WO2021047677A1 - 一类irak4激酶抑制剂及其制备和应用 - Google Patents

一类irak4激酶抑制剂及其制备和应用 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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    • A61K31/5375—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.

Abstract

提供了一类IRAK4激酶抑制剂及其制备和应用，具体地提供了一种式(I)所示化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物及其制备方法和用途。所述的化合物相较于现有技术的IRAK4抑制剂，活性有明显提升，因此可以用于制备预防和/或治疗癌症、炎症性疾病和自身免疫疾病等IRAK4介导的相关疾病。

Description

一类IRAK4激酶抑制剂及其制备和应用 技术领域
本发明涉及药物化学领域，具体地，本发明涉及一种具有IRAK4激酶抑制活性的化合物及其制备和应用。
背景技术
白细胞介素-1受体相关激酶4(IRAK4)是一种丝氨酸/苏氨酸激酶，直接位于白细胞介素-1(IL-1)受体家族(IL-1，IL-18和IL-33受体)和Toll样受体(TLRs，除了TLR3)下游，是转导固有免疫的关键信号节点。当配体结合后，IL-1家族受体和TLRs通过保守的Toll/IL受体(TIR)结构域招募支架衔接蛋白髓样分化初级应答基因88(MyD88)。MyD88反过来利用死亡结构域(death domain)的同型相互作用招募IRAK4，从而激活下游信号通路，如NF-κB和AP-1。IRAK4具有激酶和骨架双重作用，其通过与MyD88和IRAK1形成更大的信号复合物—myd小体来介导下游的信号通路。IRAK4组成型激活的，并且在表达IL-1受体的HEK293细胞，Pam3CSK4刺激的人THP1单核细胞或原代人巨噬细胞中,IL-1的刺激不会显著增加其对Pellino1的内在活性。在IRAK4激酶失活的浆细胞样树突状细胞中，TLR7和TLR9介导的IFN-α/β的产生被消除。显然IRAK4的激酶活性不仅是TLRs(2,4,5,7和9)诱导产生促炎细胞因子和趋化因子所必需的，同时也是TLR7和TLR9介导的IFN-α/β诱导产生所必需的。虽然IRAK4在固有免疫中占据着极其重要的位置研究表明TIR-MyD88-IRAK4信号通路对于少数化脓性细菌的保护性免疫是必不可少的，但对于大多数自然感染的宿主防御却是多余的。
先天免疫***的异常激活是许多慢性自身免疫疾病的重要特征。例如，类风湿性关节炎(RA)特有的抗酸化抗体免疫复合物和***性红斑狼疮(SLE)特征性的抗核酸免疫复合物都是通过TLRs介导信号通路。此外，TLR的激活可以促使B细胞分化为产生抗体的浆细胞，从而用于激活获得性免疫***。具有IRAK4缺失或表达激酶失活IRAK4的基因修饰小鼠表现一定程度的免疫应答受损，例如在受到细菌脂多糖(LPS)诱导时TNFα和IL-6诱导产生的受损。这些小鼠也对实验诱导的关节炎、动脉粥样硬化以及MOG诱导的脑脊髓炎具有抗性。IRAK4激酶失活小鼠也被证明对阿尔茨海默病的发展具有抗性，这一过程被认为是由于IL-1产生和信号传导减少所致。目前已有IRAK4的小分子抑制剂被用于体外和体内抑制TLR诱导的炎症信号传导。研究表明IRAK4抑制剂可减少尿酸诱导的腹膜炎模型中的痛风样炎症，5/6肾切除大鼠中的缺血诱导的炎症以及红斑狼疮的小鼠模型。因此，IRAK4被认为是治疗慢性炎症性疾病的重要药理学靶点。
在激活型B细胞样(ABC)弥漫性大B细胞淋巴瘤(DLBCL)中，有29％的病例发生了MyD88 265位亮氨酸突变为脯氨酸(L265P)，是ABC DLBCL中的最主要的激活突变，其中IRAK4承担了大部分MYD88的功能。Nimbus公司化合物ND-2110，ND-2158在异种移植OCI-Ly10小鼠模型中据有突出的抗肿瘤作用，同时与BTK抑制剂ibrutinib和BCL-2抑制剂ABT-199表现良好的联合用药作用。
胰腺导管癌(PDAC)5年总体生存率不超过6％。研究表明相比于p-IRAK4阴性的 肿瘤患者，pIRAK4阳性的PDAC患者具有更高的手术后复发几率以及更差的预后。通过shRNA和CRISPR/Cas9n技术，研究人员发现抑制IRAK4后，吉西他滨和5-氟尿嘧啶能更有效杀伤胰腺导管癌细胞。同时还发现IRAK1/4能驱动炎症细胞因子和趋化因子的产生，使得癌症相关成纤维细胞(CAFs)转移、入侵和增殖。另一项研究表明，通过敲除小鼠IRAK4能有效减少小鼠肺部肿瘤数并且不改变支气管肺泡灌输液(BALF)的细胞组成。
发明内容
本发明的目的在于提供一种具有IRAK4抑制活性的式(I)所示化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物及其制备方法和用途。
本发明的第一方面，提供了一种式(I)所示化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物：
Figure PCTCN2020115143-appb-000001
其中，
X、Y、Z或W分别独立选自CH或N；且当X、Y、Z或W为CH时，所述的H原子可以被选自下组的取代基取代：卤素、C1-C3烷基、C2-C6酰基、C1-C3烷氧基、三氟甲氧基、三氟乙氧基；
环A为含1-2个选自N、O和S的杂原子的3-8元饱和杂环(包括单环、并环或螺环)，所述饱和杂环任选地被一个或多个卤素、氧代、羧基、氰基、羟基、取代或未取代的5-6元杂环、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基取代，所述取代指被一个或多个卤素、C1-C3烷基或羟基取代；
R 1选自-NR 2R 3、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-11元饱和或部分饱和杂环基，所述取代基由R a表示；
各个R a各自独立地选自卤素、氧代、-(C0-C3烷基)-CN、-(C0-C3烷基)-OH、-(C0-C3烷基)-COOH、-(C0-C3烷基)C(＝O)OR 5、-(C0-C3烷基)C(＝O)R 5、-(C0-C3烷基)NR 5R 6、-C(＝O)(C1-C3烷基)、-(C0-C3烷基)C(＝O)NR 5R 6、-(C0-C3烷基)S(＝O)NR 5R 6、-(C0-C3烷基)S(＝O) 2NR 5R 6、-(C0-C3烷基)S(＝O) 2(C1-C3烷基)、-(C0-C3烷基)OP(＝O)(OC1-C3烷基) 2、取代或未取代的C1-C3烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷硫基、所述取代是指被一个或多个卤素取代；
R 2和R 3各自独立地选自氢原子、取代或未取代的C1-C3烷基、取代或未取代的C3-C10环烷基、-(C0-C3烷基)-6-10元芳基、-(C0-C3烷基)-5-10元杂芳基、-(C0-C3烷基)-饱和或部分饱和4-10元杂环基，所述取代指被卤素、羟基、氨基、氰基或酰胺基取代；
或者R 2和R 3可以和与它们所连接的氮原子一起形成4-8元杂环，所述杂环任选被一个或多个R a取代；
R 5、R 6分别独立选自氢原子、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的4-6元杂环，所述取代指被一个或多个C1-C3烷基、羟基、卤素、羧酸、C2-C6羧酸酯取代。
在另一优选例中，R 2和R 3与其所连接的氮原子一起形成4-7元杂环，所述杂环任选被一个或多个R b取代；
R b独立选自卤素、氧代、氰基、羟基、-(C0-C3烷基)C(＝O)NHR 5R 6、-(C0-C3烷基)-NR 5R 6、取代或未取代的C1-C3烷基，所述取代指被一个或多个卤素、氧代、氰基、羟基取代。
在另一优选例中，R 1为取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，且所述的芳基或杂芳基任选被一个或多个R c取代；
R c独立选自卤素、氰基、羟基、-COOH、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)(C1-C3烷基)、-(C0-C3烷基)NR 5R 6、-(C0-C3烷基)C(＝O)NR 5R 6、-(C0-C3烷基)S(＝O)NR 5R 6、-(C0-C3烷基)S(＝O) 2NR 5R 6、-S(＝O) 2(C1-C3烷基)、-(C0-C3烷基)OP(＝O)(OC1-C3烷基) 2、取代或未取代的C1-C3烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷硫基、所述取代是指被一个或多个卤素或羟基取代。
在另一优选例中，R 1为取代或未取代的5-6元芳杂环，所述芳杂环任选被一个或多个R c取代。
在另一优选例中，所述的环A为取代或未取代的选自下组的基团：
Figure PCTCN2020115143-appb-000002
其中，各个p各自独立地为1、2或3。
在另一优选例中，所述的R 1选自下组：-NR 2R 3、取代或未取代的C3-C6环烷基、取代或未取代的芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-6元饱和或部分饱和杂环基、取代或未取代的(3-6元饱和或部分饱和杂环基)并5-6元杂芳基。
在另一优选例中，环A选自下组：
Figure PCTCN2020115143-appb-000003
R 4选自氢原子、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基，所述取代指被一个或多个卤素取代。
在另一优选例中，
Figure PCTCN2020115143-appb-000004
选自下组：
Figure PCTCN2020115143-appb-000005
在另一优选例中，所述化合物选自表1所示的化合物。
本发明的第二方面，提供了一种药物组合物，所述的药物组合物包含如下组分：
1)治疗有效量的一种或多种如本发明第一方面所述化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物；和
2)药学上可接受的载体或赋形剂。
在另一优选例中，所述的药物组合物还包括一种或多种选自以下的活性物质：免疫抑制剂、糖皮质激素、非甾体抗炎药、长春碱类化合物、紫杉醇、DNA损伤剂、Bcl-2抑制剂、BTK抑制剂、JAK抑制剂、Hsp90抑制剂、ALK抑制剂、FLT3抑制剂、PI3K抑制剂和SYK抑制剂。
本发明的第三方面，提供了一种本发明第一方面所述化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物或本发明第二方面所述药物组合物的用途，其用于选自下组的用途：
1)制备用于预防和/或治疗IRAK4介导的疾病的药物；
2)制备用于抑制IRAK4的药物。
在另一优选例中，所述的药物还用于抑制选自下组的蛋白激酶：FLT3、RET、VEGFR、ErbB2，或其组合。
在另一优选例中，所述IRAK4介导的疾病选自下组：癌症、自身免疫性疾病、炎性疾病和血栓栓塞疾病。
在另一优选例中，其中所述癌症选自下组：弥漫性大B细胞淋巴瘤、多发性骨髓瘤、套细胞淋巴瘤、华氏巨球蛋白血症、急性髓系白血病、慢性淋巴细胞白血病、小淋巴细胞性淋巴瘤、胰腺导管癌。
在另一优选例中，其中所述自身免疫疾病和炎性疾病选自下组：类风湿性关节炎、骨关节炎、青少年关节炎、慢性阻塞性肺疾病、多发性硬化症、***性红斑狼疮、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎和肠道应激综合症。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，提供了一种结构新颖的IRAK4抑制剂化合物，所述的化合物相较于现有技术的IRAK4抑制剂，活性有明显提升，因此可以用于制备预防和/或治疗癌症、炎症性疾病和自身免疫疾病等IRAK4介导的相关疾病。基于上述发现，发明人完成了本发明。
术语
如本文所用，术语“杂环基”是具有1、2、3、4或5个选自下组的杂原子的环状基 团：O、N或S。
在本文中，所述的烷基优选为脂肪族烷基，可以是直链烷基、支链烷基、螺环烷基、桥环烷基、烯烷基、炔烷基、环烷基、环烯基、环炔基、烷氧烷基、烷氧酰基烷基、环烷基烷基，非限制性地包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、烯丙基、炔丙基、环丁烯基、环己烯基；形如“C1-C8”的表述意在包括具有1个、2个、3个、4个、5个、6个、7个或8个碳原子的相应基团，例如，“C1-C8烷基”指具有1个、2个、3个、4个、5个、6个、7个或8个碳原子的烷基，“C2-C10烯基”指具有2个、3个、4个、5个、6个、7个、8个、9个或10个碳原子的烯基。特别地，本发明权利要求中提到的“C0烷基”，指基团为化学键的情况。
在本文中，所述烯基优选为乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基，或类似基团。
在本文中，所述环烷基可以为饱和或者部分不饱和单环或多环环状烃取代基，其中包括3至10个碳原子，优选包括3至8个碳原子，更优选环烷基包含3至6个碳原子。单环环烷基非限制实施例包含环丙基、环丁基、环戊烯基、环己基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
所述杂环基指饱和或部分饱和单环或者多环的环状取代基，其中包括4至10元杂环基，且所述的杂环基为其中含有一个或多个杂原子(氮、氧、硫)的饱和或者非饱和的单环、并环、螺环、稠环、桥环等。本文中所述的杂环基包括，但不局限于选自下组的基团：吗啉环，哌啶环，哌嗪环，N-烷基或酰基取代的哌嗪环，高哌嗪环，N-烷基或酰基取代的高哌嗪环，吡咯，四氢吡咯，7H-嘌呤等。
所述芳基指6至10元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，且所述的基团具有共轭的π电子体系，例如苯基和萘基。所述芳基环可以与杂环基、杂芳基或环烷基环稠合，非限制性实施例含苯并咪唑、苯并噻唑、苯并恶唑、苯并异恶唑、苯并吡唑、喹啉、苯并吲哚、苯并二氢呋喃。
所述杂芳基指包含1至4个杂原子，5至10个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。杂芳基优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述的杂芳基可以稠合于芳基、杂环基或者环烷基环上，其中与母体结构连接在一起的环为杂芳基环。
除非特别说明，本发明所描述的结构式意在包括所有的互变异构、光学异构和立体异构形式(如对映异构体、非对映异构体，几何异构体或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体、互变异构体或其对映异构体、非对映异构体或几何异构体或构象异构体或互变异构体的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中，所述的药学上可接受的盐没有特别的限制，优选包括：无机酸盐、有 机酸盐、烷基磺酸盐和芳基磺酸盐；所述无机酸盐包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐等；所述有机酸盐包括甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐等；所述烷基磺酸盐包括甲基磺酸盐、乙基磺酸盐等；所述芳基磺酸盐包括苯磺酸盐、对甲苯磺酸盐等。
在本文中，所述通式(I)表示的化合物的药学上可接受的溶剂合物没有特别的限制，优选包括：通式(I)表示的化合物与水、乙醇、异丙醇、***、丙酮等的溶剂合物。
化合物
本发明提供了一种式(I)所示化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，
Figure PCTCN2020115143-appb-000006
其中，各基团定义同上。
在另一优选例中，所述的化合物中，X、Y、Z、W、环A、R 1中任一个分别为表1中所述具体化合物中所对应的基团。
在另一优选例中，所述化合物优选为实施例中所制备的化合物。
在另一优选例中，所述化合物选自表1所列化合物。
表1
Figure PCTCN2020115143-appb-000007
Figure PCTCN2020115143-appb-000008
Figure PCTCN2020115143-appb-000009
Figure PCTCN2020115143-appb-000010
Figure PCTCN2020115143-appb-000011
Figure PCTCN2020115143-appb-000012
Figure PCTCN2020115143-appb-000013
Figure PCTCN2020115143-appb-000014
盐型
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成的一类化合物，或该化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
本发明化合物的制备
以下反应路线示例性地说明本发明的化合物的制备方法。
反应路线I
Figure PCTCN2020115143-appb-000015
本发明的一类化合物的通用合成方法如反应路线I。包括如下步骤：
1、化合物1a/1b在-78℃下通过与甲基溴化镁发生格氏反应得到化合物2a/2b；
2、化合物2a/2b在叔丁醇钾的条件下发生关环反应得到化合物3a/3b；
3、化合物3a/3b在硝酸的作用下发生硝化反应得到化合物4a/4b
4、化合物4a在钯催化剂作用下发生Suzuki偶联反应，化合物4b在碱的作用下发生取代反应，可得到不同形式的式5；
5、化合物5在钯碳/氢气下还原或者在铁粉/氯化铵条件下还原，可得到化合物6；
6、化合物6在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并***缩合剂条件下反应得到目标化合物7。
反应路线Ⅱ
Figure PCTCN2020115143-appb-000016
本发明的一类化合物的通用合成方法如反应路线Ⅱ。包括如下步骤：
1、化合物Ⅱ-1在正丁基锂作用下脱溴与二甲基环丙烷反应得到化合物Ⅱ-2；
2、化合物Ⅱ-2在叔丁醇钾作用下关环得到化合物Ⅱ-3；
3、化合物Ⅱ-3在乙酸酐/硝酸铜作用下发生硝化反应得到化合物Ⅱ-4；
4、化合物Ⅱ-4在有机碱的作用下发生取代反应得到化合物Ⅱ-5；
5、化合物Ⅱ-5在钯碳/氢气下还原可得到化合物化合物Ⅱ-6；
6、化合物Ⅱ-6在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并***缩合剂条件下反应得到目标化合物Ⅱ-7。
含有式(I)化合物的药物组合物
本发明还涉及一种药物组合物，所述药物组合物包含治疗有效量的选自式(I)所示化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种以及任选地，药学上可接受的载体，其可用于治疗IRAK4活性或表达量相关的疾病。所述药物组合物可以根据不 同给药途径而制备成各种形式。
由于本发明化合物具有优异的对IRAK4的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与IRAK4活性或表达量相关的疾病，例如预防和/或治疗与IRAK4信号通路异常表达相关疾病的。根据现有技术，本发明化合物可用于治疗以下疾病：癌症、自身免疫性疾病、炎性疾病和血栓栓塞疾病，优选地，所述的化合物可以用于治疗以下疾病：弥漫性大B细胞淋巴瘤、多发性骨髓瘤、套细胞淋巴瘤、华氏巨球蛋白血症、急性髓性白血病、慢性淋巴细胞白血病、小淋巴细胞性淋巴瘤、胰腺导管癌、类风湿性关节炎、骨关节炎、青少年关节炎、慢性阻塞性肺疾病、多发性硬化症、***性红斑狼疮、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎和肠道应激综合症。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020115143-appb-000017
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂， 增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
中间体1
6-氟-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃(根据WO2017/108723报道方法制备)
Figure PCTCN2020115143-appb-000018
步骤1：2-(2,4-二氟苯基)乙酸甲酯的制备
Figure PCTCN2020115143-appb-000019
将2-(2,4-二氟苯基)乙酸(5g，29.0mmol)溶于100mL甲醇，加入5mL浓硫酸，回流反应过夜，减压浓缩，剩余物溶于乙酸乙酯，水洗，饱和碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，得5g淡黄色油状物，直接投入下一步反应。
步骤2：1-(2,4-二氟苯基)-2-甲基丙-2-醇
Figure PCTCN2020115143-appb-000020
将2-(2,4-二氟苯基)乙酸甲酯(5g，26.8mmol)溶于无水四氢呋喃(60mL)，氩气置换保护，-78℃下滴加甲基溴化镁溶液(27mL 3M***溶液，80.5mmol),滴毕，10分钟后转至室温反应1小时，TLC检测反应完毕。冰浴下滴加饱和氯化铵溶液淬灭，乙酸乙酯(150mL)和水萃取，乙酸乙酯层饱和食盐水洗，无水硫酸钠干燥。减压浓缩至干得淡黄色油状物，直接投入下一步反应。 1H NMR(300MHz,Chloroform-d)δ7.24–7.15(m,1H),6.90–6.73(m,2H),2.77(d,J＝1.6Hz,2H),1.23(s,6H).
