preparation of tert-butyl (4-bromopyridin-2-yl)carbamate
  • Step 2 (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl) t-butyl carbamate preparation
  • Step 3 Preparation of ethyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylate
  • Ethyl 2-chlorooxazole-4-carboxylate (110mg, 626 ⁇ mol), (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyridin-2-yl)tert-butyl carbamate (240mg, 751 ⁇ mol), sodium carbonate (199mg, 1.88 ⁇ mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride
  • Palladium (23mg, 31 ⁇ mol) and ethylene glycol dimethyl ether/water (10mL/1mL) were added to the reaction flask, replaced with argon several times, and reacted at 90°C overnight.
  • Step 3 (4-(4-((6-(4-(hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl ) Preparation of carbamoyl) oxazol-2-yl) pyridin-2-yl) tert-butyl carbamate
  • Step: 4 2-(2-Aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3- Preparation of dihydrobenzofuran-5-yl)oxazole-4-carboxamide
  • Step 1 R)-(4-(4-((6-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2,2-dimethyl-2,3-di Preparation of tert-butyl hydrobenzofuran-5-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate
  • Step 2 (R)-N-(6-(3-Aminopiperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-( Preparation of 2-aminopyridin-4-yl)oxazole-4-carboxamide trifluoroacetate
  • N-(6-(4-(aminomethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5 can be prepared by a similar method in Example 2.
  • 2-(2-Aminopyridin-4-yl)-N-(6-(4-cyanopiperidin-1-yl)-2,2-dimethyl-2 can be prepared by a similar method in Example 1. ,3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(6-(3-(hydroxymethyl)pyrrolidin-1-yl)-2,2-dimethyl can be prepared by a similar method in Example 1.
  • Yl-2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxamide can be prepared by a similar method in Example 1.
  • Step 2 Preparation of 6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine
  • 6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2,2-dimethyl-2,3-dihydro can be prepared by a method similar to steps 1 and 2 of Example 1.
  • Step 3 2-(2-Aminopyridin-4-yl)-N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2,2-dimethyl- Preparation of 2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxamide
  • 2-(2-Aminopyridin-4-yl)-N-(6-(4-(2-hydroxypropane-2-yl)piperidin-1-yl)-2 can be prepared by a similar method in Example 1. ,2-Dimethyl-2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2,2-dimethyl-2 can be prepared by a similar method in Example 1. 3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(6-(4-(cyanomethyl)piperidin-1-yl)-2,2-di can be prepared by a similar method in Example 1. Methyl-2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • Step 1 Preparation of tert-butyl 4-(2-amino-2-oxoethyl)piperazine-1-carboxylate
  • Step 4 N-(6-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5 -Yl)-2-(2-aminopyridin-4-yl)oxazole-4-carboxamide
  • Step 1 Preparation of methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methylpropionate
  • Methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methylpropionate (2.88g, 12.51mmol) was dissolved in anhydrous tetrahydrofuran (75mL), and potassium tert-butoxide (3.51g , 31.28mmol) and reacted at 50°C overnight. TLC detected the completion of the reaction. Ethyl acetate (100mL) was added to separate the organic layer, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a brownish-yellow solid.
  • Step 4 Preparation of methyl 6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylate
  • Step 7 Preparation of (1-(5-amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol
  • Step 8 2-(2-Aminopyridin-4-yl)-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl- Preparation of 2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxamide
  • the 2-(2-aminopyridin-4-yl)-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-bis-form can be prepared by a similar method in Example 14. Hydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • Step 4 2-(2-Aminopyridin-4-yl)-N-(7-morpholino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxa Preparation of azin-6-yl)oxazole-4-carboxamide
  • the 2-(2) can be prepared from 6-amino-7-morpholino-2H-benzo[b][1,4]oxazine-3(4H)-one by a method similar to steps 3 and 4 in Example 1. -Aminopyridin-4-yl)-N-(7-morpholino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-yl)oxa Azole-4-carboxamide.
  • Example 16 The method similar to Example 16 can be used to prepare 2-(2-aminopyridin-4-yl)-N- from 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine. (7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)oxazole-4-carboxamide.
  • Example 26 The method similar to Example 26 can be used to prepare 2-(2-aminopyridin-4-yl)-N- from 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine. (7-(4-(Hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)oxazole-4- Formamide.
  • Methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (prepared according to the method reported in WO2013/079505) (200mg, 648 ⁇ mol) was dissolved in methanol (8mL), and triethylamine (108 ⁇ L, 777 ⁇ mol) was added ) And isopropylamine (66 ⁇ L, 777 ⁇ mol), reacted at 70°C for 6 hours. TLC detects the completion of the reaction. Extracted with ethyl acetate and 1 mol/L hydrochloric acid aqueous solution. The aqueous layer was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. Concentrate to dryness. Put directly into the next step reaction.
  • Step 4 2-(2-Aminopyridin-4-yl)-N-(2-isopropyl-6-morpholino-1-oxoisoindol-5-yl)oxazole-4-carboxamide
  • 2-(2-Aminopyridin-4-yl)-N can be prepared from 5-amino-2-isopropyl-6-morpholine isoindol-1-one by a method similar to steps 3 and 4 in Example 1. -(2-isopropyl-6-morpholino-1-oxoisoindol-5-yl)oxazole-4-carboxamide.
  • 6-Fluoro-2,2-dimethyl-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (40mg, 188 ⁇ mol) was dissolved in morpholine (1mL) and N, N -Dimethylformamide (1 mL), react at room temperature for 2 hours, TLC detects that the reaction is complete, extract with ethyl acetate and water, wash the ethyl acetate layer with water, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter, concentrate under reduced pressure to dryness, and put directly into the next step reaction.
  • Step 7 2-(2-Aminopyridin-4-yl)-N-(2,2-dimethyl-6-morpholino-2,3-dihydrofuro[2,3-b]pyridine- Preparation of 5-yl)oxazole-4-carboxamide
  • 2-(2-Aminopyridin-4-yl)-N-(6-(furan-3-yl)-2,2-dimethyl-2,3-dihydro can be prepared by a similar method in Example 24 Benzofuran-5-yl)oxazole-4-carboxamide.
  • 6-Fluoro-5-nitro-3H-spiro tert-butyl[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl can be prepared by a method similar to steps 1-5 in Example 29 ester.
  • Step 4 2-(2-Aminopyridin-4-yl)-N-(6-(pyridin-4-yl)-1'-(2,2,2-trifluoroacetyl)-3H-spiro[benzene Preparation of 2-furan-2,4'-piperidin]-5-yl)oxazole-4-carboxamide
  • 2-(2-Aminopyridin-4-yl)-N-(6-morpholino-3H-spiro[benzofuran-2,4'-piperidine] can be prepared by a method similar to step 6 in Example 29 -5-yl)oxazole-4-carboxamide.
  • Step 1 Preparation of tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate
  • Step 2 Preparation of 6-chloro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 4 Preparation of 1-(6-chloro-3H-spiro[benzofuran-2,4'-piperidine]-1'-yl)-2,2,2-trifluoroethane-1-one
  • Step 7 Preparation of 6-chloro-5-nitro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 8 Preparation of 5-nitro-6-(pyridin-4-yl)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 9 Preparation of 5-amino-6-(pyridin-4-yl)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 10 2-(2-Aminopyridin-4-yl)-N-(6-(pyridin-4-yl)-3H-spiro[benzofuran-2,4'-piperidin]-5-yl) Preparation of oxazole-4-carboxamide trifluoroacetate
  • 2-(2-Aminopyridin-4-yl)-N-(6-(4-chloro-2-fluorophenyl)-2,2-dimethyl-2 can be prepared by a similar method in Example 24 3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(2,2-dimethyl-6-(2-methylpyridin-4-yl)-2 can be prepared by a similar method in Example 24, 3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(2,2-dimethyl-6-(6-methylpyridin-3-yl)-2 can be prepared by a similar method in Example 24, 3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(2,2-dimethyl-6-(6-(trifluoromethyl)pyridin-3-yl) can be prepared by a similar method in Example 24 )-2,3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(6-(2-methoxypyridin-4-yl)-2,2-dimethyl-2 can be prepared by a similar method in Example 24 ,3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • the 2-(2-aminopyridine-) can be prepared from 6-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine by a method similar to steps 3 and 4 in Example 1. 4-yl)-N-(6-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(6-(6-cyanopyridin-3-yl)-2,2-dimethyl-2 can be prepared by a similar method in Example 24 3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • Methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (prepared according to WO2013/079505 report method) (975mg, 3.16mmol) and (R)-4-amino-3-fluoro-2 -Methylbutan-2-ol (prepared according to the method reported in WO2015/103453) (459mg, 3.79mmol) was dissolved in methanol (30mL) and placed in a sealed tube, added with triethylamine (527 ⁇ 5), and reacted at 70 7 for 4 hours, Concentrate under reduced pressure, add ethyl acetate (50mL) to dissolve, wash with 1mol/L HCl solution, and then extract the aqueous layer with ethyl acetate (15mL*2).
