WO2021004533A1 - 作为irak4和btk多靶点抑制剂的噁唑类化合物 - Google Patents

作为irak4和btk多靶点抑制剂的噁唑类化合物 Download PDF

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WO2021004533A1
WO2021004533A1 PCT/CN2020/101369 CN2020101369W WO2021004533A1 WO 2021004533 A1 WO2021004533 A1 WO 2021004533A1 CN 2020101369 W CN2020101369 W CN 2020101369W WO 2021004533 A1 WO2021004533 A1 WO 2021004533A1
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compound
alkyl
pharmaceutically acceptable
present
isomers
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PCT/CN2020/101369
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English (en)
French (fr)
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王建非
谭海忠
李婕
张杨
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to JP2022500996A priority Critical patent/JP7340680B2/ja
Priority to US17/625,599 priority patent/US20220267322A1/en
Priority to CN202080047753.1A priority patent/CN114072401B/zh
Priority to EP20836225.1A priority patent/EP3998264A4/en
Publication of WO2021004533A1 publication Critical patent/WO2021004533A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a class of multi-target inhibitors of IRAK4 and BTK, and its application in preparing drugs for treating diseases related to IRAK4 and BTK. Specifically, it relates to a compound represented by formula (II), its isomers or a pharmaceutically acceptable salt thereof.
  • Interleukin-1 receptor-associated kinase 4 is a serine/threonine-specific protein kinase, a member of the tyrosine kinase (TLK) family, and interleukin-1, 18, 33 receptors and Toll-like The key node in the innate immune response involving receptors. After extracellular signaling molecules bind to interleukin receptors or Toll-like receptors, they recruit to form a MyD88:IRAK4:IRAK1/2 multi-protein complex, which leads to phosphorylation of IRAK1/2, mediates a series of downstream signal transduction, and activates p38 and JNK.
  • TKI tyrosine kinase
  • IRAK4 has become an important therapeutic target, which can be widely used in the treatment of inflammatory diseases, immune diseases, tumor diseases and other diseases.
  • BAY-1830839 and BAY-1834845 are small molecule IRAK4 inhibitors developed by Bayer. Currently, clinical research on immune and tumor diseases has been carried out.
  • Activated B-cell-like diffuse large B-cell lymphoma is a highly aggressive and poor prognostic DLBCL, which is usually manifested by the B cell receptor (BCR) pathway and myeloid differentiation factor 88 (MyD88 ) Abnormality of the pathway, which further leads to the continuous activation of the nuclear factor ⁇ B protein (NF- ⁇ B) signaling pathway.
  • CD79 mutation is a common abnormal mutation in the BCR pathway.
  • BTK inhibitors such as Ibrutinib can inhibit the abnormal activation of the NF- ⁇ B signaling pathway caused by this mutation, thereby inhibiting the proliferation of ABC-DLBCL cells.
  • the abnormal MyD88 pathway is dominated by the MyD88 L265P point mutation, which accounts for about 30%.
  • IRAK4 inhibitors can effectively block the abnormally activated MyD88 signaling pathway and further block the abnormal activation of the NF- ⁇ B pathway.
  • ABC-DLBCL patients with MyD88 L265P mutation have a poor response to BCR inhibitors due to abnormal MyD88 signaling pathways, and a large number of research data from Bayer, Nimbus and AstraZeneca indicate that IRAK4 is inhibited in ABC-DLBCL xenograft animal models
  • the combination of Ibrutinib and BTK inhibitor can significantly improve the in vivo efficacy of Ibrutinib. If it can effectively inhibit the abnormalities of the BCR pathway and MyD88 pathway at the same time, it will be a more effective way to treat ABC-DLBCL. Therefore, the development of dual target inhibitors of RAK4 and BTK can achieve double benefits in blocking the NF- ⁇ B pathway. Mechanism is a very efficient and effective strategy, providing a potentially effective new treatment method for patients with ABC-DLBCL.
  • the present invention provides a compound represented by formula (II), its isomers or a pharmaceutically acceptable salt thereof,
  • R 2 is selected from thienyl, phenyl, pyridyl, cyclopropyl, cyclohexyl and The thienyl, phenyl, pyridyl, cyclopropyl, cyclohexyl and Optionally substituted by 1, 2, 3, 4 or 5 R b ;
  • T 1 is selected from CH 2 , NH and O;
  • R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R a is independently selected from F, OH, NH 2 and CN;
  • R c is independently selected from F, OH, NH 2 , CN, CH 3 , COOH and -SO 2 CH 3 ;
  • R is each independently selected from F, OH, NH 2 and CH 3 .
  • the present invention provides a compound represented by formula (II), its isomers or a pharmaceutically acceptable salt thereof,
  • R 1 is H, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl and cyclopropyl, and the C 1-6 alkyl and cyclopropyl are optionally selected by 1, 2 or 3 R a substitutions;
  • R 2 is selected from thienyl, phenyl, pyridyl, cyclopropyl, cyclohexyl and The thienyl, phenyl, pyridyl, cyclopropyl, cyclohexyl and Optionally substituted by 1, 2, 3, 4 or 5 R b ;
  • T 1 is selected from CH 2 , NH and O;
  • R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R a is independently selected from F, OH, NH 2 and CN;
  • the alkyl group is optionally substituted with 1, 2 or 3 R;
  • R c is independently selected from F, OH, NH 2 , CN, CH 3 , COOH and -SO 2 CH 3 ;
  • R is each independently selected from F, OH, NH 2 and CH 3 .
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2, CN, C 1-3 alkyl and cyclopropyl, a C 1- 3 alkyl and cyclopropyl, optionally substituted with 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • R 1 is selected from CN, CH 3 , CF 3 , Other variables are as defined in the present invention.
  • the above-mentioned R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , COOH, The OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , Optionally substituted by 1, 2 or 3 R, other variables are as defined in the present invention.
  • the above-mentioned R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , COOH, The OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , Optionally substituted by 1, 2 or 3 R, other variables are as defined in the present invention.
  • R b is independently selected from H, D, F, Cl, OH, OCH 3 , CN, CH 3 , CH 2 OH, CH 2 NH 2 , COOH, Other variables are as defined in the present invention.
  • the above-mentioned R 2 is selected from thienyl, phenyl, pyridyl, cyclopropyl, cyclohexyl, The thienyl, phenyl, pyridyl, cyclopropyl, cyclohexyl, Optionally substituted by 1, 2, 3, 4 or 5 R b , other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 3 is selected from C 2-5 alkyl group, and the C 2-5 alkyl group is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the above-mentioned R 3 is selected from CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 and CH 2 CH 2 CH(CH 3 ) 2 , the CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 and CH 2 CH 2 CH(CH 3 ) 2 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • R 3 is selected from Other variables are as defined in the present invention.
  • the present invention also provides the compound represented by formula (II), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is H, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl and cyclopropyl, and the C 1-6 alkyl and cyclopropyl are optionally selected by 1, 2 or 3 R a substitutions;
  • R 2 is selected from phenyl, pyridyl, cyclopropyl, cyclohexyl and The phenyl, pyridyl, cyclopropyl, cyclohexyl and Optionally substituted by 1, 2 or 3 R b ;
  • T 1 is selected from CH 2 , NH and O;
  • R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R a is independently selected from F, OH, NH 2 and CN;
  • R is each independently selected from F, OH and NH 2 .
  • the R 1 is selected H, F, Cl, Br, I, OH, NH 2, CN, C 1-3 alkyl and cyclopropyl, a C 1- 3 alkyl and cyclopropyl optionally substituted with 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • the R 1 is selected from CN, CH 3 , CF 3 , Other variables are as defined in the present invention.
  • the R b is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , The CH 3 , Optionally substituted by R, other variables are as defined in the present invention.
  • the R b is independently selected from H, F, OH, CN, CH 3 , CH 2 OH, CH 2 NH 2 , Other variables are as defined in the present invention.
  • the R 2 is selected from phenyl, pyridyl, cyclopropyl, cyclohexyl, The phenyl, pyridyl, cyclopropyl, cyclohexyl, Optionally substituted by 1, 2 or 3 R b , other variables are as defined in the present invention.
  • the R 2 is selected from Other variables are as defined in the present invention.
  • the R 2 is selected from Other variables are as defined in the present invention.
  • the R 3 is selected from a C 2-5 alkyl group, and the C 2-5 alkyl group is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the R 3 is selected from Other variables are as defined in the present invention.
  • the present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is H, F, Cl, Br, I, OH, NH 2, CN and C 1-6 alkyl, said C 1-6 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from C 3-8 cycloalkyl group and 3 to 8-membered heterocycloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl optionally substituted with 1,2 or 3 R b replace;
  • L 1 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R a is independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R c are each independently selected from F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • the 3-8 membered heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -NH-, N and O.
  • the R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl, and the C 1-3 alkyl is optionally selected by 1 , 2 or 3 Ra substitutions, other variables are as defined in the present invention.
  • the R 1 is CH 3 , and other variables are as defined in the present invention.
  • the R b is selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , Other variables are as defined in the present invention.
  • R 2 is selected from the C 3-6 cycloalkyl and a 4 to 6 membered heterocycloalkyl, a C 3 ⁇ 8 cycloalkyl group, the alkyl group is 4 to 6-membered heterocyclic ring
  • R b other variables are as defined in the present invention.