步骤3：6-氟-2,2-二甲基-2,3-二氢苯并呋喃的制备
Figure PCTCN2020115143-appb-000021
将1-(2,4-二氟苯基)-2-甲基丙-2-醇(5.41g，29.0mmol)溶于无水四氢呋喃(120mL)，加入叔丁醇钾(8.15g，72.6mmol)，回流反应2小时，TLC检测反应完毕，减压浓缩，加入乙酸乙酯(150mL)和水萃取，乙酸乙酯层饱和食盐水洗，无水硫酸钠干燥，过滤，硅胶柱层析(乙酸乙酯/石油醚＝1％洗脱)得无色油状物2.62g。三步反应收率：49％。 1H NMR(400MHz,Chloroform-d)δ7.02(ddt,J＝8.1,5.8,1.1Hz,1H),6.57–6.37(m,2H),2.95(t,J＝1.4Hz,2H),1.47(s,6H).
步骤4：6-氟-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃的制备
Figure PCTCN2020115143-appb-000022
将6-氟-2,2-二甲基-2,3-二氢苯并呋喃(2.62g，15.7mmol)溶于50mL二氯甲烷，冰浴下滴加硝酸(2.4mL)，室温反应至TLC检测反应完毕，乙酸乙酯(150mL)和水萃取，乙酸乙酯层饱和碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，过滤，硅胶柱层析(乙酸乙酯/石油醚＝3％～10％梯度洗脱)得橙黄色固体2.29g。收率：69％。 1H NMR(300MHz,DMSO-d 6)δ8.04(dt,J＝8.2,1.3Hz,1H),6.97(d,J＝12.5Hz,1H),3.06(d,J＝1.4Hz,2H),1.45(s,6H).
中间体2
6-氯-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃(根据WO2017/108723报道方法制备)
Figure PCTCN2020115143-appb-000023
步骤1：2-(4-氯-2-氟苯基)乙酸甲酯的的制备
Figure PCTCN2020115143-appb-000024
将2-(4-氯-2-氟苯基)乙酸(5g，26.5mmol)溶于50mL甲醇，加入3mL浓硫酸，回流反应过夜，减压浓缩，剩余物溶于乙酸乙酯，水洗，饱和碳酸氢钠溶液洗，饱和食盐 水洗，无水硫酸钠干燥，过滤，减压浓缩至干，得5g淡黄色油状物。 1H NMR(400MHz,Chloroform-d)δ7.20(t,J＝8.2Hz,1H),7.10(dt,J＝9.8,2.3Hz,2H),3.71(s,3H),3.64(d,J＝1.4Hz,2H).
步骤2：1-(4-氯-2-氟苯基)-2-甲基丙-2-醇的制备
Figure PCTCN2020115143-appb-000025
将2-(4-氯-2-氟苯基)乙酸甲酯(5.37g，26.5mmol)溶于无水四氢呋喃(60mL)，氩气置换保护，-78℃下滴加甲基溴化镁溶液(26.5mL 3M***溶液),滴毕，15分钟后转至室温反应1小时，TLC检测反应完毕。冰浴下滴加饱和氯化铵溶液淬灭，乙酸乙酯(200mL)和水萃取，乙酸乙酯层饱和食盐水洗，无水硫酸钠干燥。减压浓缩至干得淡黄色油状物。 1H NMR(400MHz,Chloroform-d)δ7.20(dd,J＝9.2,7.3Hz,1H),7.13–7.05(m,2H),2.78(d,J＝1.6Hz,2H),1.24(d,J＝1.0Hz,6H).
步骤3：6-氯-2,2-二甲基-2,3-二氢苯并呋喃的制备
Figure PCTCN2020115143-appb-000026
将1-(4-氯-2-氟苯基)-2-甲基丙-2-醇(5.37g，26.5mmol)溶于无水四氢呋喃(125mL)，加入叔丁醇钾(7.43g，66.2mmol)，回流反应过夜，TLC检测反应完毕，减压浓缩，加入乙酸乙酯(150mL)和水萃取，乙酸乙酯层饱和食盐水洗，无水硫酸钠干燥，过滤，硅胶柱层析(乙酸乙酯/石油醚＝1％洗脱)得无色油状物3.57g。三步反应收率：74％。 1H NMR(400MHz,Chloroform-d)δ7.05(dt,J＝7.9,1.1Hz,1H),6.81(dd,J＝7.9,1.9Hz,1H),6.74(d,J＝1.8Hz,1H),2.98(s,2H),1.49(s,6H).
步骤4：6-氯-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃的制备
Figure PCTCN2020115143-appb-000027
将6-氟-2,2-二甲基-2,3-二氢苯并呋喃(3.57g，19.5mmol)溶于40mL二氯甲烷，室温下滴加硝酸(2.4mL)，室温反应至TLC检测反应完毕，乙酸乙酯(150mL)和水萃取，乙酸乙酯层饱和碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，过滤，硅胶柱层析(乙酸乙酯/石油醚＝1％～10％梯度洗脱)得橙黄色固体4.45g,石油醚重结晶得白色针状固体2.02g。收率：45％。 1H NMR(400MHz,Chloroform-d)δ7.84(s,1H),6.82(s,1H),3.04(d,J＝1.3Hz,2H),1.52(s,6H).
中间体3
2-(2-((叔丁氧基羰基)氨基)吡啶-4-基)恶唑-4-羧酸
Figure PCTCN2020115143-appb-000028
步骤1：(4-溴吡啶-2-基)氨基甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000029
将2-氨基4-溴吡啶(0.4g，2.31mmol)、二碳酸二叔丁酯(605mg，2.77mmol)和4-二甲氨基吡啶(423mg，3.47mmol)溶于二氯甲烷(12mL)，室温反应过夜，TLC检测反应结束，
硅胶柱层析(乙酸乙酯/石油醚＝3％～20％梯度洗脱)得白色固体354mg。收率：56％。 1H NMR(300MHz,Chloroform-d)δ8.22(d,J＝1.8Hz,1H),8.10–8.04(m,1H),7.97(s,1H),7.11(dd,J＝5.4,1.7Hz,1H),1.53(s,9H).
步骤2：(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)氨基甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000030
将(4-溴吡啶-2-基)氨基甲酸叔丁酯(0.2g，732μmol)、联硼酸频那醇酯(223mg，878μmol)和醋酸钾(215mg，2.20mmol)溶于四氢呋喃(12mL)，氩气置换保护，加入[1,1’-双(二苯基膦基)二茂铁]二氯化钯(21mg，29.2μmol)，回流反应过夜，TLC检测反应完毕，硅藻土抽滤，浓缩后直接投入下步反应。
步骤3：2-(2-((叔丁氧基羰基)氨基)吡啶-4-基)恶唑-4-羧酸乙酯的制备
Figure PCTCN2020115143-appb-000031
将2-氯恶唑-4-羧酸乙酯(110mg，626μmol)、(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)氨基甲酸叔丁酯(240mg，751μmol)、碳酸钠(199mg，1.88μmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(23mg，31μmol)、乙二醇二甲醚/水(10mL/1mL)加入反应瓶，氩气置换数次，90℃反应过夜。TLC检测反应结束，硅藻土抽滤，乙酸乙酯(30mL)和水萃取，饱和食盐水洗，无水硫酸钠干燥。过滤，硅胶柱层析(乙酸乙酯/石油醚＝1:5洗脱)得白色固体121mg。收率：58％。 1H NMR(300MHz,DMSO-d 6)δ10.15(s,1H),9.06(d,J＝1.2Hz,1H),8.49–8.40(m,2H),7.56(dd,J＝5.2,1.5Hz,1H),4.34(q,J＝7.0Hz,2H),1.50(d,J＝1.1Hz,9H),1.32(t,J＝7.1Hz,3H).
步骤4：2-(2-((叔丁氧基羰基)氨基)吡啶-4-基)恶唑-4-羧酸的制备
Figure PCTCN2020115143-appb-000032
将2-(2-((叔丁氧基羰基)氨基)吡啶-4-基)恶唑-4-羧酸乙酯(118mg，356μmol)溶于四氢呋喃/甲醇/水(4mL/2mL/1mL),加入一水合氢氧化锂(45mg，1.07mmol)，室温反应20分钟，TLC检测反应完毕，浓缩，用1N盐酸溶液调pH至弱酸性，析出固体，抽滤，干燥，得白色固体83mg。收率：77％。 1H NMR(300MHz,DMSO-d 6)δ8.93(s,1H),8.49–8.39(m,2H),7.54(dd,J＝5.2,1.5Hz,1H),1.50(s,9H).
实施例1
2-(2-氨基吡啶-4-基)-N-(6-(4-(羟基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-1)
Figure PCTCN2020115143-appb-000033
步骤1：(1-(2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-6-基)哌啶-4-基)甲醇的制备
Figure PCTCN2020115143-appb-000034
将6-氟-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃(200mg，94.7μmol)，4-羟甲基哌啶(218mg，1.89mmol)溶于N，N-二甲基甲酰胺(5mL)，加入碳酸钾(262mg，1.89mmol)，40℃反应两小时，TLC检测反应结束，加入乙酸乙酯(25mL)和水萃取，乙酸乙酯层水洗，饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩至干，直接投入下步反应。
步骤2：(1-(5-氨基-2,2-二甲基-2,3-二氢苯并呋喃-6-基)哌啶-4-基)甲醇的制备
Figure PCTCN2020115143-appb-000035
将上步反应产物溶于甲醇(30mL)加入10％钯碳(42mg),氢气氛围下常温反应6小时，TLC检测反应结束，硅藻土抽滤，浓缩，硅胶柱层析(二氯甲烷/甲醇＝1:100至1:50梯度洗脱)得黄白色固体208mg。两步收率：79％。 1H NMR(300MHz,DMSO-d 6)δ6.49(s,1H),6.30(s,1H),4.46(t,J＝5.3Hz,1H),4.15(s,2H),3.27(t,J＝5.8Hz,2H),2.96(d,J＝11.3Hz,2H),2.80(s,2H),2.39(t,J＝11.2Hz,2H),1.70(d,J＝12.3Hz,2H),1.47- 1.35(m，1H)1.31(s,6H),1.22(td,J＝12.4,11.1,3.3Hz,2H).
步骤3：(4-(4-((6-(4-(羟甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)氨基甲酰基)恶唑-2-基)吡啶-2-基)氨基甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000036
将2-(2-((叔丁氧基羰基)氨基)吡啶-4-基)恶唑-4-羧酸(80mg，263μmol)，1-(5-氨基-2,2-二甲基-2,3-二氢苯并呋喃-6-基)哌啶-4-基)甲醇(69mg，251μmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(58mg，301μmol)和1-羟基苯并***(41mg，301μmol)溶于N，N-二甲基甲酰胺(5mL),加入N，N-二异丙基乙胺(104μL，627μmol)，室温反应4小时，TLC检测反应完毕，加入乙酸乙酯(25mL)和水萃取，乙酸乙酯层水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，硅胶柱层析(二氯甲烷/甲醇＝2％洗脱)得淡黄色固体80mg。收率：56％。 1H NMR(300MHz,DMSO-d 6)δ10.19(s,1H),9.98(s,1H),8.99(s,1H),8.49(s,1H),8.45(d,J＝5.2Hz,1H),8.18(s,1H),7.67–7.59(m,1H),6.69(s,1H),4.53(t,J＝5.1Hz,1H),2.96(d,J＝27.2Hz,4H),2.65(t,J＝10.3Hz,2H),1.80(d,J＝10.0Hz,2H),1.49(s,9H),1.42-1.35(m,6H).
步骤:4：2-(2-氨基吡啶-4-基)-N-(6-(4-(羟基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000037
将(4-(4-((6-(4-(羟甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)氨基甲酰基)恶唑-2-基)吡啶-2-基)氨基甲酸叔丁酯(35mg，62μmol)溶于二氯甲烷(4.5mL)，加入三氟乙酸(1.5mL)室温反应两小时，TLC检测反应完毕，浓缩，加入饱和碳酸氢钠和二氯甲烷萃取，二氯甲烷层无水硫酸钠干燥，过滤，浓缩，制备薄层色谱纯化(二氯甲烷/甲醇＝16:1作为展开剂)得26mg黄色固体。 1H NMR(300MHz,DMSO-d 6)δ9.97(s,1H),8.92(s,1H),8.22(s,1H),8.09(d,J＝5.3Hz,1H),7.16–6.98(m,2H),6.69(s,1H),6.39(s,2H),4.73(t,J＝5.3Hz,1H),3.43(s,2H),2.96(d,J＝23.8Hz,4H),2.67(t,J＝11.0Hz,2H),1.80(d,J＝11.4Hz,2H),1.73–1.52(m,3H),1.40(s,6H).
实施例2
(R)-N-(6-(3-氨基哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-(2-氨基吡啶-4- 基)恶唑-4-甲酰胺三氟乙酸盐(I-2)
Figure PCTCN2020115143-appb-000038
步骤1：R)-(4-(4-((6-(3-((叔丁氧基羰基)氨基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基叔丁基)氨基甲酰基)恶唑-2-基)吡啶-2-基)氨基甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000039
可通过实施例1步骤4中类似的方法制备(R)-(4-(4-((6-(3-((叔丁氧基羰基)氨基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基叔丁基)氨基甲酰基)恶唑-2-基)吡啶-2-基)氨基甲酸叔丁酯。 1H NMR(400MHz,Chloroform-d)δ10.15(s,1H),8.65(s,1H),8.41(d,J＝5.2Hz,1H),8.37(s,1H),8.31(s,1H),7.99(s,1H),7.63(dd,J＝5.2,1.5Hz,1H),6.60(s,1H),3.14(s,1H),3.02(s,2H),2.77(s,3H),1.90(s,1H),1.67(s,3H),1.55(s,9H),1.47(s,6H),1.19(s,9H).
步骤2：(R)-N-(6-(3-氨基哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺三氟乙酸盐的制备
将(R)-(4-(4-((6-(3-((叔丁氧基羰基)氨基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基叔丁基)氨基甲酰基)恶唑-2-基)吡啶-2-基)氨基甲酸叔丁酯溶于二氯甲烷(4mL)加入三氟乙酸(1mL)室温反应两小时，TLC检测反应结束，减压浓缩至干，甲醇/***打浆，抽滤得淡黄色固体34mg。 1H NMR(400MHz,DMSO-d 6)δ9.69(s,1H),9.07(s,1H),8.15(d,J＝6.1Hz,1H),8.06(s,4H),7.75(s,2H),7.33(s,1H),7.19(dd,J＝6.1,1.6Hz,1H),6.67(s,1H),3.46–3.33(m,2H),3.13(d,J＝10.8Hz,1H),3.01(s,2H),2.85(d,J＝11.9Hz,1H),2.77–2.61(m,2H),2.08(s,1H),1.91(d,J＝13.3Hz,1H),1.80(d,J＝11.3Hz,1H),1.50(d,J＝8.6Hz,1H),1.42(d,J＝4.1Hz,6H).
实施例3
N-(6-(4-(氨基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺三氟乙酸盐(I-3)
Figure PCTCN2020115143-appb-000040
可通过实施例2中类似的方法制备N-(6-(4-(氨基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺的三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),9.05(s,1H),8.21–8.09(m,2H),7.86(s,5H),7.32(s,1H),7.18(dd,J＝6.1,1.6Hz,1H),6.74(s,1H),2.98(d,J＝24.2Hz,4H),2.81(t,J＝6.4Hz,2H),2.68(t,J＝11.5Hz,2H),1.91(d,J＝12.5Hz,2H),1.74(s,1H),1.49(q,J＝11.0Hz,2H),1.41(s,6H).