  • Step 3 Preparation of (R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(pyridin-4-yl)isoindolin-1-one
  • Step 4 (R)-2-(2-Aminopyridin-4-yl)-N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxo-6-( (Pyridin-4-yl)isoindolin-5-yl)oxazole-4-carboxamide
  • 2-(2-Aminopyridin-4-yl)-N-(6-(3-fluoropyridin-4-yl)-2,2-dimethyl-2,3 can be prepared by a similar method in Example 24 -Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • Step 2 Preparation of tert-butyl (5-chloro-2-ethoxy-4-nitrophenyl) carbamate
  • Step 4 Preparation of tert-butyl (4-amino-2-ethoxy-5-(methylamino)phenyl)carbamate
  • Step 5 4-(6-((tert-butoxycarbonyl)amino)-5-ethoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2-dimethyl Preparation of methyl butyrate
  • Step 6 Preparation of methyl 4-(6-amino-5-ethoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2-dimethylbutyrate
  • Step 7 4-(6-(2-(2-Aminopyridin-4-yl)oxazole-4-carboxamido)-5-ethoxy-1-methyl-1H-benzo[d]imidazole -2-yl)-2,2-dimethylbutyrate methyl ester
  • Step 3 Preparation of tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate
  • Step 4 Preparation of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate
  • 2-(2-Aminopyridine-) can be prepared from tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate by a similar method in Example 2. 4-yl)-N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)oxazole-4-carboxamide trifluoroacetate.
  • Step 4 2-(2-Aminopyridin-4-yl)-N-(2-(hydroxymethyl)-2-methyl-6-(pyridin-4-yl)-2,3-dihydrobenzo Preparation of furan-5-yl)oxazole-4-carboxamide
  • 2-(2-Aminopyrimidin-4-yl)-N-(2,2-dimethyl-6-(pyridin-4-yl)-2,3-dihydro can be prepared by a similar method in Example 24 Benzofuran-5-yl)oxazole-4-carboxamide.
  • 2-(2-Aminopyridin-4-yl)-N-(2,2-dimethyl-6-(2-methylpyrimidin-5-yl)-2 can be prepared by a similar method in Example 24, 3-Dihydrobenzofuran-5-yl)oxazole-4-carboxamide.
  • Comparative compound 1 is the same as compound I-5, except that the ortho position of the N atom of pyridine is a methyl group.
  • Comparative compound 2 is the same as compound I-1, except that the N atom pyridine ortho position is a methyl group.
  • Comparative compound 3 is the same as compound I-5, the difference is that the pyridine N atom is not substituted at the ortho position.
  • 1 H NMR 400MHz, Chloroform-d
  • ⁇ 10.00 s, 1H
  • 8.95-8.76 m, 2H
  • 8.01-7.86 m, 2H
  • 6.65 s, 1H
  • Comparative compound 4 is the same as compound I-5, except that the ortho amino group of the N atom of pyridine is substituted by acetyl.
  • Z'-LYTE TM Kinase Kit was used to detect the kinase inhibitory activity of the compound.
  • the main steps are as follows: add compound solutions of different concentrations or solvent controls at 2.5 ⁇ L/well in a 384-well plate, and set up two replicate wells for each concentration.
  • the solvent control group is divided into three types: 0% phosphorylation, 0% inhibition and 100% phosphorylation.
  • the enzyme and substrate were diluted with kinase buffer to a mixture of 1.5 ng/well and 2 ⁇ M/well. The mixture was used in the test compound group and the 0% phosphorylation and 0% inhibition group, and 5 ⁇ L was added to each well.
  • the compound of the present invention has a significant inhibitory effect on IRAK4 kinase, wherein the inhibitory activity of compound I-5 on IRAK4 is significantly improved compared to comparative compounds 1, 3, and 4, and compound I-1 is compared with comparative compounds 1.
  • Compound 2 has a significant improvement, indicating that the ortho amino group of the pyridine N atom plays an important role in the inhibitory activity of IRAK4. When the ortho amino substituent of the pyridine N atom is replaced, the activity of the compound deteriorates significantly.
  • the compound inhibits the growth of OCI-LY-10 cell line (including MYD88 L265P mutant cells)
  • CCK-8 (Cell Counting Kit-8) staining method was used to detect the compound's inhibitory effect on cell proliferation.