  • the R 2 is selected from morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl and cyclopropyl, the morpholinyl, piperidinyl, piperazinyl, Tetrahydropyranyl and cyclopropyl are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the R 2 is selected from Other variables are as defined in the present invention.
  • the L 1 is selected from C 3-5 alkyl, and the C 3-5 alkyl is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the L 1 is Other variables are as defined in the present invention.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • L 1 is selected from C 2-5 alkyl groups, and R 1 , R 3 and R b are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula, its isomers or a pharmaceutically acceptable salt thereof
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the above-mentioned compound, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention also provides the application of the above-mentioned compound, its isomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a medicine for treating diseases related to IRAK4 and BTK.
  • the compounds of the present invention generally exhibit good inhibitory activity against IRAK4 and BTK.
  • the compound of the present invention generally exhibits a good activity of inhibiting cell TNF- ⁇ production in THP-1 cells, and exhibits a good activity of inhibiting cell proliferation in OCI-LY10, OCI-LY3 and TMD-8 cells.
  • Cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor model showed good in vivo efficacy.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • D in the present invention represents deuterium ( 3 H).
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of two of formula (B-1) and formula (B-2) A mixture of isomers exists.
  • the following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) Exist as a mixture.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dotted key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 2-5 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 2 to 5 carbon atoms.
  • the C 2-5 alkyl group includes C 2-5 , C 2-4 , C 2-3 , C 2 , C 3 , C 4 and C 5 alkyl groups and the like.
  • Examples of C 2-5 alkyl groups include, but are not limited to, ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl) and so on.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy and the like.
  • Examples of C 1-3 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 3-8 cycloalkyl refers to a saturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms, which includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro ring, fused ring and Bridge ring.
  • the C 3-8 cycloalkyl group includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl group, etc.; It can be one price, two price or multiple price.
  • C 3-8 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] dicyclooctane and the like.
  • the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-8 membered heterocycloalkyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolidin
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, a nucleophilic substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethyls
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; MeOH stands for methanol; M stands for mol/L; N/A stands for undetected; MgCl 2 stands for magnesium chloride; EGTA stands for ethylene glycol bis(2 -Aminoethyl ether) tetraacetic acid; Na 3 VO 4 stands for sodium vanadate.
  • Figure 1 is a graph of plasma TNF- ⁇ concentration.
  • Figure 2 is a graph showing the weight change of mice in different groups.
  • Figure 3 is a graph of relative weight change (%).
  • Figure 4 is a graph of tumor growth curve.
  • Raney nickel (3.0 g) was added to the EtOH (50.0 mL) solution of WX001-2 (3.0 g), and stirred under H 2 (50 Psi) at 30°C for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain compound WX001-3.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product.
  • LCMS(ESI)m/z 489.3[M+H] + .
  • Example 3 Refer to the synthesis steps of Example 1, the difference is that the B4 (piperidine ring) of step 1 in Example 1 is replaced with the corresponding B fragment in fragment 1.
  • the synthesis step may undergo de-Boc, hydrolysis, and use of A
  • the base format reagent and ester generate tertiary alcohol or use Suzuki coupling and other conventional operations, and the final synthesis is as shown in the following Table 3.
  • the difference is that the B10 (phenylboronic acid) in step 21 is replaced with the corresponding B fragment in fragment 1.
  • the synthesis step may be simple hydrogenation and hydrolysis of cyano groups to amides. , And the final synthesis of the examples in Table 5 below.
  • WX037-1 (10.0g, 37.1mmol) and absolute ethanol (100.0mL) were added to a reaction flask, and then concentrated sulfuric acid (3.7g, 37.1mmol, 2.0mL, 98% purity) was added, and the reaction was stirred at 80°C for 12 hour.
  • the reaction solution was concentrated to dryness under reduced pressure.
  • WX037-5 (0.05g, 92.9 ⁇ mol), sodium hydroxide (2M, 919.9 ⁇ L), methanol (5.0mL) to a reaction flask, replace with nitrogen three times, and then stir at 25°C for 2 hours.
  • the methanol was concentrated to dryness under reduced pressure, then the pH was adjusted to 7 with 2N hydrochloric acid, and then concentrated to dryness under reduced pressure.
  • the crude product was purified by machine (column: Phenomenex Gemini NX-C18 (75*30mm*3 ⁇ m); mobile phase: [aqueous solution containing (10.0mM) NH 4 HCO 3 )-acetonitrile]; gradient B%: 15%-40% ,8min) to get WX037.
  • Example 37 With reference to the synthesis step of Example 37, each of the examples in the following table was synthesized. The difference is that B-19 in step 5 was replaced with fragment 1. The final synthesis of the examples shown in Table 6 below.
  • WX001-1 (5.4g, 24.3mmol) was added to a flask containing ethyl bromopyruvate (47.4g, 243.0mmol, 30.4mL), and the reaction was stirred at 90°C for 12 hours. Pour the reaction solution into ethyl acetate (150.0 mL) while it is hot, stir at 15°C for 15 minutes, filter with suction, rinse the filter cake with ethyl acetate (20.0 mL ⁇ 3), and concentrate the filter cake to dryness under reduced pressure to obtain WX040 -1.
  • ethyl bromopyruvate 47.4g, 243.0mmol, 30.4mL
  • Raney nickel (942.0mg,) was added to a hydrogenation flask under the protection of argon, then wetted with ethanol (30.0mL), WX040-1 (1.0g, 3.1mmol) was added to the reaction system, the reaction Stir under 50 psi of hydrogen at 25°C for 2 hours.
  • the reaction solution was suction filtered through Celite, and the filtrate was concentrated under reduced pressure to dryness to obtain WX040-2.
  • the crude product was purified by mechanical separation (column: Welch Xtimate BEH C18 100*30mm*10 ⁇ m; mobile phase: A: aqueous solution containing 10mM NH 4 HCO 3 , B: acetonitrile; gradient: B%: 30%-50%, 6 minutes) After freeze-drying, WX042 was obtained.
  • Example 42 Refer to the synthesis steps of Example 42 to synthesize the examples in the following table. The difference is that the piperidine at the bottom right is replaced with fragment 1, and finally the examples shown in Table 8 are synthesized.
  • Test Example 1 Evaluation of IRAK4 kinase activity in vitro
  • Buffer conditions 20mM Hepes (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% Brij35, 0.02mg/mL BSA, 0.1mM Na 3 VO 4 , 2mM DTT, 1% DMSO.
  • Test procedure At room temperature, the test compound was dissolved in DMSO to prepare a 10 mM solution for later use. Dissolve the substrate in the newly prepared buffer, add the tested IRAK4 kinase to it and mix well. Using acoustic technology (Echo 550), the DMSO solution in which the test compound is dissolved is added to the mixed reaction solution. After 15 minutes of incubation, 33 P-ATP was added to start the reaction. After the reaction was carried out at room temperature for 120 minutes, the reaction liquid was spotted on P81 ion exchange filter paper (Whatman#3698-915). After washing the filter paper repeatedly with 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured.
  • P81 ion exchange filter paper Whatman#3698-915
  • the kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (only containing DMSO).
  • the IC 50 value is obtained by curve fitting with Prism4 software (GraphPad). The experimental results are shown in Table 9.
  • the compound of the present invention generally exhibits good inhibitory activity against IRAK4.
  • Test Example 2 Evaluation of BTK kinase activity in vitro:
  • Buffer conditions 20mM Hepes (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% Brij35, 0.02mg/mL BSA, 0.1mM Na 3 VO 4 , 2mM DTT, 1% DMSO.
  • Test procedure At room temperature, the test compound was dissolved in DMSO to prepare a 10 mM solution for later use. Dissolve the substrate in the newly prepared buffer, add the tested BTK kinase to it and mix well. The compound dissolved in DMSO was added to the kinase reaction mixture via Echo550 (Acoustic technology; nanoliter range). After incubating for 20 minutes at room temperature, 33 P-ATP was added to start the reaction. After the reaction was carried out at room temperature for 2 hours, the reaction liquid was spotted using P81 ion exchange filter paper and the radioactivity was detected by the filtration-binding method. Kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (only DMSO), through Prism4 software
  • WX016 8.9 WX018 47.5 WX020 8.5 WX021 13.9 WX022 43.1 WX024 30.5 WX025 21.8 WX026 30.7 WX029 24.2 WX031 39.6 WX032 26.5 WX033 20.2 WX039 29 WX040 3.3 WX042 3.8 WX045 28.6 WX046 43.1
  • the compound of the present invention generally exhibits good inhibitory activity on BTK.
  • the THP-1 human acute monocytic leukemia cell line was purchased from ATCC (Cat#TIB-202) and cultured in a 37°C, 5% CO 2 incubator.
  • the medium composition is RPMI1640 (Gibco, Cat#22400-105), and the supplementary composition is 10% FBS (Gibco, Cat#10091148); 1% PenStrep (Gibco, Cat#15140); 0.05mM 2-Mercaptoethanol (Sigma, Cat #M6250).
  • TNF- ⁇ Elisa kit was used to detect the content of TNF- ⁇ in cell culture supernatant samples.