实施例4
2-(2-氨基吡啶-4-基)-N-(6-(4-氰基哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-4)
Figure PCTCN2020115143-appb-000041
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-氰基哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ9.93(s,1H),8.35(s,2H),8.23(d,J＝5.3Hz,1H),7.20(dd,J＝5.3,1.4Hz,1H),7.17–7.11(m,1H),6.55(s,1H),3.49(s,2H),3.12(d,J＝12.2Hz,2H),3.08–2.98(m,2H),2.75(t,J＝11.9Hz,3H),2.44–2.23(m,4H),1.48(s,6H).
实施例5
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-吗啉代-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-5)
Figure PCTCN2020115143-appb-000042
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-吗啉代-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ10.16(s, 1H),8.34(d,J＝6.7Hz,2H),8.19(d,J＝5.4Hz,1H),7.13(d,J＝5.3Hz,1H),6.97(s,1H),6.63(s,1H),4.90(s,2H),3.25(t,J＝6.0Hz,4H),3.04(s,2H),2.84(t,J＝6.0Hz,4H),1.48(s,6H).
实施例6
2-(2-氨基吡啶-4-基)-N-(6-(3-(羟甲基)吡咯烷-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-6)
Figure PCTCN2020115143-appb-000043
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(3-(羟甲基)吡咯烷-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ9.71(s,1H),8.33(s,1H),8.24(s,1H),8.17(d,J＝5.4Hz,1H),7.27(d,J＝1.2Hz,1H),7.19(dd,J＝5.4,1.4Hz,1H),6.63(s,1H),5.14(s,2H),3.98–3.81(m,2H),3.26(td,J＝8.7,3.2Hz,1H),3.13–2.96(m,4H),2.87(q,J＝8.5Hz,1H),2.58(d,J＝7.2Hz,1H),1.99–1.85(m,1H),1.47(s,6H).
实施例7
2-(2-氨基吡啶-4-基)-N-(6-(4-(2,2-二氟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-7)
Figure PCTCN2020115143-appb-000044
步骤1：1-(2,2-二氟乙基)哌嗪盐酸盐的制备
Figure PCTCN2020115143-appb-000045
将1-叔丁基氧羰基哌嗪(1g，5.37mmol)，2,2-二氟乙醇(528mg，6.44mmol)溶于无水二氯甲烷，加入三乙胺，氩气保护，冰浴下缓慢滴加三氟甲磺酸酐，冰浴反应30分钟，转至室温反应过夜。TLC检测反应完毕，二氯甲烷和水萃取，二氯甲烷层水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩至干，溶于二氧六环(10mL)，冰浴，加入盐酸二氧六环溶液(10mL，4.5mol/L)，转至室温反应三小时，反应完毕，冰浴，趁冷抽滤，得黄棕色固体123mg。收率：12％。 1H NMR(400MHz,DMSO-d 6)δ9.78(s, 2H),6.45(tt,J＝54.5,4.2Hz,1H),3.44(td,J＝15.3,4.1Hz,2H),3.36–3.17(m,8H).
步骤2：6-(4-(2,2-二氟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-胺的制备
Figure PCTCN2020115143-appb-000046
可通过实施例1步骤1和2类似的方法制备6-(4-(2,2-二氟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-胺。 1H NMR(400MHz,Chloroform-d)δ6.58(s,1H),6.49(s,1H),5.92(tt,J＝55.9,4.4Hz,1H),3.48(s,6H),2.94–2.85(m,6H),1.43(s,6H).
步骤3：2-(2-氨基吡啶-4-基)-N-(6-(4-(2,2-二氟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000047
可通过实施例1步骤3、4类似的反应由6-(4-(2,2-二氟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-胺制备2-(2-氨基吡啶-4-基)-N-(6-(4-(2,2-二氟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ9.96(s,1H),8.34(s,1H),8.31(s,1H),7.31(dd,J＝5.3,1.4Hz,1H),7.14(t,J＝1.0Hz,1H),6.63(s,1H),5.99(tt,J＝55.7,4.2Hz,1H),4.72(s,2H),3.49(s,2H),3.06–2.99(m,2H),2.97–2.91(m,8H),1.48(s,6H).
实施例8
2-(2-氨基吡啶-4-基)-N-(6-(4-(2-羟基丙烷-2-基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-8)
Figure PCTCN2020115143-appb-000048
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-(2-羟基丙烷-2-基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ10.06(s,1H),8.89(q,J＝1.5Hz,1H),8.27(s,1H),8.11(d,J＝5.3Hz,1H),7.60(s,1H),7.28(s,1H),7.16–6.94(m,2H),6.72(d,J＝2.5Hz,1H),6.48(s,2H),2.97(d,J＝18.3Hz,4H),2.70(t,J＝11.6Hz,2H),2.34(d,J＝11.5Hz,1H),2.07(q,J＝12.2, 11.8Hz,2H),1.85(d,J＝12.6Hz,2H),1.40(d,J＝2.6Hz,6H).
实施例9
2-(2-氨基吡啶-4-基)-N-(6-(4-羟基哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-9)
Figure PCTCN2020115143-appb-000049
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-羟基哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H),8.91(s,1H),8.18(s,1H),8.10(d,J＝5.3Hz,1H),7.24–7.04(m,2H),6.68(s,1H),6.30(s,2H),5.02(s,1H),3.72(s,1H),3.00(s,2H),2.95–2.84(m,2H),2.72(t,J＝10.7Hz,2H),1.97(d,J＝12.0Hz,2H),1.81(q,J＝10.2,9.1Hz,2H),1.40(s,6H).
实施例10
2-(2-氨基吡啶-4-基)-N-(6-(4-(氰基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-10)
Figure PCTCN2020115143-appb-000050
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-(氰基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ9.58(s,1H),8.35(d,J＝8.1Hz,2H),8.19(d,J＝5.4Hz,1H),7.27(s,1H),7.19(dd,J＝5.3,1.5Hz,1H),6.61(s,1H),5.09(s,2H),3.15(d,J＝11.8Hz,2H),3.03(s,2H),2.70(t,J＝11.5Hz,2H),2.54(d,J＝4.2Hz,2H),2.03–1.81(m,5H),1.48(s,6H).
实施例11
2-(2-氨基吡啶-4-基)-N-(6-(4-(2-羟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-11)
Figure PCTCN2020115143-appb-000051
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-(2-羟乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.92(s,1H),8.19(s,1H),8.11(d,J＝5.3Hz,1H),7.14(d,J＝5.3Hz,1H),7.05(s,1H),6.72(s,1H),6.37(s,2H),4.65(s,1H),3.62(s,2H),3.00(s,3H),2.97–2.55(m,10H),1.41(s,6H).
实施例12
N-(6-(4-(2-氨基-2-氧代乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺(I-12)
Figure PCTCN2020115143-appb-000052
步骤1：4-(2-氨基-2-氧代乙基)哌嗪-1-羧酸叔丁酯的制备
Figure PCTCN2020115143-appb-000053
将1-叔丁基氧羰基哌嗪(550mg，2.95mmol)、溴乙酰胺(611mg，4.43mmol)溶于四氢呋喃(20mL)，加入N，N-二异丙基乙胺(763mg，5.91mmol)室温反应过夜，TLC检测反应结束，乙酸乙酯和水萃取，乙酸乙酯层饱和食盐水洗，无水硫酸钠干燥，浓缩至干得白色固体464mg。收率64％。 1H NMR(400MHz,DMSO-d 6)δ7.17(d,J＝30.9Hz,2H),2.86(s,2H),2.36(t,J＝4.9Hz,4H),1.39(s,9H).
步骤2：2-(哌嗪-1-基)乙酰胺三氟乙酸盐的制备
Figure PCTCN2020115143-appb-000054
将4-(2-氨基-2-氧代乙基)哌嗪-1-羧酸叔丁酯(150mg，616μmol)溶于二氯甲烷(8mL),加入三氟乙酸(1.5mL)，室温反应两小时，TLC检测反映完毕，浓缩之干，加入***/甲醇打浆，抽滤得209mg白色固体。收率：91％。 1H NMR(400MHz,DMSO-d 6) δ9.01(s,2H),7.55(d,J＝79.8Hz,2H),3.47(s,2H),3.26(t,J＝5.1Hz,4H),3.06(s,4H).
步骤3
2-(4-(5-氨基-2,2-二甲基-2,3-二氢苯并呋喃-6-基)哌嗪-1-基)乙酰胺的制备
Figure PCTCN2020115143-appb-000055
可通过实施例1步骤1和2类似的方法制备2-(4-(5-氨基-2,2-二甲基-2,3-二氢苯并呋喃-6-基)哌嗪-1-基)乙酰胺。 1H NMR(400MHz,DMSO-d 6)δ7.16(d,J＝16.7Hz,2H),6.52(s,1H),6.32(s,1H),4.18(s,2H),2.90(s,2H),2.83(s,2H),2.77(s,4H),2.57(s,4H),1.33(s,6H).
步骤4：N-(6-(4-(2-氨基-2-氧代乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000056
可通过实施例1步骤3、4类似的反应由2-(4-(5-氨基-2,2-二甲基-2,3-二氢苯并呋喃-6-基)哌嗪-1-基)乙酰胺制备N-(6-(4-(2-氨基-2-氧代乙基)哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.91(s,1H),8.21(s,1H),8.14(d,J＝5.3Hz,1H),7.30(s,1H),7.17(s,1H),7.12(dd,J＝5.3,1.4Hz,1H),7.06(s,1H),6.70(s,1H),6.41(s,2H),3.04(s,2H),3.01(s,2H),2.86(d,J＝4.7Hz,4H),2.78(s,4H),1.41(s,6H).
实施例13
2-(2-氨基吡啶-4-基)-N-(6-(4-氨甲酰基哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-13)
Figure PCTCN2020115143-appb-000057
可通过实施例1中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-氨甲酰基哌嗪-1-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ9.81(s,1H),8.91(d,J＝2.7Hz,1H),8.25(s,1H),8.04(d,J＝4.9Hz,1H),7.10(t,J＝ 3.2Hz,2H),6.69(d,J＝2.8Hz,1H),6.35(s,2H),4.40(s,1H),3.00(s,3H),2.62(t,J＝11.5Hz,2H),1.95–1.55(m,4H),1.40(d,J＝3.8Hz,6H),1.14(d,J＝3.6Hz,6H).
实施例14
2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-6-(4-(羟甲基)哌啶-1-基)-2-甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-14)
Figure PCTCN2020115143-appb-000058
步骤1：3-(2,4-二氟苯基)-2-羟基-2-甲基丙酸甲酯的制备
Figure PCTCN2020115143-appb-000059
将镁屑(2.47g，104mmol)和碘单质(147mg，579μmol)加入两颈瓶，置换氩气，加入无水***30mL，加热使溶液保持微沸，缓慢加入1-(溴甲基)-2,4-二氟苯(6g，28.9mmol)，加毕，保持沸腾搅拌半小时，即制得(2,4-二氟苄基)溴化镁待用。将2-氧代丙酸甲酯(2.96g，28.9mmol)溶于无水***，氩气保护下于-78℃搅拌30分钟，缓慢加入新鲜制备的(2,4-二氟苄基)溴化镁，转至室温反应2小时，TLC检测反映完毕，加入氯化铵溶液淬灭，过滤掉不溶物后，滤液用乙酸乙酯和水萃取，乙酸乙酯层饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，胶柱层析(乙酸乙酯/石油醚洗脱)得2.88g黄色油状物。收率：43％。 1H NMR(400MHz,Chloroform-d)δ7.24(dd,J＝8.6,6.5Hz,1H),6.88–6.75(m,2H),3.79(s,3H),3.18–3.07(m,2H),2.94(dd,J＝13.9,1.2Hz,1H),1.50(s,3H).
步骤2：6-氟-2-甲基-2,3-二氢苯并呋喃-2-羧酸的制备
Figure PCTCN2020115143-appb-000060
将3-(2,4-二氟苯基)-2-羟基-2-甲基丙酸甲酯(2.88g，12.51mmol)溶于无水四氢呋喃(75mL)，加入叔丁醇钾(3.51g，31.28mmol)50℃反应过夜，TLC检测反应完毕，加入乙酸乙酯(100mL)将有机层分出，无水硫酸钠干燥，过滤，浓缩至干，得棕黄色固体。 1H NMR(400MHz,DMSO-d 6)δ12.99(s,1H),7.21–7.13(m,1H),6.77–6.51(m,2H),3.46(d,J＝16.0Hz,1H),3.11(d,J＝16.0Hz,1H),1.59(s,3H).
步骤3：6-氟-2-甲基-2,3-二氢苯并呋喃-2-羧酸甲酯
Figure PCTCN2020115143-appb-000061
将6-氟-2-甲基-2,3-二氢苯并呋喃-2-羧酸(500mg，2.55mmol)溶于N，N-二甲基甲酰胺(10mL)，加入碳酸铯(765mg，3.82mmol)，搅拌下加入碘甲烷(434mg，3.06mmol)，室温反应5小时，TLC检测反应完毕。加入乙酸乙酯和水萃取，乙酸乙酯层饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，胶柱层析(乙酸乙酯/石油醚＝1:50洗脱)得444mg淡黄色油状物。收率：83％。
步骤4：6-氟-2-甲基-5-硝基-2,3-二氢苯并呋喃-2-羧酸甲酯的制备
Figure PCTCN2020115143-appb-000062
将6-氟-2-甲基-2,3-二氢苯并呋喃-2-羧酸(444mg，2.11mmol)溶于二氯甲烷(8mL)，室温下缓慢滴加硝酸(0.5mL)室温反应至TLC检测反应完毕，加入水二氯甲烷和水萃取，分出二氯甲烷层，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压浓缩，胶柱层析(乙酸乙酯/石油醚＝1:20～1:8梯度洗脱)得227mg淡黄色油状物。收率：42％。 1H NMR(300MHz,Chloroform-d)δ7.93(d,J＝7.5Hz,1H),6.70(d,J＝11.2Hz,1H),3.81(d,J＝1.5Hz,3H),3.65(d,J＝16.3Hz,1H),3.17(d,J＝16.3Hz,1H),1.76(s,2H).
步骤5：(6-氟-2-甲基-5-硝基-2,3-二氢苯并呋喃-2-基)甲醇的制备
Figure PCTCN2020115143-appb-000063
将6-氟-2-甲基-5-硝基-2,3-二氢苯并呋喃-2-羧酸甲酯(227mg，889μmol)溶于四氢呋喃/乙醇(8mL/2mL)，冰浴下加入硼氢化钠(101mg，2.67mmol)和氯化锂(113mg，2.67mmol)，转至室温反应3小时，TLC检测反应完毕，饱和氯化铵溶液淬灭，加入二氯甲烷萃取，分出有机层饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，胶柱层析(乙酸乙酯/石油醚＝1：1梯度洗脱)得200mg棕黄色油状物。收率：99％。 1H NMR(300MHz,DMSO-d 6)δ8.03(d,J＝8.1Hz,1H),6.95(dt,J＝11.0,2.4Hz,1H),5.19(dq,J＝8.0,4.9,4.1Hz,1H),3.60–3.40(m,2H),2.92(d,J＝16.2Hz,1H),1.38(q,J＝2.4Hz,3H).
步骤6：(1-(2-(羟甲基)-2-甲基-5-硝基-2,3-二氢苯并呋喃-6-基)哌啶-4-基)甲醇的制备
Figure PCTCN2020115143-appb-000064
将(6-氟-2-甲基-5-硝基-2,3-二氢苯并呋喃-2-基)甲醇和4-羟甲基哌啶(29mg，248μmol)溶于DMF(4mL)，加入碳酸钾(57mg，413μmol)，室温反应过夜，TLC检测反应完毕，加入乙酸乙酯(20mL)，水洗两次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩之干，无需纯化直接投入下步反应。
步骤7：(1-(5-氨基-2-(羟甲基)-2-甲基-2,3-二氢苯并呋喃-6-基)哌啶-4-基)甲醇的制备
Figure PCTCN2020115143-appb-000065
将上步产物溶于甲醇(18mL)，加入5％钯碳(20mg)，氢气氛围下反应6小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩至干，无需纯化直接投入下步反应。
步骤8：2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-6-(4-(羟甲基)哌啶-1-基)-2-甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000066
可通过实施例1中步骤3、4类似的方法由(1-(5-氨基-2-(羟甲基)-2-甲基-2,3-二氢苯并呋喃-6-基)哌啶-4-基)甲醇制备2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-6-(4-(羟甲基)哌啶-1-基)-2-甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ9.97(s,1H),8.90(s,1H),8.21(s,1H),8.10(d,J＝5.2Hz,1H),7.09(dd,J＝5.3,1.5Hz,1H),7.06(s,1H),6.67(s,1H),6.34(s,2H),5.04(t,J＝5.8Hz,1H),4.70(t,J＝5.4Hz,1H),3.43(dd,J＝5.8,3.5Hz,4H),3.25–3.16(m,1H),2.94(d,J＝11.3Hz,2H),2.83(d,J＝15.8Hz,1H),2.67(t,J＝11.0Hz,2H),1.81(d,J＝11.3Hz,2H),1.72–1.47(m,3H),1.33(s,3H).
实施例15
2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-2-甲基-6-吗啉代-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-15)
Figure PCTCN2020115143-appb-000067
可通过实施例14中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-2-甲基-6-吗啉代-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ9.86(s,1H),8.92(s,1H),8.15(d,J＝10.2Hz,2H),7.03(s,2H),6.72(s,1H),6.39(s,2H),5.05(s,1H),3.86(s,4H),3.43(s,2H),3.20(d,J＝16.2Hz,1H),2.82(d,J＝5.3Hz,4H),1.34(s,3H).