  • the steps of the CCK-8 staining method are as follows: According to the cell growth rate, the OCI-LY-10 cells in the logarithmic growth phase are seeded in a 96-well culture plate at different concentrations at 90 ⁇ L/well. After the cells have grown overnight, add different concentrations The compound is 10 ⁇ L/well, each concentration is set with three multiple wells, and the corresponding solvent control and cell-free blank control wells are set. Place the cells in the incubator for 72 hours and discard the cell culture solution, and add 10 ⁇ L/well of CCK-8 reagent.
  • the IC 50 value of the half inhibition amount was obtained by fitting the inhibition curve with the four-parameter method with the software attached to the microplate reader.
  • Example Compound IC 23 (I-23) Embodiment 50 is 0.291 ⁇ 0.096 ⁇ M;
  • Example 24 (I-24) Compound IC 50 value of 1.586 ⁇ 0.280 ⁇ M.
  • the compound inhibits the growth of U2932 cell line (without MYD88 L265P mutant cells)
  • CCK-8 (Cell Counting Kit-8) staining method was used to detect the compound's inhibitory effect on cell proliferation.
  • the steps of the CCK-8 staining method are as follows: According to the cell growth rate, the OCI-LY-10 cells in the logarithmic growth phase are seeded in a 96-well culture plate at different concentrations at 90 ⁇ L/well. After the cells have grown overnight, add different concentrations The compound is 10 ⁇ L/well, each concentration is set with three multiple wells, and the corresponding solvent control and cell-free blank control wells are set. Place the cells in the incubator for 72 hours and discard the cell culture solution, and add 10 ⁇ L/well of CCK-8 reagent.
  • the IC 50 value of the half inhibition amount was obtained by fitting the inhibition curve with the four-parameter method with the software attached to the microplate reader.
  • the IC 50 value of the compound of Example 24 (I-24) is greater than 50 ⁇ M, indicating that the compound of Example 24 (I-24) has the effect of selectively inhibiting MYD88 L265P mutant diffuse large B-cell lymphoma.
  • the ELISA method was used to detect the inhibitory effects of the compounds on a series of kinase activities.
  • This series of kinases includes VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- ⁇ , PDGFR- ⁇ , RET, C-Kit, FLT3, EGFR, ErbB2, ErbB4, Src, Abl, EPH-A2, IGF1R, IR , FGFR1, FGFR2, FGFR3, FGFR4, BTK, FAK, CSF1R and ITK, all purchased from Europhins.
  • the main steps of ELISA are as follows: the enzyme reaction substrate Poly(Glu, Tyr) 4:1 is reacted at 37°C for 12-16h to coat the plate with potassium ion-free PBS, and then the liquid in the well is discarded. Wash the plate three times with T-PBS, and place it in a 37°C oven to dry the ELISA plate for 1-2 hours for later use. Add ATP diluted in reaction buffer (final concentration 5mM) solution, compound or solvent control to each well, then add kinase to start the reaction, and react at 37°C in a shaker for 1 hour. The plate was washed three times with T-PBS, and the antibody PY99 was added to react at 37°C for 0.5h.
  • Example 23 (I-23) and Example (I-24) have good selectivity to the tyrosine kinase profile, and at the same time have inhibitory effects on VEGFR-3, RET, FLT3, and ErbB2 .
  • the enzyme-linked immunosorbent assay (Enzyme-Linked Immunosorbent Assay, ELISA) was used to detect the kinase's ability to phosphorylate the substrate, and to calculate the inhibitory effect of the compound on the kinase activity.
  • the kinases were Flt-3, Flt-3 ITD and Flt-3 D835Y (purchased from Eurofins).
  • the main steps of ELISA are as follows: Enzyme reaction substrate Poly(Glu, Tyr) 4:1 is diluted with potassium ion-free PBS to 2.5 ⁇ g/well, and reacted at 37°C for 12-16h to coat the ELISA plate for use.
  • reaction buffer 50mM HEPES pH 7.4, 20mM MgCl 2 , 0.1mM MnCl 2 , 0.2mM Na 3 VO 4 , 1mM DTT
  • ATP final concentration 5 ⁇ M
  • reaction buffer 50mM HEPES pH 7.4, 20mM MgCl 2 , 0.1mM MnCl 2 , 0.2mM Na 3 VO 4 , 1mM DTT
  • the kinase starts the reaction, and the reaction is performed on a shaker at 37°C for 1 hour.