  • TNF- ⁇ is produced by THP-1 cells stimulated by 150ng/mL LPS (Sigma, Cat#L6529).
  • Normally cultured THP-1 cells in the logarithmic growth phase are planted in a 96-well plate (Corning#3599) at a certain concentration (1*10 5 /100 ⁇ L), and then incubated in a cell incubator. Two hours later, 16.7 ⁇ L of the test compound of different concentrations (8*final concentration) was added and incubated in an incubator. One hour later, 16.7 ⁇ L of 1200ng/mL LPS was added and incubated in an incubator. After 18 hours, centrifuge and collect the culture supernatant sample, and use the TNF- ⁇ Elisa kit to detect the content of TNF- ⁇ . Finally, read the OD signal (OD450-OD570) on the envision plate reader.
  • Inhibition rate % (ZPE-sample)/(ZPE-HPE)*100.
  • HPE indicates the OD450-OD570 signal value of the control well without LPS stimulated cells
  • ZPE indicates the OD450-OD570 signal value of the control well with LPS stimulated cells.
  • the IC 50 value of the compound was calculated by XLFit in the excel add-in.
  • Equation: Y Bottom+(Top-Bottom)/(1+(IC50/X) ⁇ HillSlope).
  • the compound of the present invention generally exhibits a good activity of inhibiting cell TNF- ⁇ production in THP-1 cell activity experiments.
  • Test Example 4 Evaluation of OCI-LY10 and TMD-8 Cytological Activity in Vitro
  • OCI-LY10 human B-cell lymphoma cells are cultured in a 37°C, 5% CO 2 incubator.
  • the medium composition is IMDM (GIBCO, Cat#12440053); the supplementary composition is 20% FBS (Hyclone, Cat#SH30084.03); 1% PenStrep (Thermo, Cat#SV30010).
  • TMD8 human B-cell lymphoma cells were cultured in a 37°C, 5% CO 2 incubator.
  • the medium composition is RPMI1640 (GIBCO, Cat#22400-089); the supplementary composition is 10% FBS (Hyclone, Cat#SH30084.03); 1% PenStrep (Thermo, Cat#SV30010).
  • the tumor cell lines OCI-LY10 and TMD8 were used to detect the effect of the compound on inhibiting tumor cell proliferation in vitro.
  • the tumor cell line was cultured in an incubator at 37°C and 5% CO 2 according to the indicated culture conditions, and passaged regularly.
  • the cells in the logarithmic growth phase were taken, counted, and spread in a 96-well plate (the cells in each well were adjusted to the appropriate Concentration, add a total of 90 cell suspensions per well).
  • After culturing overnight in a 37°C, 5% CO 2 incubator add different concentration gradient drugs (add 10 ⁇ L of drug solution) for 3 days, then add 50 ⁇ L of CellTiter-Glo working solution to each well, wrap the cell plate with aluminum foil to avoid light .
  • the culture plate was shaken on an orbital shaker for 2 minutes to induce cell lysis, and placed at room temperature for 10 minutes to stabilize the luminescence signal. The luminescence signal was detected on the 2104 EnVision plate reader.
  • IR (%) (1-(RLU compound-RLU blank control) / (RLU vehicle control-RLU blank control)) * 100%.
  • the inhibition rate of different concentration of compound in Excel and GraphPad Prism software used for calculating inhibition curves and associated parameters, including the minimum inhibitory rate, the maximum inhibition rate and IC 50.
  • the compounds of the present invention generally exhibit good inhibitory activity on cell proliferation in OCI-LY10 and TMD-8 cell lines, respectively. Note: “/" means not detected.
  • the tumor cell line used in this experiment was provided by Nanjing Kebai Biotechnology Co., Ltd., and the specific information is shown in Table 13 below.
  • the tumor cell line OCI-LY3 was used to detect the effect of the compound on inhibiting tumor cell proliferation in vitro.
  • the OCI-LY3 cell line was cultured in the corresponding medium and cultured at 37° C. and 5% CO 2. The cells reaching the logarithmic growth phase were used for experimental plating. The cells were collected, centrifuged at 800 rpm for 5 minutes, resuspended in the medium, and spread on a 96-well plate. After culturing overnight in a 37°C, 5% CO 2 incubator, add different concentration gradient drugs (add 10 ⁇ L of the prepared test compound dilution) and incubate for 72 hours. Incubate the cell culture plate and CTG reagent at room temperature for 30 minutes in the dark to recover. To room temperature.
  • the result of the luminescence value measured at each drug concentration was normalized with the luminescence value of the blank control group, and the ratio of this value to the DMSO group was taken as the cell inhibition rate (%).
  • Use GraphPad software to plot the logarithm of the drug concentration (log drug concentration) against the inhibition rate. The software will automatically fit the log (inhibitor) vs. normalized response algorithm of Nonlinear Regression to calculate the IC50 value and 95 % Confidence limit value.
  • the compound of the present invention has a significant inhibitory effect on the proliferation of OCI-LY3 cell lines.
  • Test Example 6 In vivo pharmacodynamic study of TNF- ⁇ secretion in SD rats induced by lipopolycollagen (LPS)
  • SD rats were orally given the solvent, the positive drug dexamethasone (DEX, 0.5 mg/kg), and the test compound, and LPS (1 mg/kg) was intraperitoneally injected 0.5 hours after the administration.
  • LPS 1 mg/kg
  • the plasma was taken out from the refrigerator at -80°C, thawed at room temperature, and the concentration of TNF- ⁇ in the plasma was detected according to the ELISA kit instructions.
  • Test Example 7 In vivo pharmacodynamic study of WX001 on human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor mouse model
  • the purpose of this experiment is to study the efficacy of WX001 test drug on human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor in CB17SCID mouse model.
  • OCI-LY10 human B-cell lymphoma cells are cultured in a 37°C, 5% CO 2 incubator.
  • the medium composition is IMDM (GIBCO, Cat#12440053); the supplementary composition is 20% FBS (Hyclone, Cat#SH30084.03); 1% PenStrep (Thermo, Cat#SV30010).
  • OCI-LY10 tumor cells were cultured and passaged. 0.2mL (1 ⁇ 10 7 cells) OCI-LY10 cells were subcutaneously inoculated on the right back of each nude mouse (with Matrigel, volume ratio 1:1), and the average tumor volume When it reaches 167mm 3 , group administration is started. Monitor the animal’s health and death every day. Routine inspections include observation of tumor growth and drug treatment’s impact on the animals’ daily behavior, such as behavioral activities, food and water intake, weight changes (weight measurements twice a week), tumor size (each Measure the tumor volume twice a week), physical signs or other abnormalities.
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured. Including the measurement of tumor volume (TV), the calculation of the compound's anti-tumor efficacy using TGI (%) or relative tumor proliferation rate T/C (%).
  • TV 0.5a ⁇ b 2
  • a and b represent the long diameter and short diameter of the tumor, respectively.
  • TGI(%) (1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the start of the treatment group))/(Average tumor volume at the end of the solvent control group treatment-when the solvent control group starts treatment Average tumor volume)) ⁇ 100%.
  • T/C% T RTV /C RTV ⁇ 100% (T RTV : RTV of the treatment group; C RTV : RTV of the negative control group).
  • RTV relative tumor volume
  • mice in the experimental groups were normal and showed good drug tolerance.
  • Figure 2 shows the body weight changes of human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor model tumor-bearing mice after administration of WX compound.
  • the data points represent the average body weight within the group, and the error bars represent the standard error (SEM).
  • the relative weight change shown in Figure 3 is calculated based on the animal's weight at the start of the administration.
  • the data points represent the average weight change percentage within the group, and the error bars represent the standard error (SEM).
  • Figure 4 shows the tumor growth curve of human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor model tumor-bearing mice after administration of WX001 compound. Data points represent the average tumor volume within the group, and error bars represent standard errors (SEM).
  • the T/C value of Ibrutinib (10mpk) group was 39%, the TGI value was 85%, and the p value was ⁇ 0.001.
  • the T/C value of WX001 (50mpk) group was 22%, TGI value was 109%, p ⁇ 0.001, compared with the solvent control group, it had a significant anti-tumor effect, and was significantly better than the Ibrutinib (10mpk) group.
  • the OCI-LY10 cell line is an ABC-DLBCL cell line that is highly dependent on both MyD88-L265P and BCR (CD79A/B) double mutations.