实施例16
2-(2-氨基吡啶-4-基)-N-(7-吗啉代-3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶 唑-4-甲酰胺(I-16)
Figure PCTCN2020115143-appb-000068
步骤1：7-氟-6-硝基-2H-苯并[b][1,4]恶嗪-3(4H)-酮的制备
Figure PCTCN2020115143-appb-000069
将7-氟-2H-1,4-苯并恶嗪-3(4H)-酮(1g，5.98mmol)和80％硫酸(10mL)冰盐浴至-10℃，将65％硝酸(580mg，5.98mmol)和80％(1mL)硫酸缓慢加入反应液，室温反应30分钟，TLC检测反应结束，将反应液倒入碎冰中搅拌，抽滤，得g黄色固体。 1H NMR(300MHz,DMSO-d 6)δ11.03(s,1H),7.64(d,J＝7.5Hz,1H),7.27(d,J＝12.3Hz,1H),4.79(s,2H),4.03(q,J＝7.1Hz,2H),1.99(s,3H),1.18(t,J＝7.1Hz,3H).
步骤2：7-吗啉代-6-硝基-2H-苯并[b][1,4]恶嗪-3(4H)-酮
Figure PCTCN2020115143-appb-000070
将7-氟-6-硝基-2H-苯并[b][1,4]恶嗪-3(4H)-酮(100mg，471μmol)溶于N，N-二甲基甲酰胺(1mL)和***啉(1mL)，50℃反应2小时，TLC检测反应完毕，加入乙酸乙酯，水洗两次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩至干，直接投入下步反应。 1H NMR(300MHz,Chloroform-d)δ7.30–7.24(m,1H),6.61(d,J＝5.3Hz,1H),4.33(q,J＝5.0Hz,2H),3.86(q,J＝4.9Hz,4H),3.44(s,2H),2.97(q,J＝4.8Hz,4H).
步骤3：6-氨基-7-吗啉代-2H-苯并[b][1,4]恶嗪-3(4H)-酮
Figure PCTCN2020115143-appb-000071
将上步产物溶于甲醇(10mL)，加入5％钯碳(20mg)，氢气氛围下反应6小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩至干，直接投入下步反应。 1H NMR(300MHz,DMSO-d 6)δ10.42(s,1H),6.56(d,J＝1.8Hz,1H),6.29(d,J＝1.7Hz,1H),4.64(s,2H),4.37(d,J＝1.8Hz,2H),3.71(t,J＝4.4Hz,4H),2.71(t,J＝4.5Hz,4H).
步骤4：2-(2-氨基吡啶-4-基)-N-(7-吗啉代-3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000072
可通过实施例1中步骤3、4类似的方法由6-氨基-7-吗啉代-2H-苯并[b][1,4]恶嗪-3(4H)-酮制备2-(2-氨基吡啶-4-基)-N-(7-吗啉代-3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ10.76(s,1H),9.95(s,1H),9.03(s,1H),8.17(d,J＝5.7Hz,1H),8.08(s,1H),7.19(s,1H),7.13(d,J＝5.9Hz,1H),7.00(s,1H),4.55(s,2H),2.84(s,4H).
实施例17
2-(2-氨基吡啶-4-基)-N-(7-(4-(羟甲基)哌啶-1-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺(I-16)
Figure PCTCN2020115143-appb-000073
可通过实施例16类似的方法制备2-(2-氨基吡啶-4-基)-N-(7-(4-(羟甲基)哌啶-1-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ10.72(s,1H),10.06(s,1H),9.00(d,J＝2.1Hz,1H),8.10(d,J＝5.1Hz,2H),7.19(d,J＝8.5Hz,2H),6.93(s,1H),4.74(s,1H),4.53(d,J＝2.1Hz,2H),2.93(d,J＝11.0Hz,2H),2.69(t,J＝11.0Hz,2H),1.79(d,J＝11.3Hz,2H),1.64(d,J＝11.9Hz,2H),1.58(s,1H).
实施例18
2-(2-氨基吡啶-4-基)-N-(7-吗啉代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺(I-18)
Figure PCTCN2020115143-appb-000074
可通过实施例16类似的方法由7-氟-3,4-二氢-2H-苯并[b][1,4]恶嗪制备2-(2-氨基吡啶-4-基)-N-(7-吗啉代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺。 1H NMR (300MHz,DMSO-d 6)δ10.01(s,1H),8.91(d,J＝1.8Hz,1H),8.19–8.07(m,1H),7.72(s,1H),7.03(s,2H),6.68(d,J＝1.9Hz,1H),6.39(s,2H),5.88(s,1H),4.10(s,2H),3.84(s,4H),2.76(s,4H).
实施例19
2-(2-氨基吡啶-4-基)-N-(7-(4-(羟甲基)哌啶-1-基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺(I-19)
Figure PCTCN2020115143-appb-000075
可通过实施例26类似的方法由7-氟-3,4-二氢-2H-苯并[b][1,4]恶嗪制备2-(2-氨基吡啶-4-基)-N-(7-(4-(羟甲基)哌啶-1-基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ10.13(s,1H),8.89(d,J＝2.1Hz,1H),8.09(d,J＝5.3Hz,1H),7.73(s,1H),7.14–7.02(m,2H),6.62(s,1H),6.37(s,2H),5.82(s,1H),4.71(s,1H),4.09(s,2H),2.86(d,J＝11.1Hz,2H),2.65(d,J＝11.1Hz,2H),1.77(s,2H),1.55(s,1H),1.26(d,J＝19.2Hz,2H).
实施例20
2-(2-氨基吡啶-4-基)-N-(2-异丙基-6-吗啉代-1-氧代异吲哚-5-基)恶唑-4-甲酰胺(I-20)
Figure PCTCN2020115143-appb-000076
步骤1：6-氯-2-异丙基-5-硝基异吲哚-1-酮的制备
Figure PCTCN2020115143-appb-000077
将2-(溴甲基)-5-氯-4-硝基苯甲酸甲酯(根据WO2013/079505报道方法制备)(200mg，648μmol)溶于甲醇(8mL)，加入三乙胺(108μL，777μmol)和异丙胺(66μL，777μmol)，70℃反应6小时，TLC检测反应完毕，乙酸乙酯和1mol/L盐酸水溶液萃取，水层乙酸乙酯再萃取两遍，无水硫酸钠干燥。浓缩至干。直接投入下步反应。 1H NMR(300MHz,DMSO-d 6)δ8.34(s,1H),8.00(s,1H),4.54(s,2H),4.47–4.35(m,1H),1.26–1.22(m,6H).
步骤2：2-异丙基-6-吗啉代-5-硝基异吲哚-1-酮
Figure PCTCN2020115143-appb-000078
将6-氯-2-异丙基-5-硝基异吲哚-1-酮(100mg，392μmol)和***啉(69μL，785μmol)，N,N-二异丙基乙胺(129μL，785μmol)溶于二甲亚砜(2mL)，90℃反应过夜，冷至室温，乙酸乙酯和水萃取，乙酸乙酯层水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，胶柱层析(乙酸乙酯/石油醚洗脱)得32mg橙色油状物。收率：26％。 1H NMR(300MHz,Chloroform-d)δ7.81(s,1H),7.65(d,J＝4.3Hz,1H),4.68(s,1H),4.37(d,J＝5.0Hz,2H),3.85(s,4H),3.08(s,4H),1.36–1.25(m,6H).
步骤3：5-氨基-2-异丙基-6-***啉异吲哚-1-酮
Figure PCTCN2020115143-appb-000079
可通过实施例1步骤2类似的方法制备由2-异丙基-6-吗啉代-5-硝基异吲哚-1-酮制备5-氨基-2-异丙基-6-***啉异吲哚-1-酮。 1H NMR(300MHz,Chloroform-d)δ7.54(s,1H),6.80(s,1H),4.66(d,J＝7.0Hz,1H),4.24(s,2H),3.89(d,J＝5.4Hz,4H),2.96(d,J＝4.8Hz,4H),1.31–1.27(m,6H).
步骤4：2-(2-氨基吡啶-4-基)-N-(2-异丙基-6-吗啉代-1-氧代异吲哚-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000080
可通过实施例1中步骤3、4类似的方法由5-氨基-2-异丙基-6-***啉异吲哚-1-酮制备2-(2-氨基吡啶-4-基)-N-(2-异丙基-6-吗啉代-1-氧代异吲哚-5-基)恶唑-4-甲酰胺。 1H NMR(300MHz,DMSO-d 6)δ10.29(s,1H),9.02(s,1H),8.59(s,1H),8.14(d,J＝5.4Hz,1H),7.57(s,1H),7.04(d,J＝9.1Hz,2H),6.39(s,2H),4.42(s,2H),3.90(s,4H),2.92(s,4H),1.21(d,J＝6.8Hz,6H).
实施例21
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-吗啉代-2,3-二氢呋喃并[2,3-b]吡啶-5-基)恶唑-4-甲酰胺(I-21)
Figure PCTCN2020115143-appb-000081
步骤1：3-溴-2,6-二氟吡啶的制备
Figure PCTCN2020115143-appb-000082
将3-溴-2,6-二氯吡啶(2.8g，12.3mmol)和氟化铯(7.5g，49.3mmol)溶于二甲亚砜(35mL)，80℃反应8小时，加乙酸乙酯和水萃取，乙酸乙酯层水洗两次，饱和食盐水洗，无水硫酸钠干燥。过滤，减压浓缩，胶柱层析(石油醚洗脱)得1.01g无色油状物。 1H NMR(400MHz,Chloroform-d)δ8.15–7.97(m,1H),6.79(dq,J＝8.3,2.7,2.2Hz,1H).
步骤2：1-(2,6-二氟吡啶-3-基)-2-甲基丙-2-醇的制备
Figure PCTCN2020115143-appb-000083
将3-溴-2,6-二氟吡啶(1.01g，5.21mmol)溶于无水四氢呋喃(60mL)，氩气置换保护，于-78℃下加入正丁基锂(2.2mL，6.25mmol)，30分钟后依次加入二甲基环氧丙烷(0.53mL，6.25mmol)和三氟化硼***溶液(0.75mL，6.25mmol)，转至室温反应1小时，加入饱和氯化铵淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥。过滤，减压浓缩，胶柱层析(乙酸乙酯/石油醚＝10％～15％梯度洗脱)得146mg黄色油状物。 1H NMR(400MHz,Chloroform-d)δ7.82(dt,J＝9.3,7.9Hz,1H),6.79(ddd,J＝8.0,2.9,0.6Hz,1H),2.78(s,2H),1.26(d,J＝0.8Hz,7H).
步骤3：6-氟-2,2-二甲基-2,3-二氢呋喃并[2,3-b]吡啶的制备
Figure PCTCN2020115143-appb-000084
将1-(2,6-二氟吡啶-3-基)-2-甲基丙-2-醇(146mg，779μmol)和叔丁醇钾(218mg，1.95mmol)溶于无水四氢呋喃(6mL)，室温反应1小时，TLC检测反应完毕，乙酸乙酯和水萃取，乙酸乙酯层水洗，饱和食盐水洗，无水硫酸钠干燥。过滤，减压浓缩，胶柱层析(乙酸乙酯/石油醚＝5％洗脱)得67mg无色油状物。收率：51％。 1H NMR(400MHz,Chloroform-d)δ7.45(tt,J＝7.8,1.2Hz,1H),6.35(dd,J＝7.8,1.5Hz,1H),2.99(dd,J＝2.0,1.2Hz,2H),1.51(s,6H).
步骤4：6-氟-2,2-二甲基-5-硝基-2,3-二氢呋喃并[2,3-b]吡啶的制备
Figure PCTCN2020115143-appb-000085
将6-氟-2,2-二甲基-2,3-二氢呋喃并[2,3-b]吡啶(136mg，813μmol)溶于乙酸/乙酸酐(4mL/4mL)，冰浴下加入硝酸铜(457mg，2.44mmol)，转至室温反应过夜，TLC检测基本反应完毕，乙酸乙酯和水萃取，乙酸乙酯层水洗，饱和食盐水洗，无水硫酸钠干燥。过滤，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝5％～15％梯度洗脱)得80mg无色油状物。收率：46％。 1H NMR(400MHz,Chloroform-d)δ8.28(dt,J＝8.8,1.5Hz,1H),3.12(t,J＝1.7Hz,2H),1.59(s,6H).
步骤5：2,2-二甲基-6-吗啉代-5-硝基-2,3-二氢呋喃并[2,3-b]吡啶的制备
Figure PCTCN2020115143-appb-000086
将6-氟-2,2-二甲基-5-硝基-2,3-二氢呋喃并[2,3-b]吡啶(40mg，188μmol)溶于***啉(1mL)和N，N-二甲基甲酰胺(1mL)，室温反应2小时，TLC检测反应完毕，乙酸乙酯和水萃取，乙酸乙酯层水洗，饱和食盐水洗，无水硫酸钠干燥。过滤，减压浓缩至干，直接投入下步反应。 1H NMR(400MHz,DMSO-d 6)δ8.18(s,1H),3.65(t,J＝4.5Hz,4H),2.99(s,2H),1.46(s,6H).
步骤6：2,2-二甲基-6-吗啉代-2,3-二氢呋喃并[2,3-b]吡啶-5-胺的制备
Figure PCTCN2020115143-appb-000087
可通过实施例1步骤2类似的方法制备由2,2-二甲基-6-吗啉代-5-硝基-2,3-二氢呋喃并[2,3-b]吡啶制备2,2-二甲基-6-吗啉代-2,3-二氢呋喃并[2,3-b]吡啶-5-胺。 1H NMR(400MHz,Chloroform-d)δ6.89(t,J＝1.1Hz,1H),3.88–3.80(m,4H),3.45(s,2H),3.13–3.04(m,4H),2.93(d,J＝1.1Hz,2H).
步骤7：2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-吗啉代-2,3-二氢呋喃并[2,3-b]吡啶-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000088
可通过实施例1中步骤3、4类似的方法由2,2-二甲基-6-吗啉代-2,3-二氢呋喃并[2,3-b]吡啶-5-胺制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-吗啉代-2,3-二氢呋喃并[2,3-b]吡啶-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ9.36(s,1H),8.50(s,1H),8.33(s,1H),8.23(d,J＝5.3Hz,1H),7.24(s,1H),7.09(s,1H),4.72(s,2H),3.95(s,4H),3.09(t,J＝4.2Hz,4H),3.05(s,2H),1.50(s,6H).
实施例22
2-(2-氨基吡啶-4-基)-N-(6-(4-(羟基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢呋喃并[2,3-b]吡啶-5-基)恶唑-4-甲酰胺(I-22)
Figure PCTCN2020115143-appb-000089
可通过实施例31中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-(羟基甲基)哌啶-1-基)-2,2-二甲基-2,3-二氢呋喃并[2,3-b]吡啶-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.97(s,1H),8.41(d,J＝2.9Hz,1H),8.16–8.04(m,1H),7.09(d,J＝3.5Hz,2H),6.50(s,2H),4.70(s,1H),3.41(s,2H),3.16(d,J＝11.6Hz,2H),3.03(s,2H),2.72(t,J＝11.2Hz,2H),1.78(d,J＝10.4Hz,2H),1.57(t,J＝10.1Hz,3H),1.43(s,6H).
实施例23
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-23)
Figure PCTCN2020115143-appb-000090
步骤1：4-(2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-6-基)-1-甲基-1H-吡唑的制备
Figure PCTCN2020115143-appb-000091
将6-氯-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃(0.1g，0.439mmol)、1-甲基吡唑-4-硼酸频哪醇酯(0.183g，0.878mmol)和碳酸铯(0.286g，0.878mmol)溶于二氧六环/水(4mL/0.5mL)，氩气流下加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(33mg，0.043mmol)，100℃反应过夜，TLC检测反应完毕，硅藻土抽滤，乙酸乙酯稀释(15mL)，水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝0～5％梯度洗脱)得119mg黄色油状物。收率：99％。 1H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.54(d,J＝10.6Hz,2H),6.69(s,1H),3.93(s,3H),3.06(s,2H),1.52(s,6H).
步骤2：2,2-二甲基-6-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并呋喃-5-胺的制备
Figure PCTCN2020115143-appb-000092
将4-(2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-6-基)-1-甲基-1H-吡唑(101mg，0.369mmol)溶于甲醇(10mL)，加入钯/碳(30mg)，氢气氛围下，30℃水浴反应6小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，无需进一步纯化直接投入下步反应。 1H NMR(400MHz,Chloroform-d)δ7.65(s,1H),7.53(s,1H),6.60(d,J＝9.9Hz,2H),3.94(s,3H),2.95(s,2H),1.46(s,6H).
步骤3：2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000093
可通过实施例1中步骤3、4类似的方法由2,2-二甲基-6-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并呋喃-5-胺制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.58(s,1H),8.88(s,1H),8.11(d,J＝5.1Hz,1H),7.97(s,1H),7.70(s,1H),7.50(d,J＝10.9Hz,1H),7.02(d,J＝4.6Hz,2H),6.82(s,1H),6.36(d,J＝4.6Hz,1H),3.85(s,3H),3.03(s,2H),1.44(s,6H).