  • the plate was washed three times with T-PBS, and the antibody PY99 was added and reacted in a shaker at 37°C for 0.5h.
  • Example 24 has high inhibitory activity on FLT3 kinase, FLT3-ITD and FLT3 D835Y mutant kinase.
  • Leukemia cell line Acute myeloid leukemia cell line MV4-11 (expressing FLT3-ITD mutant gene) MOLM-3 (expressing FLT3-ITD mutant gene and wild-type FLT3 gene)
  • inhibition rate (%) (OD negative control well-OD administration well)/OD negative control well ⁇ 100%.
  • IC 50 value was obtained by the four-parameter regression using the software that came with the microplate reader.
  • Example 24 significantly inhibited the proliferation activity of the acute myeloid leukemia cell lines MV4-11 and MOLM-3 expressing the FLT3-ITD mutation.

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Abstract

L'invention concerne un inhibiteur d'IRAK4 kinase, et son mode de préparation et son utilisation, et porte plus précisément sur un composé représenté par la formule (I), un stéréoisomère de ce dernier, un isomère géométrique de ce dernier, un tautomère de ce dernier, un sel pharmaceutiquement acceptable de ce dernier, un promédicament de ce dernier, un hydrate ou un solvate de ce dernier, et un procédé de préparation de ces derniers et leur utilisation. Par comparaison avec l'inhibiteur de l'IRAK4 de l'était de la technique, le composé présente une nette amélioration de l'activité, et peut donc être utilisé pour préparer des médicaments destinés à la prévention et/ou au traitement de maladies associées médiées par l'IRAK4 telles que les cancers, les maladies inflammatoires et les maladies auto-immunes. (I)
PCT/CN2020/115143 2019-09-12 2020-09-14 Inhibiteur de l'irak4 kinase et sa préparation et son utilisation WO2021047677A1 (fr)

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WO2022156788A1 (fr) * 2021-01-22 2022-07-28 武汉人福创新药物研发中心有限公司 Composé de benzimidazole et son utilisation
WO2024017381A1 (fr) * 2022-07-22 2024-01-25 深圳众格生物科技有限公司 Composé pour inhiber l'activité de l'irak 4 et son utilisation

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CN106456609A (zh) * 2014-06-20 2017-02-22 奥瑞基尼探索技术有限公司 作为irak4抑制剂的取代的吲唑化合物
CN108026065A (zh) * 2015-07-15 2018-05-11 奥列基因发现技术有限公司 作为irak-4抑制剂的吲唑及氮杂吲唑化合物
WO2018178947A2 (fr) * 2017-03-31 2018-10-04 Aurigene Discovery Technologies Limited Composés et compositions pour le traitement de troubles hématologiques
WO2018234343A1 (fr) * 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag Benzofuranes utilisés en tant que modulateurs d'irak4
WO2018234342A1 (fr) * 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag Dérivés d'isoindolinone utilisés en tant que modulateurs d'irak4

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CN1950347B (zh) * 2003-10-23 2012-04-04 Ab科学公司 作为酪氨酸激酶抑制剂的2-氨基芳基噁唑化合物
US20070004660A1 (en) * 2005-06-10 2007-01-04 Baumann Christian A Synergistic Modulation of Flt3 Kinase Using Alkylquinolines and Alkylquinazolines
SG11201401236XA (en) * 2011-10-14 2014-05-29 Ambit Biosciences Corp Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases
KR20160115933A (ko) * 2014-01-10 2016-10-06 오리진 디스커버리 테크놀로지스 리미티드 Irak4 억제제로서의 인다졸 화합물

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Publication number Priority date Publication date Assignee Title
CN106456609A (zh) * 2014-06-20 2017-02-22 奥瑞基尼探索技术有限公司 作为irak4抑制剂的取代的吲唑化合物
CN108026065A (zh) * 2015-07-15 2018-05-11 奥列基因发现技术有限公司 作为irak-4抑制剂的吲唑及氮杂吲唑化合物
WO2018178947A2 (fr) * 2017-03-31 2018-10-04 Aurigene Discovery Technologies Limited Composés et compositions pour le traitement de troubles hématologiques
WO2018234343A1 (fr) * 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag Benzofuranes utilisés en tant que modulateurs d'irak4
WO2018234342A1 (fr) * 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag Dérivés d'isoindolinone utilisés en tant que modulateurs d'irak4

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