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Abstract

一类IRAK4和BTK的多靶点抑制剂，及其在制备治疗与IRAK4和BTK相关疾病的药物中的应用，具体涉及式(II)所示化合物、其异构体或其药学上可接受的盐。

Description

作为IRAK4和BTK多靶点抑制剂的噁唑类化合物
本申请主张如下优先权：
CN201910619602.8，申请日2019.7.10；
CN201911240843.8，申请日2019.12.6；
CN202010470469.7，申请日2020.5.28。
技术领域
本发明涉及一类IRAK4和BTK的多靶点抑制剂，及其在制备治疗与IRAK4和BTK相关疾病的药物中的应用。具体涉及式(II)所示化合物、其异构体或其药学上可接受的盐。
背景技术
白细胞介素1受体相关激酶4(IRAK4)是一种丝氨酸/苏氨酸特异性蛋白激酶，属于类酪氨酸激酶(TLK)家族成员，是白介素-1、18、33受体和Toll样受体参与的先天性免疫应答中的关键节点。细胞外信号分子与白介素受体或Toll样受体结合后，募集形成MyD88:IRAK4:IRAK1/2多蛋白复合体，导致IRAK1/2磷酸化，介导一系列下游信号传导，从而激活p38、JNK和NF-κB信号通路，最终导致前炎症细胞因子的表达。临床病理学研究表明，具有IRAK4突变的个体对慢性肺病、炎症性肠病有防护作用。IRAK4缺陷本身无致死性，个体能够存活至成年，且随年龄增长受感染风险降低。因此，IRAK4成为了一类重要治疗靶点，可以广泛用于炎症类疾病、免疫类疾病、肿瘤类疾病等多种疾病的治疗。如下图所示，BAY-1830839和BAY-1834845是由Bayer公司研发的小分子IRAK4抑制剂，目前已经开展免疫和肿瘤类疾病的临床研究。
Figure PCTCN2020101369-appb-000001
活化B细胞样弥漫性大B细胞淋巴瘤(ABC-DLBCL)是一种强侵袭性并且预后效果很差的DLBCL，其通常表现为B细胞受体(BCR)通路和髓样分化因子88(MyD88)通路的异常，从而进一步导致核因子κB蛋白(NF-κB)信号通路的持续激活。CD79突变是BCR通路中常见异常突变，BTK抑制剂如Ibrutinib等可以抑制该突变引起的NF-κB信号通路异常激活，从而抑制ABC-DLBCL细胞的增殖。MyD88通路的异常以约占30％的MyD88 L265P点突变为主，IRAK4抑制剂可有效阻断异常活化的MyD88信号通路，进一步阻断NF-κB通路异常激活。但具有MyD88 L265P突变的ABC-DLBCL患者，因具有异常的MyD88信号通路，对BCR抑制剂响应较差，而且Bayer、Nimbus和AstraZeneca的大量研究数据表明在ABC-DLBCL异种移 植动物模型中，IRAK4抑制剂与BTK抑制剂的联用能显著提高Ibrutinib的体内药效。如果能同时有效抑制BCR通路和MyD88通路的异常，将是治疗ABC-DLBCL更为有效的途径，因此开发RAK4和BTK双靶点抑制剂能在阻断NF-κB通路上获得双重收益，从治疗机制上讲是非常高效并有效的策略，为ABC-DLBCL患者提供一种潜在有效的新治疗方法。
发明内容
本发明提供了式(II)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020101369-appb-000002
其中，
R 1为H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基、环丙基和-C(＝O)-NH 2，所述C 1-6烷基、环丙基和-C(＝O)-NH 2任选被1、2或3个R a取代；
R 2选自噻吩基、苯基、吡啶基、环丙基、环己基和
Figure PCTCN2020101369-appb-000003
所述噻吩基、苯基、吡啶基、环丙基、环己基和
Figure PCTCN2020101369-appb-000004
任选被1、2、3、4或5个R b取代；
T 1选自CH 2、NH和O；
R 3选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R c取代；
R a分别独立地选自F、OH、NH 2和CN；
R b分别独立地选自H、D、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、COOH、-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基和-C(＝O)-NH 2，所述OH、NH 2、C 1-3烷基、-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基和-C(＝O)-NH 2任选被1、2或3个R取代；
R c分别独立地选自F、OH、NH 2、CN、CH 3、COOH和-SO 2CH 3；
R分别独立地选自F、OH、NH 2和CH 3。
本发明提供了式(II)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020101369-appb-000005
其中，
R 1为H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基和环丙基，所述C 1-6烷基和环丙基任选被1、2或3个R a取代；
R 2选自噻吩基、苯基、吡啶基、环丙基、环己基和
Figure PCTCN2020101369-appb-000006
所述噻吩基、苯基、吡啶基、环丙基、环己基和
Figure PCTCN2020101369-appb-000007
任选被1、2、3、4或5个R b取代；
T 1选自CH 2、NH和O；
R 3选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R c取代；
R a分别独立地选自F、OH、NH 2和CN；
R b分别独立地选自H、D、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、-C(＝O)-C 1-3烷基和-C(＝O)-O-C 1-3烷基，所述OH、NH 2、C 1-3烷基、-C(＝O)-C 1-3烷基和-C(＝O)-O-C 1-3烷基任选被1、2或3个R取代；
R c分别独立地选自F、OH、NH 2、CN、CH 3、COOH和-SO 2CH 3；
R分别独立地选自F、OH、NH 2和CH 3。
在本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、环丙基和-C(＝O)-NH 2，所述C 1-3烷基、环丙基和-C(＝O)-NH 2任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和环丙基，所述C 1- 3烷基和环丙基，任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 1选自CN、CH 3、CF 3、
Figure PCTCN2020101369-appb-000008
和-C(＝O)-NH 2，其他变量如本发明所定义。
在本发明的一些方案中，上述R 1选自CN、CH 3、CF 3、
Figure PCTCN2020101369-appb-000009
其他变量如本发明所定义。
在本发明的一些方案中，上述R b分别独立地选自H、D、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3、 CH 2CH 2CH 3、CH(CH 3) 2、COOH、
Figure PCTCN2020101369-appb-000010
所述OH、NH 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、
Figure PCTCN2020101369-appb-000011
任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R b分别独立地选自H、D、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、COOH、
Figure PCTCN2020101369-appb-000012
所述OH、NH 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、
Figure PCTCN2020101369-appb-000013
任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R b分别独立地选自H、D、F、Cl、OH、OCH 3、CN、CH 3、CH 2OH、CH 2NH 2、COOH、
Figure PCTCN2020101369-appb-000014
其他变量如本发明所定义。
在本发明的一些方案中，上述R 2选自噻吩基、苯基、吡啶基、环丙基、环己基、
Figure PCTCN2020101369-appb-000015
Figure PCTCN2020101369-appb-000016
所述噻吩基、苯基、吡啶基、环丙基、环己基、
Figure PCTCN2020101369-appb-000017
任选被1、2、3、4或5个R b取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 2选自
Figure PCTCN2020101369-appb-000018
Figure PCTCN2020101369-appb-000019
其他变量如本发明所定义。
在本发明的一些方案中，上述R 2选自
Figure PCTCN2020101369-appb-000020
Figure PCTCN2020101369-appb-000021
Figure PCTCN2020101369-appb-000022
Figure PCTCN2020101369-appb-000023
其他变量如本发明所定义。
在本发明的一些方案中，上述R 2选自
Figure PCTCN2020101369-appb-000024
Figure PCTCN2020101369-appb-000025
其他变量如本发明所定义。
在本发明的一些方案中，上述R 3选自C 2-5烷基，所述C 2-5烷基任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 3选自CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、CH 2CH 2CH 2CH 3、CH 2CH(CH 3) 2和CH 2CH 2CH(CH 3) 2，所述CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、CH 2CH 2CH 2CH 3、CH 2CH(CH 3) 2和CH 2CH 2CH(CH 3) 2任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 3选自
Figure PCTCN2020101369-appb-000026
其他变量如本发明所定义。
本发明还提供了式(II)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020101369-appb-000027
其中，
R 1为H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基和环丙基，所述C 1-6烷基和环丙基任选被1、2或3个R a取代；
R 2选自苯基、吡啶基、环丙基、环己基和
Figure PCTCN2020101369-appb-000028
所述苯基、吡啶基、环丙基、环己基和
Figure PCTCN2020101369-appb-000029
任选被1、2或3个R b取代；
T 1选自CH 2、NH和O；
R 3选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R c取代；
R a分别独立地选自F、OH、NH 2和CN；
R b分别独立地选自H、F、OH、NH 2、CN、CH 3、-C(＝O)-C 1-3烷基和-C(＝O)-O-C 1-3烷基，所述CH 3、-C(＝O)-C 1-3烷基和-C(＝O)-O-C 1-3烷基任选被1、2或3个R取代；
R c分别独立地选自F、OH、NH 2、CN、CH 3和C(＝O)；
R分别独立地选自F、OH和NH 2。
在本发明的一些方案中，所述R 1选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和环丙基，所述C 1- 3烷基和环丙基任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R 1选自CN、CH 3、CF 3、
Figure PCTCN2020101369-appb-000030
其他变量如本发明所定义。
在本发明的一些方案中，所述R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、
Figure PCTCN2020101369-appb-000031
Figure PCTCN2020101369-appb-000032
所述CH 3、
Figure PCTCN2020101369-appb-000033
任选被R取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R b分别独立地选自H、F、OH、CN、CH 3、CH 2OH、CH 2NH 2、
Figure PCTCN2020101369-appb-000034
Figure PCTCN2020101369-appb-000035
其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自苯基、吡啶基、环丙基、环己基、