实施例24
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-24)
Figure PCTCN2020115143-appb-000094
步骤1：4-(2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-6-基)吡啶的制备
Figure PCTCN2020115143-appb-000095
可通过实施例23中步骤1类似的方法由6-氯-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃制备4-(2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-6-基)吡啶。 1H NMR(400MHz,Chloroform-d)δ8.70–8.58(m,2H),7.93(t,J＝1.3Hz,1H),7.24–7.14(m,2H),6.60(s,1H),3.12(d,J＝1.3Hz,2H),1.55(s,6H).MS(ESI,m/z):[M+H] +:271.2。
步骤2：2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-胺的制备
将4-(2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-6-基)吡啶(0.1g，0.370mmol)溶于乙醇/水(6mL/2mL)，加入还原铁粉(0.124g，2.20mmol)和氯化铵(0.119g，2.20mmol)，50℃油浴反应1.5小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯溶解(15mL)，1mol/L稀盐酸萃取(15mL)，收集水层，饱和碳酸钠溶液调至碱性，乙酸乙酯(15mL*2)萃取，无水硫酸钠干燥，过滤，减压浓缩得75mg淡黄色固体。收率：84％。 1H NMR(400MHz,Chloroform-d)δ8.72–8.59(m,2H),7.46–7.36(m,2H),6.64(s,1H),6.53(s,1H),3.32(brs,2H),2.99(s,2H),1.47(s,6H).
步骤3：2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000096
可通过实施例1中步骤3、4类似的方法由2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-胺制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.72(s,1H),8.76(s,1H),8.64–8.52(m,2H),8.08(d,J＝5.2Hz,1H),7.52–7.34(m,3H),7.04–6.89(m,2H),6.77(s,1H),6.35(s,2H),3.09(s,2H),1.46(s,6H).
实施例25
2-(2-氨基吡啶-4-基)-N-(6-(呋喃-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-25)
Figure PCTCN2020115143-appb-000097
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(呋喃-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.61(s,1H),8.87(s,1H),8.20–8.06(m,1H),7.95(t,J＝1.2Hz,1H),7.77(t,J＝1.7Hz,1H),7.50(s,1H),7.12–6.97(m,2H),6.86(s,1H),6.82(dd,J＝1.9,0.9Hz,1H),6.38(s,2H),3.05(s,2H),1.44(s,6H).
实施例26
2-(2-氨基吡啶-4-基)-N-(6-(3,5-二甲基异恶唑-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-26)
Figure PCTCN2020115143-appb-000098
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(3,5-二甲基异恶唑-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ8.68(s,1H),8.29(d,J＝2.6Hz,2H),8.20(d,J＝5.4Hz,1H),7.13(dd,J＝5.4,1.4Hz,1H),7.03(s,1H),6.55(s,1H),4.88(s,2H),3.11(s,2H),2.33(d,J＝2.0Hz,3H),2.20(d,J＝2.0Hz,3H),1.52(s,6H).
实施例27
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(吡啶-3-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-27)
Figure PCTCN2020115143-appb-000099
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(吡啶-3-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ8.73(s,1H),8.68(d,J＝4.6Hz,2H),8.27(s,1H),8.17(d,J＝5.3Hz,1H),8.08(s,1H),7.77(d,J＝7.8Hz,1H),7.41(dd,J＝7.8,4.8Hz,1H),7.06(d,J＝5.3Hz,1H),6.97(s,1H),6.69(s,1H),4.76(s,2H),3.11(s,2H),1.53(s,6H).
实施例28
2-(2-氨基吡啶-4-基)-N-(6-吗啉代-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺(I-28)
Figure PCTCN2020115143-appb-000100
步骤1：2,2,2-三氟-1-(6-氟-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)乙烷-1-酮的制备
Figure PCTCN2020115143-appb-000101
可通过实施例29中步骤1-5类似的方法制备6-氟-5-硝基-3H-螺叔丁基[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯。 1H NMR(400MHz,Chloroform-d)δ7.96(d,J＝7.6Hz,1H),6.65(d,J＝11.2Hz,1H),4.39(d,J＝13.7Hz,1H),3.92(d,J＝14.4Hz,1H),3.64(t,J＝12.9Hz,1H),3.36(t,J＝12.7Hz,1H),3.08(s,2H),2.09(d,J＝14.1Hz,2H),1.93–1.76(m,2H).
步骤2：2,2,2-三氟-1-(6-吗啉代-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)乙烷-1-酮的制备
Figure PCTCN2020115143-appb-000102
将2,2,2-三氟-1-(6-氟-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)乙烷-1-酮(259mg,0.744mmol)溶于***啉(5mL),50℃反应45分钟，加水(25mL)析出固体，过滤，真空干燥得303mg黄色固体。收率：98％。 1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),6.51(s,1H),4.37(d,J＝13.9Hz,1H),3.87(d,J＝5.1Hz,5H),3.64(t,J＝12.7Hz,1H),3.36(t,J＝12.8Hz,1H),3.03(d,J＝6.0Hz,6H),2.06(d,J＝14.1Hz,2H),1.84(d,J＝13.4Hz,2H).
步骤3：1-(5-氨基-6-吗啉代-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-2,2,2-三氟乙烷-1-酮的制备
Figure PCTCN2020115143-appb-000103
将2,2,2-三氟-1-(6-吗啉代-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)乙烷-1-酮(303mg，0.729mmol)溶于乙醇/水(24mL/8mL)，加入还原铁粉(244mg，4.38mmol)和氯化铵(234mg，4.38mmol)，50℃油浴反应1.5小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯溶解(100mL)，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得277mg棕黄色固体。收率：99％。 1H NMR(400MHz,Chloroform-d)δ6.60(s,1H),6.53(s,1H),4.33(d,J＝13.2Hz,1H),3.84(t,J＝4.6Hz,5H),3.65(t,J＝12.8Hz,1H),3.36(t,J＝12.5Hz,1H),2.93(s,2H),2.87(t,J＝4.6Hz,4H),2.03(d,J＝13.6Hz,2H),1.73(t,J＝13.0Hz,3H).
步骤4：2-(2-氨基吡啶-4-基)-N-(6-(吡啶-4-基)-1'-(2,2,2-三氟乙酰基)-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000104
可通过可通过实施例1中步骤3、4类似的方法由1-(5-氨基-6-吗啉代-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-2,2,2-三氟乙烷-1-酮制备2-(2-氨基吡啶-4-基)-N-(6-(吡啶-4-基)-1'-(2,2,2-三氟乙酰基)-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺。MS(ESI):573.3[M+H].
步骤5：2-(2-氨基吡啶-4-基)-N-(6-吗啉代-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000105
可通过实施例29中步骤6类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-吗啉代-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.86(s,1H),8.92(s,1H),8.18(s,1H),8.14(d,J＝5.2Hz,1H),7.12–6.98(m,2H),6.78(s,1H),6.38(s,2H),3.95–3.80(m,4H),2.99(s,2H),2.86(dq,J＝18.6,4.6Hz,6H),2.71–2.59(m,2H),1.68(dq,J＝15.5,10.5,9.4Hz,4H).
实施例29
2-(2-氨基吡啶-4-基)-N-(6-(吡啶-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺三氟乙酸盐(I-29)
Figure PCTCN2020115143-appb-000106
步骤1：4-(4-氯-2-氟苄基)-4-羟基哌啶-1-羧酸叔丁酯的制备
Figure PCTCN2020115143-appb-000107
将镁屑(2.18g,35.8mmol)和碘粒(151mg)加入到二颈瓶，氩气保护，加入无水***(25mL)加热至回流，缓慢滴加1-(溴甲基)-4-氯-2-氟苯(8.0g,35.8mmol),滴毕，保持回流反应30分钟，即制备(4-氯-2-氟苄基)溴化镁。将4-氧哌啶-1-羧酸叔丁酯(5.94g,29.8mmol)溶于***(190mL)，-78 7低温浴下滴加所制备的4-氯-2-氟苄基)溴化镁，转至室温反应2小时。加入水和乙酸乙酯(200mL)，分出有机层，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(甲醇/二氯甲烷＝5％洗脱)得5.18g淡黄色固体。收率：51％。 1H NMR(400MHz,Chloroform-d)δ7.16(t,J＝8.0Hz,1H),7.11(d,J＝1.9Hz,1H),7.08(q,J＝2.0,1.6Hz,1H),3.85(s,2H),3.09(t,J＝12.5Hz,2H),2.78(d,J＝1.6Hz,2H),1.49(s,2H),1.45(s,9H).
步骤2：6-氯-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯的制备
Figure PCTCN2020115143-appb-000108
将4-(4-氯-2-氟苄基)-4-羟基哌啶-1-羧酸叔丁酯(2.91g,8.46mmol)溶于无水四氢呋喃(100mL)，65℃反应3小时，加入水和乙酸乙酯，分出有机层，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝0～10％梯度洗脱)得1.10g白色固体。收率：40％。 1H NMR(400MHz,Chloroform-d)δ7.03(d,J＝7.9Hz,1H),6.80(dd,J＝7.9,1.9Hz,1H),6.75(d,J＝1.8Hz,1H),3.74(s,2H),3.52–3.31(m,2H),2.94(s,2H),1.89(d,J＝13.4Hz,2H),1.69(td,J＝13.9,12.0,4.4Hz,2H),1.47(s,9H).
步骤3：6-氯-3H-螺[苯并呋喃-2,4'-哌啶]三氟乙酸盐的制备
Figure PCTCN2020115143-appb-000109
将6-氯-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯(300mg,0.926mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(3mL)室温反应1.5小时。减压浓缩，***打浆，过滤，得280mg白色固体。收率：89％。 1H NMR(400MHz,DMSO-d 6)δ8.70(d,J＝38.2Hz,2H),7.22(d,J＝7.8Hz,1H),6.89(d,J＝9.3Hz,2H),3.20(s,4H),3.08(s,2H),2.08–1.86(m,4H).
步骤4：1-(6-氯-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-2,2,2-三氟乙烷-1-酮的制备
Figure PCTCN2020115143-appb-000110
将6-氯-3H-螺[苯并呋喃-2,4'-哌啶]三氟乙酸盐(200mg)加入到二颈瓶，氩气保护下，加入二氯甲烷(8mL)和N,N-二异丙基乙胺(294μ9,1.78mmol)，冰浴10分钟后加入三氟乙酸酐，转至室温反应3小时，加入水和二氯甲烷，分出有机层，无水硫酸钠干燥，过滤，减压浓缩，真空干燥得200mg油状物，无需进一步纯化直接投入下步反应。 1H NMR(400MHz,Chloroform-d)δ7.06(dd,J＝7.9,1.3Hz,1H),6.84(dd,J＝7.9,1.9Hz,1H),6.78(d,J＝1.9Hz,1H),4.35(d,J＝13.3Hz,1H),3.88(d,J＝14.2Hz,1H),3.65(ddd,J＝14.3,12.0,2.7Hz,1H),3.45–3.29(m,1H),3.08–2.92(m,2H),2.14–1.98(m,2H),1.89–1.70(m,2H).
步骤5：1-(6-氯-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-2,2,2-三氟乙烷-1-酮的制备
Figure PCTCN2020115143-appb-000111
将1-(6-氯-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-2,2,2-三氟乙烷-1-酮(72mg,0.225mmol)溶于二氯甲烷(3mL)，加入浓硝酸(0.5mL)反应2小时，加入水和二氯甲烷，分出有机层，无水硫酸钠干燥，过滤，减压浓缩，制备型TLC纯化得46mg淡黄油状物。收率：56％。 1H NMR(400MHz,Chloroform-d)δ7.86(t,J＝1.3Hz,1H),6.92(s, 1H),4.39(d,J＝13.6Hz,1H),3.92(d,J＝14.2Hz,1H),3.64(t,J＝12.8Hz,1H),3.35(t,J＝12.7Hz,1H),3.08(d,J＝1.3Hz,2H),2.20–2.01(m,2H),1.96–1.76(m,2H).
步骤6：6-氯-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]的制备
Figure PCTCN2020115143-appb-000112
将1-(6-氯-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-2,2,2-三氟乙烷-1-酮(46mg,0.126mmol)溶于甲醇，加入碳酸钾(52mg)室温反应40分钟，加入水和二氯甲烷(含5％甲醇)，分出有机层，无水硫酸钠干燥，过滤，减压浓缩，无需进一步纯化直接投入下步反应。
步骤7：6-氯-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯的制备
Figure PCTCN2020115143-appb-000113
将上步产物溶于二氧六环(3mL)，加入二碳酸二叔丁酯(35mg,0.152mmol)，室温反应2小时，加入水和乙酸乙酯，分出有机层，无水硫酸钠干燥，过滤，减压浓缩，得56mg黄色油状物。 1H NMR(400MHz,Chloroform-d)δ7.84(t,J＝1.2Hz,1H),6.89(s,1H),3.93–3.74(m,2H),3.37(t,J＝11.9Hz,2H),3.03(d,J＝1.4Hz,2H),1.92(d,J＝13.6Hz,2H),1.74(td,J＝14.1,12.2,4.5Hz,2H),1.48(s,9H).
步骤8：5-硝基-6-(吡啶-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯的制备
Figure PCTCN2020115143-appb-000114
将6-氯-5-硝基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯(405mg,1.10mmol)、吡啶-4-硼酸(540mg,4.39mmol)和碳酸铯(716mg,2.20mmol)溶于二氧六环/水(20mL/2mL)，氩气流下加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg，0.110mmol)，100℃反应过夜，TLC检测反应完毕，硅藻土抽滤，乙酸乙酯稀释(100mL)，水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝30％洗脱)得291mg黄色固体。收率：76％。 1H NMR(400MHz,Chloroform-d)δ8.71–8.61(m,2H),7.99–7.90(m,1H),7.24–7.16(m,2H),6.67(s,1H),3.81(s,2H),3.39(t,J＝11.9Hz,2H),3.11(s,2H),1.96(d,J＝13.4Hz,2H),1.78(td,J＝14.1,12.3,4.4Hz,3H),1.48(s,9H).
步骤9：5-氨基-6-(吡啶-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯的制备
Figure PCTCN2020115143-appb-000115
将5-硝基-6-(吡啶-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯(42mg，0.102mmol)溶于乙醇/水(1.5mL/0.5mL)，加入还原铁粉(34mg，0.612mmol)和氯化铵(33 mg，0.612mmol)，50℃油浴反应1.5小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯溶解(15mL)，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得38mg黄色固体。收率：98％。 1H NMR(400MHz,Chloroform-d)δ8.71–8.60(m,2H),7.46–7.35(m,2H),6.64(s,1H),6.57(s,1H),3.75(s,2H),3.39(t,J＝11.9Hz,2H),2.97(d,J＝1.1Hz,2H),1.91(d,J＝13.6Hz,2H),1.78–1.63(m,4H),1.47(s,9H).
步骤10：2-(2-氨基吡啶-4-基)-N-(6-(吡啶-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺三氟乙酸盐的制备
Figure PCTCN2020115143-appb-000116
可通过可通过实施例1中步骤3、4类似的方法由5-氨基-6-(吡啶-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯制备2-(2-氨基吡啶-4-基)-N-(6-(吡啶-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.03(s,1H),8.91(s,1H),8.83–8.66(m,3H),8.63(s,1H),8.12(d,J＝6.5Hz,3H),7.67(d,J＝5.5Hz,2H),7.41(s,1H),7.39(d,J＝1.6Hz,1H),7.21(dd,J＝6.4,1.6Hz,1H),6.94(s,1H),3.23(s,6H),2.03(dt,J＝18.4,12.3Hz,4H).
实施例30
2-(2-氨基吡啶-4-基)-N-(6-(1-甲基-1H-吡唑-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺三氟乙酸盐(I-30)
Figure PCTCN2020115143-appb-000117
可通过实施例29中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(1-甲基-1H-吡唑-4-基)-3H-螺[苯并呋喃-2,4'-哌啶]-5-基)恶唑-4-甲酰胺三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ9.71(s,1H),9.01(s,1H),8.68(d,J＝42.0Hz,2H),8.16(d,J＝6.4Hz,1H),7.98(s,3H),7.72(s,1H),7.47(s,1H),7.40(s,1H),7.24(d,J＝6.2Hz,1H),6.93(s,1H),3.84(s,3H),3.23(s,4H),3.15(s,2H),2.12–1.88(m,4H).
实施例31
2-(2-氨基吡啶-4-基)-N-(6-(1-异丙基-1H-吡唑-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-31)
Figure PCTCN2020115143-appb-000118
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(1-异丙基-1H-吡唑-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.55(s,1H),8.89(s,1H),8.09(d,J＝5.2Hz,1H),8.06(s,1H),7.71(s,1H),7.50(s,1H),7.02(d,J＝5.2Hz,2H),6.86(s,1H),6.35(s,2H),4.47(hept,J＝6.7Hz,1H),3.04(s,2H),1.44(s,6H),1.37(d,J＝6.7Hz,6H).
实施例32
2-(2-氨基吡啶-4-基)-N-(6-(4-氯-2-氟苯基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-32)
Figure PCTCN2020115143-appb-000119
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(4-氯-2-氟苯基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ8.67(s,1H),8.26(s,1H),8.20(d,J＝5.3Hz,1H),8.14(s,1H),7.31(q,J＝9.3,8.0Hz,3H),7.08(d,J＝5.4Hz,1H),6.90(s,1H),6.67(s,1H),4.79(s,2H),3.11(s,2H),1.52(s,6H).
实施例33
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(2-甲基吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-33)
Figure PCTCN2020115143-appb-000120
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(2-甲基吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ8.89(s,1H),8.65(d,J＝5.1Hz,1H),8.26(d,J＝4.0Hz,2H),8.17(d,J＝5.3Hz,1H), 7.22(d,J＝5.2Hz,1H),7.04(d,J＝5.3Hz,1H),6.85(s,1H),6.68(s,1H),5.05(s,2H),3.11(s,2H),2.63(s,3H),1.52(s,6H).
实施例34
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(6-甲基吡啶-3-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-34)
Figure PCTCN2020115143-appb-000121
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(6-甲基吡啶-3-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.62(s,1H),8.77(s,1H),8.46(d,J＝2.3Hz,1H),8.08(d,J＝5.3Hz,1H),7.71(dd,J＝8.0,2.4Hz,1H),7.43(s,1H),7.28(d,J＝8.0Hz,1H),6.96(s,1H),6.94(dd,J＝5.3,1.5Hz,1H),6.73(s,1H),6.34(s,2H),3.08(s,2H),2.46(s,3H),1.46(s,6H).
实施例35
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(6-(三氟甲基)吡啶-3-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-35)
Figure PCTCN2020115143-appb-000122
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(6-(三氟甲基)吡啶-3-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.85(s,1H),8.78(d,J＝2.1Hz,1H),8.75(s,1H),8.17–8.01(m,2H),7.93(d,J＝8.1Hz,1H),7.37(s,1H),6.98(s,1H),6.96(dd,J＝5.3,1.4Hz,1H),6.86(s,1H),6.34(s,2H),3.10(s,2H),1.47(s,6H).
实施例36
2-(2-氨基吡啶-4-基)-N-(6-(2-甲氧基吡啶-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-36)
Figure PCTCN2020115143-appb-000123
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(2-甲氧基吡啶-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ8.98(s,1H),8.31(d,J＝5.3Hz,1H),8.27(s,1H),8.25(s,1H),8.18(d,J＝5.4Hz,1H),7.10(d,J＝5.4Hz,1H),7.02–6.95(m,1H),6.93(s,1H),6.86(s,1H),6.68(s,1H),4.86(s,2H),4.00(s,3H),3.11(s,2H),1.52(s,6H).
实施例37
2-(2-氨基吡啶-4-基)-N-(6-氟-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-37)
Figure PCTCN2020115143-appb-000124
步骤1：6-氟-2,2-二甲基-2,3-二氢苯并呋喃-5-胺的制备
Figure PCTCN2020115143-appb-000125
将6-氟-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃(60mg，0.284mmol)溶于乙醇/水(6mL/2mL)，加入还原铁粉(95mg，1.70mmol)和氯化铵(91mg，1.70mmol)，50℃油浴反应2小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯溶解(15mL)，1mol/L稀盐酸萃取(15mL)，收集水层，饱和碳酸钠溶液调至碱性，乙酸乙酯(15mL*2)萃取，无水硫酸钠干燥，过滤，减压浓缩得42mg棕色油状物。收率：82％。 1H NMR(400MHz,Chloroform-d)δ6.61(dt,J＝9.1,1.2Hz,1H),6.44(d,J＝11.1Hz,1H),3.35(s,2H),2.90(t,J＝1.4Hz,2H),1.44(s,6H).
步骤2：2-(2-氨基吡啶-4-基)-N-(6-氟-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000126
可通过可通过实施例1中步骤3、4类似的方法由6-氟-2,2-二甲基-2,3-二氢苯并呋喃-5-胺制备2-(2-氨基吡啶-4-基)-N-(6-氟-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4- 甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.69(s,1H),8.90(s,1H),8.18–8.02(m,1H),7.41(d,J＝8.0Hz,1H),7.05(d,J＝4.1Hz,2H),6.73(d,J＝10.9Hz,1H),6.36(s,2H),3.00(s,2H),1.43(s,6H).
实施例38
2-(2-氨基吡啶-4-基)-N-(6-氯-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-38)
Figure PCTCN2020115143-appb-000127
可通过实施例37中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-氯-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),8.92(s,1H),8.10(dd,J＝5.1,1.0Hz,1H),7.65(s,1H),7.05(dd,J＝6.5,1.3Hz,2H),6.94(s,1H),6.34(s,2H),3.04(s,2H),1.43(s,6H).
实施例39
2-(2-氨基吡啶-4-基)-N-(6-(6-氰基吡啶-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-39)
Figure PCTCN2020115143-appb-000128
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(6-氰基吡啶-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.77(s,1H),8.73(s,1H),8.08(d,J＝5.9Hz,1H),8.05(s,2H),7.33(s,1H),6.98(d,J＝4.2Hz,2H),6.85(s,1H),6.33(s,2H),3.10(s,2H),1.47(s,6H).
实施例40
2-(2-氨基吡啶-4-基)-N-(6-(6-甲氧基吡啶-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-40)
Figure PCTCN2020115143-appb-000129
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(6-甲氧基吡啶-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.54(s,1H),8.76(s,1H),8.19(d,J＝2.4Hz,1H),8.07(d,J＝8.5Hz,1H),7.75(dd,J＝8.5,2.5Hz,1H),7.47(s,1H),6.97(t,J＝1.1Hz,1H),6.93(dd,J＝5.2,1.5Hz,1H),6.89–6.81(m,1H),6.72(s,1H),6.31(s,2H),3.86(s,3H),3.08(s,2H),1.46(s,6H).
实施例41
2-(2-氨基吡啶-4-基)-N-(6-(1-乙基-1H-吡唑-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-41)
Figure PCTCN2020115143-appb-000130
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(1-乙基-1H-吡唑-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.52(s,1H),8.87(s,1H),8.17–8.07(m,1H),8.02(s,1H),7.71(s,1H),7.51(s,1H),7.10–6.96(m,2H),6.83(s,1H),6.33(s,2H),4.13(q,J＝7.3Hz,2H),3.04(s,2H),1.44(s,6H),1.35(t,J＝7.3Hz,3H).
实施例42
(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-1-氧代-6-(吡啶-4-基)异吲哚啉-5-基)恶唑-4-甲酰胺(I-42)
Figure PCTCN2020115143-appb-000131
步骤1：(R)-6-氯-2-(2-氟-3-羟基-3-甲基丁基)-5-硝基异吲哚-1-酮的制备
Figure PCTCN2020115143-appb-000132
将2-(溴甲基)-5-氯-4-硝基苯甲酸甲酯(根据WO2013/079505报道方法制备)(975mg，3.16mmol)和(R)-4-氨基-3-氟-2-甲基丁-2-醇(根据WO2015/103453报道方法制备)(459mg,3.79mmol)溶于甲醇(30mL)并置于封管中，加入三乙胺(527μ5)，70 7反应4小时，减压浓缩，加入乙酸乙酯(50mL)溶解，用1mol/L HCl溶液水洗，水层再用 乙酸乙酯萃取(15mL*2)萃取，有机层合并，无水硫酸钠干燥，过滤，减压浓缩得903mg淡黄色固体。收率：90％。 1H NMR(400MHz,DMSO-d 6)δ8.01(s,1H),7.91(s,1H),4.72(d,J＝17.9Hz,1H),4.65–4.41(m,2H),4.27(ddd,J＝37.0,15.1,2.2Hz,1H),3.64(ddd,J＝16.3,15.0,9.1Hz,1H),1.34(d,J＝1.8Hz,6H).
步骤2：(R)-2-(2-氟-3-羟基-3-甲基丁基)-5-硝基-6-(吡啶-4-基)异吲哚-1-酮的制备
Figure PCTCN2020115143-appb-000133
将(R)-6-氯-2-(2-氟-3-羟基-3-甲基丁基)-5-硝基异吲哚-1-酮(300mg，0.947mmol)、吡啶-4-硼酸(349mg，2.84mmol)和碳酸铯(617mg，1.89mmol)溶于二氧六环/水(10mL/1mL)，氩气流下加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(69mg，0.095mmol)，95℃反应过夜，TLC检测反应完毕，硅藻土抽滤，乙酸乙酯稀释(50mL)，水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(甲醇/二氯甲烷＝0～3％梯度洗脱)得191mg黄色固体。收率：56％。 1H NMR(400MHz,Chloroform-d)δ8.83–8.63(m,2H),8.04(s,1H),7.90(s,1H),7.27(d,J＝1.7Hz,1H),4.81(d,J＝18.0Hz,1H),4.67–4.46(m,2H),4.30(ddd,J＝36.8,15.1,2.2Hz,1H),3.78–3.60(m,1H),1.35(d,J＝1.7Hz,6H).
步骤3：(R)-5-氨基-2-(2-氟-3-羟基-3-甲基丁基)-6-(吡啶-4-基)异吲哚啉-1-酮的制备
Figure PCTCN2020115143-appb-000134
将(R)-2-(2-氟-3-羟基-3-甲基丁基)-5-硝基-6-(吡啶-4-基)异吲哚-1-酮(188mg，0.523mmol)溶于乙醇/水(10mL/3.3mL)，加入还原铁粉(175mg，3.14mmol)和氯化铵(168mg，3.14mmol)，50℃油浴反应1小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯溶解(45mL)，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得65mg黄色固体。收率：38％。 1H NMR(400MHz,Methanol-d 4)δ8.68–8.53(m,2H),7.62–7.49(m,2H),7.46(s,1H),6.91(s,1H),4.64–4.36(m,3H),4.17–4.00(m,1H),3.68(td,J＝15.2,9.3Hz,1H),1.28(d,J＝1.7Hz,6H).
步骤4：(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-1-氧代-6-(吡啶-4-基)异吲哚啉-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000135
可通过可通过实施例1中步骤3、4类似的方法由(R)-5-氨基-2-(2-氟-3-羟基-3-甲基丁基)-6-(吡啶-4-基)异吲哚啉-1-酮制备(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-1-氧代-6-(吡啶-4-基)异吲哚啉-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.89(s,1H),8.81–8.60(m,2H),8.19(s,1H),8.09(d,J＝5.2Hz,1H),7.68(s,1H),7.57(d,J＝5.0Hz,2H),6.95(s,1H),6.90(d,J＝5.1Hz,1H),6.36(s,2H),4.95(s,1H),4.76–4.59(m,2H),4.48(dd,J＝49.5,9.1Hz,1H),3.99(dd,J＝38.6,14.9Hz,1H),3.74(q,J＝15.0,14.5Hz,1H),1.21(dd,J＝14.2,3.8Hz,6H).
实施例43
2-(2-氨基吡啶-4-基)-N-(6-(5-氟吡啶-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-43)
Figure PCTCN2020115143-appb-000136
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(5-氟吡啶-3-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ8.68(s,1H),8.54(t,J＝2.2Hz,2H),8.29(s,1H),8.18(d,J＝5.3Hz,1H),8.04(s,1H),7.60–7.49(m,1H),7.10(dd,J＝5.4,1.4Hz,1H),7.04–6.95(m,1H),6.69(s,1H),4.75(s,2H),3.22–3.04(m,2H),1.53(s,6H).
实施例44
2-(2-氨基吡啶-4-基)-N-(6-(3-氟吡啶-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-44)
Figure PCTCN2020115143-appb-000137
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(6-(3-氟吡啶-4-基)-2,2-二甲基-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ8.64(s,1H),8.62(d,J＝1.6Hz,1H),8.54(d,J＝4.9Hz,1H),8.26(s,1H),8.18(d,J＝5.3Hz,1H),8.00(s,1H),7.37(t,J＝5.6Hz,1H),7.08(dd,J＝5.3,1.4Hz,1H),6.90(s,1H),6.70(s,1H),4.88(s,2H),3.12(s,2H),1.53(s,6H).
实施例45
4-(6-(2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺基)-5-乙氧基-1-甲基-1H-苯并[d]咪唑-2- 基)-2,2-二甲基丁酸甲酯(I-45)
Figure PCTCN2020115143-appb-000138
步骤1：5-氯-2-乙氧基-4-硝基苯胺的制备
Figure PCTCN2020115143-appb-000139
将2-氨基-4-氯-5-硝基苯酚(2.0g,10.6mmol)溶于N,N-二甲基甲酰胺(40mL)，加入碳酸钾(2.2g,15.9mmol)和溴乙烷(1.39g,12.7mmol),室温反应过夜，加入水和乙酸乙酯(150mL),分出有机层，水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩得2.0g棕色固体。收率：87％。 1H NMR(400MHz,DMSO-d 6)δ7.54(s,1H),6.73(s,1H),6.49(s,2H),4.10(q,J＝6.9Hz,2H),1.36(t,J＝6.9Hz,3H).
步骤2：(5-氯-2-乙氧基-4-硝基苯基)氨基甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000140
将5-氯-2-乙氧基-4-硝基苯胺(2.0g,9.23mmol)溶于二氯甲烷(30mL)，加入二碳酸二叔丁酯(2.42g,11.1mmol)和4-二甲氨基吡啶(11mg)，回流反应3小时，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝1％洗脱)得1.68g金黄色固体。收率：57％。 1H NMR(400MHz,Chloroform-d)δ8.38(s,1H),7.51(s,1H),4.17(q,J＝7.0Hz,2H),1.53(d,J＝14.0Hz,12H).
步骤3：(2-乙氧基-5-(甲基氨基)-4-硝基苯基)氨基甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000141
将(5-氯-2-乙氧基-4-硝基苯基)氨基甲酸叔丁酯(895mg,2.83mmol)和甲胺的醇溶液(40mL)加入封管中，70管反应36小时，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝5％～10％梯度洗脱)得600mg橙色固体。收率：68％。 1H NMR(400MHz,DMSO-d 6)δ8.35(q,J＝4.9Hz,1H),8.20(s,1H),7.62(s,1H),7.48(s,1H),4.06(q,J＝6.9Hz,2H),2.93(d,J＝4.9Hz,3H),1.50(s,9H),1.36(t,J＝6.9Hz,3H).
步骤4：(4-氨基-2-乙氧基-5-(甲基氨基)苯基)氨基甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000142
将(2-乙氧基-5-(甲基氨基)-4-硝基苯基)氨基甲酸叔丁酯(565mg,1.81mmol)溶于甲醇(25mL)，加入10％钯碳(200mg)和甲酸铵(686mg,10.9mmol)，60℃反应2小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯溶解(45mL)，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得485mg蓝紫色油状物，无需进一步纯化直接投入下步反应。 1H NMR(400MHz,DMSO-d 6)δ7.42(s,1H),6.63(s,1H),6.31(s,1H),4.37(s,2H),4.22(s,1H),3.85(s,2H),2.64(s,3H),1.43(s,9H),1.26(t,J＝6.9Hz,3H).
步骤5：4-(6-((叔丁氧基羰基)氨基)-5-乙氧基-1-甲基-1H-苯并[d]咪唑-2-基)-2,2-二甲基丁酸甲酯的制备
Figure PCTCN2020115143-appb-000143
将(4-氨基-2-乙氧基-5-(甲基氨基)苯基)氨基甲酸叔丁酯(485mg,1.72mmol)和5-甲氧基-4,4-二甲基-5-氧戊酸(315mg,1.81mmol)溶于N,N-二甲基甲酰胺(15mL)，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(983mg,2.59mmol)和N,N-二异丙基乙胺(712μ7,4.31mmol),室温反应过夜，乙酸乙酯(60mL)稀释,水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩得残留物溶于乙酸(15mL)，室温反应12小时，加入水和乙酸乙酯(60mL)，分出有机层，饱和碳酸氢钠和饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝20％～40％梯度洗脱)得391mg粉白色固体。收率：54％。 1H NMR(400MHz,DMSO-d 6)δ7.79(s,2H),7.14(s,1H),4.06(q,J＝7.1Hz,2H),3.65(d,J＝1.4Hz,3H),3.59(d,J＝1.4Hz,3H),2.74(t,J＝8.4Hz,2H),2.03–1.92(m,2H),1.48(d,J＝1.5Hz,9H),1.37(td,J＝6.9,1.4Hz,3H),1.21(d,J＝1.5Hz,6H).
步骤6：4-(6-氨基-5-乙氧基-1-甲基-1H-苯并[d]咪唑-2-基)-2,2-二甲基丁酸甲酯的制备
Figure PCTCN2020115143-appb-000144
将4-(6-((叔丁氧基羰基)氨基)-5-乙氧基-1-甲基-1H-苯并[d]咪唑-2-基)-2,2-二甲基丁酸甲酯(387mg,0.922mmol)溶于二氯甲烷(20mL)，加入三氟乙酸(5mL)室温反应1小时，减压浓缩，加入乙酸乙酯和饱和碳酸氢钠溶液萃取，分出有机层，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得283mg棕色固体。收率：96％。 1H NMR(400MHz,DMSO-d 6)δ6.93(s,1H),6.69–6.56(m,1H),4.65(s,2H),3.98(q,J＝6.9Hz,2H), 3.59(d,J＝1.5Hz,3H),3.55(d,J＝1.4Hz,3H),2.66(t,J＝8.5Hz,2H),1.93(t,J＝8.4Hz,2H),1.42–1.30(m,3H),1.21(s,6H).
步骤7：4-(6-(2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺基)-5-乙氧基-1-甲基-1H-苯并[d]咪唑-2-基)-2,2-二甲基丁酸甲酯的制备
Figure PCTCN2020115143-appb-000145
可通过可通过实施例1中步骤3、4类似的方法由4-(6-氨基-5-乙氧基-1-甲基-1H-苯并[d]咪唑-2-基)-2,2-二甲基丁酸甲酯制备4-(6-(2-(2-氨基吡啶-4-基)恶唑-4-甲酰胺基)-5-乙氧基-1-甲基-1H-苯并[d]咪唑-2-基)-2,2-二甲基丁酸甲酯。 1H NMR(400MHz,DMSO-d 6)δ9.66(s,1H),8.96(s,1H),8.41(s,1H),8.12(d,J＝5.2Hz,1H),7.29(s,1H),7.03(d,J＝5.7Hz,2H),6.39(s,2H),4.20(q,J＝6.9Hz,2H),3.69(s,3H),3.60(s,3H),2.85–2.71(m,2H),2.08–1.94(m,2H),1.50(t,J＝6.9Hz,3H),1.22(s,6H).