Figure PCTCN2020101369-appb-000036
所述苯基、吡啶基、环丙基、环己基、
Figure PCTCN2020101369-appb-000037
任选被1、2或3个R b取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自
Figure PCTCN2020101369-appb-000038
Figure PCTCN2020101369-appb-000039
其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自
Figure PCTCN2020101369-appb-000040
Figure PCTCN2020101369-appb-000041
Figure PCTCN2020101369-appb-000042
其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自C 2-5烷基，所述C 2-5烷基任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自
Figure PCTCN2020101369-appb-000043
其他变量如本发明所定义。
本发明还提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020101369-appb-000044
其中，
R 1为H、F、Cl、Br、I、OH、NH 2、CN和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R a取代；
R 2选自C 3-8环烷基和3～8元杂环烷基，所述C 3～8环烷基、3～8元杂环烷基任选被1、2或3个R b取代；
L 1选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R c取代；
R a分别独立地选自F、Cl、Br、I、OH、NH 2和CN；
R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、-C(＝O)-C 1-3烷基和-C(＝O)-C 1-3烷氧基；
R c分别独立地选自F、Cl、Br、I、OH、NH 2、CN和CH 3；
所述3-8元杂环烷基包含1、2或3个独立地选自-NH-、N和O的杂原子或杂原子团。
在本发明的一些方案中，所述R 1选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R 1为CH 3，其他变量如本发明所定义。
在本发明的一些方案中，所述R b选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、
Figure PCTCN2020101369-appb-000045
其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自C 3-6环烷基和4～6元杂环烷基，所述C 3～8环烷基、4～6元杂环烷基任选被1、2或3个R b取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自吗啉基、哌啶基、哌嗪基、四氢吡喃基和环丙基，所述吗啉基、哌啶基、哌嗪基、四氢吡喃基和环丙基任选被1、2或3个R b取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自
Figure PCTCN2020101369-appb-000046
Figure PCTCN2020101369-appb-000047
其他变量如本发明所定义。
在本发明的一些方案中，所述L 1选自C 3-5烷基，所述C 3-5烷基任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，所述L 1为
Figure PCTCN2020101369-appb-000048
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020101369-appb-000049
Figure PCTCN2020101369-appb-000050
其中，L 1选自C 2-5烷基，R 1、R 3和R b如本发明所定义。
本发明还有一些方案由上述任意变量组合而来。
本发明还提供了下式所示化合物、其异构体或其药学上可接受的盐
Figure PCTCN2020101369-appb-000051
Figure PCTCN2020101369-appb-000052
Figure PCTCN2020101369-appb-000053
本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物、其异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述的化合物、其异构体或其药学上可接受的盐或上述的药物组合物在制备治疗与IRAK4和BTK相关疾病的药物中的应用。
技术效果
本发明化合物对IRAK4、BTK普遍展现出较好的抑制活性。本发明化合物在THP-1细胞中普遍展现出较好的抑制细胞TNF-α生成活性，在OCI-LY10、OCI-LY3和TMD-8细胞中展现出较好的抑制细胞增值活性，在人B细胞淋巴瘤OCI-LY10细胞皮下异种移植瘤模型中展现出较好的体内药效。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有规定，本发明所述D代表氘( 3H)。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2020101369-appb-000054
和楔形虚线键
Figure PCTCN2020101369-appb-000055
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020101369-appb-000056
和直形虚线键
Figure PCTCN2020101369-appb-000057
表示立体中心的相对构型，用波浪线
Figure PCTCN2020101369-appb-000058
表示楔形实线键
Figure PCTCN2020101369-appb-000059
或楔形虚线键
Figure PCTCN2020101369-appb-000060
或用波浪线
Figure PCTCN2020101369-appb-000061
表示直形实线键
Figure PCTCN2020101369-appb-000062
和直形虚线键
Figure PCTCN2020101369-appb-000063
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子 均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2020101369-appb-000064
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2020101369-appb-000065
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构 体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2020101369-appb-000066
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2020101369-appb-000067
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2020101369-appb-000068
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2020101369-appb-000069
直形虚线键
Figure PCTCN2020101369-appb-000070
或波浪线
Figure PCTCN2020101369-appb-000071
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2020101369-appb-000072
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2020101369-appb-000073
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2020101369-appb-000074
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2020101369-appb-000075
Figure PCTCN2020101369-appb-000076
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2020101369-appb-000077
仍包括
Figure PCTCN2020101369-appb-000078
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 2-5烷基”用于表示直链或支链的由2至5个碳原子组成的饱和碳氢基团。所述C 2-5烷基包括C 2-5、C 2-4、C 2-3、C 2、C 3、C 4和C 5烷基等。C 2-5烷基的实例包括但不限于乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 1、C 2和C 3烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧 基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，“C 3-8环烷基”表示由3至8个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C 3-8环烷基包括C 3-6、C 3-5、C 4-8、C 4-6、C 4-5、C 5-8或C 5-6环烷基等；其可以是一价、二价或者多价。C 3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。
除非另有规定，术语“3-8元杂环烷基”本身或者与其他术语联合分别表示由3至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-8元杂环烷基包括3-6元、3-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：DMSO代表二甲亚砜；EtOH代表乙醇；MeOH代表甲醇；M代表mol/L；N/A代表未检测；MgCl 2代表氯化镁；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；Na 3VO 4代表钒酸钠。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020101369-appb-000079
软件命名，市售化合物采用供应商目录名称。
附图说明
图1为血浆TNF-α浓度图。
图2为不同组别的老鼠体重变化曲线图。
图3为相对体重变化(％)曲线图。
图4为肿瘤生长曲线图。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：中间体A1的合成
Figure PCTCN2020101369-appb-000080
合成路线：
Figure PCTCN2020101369-appb-000081
步骤1：化合物A1的合成
将琥珀酸单乙酯酰氯(50.0g)加到乙腈(500.0mL)中，并搅拌均匀，将三甲基硅重氮甲烷(2M,227.8mL)滴加到反应体系中，并在25℃搅拌0.5小时。随后在0℃将氢溴酸醋酸溶液(93.1g,33％含量)滴加到反应体系中，并在25℃搅拌0.5小时。反应液减压浓缩除去乙腈，将剩余物倒入乙酸乙酯(500.0mL)中，用饱和碳酸氢钠水溶液洗涤(100mL×3)。分出有机相，加入适量无水硫酸钠干燥。过滤除去干燥剂，滤液减压浓缩至干得到粗产物。粗产物经柱层析(洗脱剂：石油醚～石油醚:乙酸乙酯＝10:1)纯化后得到化合物A1。
参考例2：中间体A2的合成
Figure PCTCN2020101369-appb-000082
合成路线：
Figure PCTCN2020101369-appb-000083
步骤1：化合物A2-1的合成
向4-溴-2-甲基吡啶(8.5g)，噁唑-4-甲酸乙酯(7.0g)和N,N-二甲基甲酰胺(70.0mL)的混合溶液中加入醋酸钯(2.2g)，碳酸铯(32.3g)和三(邻甲苯基)膦(6.0g)。混合物置换氮气三次后，在100℃搅拌16小时。反应液冷却到室温后，垫硅藻土过滤。滤液减压浓缩至干得到粗产品。粗品经柱层析(洗脱剂：石油醚：乙酸乙酯＝10:1-0:1)纯化后得到化合物A2-1。
步骤2：化合物A2的合成
将化合物A2-1(6.5g)溶于甲醇(35.0mL)和水(35.0mL)中并搅拌均匀，向反应体系中加入氢氧化钠(2.2g)并在15℃搅拌2小时。减压浓缩除去甲醇，水相用甲基叔丁基醚萃取(10.0mL×1)。分出水相，并用1M盐酸调节至pH＝3。水相减压浓缩干后，向残余物加入甲苯(10.0mL)并搅拌均匀。过滤，滤液减压浓缩至干，得到化合物A2。LCMS(ESI)m/z＝205.2[M+H] +. 1H NMR(400MHz,MeOH-d 4)δ＝8.87-8.86(m,2H),8.53(s,1H),8.45(d,J＝6.0Hz,1H),2.89(s,3H).