实施例46
2-(2-氨基吡啶-4-基)-N-(6-甲氧基-2-(哌啶-4-基)-2H-吲唑-5-基)恶唑-4-甲酰胺三氟乙酸盐(I-46)
Figure PCTCN2020115143-appb-000146
步骤1：2-氟-4-甲氧基-5-硝基苯甲醛的制备
Figure PCTCN2020115143-appb-000147
将浓硫酸(1.3mL)冰盐浴至-15℃，加入2-氟-4-甲氧基苯甲醛(3.0g,19.5mmol)，并缓慢滴加浓硝酸，控制反应液温度在-10℃以下，并保温反应45分钟，将反应液倒入碎冰中，析出大量固体，过滤，真空干燥得所得固体用石油醚打浆，过滤，真空干燥得3.49g黄白色固体。收率：90％。 1H NMR(400MHz,Chloroform-d)δ10.21(s,1H),8.46(d,J＝7.2,1H),6.87(d,J＝11.5Hz,1H),4.06(s,3H).
步骤2：2-叠氮基-4-甲氧基-5-硝基苯甲醛的制备
Figure PCTCN2020115143-appb-000148
将2-氟-4-甲氧基-5-硝基苯甲醛(2.0g,10.0mmol)溶于二甲亚砜(10mL)，加入叠氮化钠(1.31g,20.1mmol)室温反应30分钟，加入水和乙酸乙酯(250mL)，乙酸乙酯层用水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩得2.13g棕色固体。收率：95％。 1H NMR(400MHz,Chloroform-d)δ10.19(s,1H),8.45(s,1H),6.80(s,1H),4.09(s,3H).
步骤3：4-(6-甲氧基-5-硝基-2H-吲唑-2-基)哌啶-1-甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000149
将2-叠氮基-4-甲氧基-5-硝基苯甲醛(1.0g,4.50mmol)溶于二氯甲烷(20mL)，将4-氨基哌啶-1-羧酸叔丁酯(902mg,4.50mmol)溶于二氯甲烷加入反应液，并加入
Figure PCTCN2020115143-appb-000150
分子筛(2g)，室温反应1.5小时后补加4-氨基哌啶-1-羧酸叔丁酯(270mg,1.35mmol)和
Figure PCTCN2020115143-appb-000151
分子筛(2g),继续室温反应14小时，硅藻土抽滤，减压浓缩后溶于无水甲苯(30mL)，120℃反应1小时，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝20％～40％梯度洗脱)得1.46g黄色固体。收率：86％。 1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),8.07(s,1H),7.10(s,1H),4.52(tt,J＝11.6,4.0Hz,1H),4.33(s,2H),3.96(s,3H),2.94(s,2H),2.32–2.18(m,2H),2.08(qd,J＝12.2,4.6Hz,2H),1.48(s,9H).
步骤4：4-(5-氨基-6-甲氧基-2H-吲唑-2-基)哌啶-1-甲酸叔丁酯的制备
Figure PCTCN2020115143-appb-000152
将4-(6-甲氧基-5-硝基-2H-吲唑-2-基)哌啶-1-甲酸叔丁酯(233mg，0.675mmol)溶于乙醇/水(12mL/4mL)，加入还原铁粉(226mg，4.05mmol)和氯化铵(217mg，4.05mmol)，50℃油浴反应6小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯溶解(60mL)，水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩，无需进一步纯化，直接投入下步反应。 1H NMR(400MHz,Chloroform-d)δ7.61(d,J＝0.9Hz,1H),6.93(s,1H),6.75(s,1H),4.42(tt,J＝11.7,4.1Hz,1H),4.25(d,J＝31.8Hz,2H),3.91(s,3H),2.91(s,2H),2.19(d,J＝12.9Hz,2H),2.04(s,3H),1.48(s,9H).
步骤5：2-(2-氨基吡啶-4-基)-N-(6-甲氧基-2-(哌啶-4-基)-2H-吲唑-5-基)恶唑-4-甲酰胺三氟乙酸盐的制备
Figure PCTCN2020115143-appb-000153
可通过实施例2中类似的方法由4-(5-氨基-6-甲氧基-2H-吲唑-2-基)哌啶-1-甲酸叔丁酯制备2-(2-氨基吡啶-4-基)-N-(6-甲氧基-2-(哌啶-4-基)-2H-吲唑-5-基)恶唑-4-甲酰胺三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ9.52(s,1H),9.11(s,1H),8.81(d,J＝11.1Hz,1H),8.57(s,2H),8.37(s,1H),8.14(d,J＝6.3Hz,1H),7.84(s,2H),7.41(s,1H), 7.27(d,J＝6.2Hz,1H),7.17(s,1H),4.82–4.69(m,1H),4.01(s,3H),3.46(d,J＝12.6Hz,2H),3.22–3.06(m,2H),2.42–2.10(m,4H).
实施例47
2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-2-甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-47)
Figure PCTCN2020115143-appb-000154
步骤1：(6-氯-2-甲基-5-硝基-2,3-二氢苯并呋喃-2-基)甲醇的制备
Figure PCTCN2020115143-appb-000155
可通过实施例14中步骤1-5类似的方法制备(6-氯-2-甲基-5-硝基-2,3-二氢苯并呋喃-2-基)甲醇。 1H NMR(400MHz,Chloroform-d)δ7.85(d,J＝1.6Hz,1H),6.86(s,1H),3.76(d,J＝5.6Hz,1H),3.66(d,J＝7.3Hz,1H),3.40–3.31(m,1H),2.99–2.90(m,1H),1.84(dd,J＝7.3,5.7Hz,1H),1.48(s,3H),1.26(dd,J＝7.5,6.8Hz,1H).
步骤2：(2-甲基-5-硝基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-2-基)甲醇的制备
Figure PCTCN2020115143-appb-000156
将6-氯-2-甲基-5-硝基-2,3-二氢苯并呋喃-2-基)甲醇(58mg，0.238mmol)、吡啶-4-硼酸(88mg，0.714mmol)和碳酸铯(155mg，0.476mmol)溶于二氧六环/水(5mL/0.5mL)，氩气流下加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(17mg，0.024mmol)，100℃反应过夜，TLC检测反应完毕，硅藻土抽滤，乙酸乙酯稀释(30mL)，水和饱和食盐水各洗一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(乙酸乙酯/石油醚＝60％洗脱)得58mg淡黄色固体。收率：85％。 1H NMR(400MHz,Chloroform-d)δ8.68–8.57(m,2H),7.94(t,J＝1.3Hz,1H),7.20–7.14(m,2H),6.54(s,1H),3.82(d,J＝12.0Hz,1H),3.67(d,J＝12.1Hz,1H),3.45(dd,J＝16.2,1.3Hz,1H),3.01(dd,J＝16.2,1.2Hz,1H),2.52(s,1H),1.51(s,3H).
步骤3：(5-氨基-2-甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-2-基)甲醇的制备
Figure PCTCN2020115143-appb-000157
将(2-甲基-5-硝基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-2-基)甲醇(50mg，0.175mmol)溶于乙醇/水(6mL/2mL)，加入还原铁粉(58mg，1.05mmol)和氯化铵(56mg，1.05mmol)，50℃油浴反应1小时，TLC检测反应完毕，硅藻土抽滤，减压浓缩，乙酸乙酯 溶解(20mL)，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得38mg黄色固体。收率：85％。 1H NMR(400MHz,Chloroform-d)δ8.70–8.60(m,2H),7.44–7.36(m,2H),6.65(s,1H),6.54(s,1H),3.75–3.61(m,2H),3.25(d,J＝16.2Hz,1H),2.88(d,J＝15.9Hz,1H),1.44(s,3H).
步骤4：2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-2-甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺的制备
Figure PCTCN2020115143-appb-000158
可通过可通过实施例1中步骤3、4类似的方法由(5-氨基-2-甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-2-基)甲醇制备2-(2-氨基吡啶-4-基)-N-(2-(羟甲基)-2-甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.70(s,1H),8.75(s,1H),8.65–8.51(m,2H),8.08(d,J＝5.3Hz,1H),7.47–7.40(m,2H),7.39(s,1H),7.03–6.91(m,2H),6.75(s,1H),6.33(s,2H),5.13(t,J＝5.8Hz,1H),3.49(qd,J＝11.5,5.8Hz,2H),3.28(s,1H),3.17(d,J＝5.3Hz,1H),2.92(d,J＝16.3Hz,1H),1.39(s,3H).
实施例48
2-(2-氨基嘧啶-4-基)-N-(2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-48)
Figure PCTCN2020115143-appb-000159
可通过实施例24中类似的方法制备2-(2-氨基嘧啶-4-基)-N-(2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Methanol-d 4)δ8.56(s,1H),8.55–8.50(m,2H),8.45(d,J＝5.2Hz,1H),7.55–7.48(m,2H),7.45(s,1H),7.28(d,J＝5.1Hz,1H),6.77(s,1H),1.51(s,6H).
实施例49
2-(6-氨基嘧啶-4-基)-N-(2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-49)
Figure PCTCN2020115143-appb-000160
可通过实施例24中类似的方法制备2-(6-氨基嘧啶-4-基)-N-(2,2-二甲基-6-(吡啶-4-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ8.82–8.69(m,3H),8.65(d,J＝1.2Hz,1H),8.34(s,1H),8.13(s,1H),7.42(d,J＝5.5Hz,2H),6.86(d,J＝1.2Hz,1H),6.70(s,1H),5.59(s,2H),3.12(d,J＝1.2Hz,2H),1.53(s,6H).
实施例50
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(嘧啶-5-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-50)
Figure PCTCN2020115143-appb-000161
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(嘧啶-5-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Chloroform-d)δ9.25(s,1H),8.85(s,2H),8.53(s,1H),8.28(s,1H),8.18(d,J＝5.4Hz,1H),7.87(s,1H),7.12(d,J＝5.9Hz,1H),7.01(s,1H),6.70(s,1H),4.72(s,2H),3.12(s,2H),1.53(s,6H).
实施例51
2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(2-甲基嘧啶-5-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺(I-51)
Figure PCTCN2020115143-appb-000162
可通过实施例24中类似的方法制备2-(2-氨基吡啶-4-基)-N-(2,2-二甲基-6-(2-甲基嘧啶-5-基)-2,3-二氢苯并呋喃-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.84(s,1H),8.75(s,1H),8.70(s,2H),8.08(d,J＝5.3Hz,1H),7.32(s,1H),6.99(d,J＝4.7Hz,2H),6.83(s,1H),6.31(s,2H),3.09(s,2H),2.60(s,3H),1.47(s,6H).
实施例52
(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-1-氧代-6-(吡啶-3-基)异吲哚啉-5-基)恶唑-4-甲酰胺(I-52)
Figure PCTCN2020115143-appb-000163
可通过实施例24中类似的方法制备(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-1-氧代-6-(吡啶-3-基)异吲哚啉-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),8.88(s,1H),8.70(d,J＝2.3Hz,1H),8.67(dd,J＝4.8,1.6Hz,1H),8.20(s,1H),8.09(d,J＝5.2Hz,1H),7.96(dt,J＝7.8,2.0Hz,1H),7.67(s,1H),7.56(dd,J＝7.9,4.8Hz,1H),6.93(t,J＝1.1Hz,1H),6.89(dd,J＝5.3,1.4Hz,1H),6.34(s,2H),4.94(s,1H),4.75–4.59(m,2H),4.58–4.39(m,1H),4.08–3.91(m,1H),3.74(td,J＝15.6,9.4Hz,1H),1.19(dd,J＝4.5,1.6Hz,6H).
实施例53
(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-6-(1-甲基-1H-吡唑-4-基)-1-氧代异吲哚-5-基)恶唑-4-甲酰胺(I-53)
Figure PCTCN2020115143-appb-000164
可通过实施例24中类似的方法制备(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-6-(1-甲基-1H-吡唑-4-基)-1-氧代异吲哚-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),8.99(s,1H),8.30(s,1H),8.20(s,1H),8.13(d,J＝5.5Hz,1H),7.85(s,1H),7.72(s,1H),7.00(d,J＝3.3Hz,2H),6.37(s,2H),4.93(s,1H),4.69–4.55(m,2H),4.47(dd,J＝49.8,9.8Hz,1H),4.09–3.86(m,4H),3.72(td,J＝15.4,9.2Hz,1H),1.19(d,J＝4.2Hz,6H).
实施例54
(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-6-(6-甲基吡啶-3-基)-1-氧代异吲哚-5-基)恶唑-4-甲酰胺(I-54)
Figure PCTCN2020115143-appb-000165
可通过实施例24中类似的方法制备(R)-2-(2-氨基吡啶-4-基)-N-(2-(2-氟-3-羟基-3-甲基丁基)-6-(6-甲基吡啶-3-基)-1-氧代异吲哚-5-基)恶唑-4-甲酰胺。 1H NMR(400MHz,Methanol-d 4)δ8.60(d,J＝2.3Hz,1H),8.57(s,1H),8.42(s,1H),8.04(d,J＝5.5Hz,1H),7.89(dd,J＝8.0,2.4Hz,1H),7.78(s,1H),7.52(d,J＝8.1Hz,1H),7.10(s,1H),7.02(dd, J＝5.5,1.6Hz,1H),4.78–4.65(m,2H),4.62–4.48(m,1H),4.16(dd,J＝37.9,14.8Hz,1H),3.80(td,J＝15.2,9.6Hz,1H),2.66(s,3H),1.31(s,6H).
实施例55
在本实施例中，采用类似方法，合成了以下比较化合物1-4。
Figure PCTCN2020115143-appb-000166
比较化合物1与化合物I-5相同，区别在于吡啶N原子邻位为甲基。 1H NMR(400MHz,DMSO-d 6)δ9.99(s,1H),9.02(s,1H),8.72(d,J＝5.1Hz,1H),8.19(s,1H),7.89–7.81(m,1H),7.75(dd,J＝5.2,1.6Hz,1H),6.76(s,1H),3.89(dd,J＝5.7,3.2Hz,4H),3.01(s,2H),2.84(t,J＝4.5Hz,4H),2.59(s,3H),1.41(s,6H).
Figure PCTCN2020115143-appb-000167
比较化合物2与化合物I-1相同，区别在于N原子吡啶邻位为甲基。 1H NMR(300MHz,DMSO-d 6)δ10.01(s,1H),9.00(s,1H),8.68(d,J＝5.0Hz,1H),8.22(s,1H),7.80(d,J＝6.7Hz,2H),6.70(s,1H),4.63(t,J＝5.1Hz,1H),3.43(d,J＝5.3Hz,2H),3.00(s,2H),2.94(d,J＝11.1Hz,2H),2.68(t,J＝10.7Hz,2H),2.60(s,3H),1.91–1.77(m,2H),1.68–1.51(m,3H),1.41(s,6H).
Figure PCTCN2020115143-appb-000168
比较化合物3与化合物I-5相同,区别在于吡啶N原子邻位无取代。 1H NMR(400MHz,Chloroform-d)δ10.00(s,1H),8.95–8.76(m,2H),8.36(d,J＝25.4Hz,2H),8.01–7.86(m,2H),6.65(s,1H),4.01(t,J＝4.5Hz,4H),3.04(s,2H),2.93(dd,J＝5.5,3.3Hz,4H),1.49(s,6H).
Figure PCTCN2020115143-appb-000169
比较化合物4与化合物I-5相同,区别在于吡啶N原子邻位氨基为乙酰基取代。 1H  NMR(400MHz,DMSO-d 6)δ10.81(s,1H),9.91(s,1H),9.01(s,1H),8.81(s,1H),8.57(dd,J＝5.1,0.8Hz,1H),8.20(s,1H),7.64(dd,J＝5.2,1.6Hz,1H),6.75(s,1H),3.87(dd,J＝5.9,3.2Hz,4H),3.01(s,2H),2.83(dd,J＝5.4,3.3Hz,4H),2.14(s,3H),1.41(s,6H)。
测试实施例1
化合物对IRAK4激酶活性抑制实验
1、试验方法
采用Z′-LYTE TM激酶试剂盒检测化合物的激酶抑制活性。主要步骤如下：在384孔板中以2.5μL/孔的量加入不同浓度的化合物溶液或溶剂对照，每个浓度设两个复孔。溶剂对照组分为三种：0％磷酸化、0％抑制和100％磷酸化。用激酶缓冲液将酶和底物稀释成1.5ng/孔和2μM/孔的混合物，该混合物在待测化合物组和0％磷酸化以及0％抑制组使用，每孔加入5μL。在100％磷酸化组中，每孔加入5μL的磷酸化底物溶液，浓度为2μM/孔。待测化合物组和0％抑制组加入2.5μL的ATP(终浓度为400μM)启动反应，将384孔板置于27℃烘箱反应1h。加入次级反应试剂，每孔5μL，27℃烘箱反应1h，加入5μL终止试剂终止反应，用荧光检测酶标仪(Synergy 2，BIOTEK)读板，分别读取400nM激发光下，445nM和520nM波长处的发射光。抑制率及半数抑制量IC 50通过两种发射光的比值及磷酸化百分比求得。
2、实验结果
由表2可以看出，本发明中的化合物对IRAK4激酶抑制作用明显，其中化合物I-5对IRAK4抑制活性相比于比较化合物1、3、4有明显提升，化合物I-1相比于比较化合物2有明显提升，说明吡啶N原子邻位氨基对于IRAK4抑制活性具有重要作用，当吡啶N原子邻位氨基取代基替换后，化合物活性出现明显变劣。
表2.化合物对IRAK4激酶活性检测
编号 IRAK4 IC 50(nM)
I-1 2.1±0.2
I-2 8.0±4.7
I-3 14.0±2.2
I-4 32.0±13.7
I-5 2.6±1.7
I-6 17.8±7.1
I-7 28.4±4.9
I-8 60.9±17.3
I-9 25.4±25.1
I-10 55.8±17.3
I-11 7.4±4.0
I-12 11.6±3.3
I-13 28.5±1.1
I-14 14.2±3.1
I-15 4.8±0.5
I-16 64.1±25.6
I-17 28.3±11.9
I-18 41.1±13.3
I-19 28.1±5.7
I-20 27.0±13.0
I-21 22.2±9.1
I-22 28.3±11.9
I-23 8.7±0.8
I-24 9.3±5.1
I-25 10.2±0.4
I-27 4.9±2.1
I-28 5.8±0.6
I-29 13.3±3.1
I-30 9.0±4.8
I-31 24.7±5.3
I-32 60.0±29.2
I-33 30.3±10.0
I-34 12.8±4.5
I-35 25.3±9.5
I-36 22.8±2.5
I-37 71.6±10.4
I-38 54.4±8.2
I-39 42.1±9.3
I-40 26.8±8.9
I-41 18.5±5.7
I-42 4.8±0.6
I-43 3.6±0.9
I-44 3.9±0.3
I-45 17.2±6.9
I-46 4.2±0.1
I-47 20.9±4.3
比较化合物1 30.5±14.1
比较化合物2 120.6±40.7
比较化合物3 32.3±14.9
比较化合物4 62.7±25.0
测试实施例2
化合物对OCI-LY-10细胞系(含MYD88 L265P突变细胞)生长抑制实验
采用CCK-8(Cell Counting Kit-8)染色法检测化合物对细胞的增殖抑制作用。CCK-8染色法方法步骤如下：根据细胞生长速率，将处于对数生长期的OCI-LY-10细胞按不同浓度以90μL/孔接种于96孔培养板，待细胞生长过夜后，加入不同浓度的化合物10μL/孔，每个浓度设三个复孔，并设相应的溶剂对照及无细胞空白对照孔。将细胞置于培养箱化合物作用72h后弃去细胞培养液，加入CCK-8试剂10μL/孔。将96孔板放回细胞培养箱中反应2h后置于酶标仪450nm波长下测定OD值。化合物对细胞生长的抑制率计算公式为：抑制率％＝(对照组OD值－给药组OD值)/对照组OD值×100％。半数抑制量IC 50值由酶标仪附带软件以四参数法拟合抑制曲线求得。实施例23(I-23)化合物IC 50值为0.291±0.096μM；实施例24(I-24)化合物IC 50值为1.586±0.280μM。
测试实施例3
化合物对U2932细胞系(不含MYD88 L265P突变细胞)生长抑制实验
采用CCK-8(Cell Counting Kit-8)染色法检测化合物对细胞的增殖抑制作用。CCK-8染色法方法步骤如下：根据细胞生长速率，将处于对数生长期的OCI-LY-10细胞按不同浓度以90μL/孔接种于96孔培养板，待细胞生长过夜后，加入不同浓度的化合物10μL/孔，每个浓度设三个复孔，并设相应的溶剂对照及无细胞空白对照孔。将细胞置于培养箱化合物作用72h后弃去细胞培养液，加入CCK-8试剂10μL/孔。将96孔板放回细胞培养箱中反应2h后置于酶标仪450nm波长下测定OD值。化合物对细胞生长的抑制率计算公式为：抑制率％＝(对照组OD值－给药组OD值)/对照组OD值×100％。半数抑制量IC 50值由酶标仪附带软件以四参数法拟合抑制曲线求得。实施例24(I-24)化合物IC 50值大于50μM，说明实施例24(I-24)化合物具有选择性抑制MYD88 L265P突变弥漫性大B细胞淋巴瘤作用。
测试实施例4
化合物对系列酪氨酸激酶活性的抑制作用实验
采用ELISA方法检测化合物对一系列激酶活性的抑制作用。这一系列激酶包括VEGFR-1、VEGFR-2、VEGFR-3、PDGFR-α、PDGFR-β、RET、C-Kit、FLT3、EGFR、ErbB2、ErbB4、Src、Abl、EPH-A2、IGF1R、IR、FGFR1、FGFR2、FGFR3、FGFR4、BTK、FAK、CSF1R和ITK，均购自Europhins公司。
ELISA主要步骤如下：用无钾离子的PBS将酶反应底物Poly(Glu,Tyr) 4:1于37℃反应12-16h包被酶标板后弃去孔中液体。用T-PBS洗板三次，放于37℃烘箱中干燥酶标板1-2h备用。每孔加入反应缓冲液稀释的ATP(终浓度5mM)溶液、化合物或溶剂对照，然后加入激酶启动反应，37℃摇床反应1h。T-PBS洗板三次，加入抗体PY99于37℃反应0.5h。T-PBS洗板三次后，加入辣根过氧化物酶标记的羊抗鼠的IgG 37℃摇床反应0.5h。弃去孔中液体，再次洗板后，加入OPD显色液100μL/孔，25℃避光反应1-10min。加入H 2SO 4终止反应，用可调波长式微孔板酶标仪读数，波长为490nm。抑制率计算公式为：抑制率％＝[1-(化合物OD值-无酶对照OD值)/(阴性对照OD值-无酶对照OD值)]×100％。IC 50值采用酶标仪附带软件以四参数法拟合抑制曲线求得。
由表3可以看出，化合物实施例23(I-23)和实施例(I-24)对酪氨酸激酶谱具有较好选择性，同时对VEGFR-3、RET、FLT3、ErbB2有抑制作用。
表3.化合物对系列酪氨酸激酶活性检测
Figure PCTCN2020115143-appb-000170
Figure PCTCN2020115143-appb-000171
测试实施例5
化合物FLT3激酶和FLT3-ITD、FLT3 D835Y突变激酶活性检测
用酶联免疫吸附法(Enzyme-Linked Immunosorbent Assay,ELISA)检测激酶磷酸化底物的能力，计算化合物对激酶活性的抑制作用。激酶采用Flt-3、Flt-3 ITD和Flt-3 D835Y(购自Eurofins公司)。ELISA主要步骤如下：酶反应底物Poly(Glu,Tyr) 4:1用无钾离子的PBS稀释成2.5μg/孔，37℃反应12-16h包被酶标板，备用。每孔加入用反应缓冲液(50mM HEPES pH 7.4，20mM MgCl 2，0.1mM MnCl 2，0.2mM Na 3VO 4，1mM DTT)稀释的ATP(终浓度5μM)溶液，加入化合物或溶剂对照，然后加入激酶启动反应，37℃摇床反应1h。T-PBS洗板三次，加入抗体PY99抗体于37℃摇床反应0.5h。T-PBS洗板后，加入辣根过氧化物酶标记的羊抗鼠的IgG，37℃摇床反应0.5h。再次洗板后，加入含0.03％H 2O 2，2mg/mL的OPD显色液，25℃避光反应1-10min。加入2M H 2SO 4终止反应，用可调波长式微孔板酶标仪(SpectraMax Plus384，Molecular Devices)读数，波长为490nm。IC 50值由抑制曲线得到。
由表4结果可看出，实施例24(I-24)对FLT3激酶、FLT3-ITD和FLT3 D835Y突变激酶均具有高度抑制活性。
表4.化合物FLT3激酶和FLT3-ITD、FLT3 D835Y突变激酶活性检测
化合物 Flt-3 IC 50(nM) Flt-3 ITD IC 50(nM) FLT3 D835Y IC 50(nM)
I-24 1.7±0.1 3.5±2.1 0.3±0.1
Quizartinib 3.8±0.8 2.6±0.4 278.0±68.4
测试实施例6
化合物对白血病细胞株细胞增殖的影响
1.实验材料
白血病细胞株：急性髓性白血病细胞株MV4-11(表达FLT3-ITD突变型基因)MOLM-3(表达FLT3-ITD突变型基因和野生型FLT3基因)
2.试验方法
将处于对数生长期的白血病细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度(1μM为起始浓度，5倍稀释)的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(上海李记生物科技)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。采用以下公式计算化合物对肿瘤细胞生长的抑制率(％)：抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC 50值采用酶标仪随机附带软件以四参数法回归求得。
3.实验结果
由表5结果可以看出，实施例24(I-24)对表达FLT3-ITD突变的急性髓系白血病细胞株MV4-11和MOLM-3细胞增殖活性抑制明显。
表5.化合物对MV4-11和MOLM-3细胞增殖的影响
化合物 MV4-11 IC 50(nM) MOLM-13 IC 50(nM)
I-24 <3.9 6.0±1.9
Quizartinib 4.8±2.7 9.8±4.0
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种式(I)所示化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物:
    Figure PCTCN2020115143-appb-100001
    其中，
    X、Y、Z或W分别独立选自CH或N；且当X、Y、Z或W为CH时，所述的H原子可以被选自下组的取代基取代：卤素、C1-C3烷基、C2-C6酰基、C1-C3烷氧基、三氟甲氧基、三氟乙氧基；
    环A为含1-2个选自N、O和S的杂原子的3-8元饱和杂环(包括单环、并环或螺环)、含1-2个选自N、O和S的杂原子的5-8元芳杂环，所述饱和杂环任选地被一个或多个卤素、氧代、羧基、氰基、羟基、取代或未取代的5-6元杂环、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基取代，所述取代指被一个或多个选自下组的取代基所取代：卤素、C1-C3烷基、羟基、C2-C6酰基、3-8元饱和或部分饱和杂环基；
    R 1选自-NR 2R 3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-11元饱和或部分饱和杂环基，所述取代基由R a表示；
    各个R a各自独立地选自卤素、氧代、-(C0-C3烷基)-CN、-(C0-C3烷基)-OH、-(C0-C3烷基)-COOH、-(C0-C3烷基)C(＝O)OR 5、-(C0-C3烷基)C(＝O)R 5、-(C0-C3烷基)NR 5R 6、-C(＝O)(C1-C3烷基)、-(C0-C3烷基)C(＝O)NR 5R 6、-(C0-C3烷基)S(＝O)NR 5R 6、-(C0-C3烷基)S(＝O) 2NR 5R 6、-(C0-C3烷基)S(＝O) 2(C1-C3烷基)、-(C0-C3烷基)OP(＝O)(OC1-C3烷基) 2、取代或未取代的C1-C3烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷硫基、所述取代是指被一个或多个卤素取代；
    R 2和R 3各自独立地选自氢原子、取代或未取代的C1-C3烷基、取代或未取代的C3-C10环烷基、-(C0-C3烷基)-6-10元芳基、-(C0-C3烷基)-5-10元杂芳基、-(C0-C3烷基)-饱和或部分饱和4-10元杂环基，所述取代指被卤素、羟基、氨基、氰基或酰胺基取代；
    或者R 2和R 3可以和与它们所连接的氮原子一起形成4-8元杂环，所述杂环任选被一个或多个R a取代；
    R 5、R 6分别独立选自氢原子、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的4-6元杂环，所述取代指被一个或多个C1-C3烷基、羟基、卤素、羧酸基、C2-C6羧酸酯基取代。
  2. 如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，其特征在于，X、Y、Z或W分别独立选自CH或N；
    环A为含1-2个选自N、O和S的杂原子的3-8元饱和杂环(包括单环、并环或螺环)， 所述饱和杂环任选地被一个或多个卤素、氧代、羧基、氰基、羟基、取代或未取代的5-6元杂环、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基取代，所述取代指被一个或多个卤素、C1-C3烷基或羟基取代；
    R 1选自-NR 2R 3、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-11元饱和或部分饱和杂环基，所述取代基由R a表示；
    各个R a各自独立地选自卤素、氧代、-(C0-C3烷基)-CN、-(C0-C3烷基)-OH、-(C0-C3烷基)-COOH、-(C0-C3烷基)C(＝O)OR 5、-(C0-C3烷基)C(＝O)R 5、-(C0-C3烷基)NR 5R 6、-C(＝O)(C1-C3烷基)、-(C0-C3烷基)C(＝O)NR 5R 6、-(C0-C3烷基)S(＝O)NR 5R 6、-(C0-C3烷基)S(＝O) 2NR 5R 6、-(C0-C3烷基)S(＝O) 2(C1-C3烷基)、-(C0-C3烷基)OP(＝O)(OC1-C3烷基) 2、取代或未取代的C1-C3烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷硫基、所述取代是指被一个或多个卤素取代；
    R 2和R 3各自独立地选自氢原子、取代或未取代的C1-C3烷基、取代或未取代的C3-C10环烷基、-(C0-C3烷基)-6-10元芳基、-(C0-C3烷基)-5-10元杂芳基、-(C0-C3烷基)-饱和或部分饱和4-10元杂环基，所述取代指被卤素、羟基、氨基、氰基或酰胺基取代；
    或者R 2和R 3可以和与它们所连接的氮原子一起形成4-8元杂环，所述杂环任选被一个或多个R a取代；
    R 5、R 6分别独立选自氢原子、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的4-6元杂环，所述取代指被一个或多个C1-C3烷基、羟基、卤素取代。
  3. 如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，其特征在于，R 2和R 3与其所连接的氮原子一起形成4-7元杂环，所述杂环任选被一个或多个R b取代；
    R b独立选自卤素、氧代、氰基、羟基、-(C0-C3烷基)C(＝O)NHR 5R 6、-(C0-C3烷基)-NR 5R 6、取代或未取代的C1-C3烷基，所述取代指被一个或多个卤素、氧代、氰基、羟基取代。
  4. 如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，其特征在于，R 1为取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，且所述的芳基或杂芳基任选被一个或多个R c取代；
    R c独立选自卤素、氰基、羟基、-COOH、-C(＝O)OR 5、-C(＝O)R 5、-C(＝O)(C1-C3烷基)、-(C0-C3烷基)NR 5R 6、-(C0-C3烷基)C(＝O)NR 5R 6、-(C0-C3烷基)S(＝O)NR 5R 6、-(C0-C3烷基)S(＝O) 2NR 5R 6、-S(＝O) 2(C1-C3烷基)、-(C0-C3烷基)OP(＝O)(OC1-C3烷基) 2、取代或未取代的C1-C3烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷硫基、所述取代是指被一个或多个卤素或羟基取代。
  5. 如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，其特征在于，R 1为取代或未取代的5-6元芳杂环，所述芳杂环任选被一个或多个R c取代。
  6. 如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、其药 学上可接受的盐、其前药、其水合物或溶剂合物，其特征在于，环A选自下组：
    Figure PCTCN2020115143-appb-100002
    R 4选自氢原子、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基，所述取代指被一个或多个卤素取代。
  7. 如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，其特征在于：
    Figure PCTCN2020115143-appb-100003
    选自下组：
    Figure PCTCN2020115143-appb-100004
  8. 如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，其中，所述化合物选自下列化合物：
    Figure PCTCN2020115143-appb-100005
    Figure PCTCN2020115143-appb-100006
    Figure PCTCN2020115143-appb-100007
    Figure PCTCN2020115143-appb-100008
    Figure PCTCN2020115143-appb-100009
    Figure PCTCN2020115143-appb-100010
    Figure PCTCN2020115143-appb-100011
  9. 一种药物组合物，其特征在于，包含如下组分：
    1)治疗有效量的一种或多种权利要求1所述化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物；和
    2)药学上可接受的载体或赋形剂。
  10. 如权利要求9所述的药物组合物，其特征在于，所述的药物组合物还包括一种或多种选自以下的活性物质：免疫抑制剂、糖皮质激素、非甾体抗炎药、长春碱类化合物、紫杉醇、DNA损伤剂、Bcl-2抑制剂、BTK抑制剂、JAK抑制剂、Hsp90抑制剂、ALK抑制剂、FLT3抑制剂、PI3K抑制剂和SYK抑制剂。
  11. 一种权利要求1所述化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物的用途，其特征在于，用于制备预防或治疗FLT3、FLT3-ITD或其他FLT3突变介导的适应症的药物组合物。
  12. 如权利要求11所述的用途，其特征在于，所述的适应症选自下组：骨髓增生异常综合征、急性髓系白血病、I型神经纤维瘤、多发性骨髓瘤、恶性胶质瘤、非小细 胞肺癌、肝癌、肝细胞癌、***、淋巴瘤、骨转移癌、激素难治性***癌、激素依赖性***癌、甲状腺瘤、甲状腺髓样癌、间皮瘤、胶质母细胞瘤、括骨转移癌、梅克尔细胞癌、泌尿生殖道肿瘤、默克尔细胞癌、膀胱癌、***状甲状腺癌、乳腺癌、软组织肉瘤、神经胶质瘤、神经内分泌瘤、肾细胞癌、晚期实体瘤、未分化的星形细胞癌、胃肠道间质瘤、希佩尔-林道综合征、小细胞肺癌、胰腺癌、胰腺内分泌癌、中枢神经***肿瘤、转移性肾癌、子宫内膜样癌、子宫内膜样腺癌、肺癌、结直肠癌、卵巢癌、横纹肌肉瘤、黑素瘤、视网膜母细胞瘤、中枢和外周神经***肿瘤、急性白血病、慢性白血病、胆管癌、支气管癌、食管癌、睾丸癌、皮肤癌、口腔癌、成神经细胞瘤、间变性大细胞淋巴瘤。
  13. 一种权利要求1所述化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物或权利要求9所述药物组合物的用途，其特征在于，用于制备用于预防和/或治疗IRAK4介导的疾病的药物。
  14. 一种权利要求1所述化合物、其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物的用途，其特征在于，用于制备治疗或预防由IRAK4和FLT3、FLT3-ITD或其他FLT3突变共同介导的适应症的药物组合物。
  15. 如权利要求14所述的用途，其特征在于，所述的适应症选自下组：骨髓增生异常综合征、急性髓系白血病、癌症。
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