参考化合物A2的合成步骤，合成下表1中的各片段化合物。
表1
Figure PCTCN2020101369-appb-000084
Figure PCTCN2020101369-appb-000085
下表2中的各个中间体均为商业市售试剂。
表2
Figure PCTCN2020101369-appb-000086
Figure PCTCN2020101369-appb-000087
Figure PCTCN2020101369-appb-000088
实施例1：化合物WX001的合成
Figure PCTCN2020101369-appb-000089
合成路线：
Figure PCTCN2020101369-appb-000090
步骤1：化合物WX001-1的合成
将4-氯-5-硝基-吡啶-2-胺(25.0g)溶于四氢呋喃(200.0mL)中，然后加入哌啶(61.3g)。在10℃搅拌12小时后，将反应液减压浓缩至干，向残留物中加入乙酸乙酯(100.0mL)并打浆。过滤，收集滤液。滤液减压浓缩至干得到粗品，粗品经柱层析(石油醚：乙酸乙酯＝5:1-0:1)纯化得到化合物WX001-1。
步骤2：化合物WX001-2的合成
化合物WX001-1(5.0g)和中间体A1(5.0g)的混合物置换氮气三次后，在100℃搅拌12小时。反应液冷却至室温后，将反应液倒入水(200.0mL)中，加二氯甲烷(200.0mL×3)萃取。合并有机相，用适量无水硫酸钠干燥。过滤除去干燥剂，滤液减压浓缩至干得到粗品。粗品经柱层析(洗脱剂:二氯甲烷:甲醇＝100:0-10:1)纯化得到化合物WX001-2。
步骤3：化合物WX001-3的合成
将雷尼镍(3.0g)加到WX001-2(3.0g)的EtOH(50.0mL)溶液中，并在H 2(50Psi)，30℃搅拌1小时。过滤除去催化剂，滤液减压浓缩至干得到化合物WX001-3。
步骤4：化合物WX001-4的合成
将化合物WX001-3(3.0g)，A2(2.9g)，O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(6.5g)和N,N-二异丙基乙基胺(3.7g)加到二氯甲烷(50.0mL)中，并在20℃搅拌12小时。反应结束后，将反应液中倒入饱和碳酸氢钠水溶液(50.0mL)中并搅拌均匀。分出有机相，加适量无水硫酸钠干燥。过滤除去干燥剂，滤液减压浓缩至干得到粗品。粗品经柱层析(纯石油醚，石油醚:乙酸乙酯＝1:1，乙酸乙酯:甲醇＝10:1)纯化得到化合物WX001-4。
步骤5：化合物WX001的合成
将化合物WX001-4(3.3g)溶于无水四氢呋喃(70.0mL)中，并反应液降温到10℃。将甲基溴化镁(3M,15.4mL)的乙醚溶液滴加到反应体系中，并在15℃搅拌20分钟。将反应液倒入饱和氯化铵水溶液中(30.0mL)，用乙酸乙酯萃取(20.0mL×3)。合并有机相，加适量无水硫酸钠干燥。过滤除去干燥剂，滤液减压浓缩至干得到粗品。粗品经柱层析纯化(纯石油醚，石油醚:乙酸乙酯＝1:1，乙酸乙酯:甲醇＝10:1)后，再经过机分纯化(柱子:Welch Xtimate C18 250*50mm*10μm；流动相:A:含10mM NH 4HCO 3的水溶液，B:乙腈；梯度：B％:30％-55％,10分钟)得到化合物WX001。LCMS(ESI)m/z＝489.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ＝9.25(s,1H),8.70(s,1H),8.63(d,J＝4.8Hz,1H),7.93(s,1H),7.83(d,J＝4.8Hz,1H),7.50(s,1H),7.31(s,1H),7.14(s,1H),4.14-4.12(m,1H),2.99-2.97(m,4H),2.81-2.77(m,2H),2.64(s,3H),1.99-1.96(m,4H),1.91-1.89(m,2H),1.87(br s,2H),1.27(s,6H).
参考实施例1的合成步骤，不同之处在于，将实施例一中的步骤1的B4(哌啶环)替换成对应片段1中相应的B片段，合成步骤可能经过脱Boc、水解、使用甲基格式试剂与酯生成叔醇或者使用Suzuki偶联等常规操作，最终合成如下表3中各实施例。
表3
Figure PCTCN2020101369-appb-000091
Figure PCTCN2020101369-appb-000092
Figure PCTCN2020101369-appb-000093
Figure PCTCN2020101369-appb-000094
实施例16：化合物WX016的合成
Figure PCTCN2020101369-appb-000095
合成路线：
Figure PCTCN2020101369-appb-000096
参考实施例16的合成步骤，合成WX016-1，不同之处在于将步骤一中的哌啶替换为4,4-二甲基哌啶。
步骤1：化合物16的合成
将化合物WX016-1(15.0mg)溶于氢氧化钠(2.3mg)的水(1.0mL)溶液中，之后加入甲醇(1.0mL)，25℃反应2小时。将反应液用1.0M盐酸调至pH＝6-7，之后用乙酸乙酯(30.0mL×4)萃取，合并有机相后，用无水硫酸钠干燥，过滤并减压浓缩。再经过机分纯化(柱子:Welch Xtimate C18 150*25mm*5μm；流动相:[含(10.0mM)NH 4HCO 3的水溶液)-乙腈]；梯度：B％:15％-50％,10.5min)。得到化合物WX016。LCMS(ESI)m/z:503.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ＝9.74(s,1H),9.35(s,1H),9.06(s,1H),8.67(d,J＝5.2Hz,1H),7.83(s,1H),7.76(d,J＝5.2Hz,1H),7.70-7.68(m,1H),7.29(s,1H),2.92-2.89(m,4H),2.87-2.83(m,4H),2.65-2.55(m,4H),1.68(s,4H),1.07(s,6H).
参考实施例16的合成步骤，合成下表4中的各实施例，不同之处在于将步骤1中的4,4-二甲基哌啶替换为片段1。
表4
Figure PCTCN2020101369-appb-000097
Figure PCTCN2020101369-appb-000098
实施例21：化合物WX021的合成
Figure PCTCN2020101369-appb-000099
合成路线：
Figure PCTCN2020101369-appb-000100
参考实施例1的类似合成步骤，合成WX021-1，不同之处在于实施例1中第一步不使用哌啶取代氯原子。步骤1：化合物WX021的合成
在一个反应瓶中加入WX020-1(3.3mg)，B10(3.33mg)和甲苯(1.0mL)，乙醇(0.5mL)，水(0.3mL)，然后加入碳酸氢钠(5.7mg)和四三苯基膦钯(5.3mg)。置换氮气三次，然后在80℃搅拌12小时。过滤，收集滤液，减压浓缩干。粗产品经过硅胶板纯化(洗脱剂：二氯甲烷：甲醇＝10:1)得到化合物WX021.LCMS(ESI)m/z:482.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ＝9.70(s,1H),8.99(s,1H),8.93(s,1H),8.68-8.67(d,J＝4Hz,1H),7.80(s,1H),7.72(s,1H),7.65-7.64(d,J＝4Hz,1H),7.57-7.45(m,6H),4.34(s,1H),2.78-2.74(m,2H),2.59(s,3H),1.82-1.78(m,2H),1.17(s,6H).
参考实施例21的合成步骤，不同之处在于，将实施21步骤中的B10(苯硼酸)替换成对应片段1中相应的B片段，合成步骤可能经过简单的氢化和氰基水解成酰胺等操作，最终合成如下表5中各实施例。
表5
Figure PCTCN2020101369-appb-000101
Figure PCTCN2020101369-appb-000102
Figure PCTCN2020101369-appb-000103
Figure PCTCN2020101369-appb-000104
实施例37：化合物WX037的合成
Figure PCTCN2020101369-appb-000105
合成路线：
Figure PCTCN2020101369-appb-000106
步骤1：化合物WX037-1的合成
在一个反应瓶中加入2-氨基-4-氯-5-硝基吡啶(10.0g,57.62mmol)和溴代乙酰丙酮酸乙酯(21.5g,97.95mmol)，混合物置换氮气三次，反应继续在110℃搅拌16小时。向反应液中加入乙醇(80mL)搅拌2小时，然后过滤，收集固体，减压浓缩干得到化合物WX037-1。
步骤2：化合物WX037-2的合成
在一个反应瓶中加入WX037-1(10.0g,37.1mmol)和无水乙醇(100.0mL)，然后加入浓硫酸(3.7g,37.1mmol,2.0mL,98％纯度)，反应在80℃搅拌12小时。反应液减压浓缩干。加入乙酸乙酯(300.0mL)溶解，然后用饱和碳酸钠水溶液调节pH到8，分液，有机相用无水硫酸钠干燥，过滤并减压浓缩干。粗品经过柱层析纯化(二氯甲烷：甲醇＝100:0-10:1)，得到WX037-2。
步骤3：化合物WX037-3的合成
在一个反应瓶中加入WX037-2(7.5g,25.2mmol)和醋酸异丙酯(140.0mL)，然后加入二水合氯化锡(34.1g,151.2mmol)。混合物在50℃搅拌12小时。向反应液中加入乙酸乙酯(200.0mL)，然后滴加氨水到pH＝9，然后加入无水硫酸钠搅拌成沙状，过滤，收集滤液并减压浓缩干。粗品经过柱层析纯化(洗脱剂：二氯甲烷：甲醇＝100:0-10:1)，得到WX037-3。
步骤4：化合物WX037-4合成
在一个反应瓶中加入WX037-3(3g,11.21mmol,1eq)，A2(3.0g,14.6mmol)，N,N-二异丙基乙胺(5.8g,44.8mmol,7.8mL)，三正丙基环磷酸酐50％乙酸乙酯溶液(21.9g,33.6mmol,20.0mL,50％纯度)和THF(50.0mL)。混合物在50℃搅拌12小时。加入乙酸乙酯(100.0mL)，用饱和碳酸钠水溶液调节pH到8，然后分液，收集有机相，用无水硫酸钠干燥，过滤并减压浓缩干。粗品经过柱层析纯化(二氯甲烷：甲醇＝100：0-10:1)得到WX037-4。
步骤5：化合物WX037-5合成
在一个反应瓶中加入WX037-4(1.0g,2.2mmol)，B19(486.8mg,2.9mmol)，磷酸钾(1.4g,6.6mmol)[甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-氨基-1,1-联苯-2-基)钯(II)(299.6mg,330.5μmol)，四氢呋喃(10.0mL)，水(3.0mL)，置换氮气三次，然后在80℃搅拌12小时。过滤，收集滤液，减压浓缩干。粗品经过柱层析(二氯甲烷：甲醇＝100:0-10:1)纯化。得到WX037-5。
步骤6：合物WX037合成
在一个反应瓶中加入WX037-5(0.05g,92.9μmol)，氢氧化钠(2M,919.9μL)，甲醇(5.0mL)，置换氮气三次，然后在25℃搅拌2小时。将甲醇减压浓缩干，然后用2N盐酸调节pH到7，然后减压浓缩干。粗品经过机分纯化(柱子:Phenomenex Gemini NX-C18(75*30mm*3μm)；流动相:[含(10.0mM)NH 4HCO 3的水溶液)-乙腈]；梯度B％:15％-40％,8min)得到WX037。
1H NMR(400MHz,DMSO-d 6)δ＝11.5(s,1H),9.21(s,1H),9.02(s,1H),8.98(s,1H),8.70-8.69(d,J＝4.0Hz,1H),7.90(s,1H),7.65-7.58(m,3H),7.49(s,1H),7.17-7.15(d,J＝8.0Hz,1H),7.09-7.04(t,1H),3.80(s,3H),2.97-2.93(t,2H),2.69-2.65(t,2H),2.61(s,3H).
LCMS(ESI)m/z:516.1[M+H] +.
参考实施例37合成步骤，合成下表中的各实施例，不同之处在于将步骤5中的B-19替换为片段1，最终合成如下表6所示实施例。
表6
Figure PCTCN2020101369-appb-000107
Figure PCTCN2020101369-appb-000108
实施例40：化合物WX040的合成
Figure PCTCN2020101369-appb-000109
合成路线：
Figure PCTCN2020101369-appb-000110
步骤1：化合物WX040-1的合成
将WX001-1(5.4g,24.3mmol)加到盛有溴代丙酮酸乙酯(47.4g,243.0mmol,30.4mL)的瓶中，该反应在90℃搅拌12小时。趁热将反应液倒入乙酸乙酯(150.0mL)中，在15℃搅拌15分钟，抽滤，滤饼用乙酸乙酯(20.0mL×3)淋洗，滤饼减压浓缩干，得到WX040-1。
步骤2：化合物WX040-2的合成
将雷尼镍(942.0mg,)加到氩气保护下的氢化瓶中，随后用乙醇(30.0mL)润湿，将WX040-1(1.0g,3.1mmol)加到反应体系中，该反应在25℃，氢气50Psi下搅拌2小时。反应液硅藻土抽滤，滤液减压浓缩干得到WX040-2。
步骤3：化合物WX040-3的合成
将WX040-2(200mg,693.6μmol)，A2(170.0mg,832.34μmol)，O-(7-氮杂苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦盐(395.6mg,1.0mmol)，N,N-二异丙基乙胺(268.9mg,2.1mmol,362.4μL)加到盛有无水二氯甲烷(15.0mL)的瓶中，该反应在25℃搅拌2小时。反应液倒入饱和氯化铵溶液(20.0mL)中，分液，有机相干燥，过滤并减压浓缩。粗品经柱分离(石油醚到石油醚:乙酸乙酯＝1:1到纯乙酸乙酯)洗脱，得到WX040-3。
步骤4：化合物WX040的合成
将甲基氯化镁(3.0mol/L,4.2mL)加到盛有无水四氢呋喃(15.0mL)的瓶中，氮气保护，在20℃下，将WX040-3(100.0mg,210.7μmol)溶于无水四氢呋喃(9.0mL)中滴加到上述溶液中，该反应在20℃搅拌0.5小时。将反应液倒入饱和氯化铵溶液(20.0mL)中萃灭，用乙酸乙酯(10.0mL×4)萃取，有机相干燥，过滤并减压浓缩。粗品经板分离(乙酸乙酯:甲醇＝10:1)纯化，得到WX040。
1H NMR 400MHz,CD 3OD-d 4)δ＝9.41(s,1H),8.75(s,1H),8.66(d,J＝5.2Hz 1H),7.99(s,1H),7.90(d,J＝5.6Hz1H),7.66(s,1H),7.20(s,1H),3.15-2.99(m,4H),2.67(s,3H),3.11-1.98(m,4H),1.85-1.64(m,2H),1.62(s,6H).LCMS(ESI)m/z:461.3[M+H] +.
参考实施例21和实施例40的合成步骤，合成下表中的各实施例，不同之处在于将右下的哌啶替换成片段1，最终合成如下表7所示实施例。
表7
Figure PCTCN2020101369-appb-000111
Figure PCTCN2020101369-appb-000112
实施例42：化合物WX042的合成
Figure PCTCN2020101369-appb-000113
合成路线：
Figure PCTCN2020101369-appb-000114
参考实施例1的合成步骤，合成WX042-1，不同之处在于将步骤2中的A1替换成溴乙酰乙酸乙酯。
步骤1：化合物WX042-2的合成
将化合物WX042-1(0.8g,1.64mmol)溶于四氢呋喃(10.0mL)中，降温到-10℃，将四氢铝锂(155.4mg)分批加到反应体系中，该反应在-10℃搅拌1小时。将反应液倒入氯化铵水溶液(50.0mL)中，之后乙酸乙酯(50.0mL×4)萃取,合并有机相，用饱和食盐水(100.0mL)洗涤有机相，有机相用无水硫酸钠干燥，过滤并减压浓缩。粗品经柱纯化：二氯甲烷:甲醇＝100:0～100:0.25纯化得到WX042-2。
步骤2：化合物WX042-3的合成
将化合物WX042-2(200.0mg)溶于氯仿(10.0mL)中，之后加入三乙胺(136.0mg)，降温至10℃后搅拌10分钟，之后缓慢滴加甲烷磺酰氯(77.0mg)的氯仿(1.0mL)溶液。该反应缓慢升温至25℃，继续搅拌20分钟。反应液减压浓缩后得到WX042-3。
步骤3：化合物WX042的合成
将化合物WX042-3(0.2g)，甲基亚磺酸钠(70.1mg,686.3μmol)溶于N,N-二甲基甲酰胺(10.0mL)中，之后加入碘化钾(189.8mg)。该反应在微波仪80℃(0bar)反应1小时。向反应液中加入10.0mL乙酸乙酯稀释后倒入半饱和食盐水(50.0mL)中，分液，水相经乙酸乙酯(50.0mL×4)萃取后合并有机相，用无水硫酸钠干燥，过滤并减压浓缩。粗品用机分纯化(柱子:Welch Xtimate BEH C18 100*30mm*10μm；流动相:A:含10mM NH 4HCO 3的水溶液，B:乙腈；梯度：B％:30％-50％,6分钟)后冻干，得到WX042。
1H NMR(400MHz,DMSO-d 6)δ＝9.87(s,1H),9.35(s,1H),9.09(s,1H),8.71(s,1H),7.83(s,2H),7.73(s,1H),7.23(s,1H),3.48–3.46(m,2H),3.44(s,2H),3.09–2.99(m,3H),2.91–2.90(m,4H),2.60–2.58(m,3H),1.87–1.86(m,4H),1.67(s,2H)
LCMS(ESI)m/z:509.1[M+H] +.
参考实施例42的合成步骤，合成下表中的各实施例，不同之处在于将右下的哌啶替换成片段1，最终合成如下表8所示实施例。
表8
Figure PCTCN2020101369-appb-000115
试验例1：体外IRAK4激酶活性评价
采用 33P同位素标记激酶活性测试(Reaction Biology Corp)测定IC 50值来评价受试化合物对人IRAK4的抑制能力。
缓冲液条件：20mM Hepes(pH 7.5),10mM MgCl 2,1mM EGTA,0.02％Brij35,0.02mg/mL BSA,0.1mM Na 3VO 4,2mM DTT,1％DMSO。
试验步骤：室温下，将受试化合物溶解在DMSO中配制成10mM溶液待用。将底物溶解在新配制的缓冲液中，向其中加入受测IRAK4激酶并混合均匀。利用声学技术(Echo 550)将溶有受试化合物的DMSO溶液加入上述混匀的反应液中。孵化15分钟后，加入 33P-ATP开始反应。反应在室温下进行120分钟后，将反应液点在P81离子交换滤纸(Whatman#3698-915)上。用0.75％磷酸溶液反复清洗滤纸后，测定滤纸 上残留的磷酸化底物的放射性。激酶活性数据用含有受试化合物的激酶活性和空白组(仅含有DMSO)的激酶活性的比对表示，通过Prism4软件(GraphPad)进行曲线拟合得到IC 50值，实验结果如表9所示。
表9：本发明化合物体外IRAK4激酶活性筛选试验结果
化合物编号 IRAK4/IC 50(nM)
WX001 1.0
WX002 1.2
WX003 2.2
WX004 1.3
WX005 1.1
WX006 1.2
WX007 2.0
WX008 2.1
WX009 0.7
WX010 2.4
WX011 1.5
WX012 1.0
WX013 0.2
WX014 0.9
WX015 0.4
WX016 0.9
WX017 1.6
WX018 0.9
WX020 0.5
WX021 0.5
WX022 0.7
WX023 8.4
WX024 0.7
WX025 0.7
WX027 11
WX033 1.6
WX039 1
WX040 1.2
WX044 1.9
WX045 3.4
WX046 2.5
结论：本发明化合物对IRAK4普遍展现出较好的抑制活性。
试验例2：体外BTK激酶活性评价：
采用 33P同位素标记激酶活性测试(Reaction Biology Corp)测定IC 50值来评价受试化合物对人BTK的抑制能力。
缓冲液条件：20mM Hepes(pH 7.5),10mM MgCl 2,1mM EGTA,0.02％Brij35,0.02mg/mL BSA,0.1mM Na 3VO 4,2mM DTT,1％DMSO。
试验步骤：室温下，将受试化合物溶解在DMSO中配制成10mM溶液待用。将底物溶解在新配制的缓冲液中，向其中加入受测BTK激酶并混合均匀。将溶解于DMSO中的化合物通过Echo550(Acoustic technology；nanoliter range)加入到激酶反应混合物中。室温下孵育20分钟后，加入 33P-ATP开始反应。反应在室温下进行2小时后，将反应液点利用P81离子交换滤纸采用过滤-结合法检测放射性。激酶活性数据用含有受试化合物的激酶活性和空白组(仅含有DMSO)的激酶活性的比对表示，通过Prism4软件
(GraphPad)进行曲线拟合得到IC 50值，实验结果如表10所示。
表10：本发明化合物体外BTK激酶活性筛选试验结果
化合物编号 BTK/IC 50(nM)
WX001 6.7
WX006 47.5
WX008 4.6
WX009 46
WX011 23.6
WX012 6.9
WX013 1.4
WX014 25.7
WX015 6.4
WX016 8.9
WX018 47.5
WX020 8.5
WX021 13.9
WX022 43.1
WX024 30.5
WX025 21.8
WX026 30.7
WX029 24.2
WX031 39.6
WX032 26.5
WX033 20.2
WX039 29
WX040 3.3
WX042 3.8
WX045 28.6
WX046 43.1
结论：本发明化合物对BTK普遍展现出较好的抑制活性。
试验例3：体外THP-1细胞学活性评价
THP-1细胞学TNFa ELISA实验
1.实验材料:
THP-1人急性单细胞白血病细胞系购自ATCC(Cat#TIB-202)，培养在37℃,5％CO 2培养箱中。培养基成分为RPMI1640(Gibco,Cat#22400-105)，补加成分为10％FBS(Gibco,Cat#10091148)；1％PenStrep(Gibco,Cat#15140)；0.05mM 2-Mercaptoethanol(Sigma,Cat#M6250)。
2.实验方法:
使用TNF-αElisa试剂盒检测细胞培养上清样品中TNF-α的含量。TNF-α是由150ng/mL的LPS(Sigma,Cat#L6529)刺激THP-1细胞所产生。
对数生长期正常培养的THP-1细胞以一定浓度(1*10 5/100μL)种在96孔板中(Corning#3599)，然后放到细胞培养箱中孵育。两个小时后加入16.7μL不同浓度的待测化合物(8*最终浓度)，在培养箱中孵育。一 个小时后加入16.7μL的1200ng/mL的LPS,在培养箱中孵育。18小时后离心并收集培养上清样品，用TNF-αElisa试剂盒可以检测TNF-α的含量。最后在envision读板机上读取OD信号(OD450-OD570)。
3.数据分析:
将OD450-OD570信号值转换为百分抑制率。
抑制率％＝(ZPE-sample)/(ZPE-HPE)*100。
“HPE”表示没有LPS刺激细胞的对照孔OD450-OD570信号值，“ZPE”表示有LPS刺激细胞的对照孔的OD450-OD570信号值。通过excel加载项中的XLFit计算出化合物的IC 50值。
方程式：Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)。
测试结果汇总如表11所示。
表11：本发明化合物体外筛选试验结果
化合物编号 THP-1/IC 50(nM)
WX001 124
WX003 557
WX004 77
WX005 256
WX006 107
WX007 240
WX010 332
WX011 140
WX016 170
WX017 321
WX018 104
WX021 15
WX024 13
WX025 21
WX040 38
结论：本发明化合物在THP-1细胞活性实验中普遍展现出较好的抑制细胞TNF-α生成活性。
试验例4：体外OCI-LY10和TMD-8细胞学活性评价
1.实验材料
OCI-LY10人B细胞淋巴瘤细胞，培养在37℃,5％CO 2培养箱中。培养基成分为IMDM(GIBCO,Cat#12440053)；补加成分为20％FBS(Hyclone,Cat#SH30084.03)；1％PenStrep(Thermo,Cat#SV30010)。
TMD8人B细胞淋巴瘤细胞，培养在37℃,5％CO 2培养箱中。培养基成分为RPMI1640(GIBCO,Cat#22400-089)；补加成分为10％FBS(Hyclone,Cat#SH30084.03)；1％PenStrep(Thermo,Cat#SV30010)。
2.实验方法
使用肿瘤细胞系OCI-LY10和TMD8检测合物体外抑制肿瘤细胞增殖的作用。将肿瘤细胞系按所示的培养条件在37℃，5％CO 2的培养箱中进行培养，定期传代，取处于对数生长期的细胞，计数，铺96孔板(每孔细胞调至合适浓度，共加入90每孔细胞悬液)。37℃,5％CO 2培养箱中培养过夜后加入不同浓度梯度的药物(加入10μL药物溶液)处理3天，然后每孔加入50μL的CellTiter-Glo工作液，用铝箔纸包裹细胞板以避光。将培养板在轨道摇床上振摇2分钟以诱导细胞裂解，室温放置10分钟以稳定发光信号，在2104EnVision读板器上检测发光信号。
3.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：
IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。
在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC 50。
4.实验结果
实验结果如表12所示。
表12：本发明化合物体外筛选试验结果
化合物编号 OCI-LY10/IC 50(nM) TMD-8/IC 50(nM)
WX001 128 300
WX016 466 221
WX021 171 215
WX024 208 /
WX025 94 /
WX026 349 /
WX029 289 /
WX030 209 /
WX031 96 /
WX032 386 /
WX040 87 /
WX045 77 /
结论：本发明化合物分别在OCI-LY10和TMD-8细胞系中，对细胞的增值普遍展现出较好的抑制活性。注：“/”代表未检测。
试验例5：体外OCI-LY3细胞学活性评价
1.实验细胞系信息及细胞培养
该实验所用的肿瘤细胞系由南京科佰生物科技有限公司提供，具体信息见下表13。
表13：实验细胞系信息
Figure PCTCN2020101369-appb-000116
2.实验方法
使用肿瘤细胞系OCI-LY3检测合物体外抑制肿瘤细胞增殖的作用。将OCI-LY3细胞系培养于对应的培养基中，于37℃和5％CO 2条件下培养，达到对数生长期的细胞用于实验铺板。收集细胞，800rpm 5分钟离心，培养基重悬，铺96孔板。37℃,5％CO 2培养箱中培养过夜后加入不同浓度梯度的药物(加入10μL配制好的受试化合物稀释液)孵育72小时，细胞培养板与CTG试剂在室温避光孵育30分钟，恢复至室温。在生物安全柜中避光加入CTG溶液100μL/孔，振板机避光振动混匀2分钟，室温避光孵育10分钟。使用Perkin Elmer Envision 2104 MuLtilabel Reader仪器读取发光值并记录。
3.数据处理及分析
通过将每个药物浓度下测得的发光值结果用空白对照组发光值归一化，并将该数值与DMSO组的比值作为细胞抑制率(％)。利用GraphPad软件，把药物浓度的对数(log药物浓度)对抑制率作图，软件会通过非线性回归(Nonlinear Regression)的log(inhibitor)vs.normalized response算法自动拟合计算出IC50值以及95％可信限的值。
4.实验结果
实验结果如表14所示。
表14：本发明化合物体外筛选试验结果
化合物编号 OCI-LY3/IC 50(μM)
WX001 1.292
WX040 0.283
WX045 0.270
结论：本发明化合物对OCI-LY3细胞系中，对细胞的增值均有显著抑制作用。
试验例6：脂多胶原(LPS)诱导的SD大鼠TNF-α分泌体内药效学研究
1.造模和给药
SD大鼠分别口服给予溶剂、阳性药地塞米松(DEX，0.5mg/kg)和待测化合物，并于给药0.5小时后腹腔注射LPS(1mg/kg)。注射LPS 2小时后CO 2安乐死动物，心脏采血置于含EDTA-K2的抗凝管中，部分抗凝血离心分离血浆冻存于-80℃。
2.TNF-α的检测
血浆从-80℃冰箱取出，室温解冻，按照ELISA试剂盒说明书方法检测血浆中TNF-α浓度。
3.统计学处理
实验数据应用平均数±标准误表示(Mean±SEM)，TNF-α水平用单因素方差分析(One-way ANOVA)，p<0.05认为有显著性差异。脂多胶原(LPS)诱导的SD大鼠TNF-α分泌体内药效学研究结果如图1所示。
4.实验结果
图1结果表明：SD大鼠化合物口服WX001后对脂多胶原(LPS)诱导的TNF-α分泌展现了显著的抑制作用，在20mpk剂量下的药效等同于0.5mpk剂量下地塞米松(DEX)的药效。
试验例7：WX001对人B细胞淋巴瘤OCI-LY10细胞皮下异种移植肿瘤小鼠模型的体内药效学研究
1.实验目的
本实验的目的是研究WX001受试药对人B细胞淋巴瘤OCI-LY10细胞皮下异种移植瘤在CB17SCID小鼠模型体内药效进行评估。
2.实验材料
OCI-LY10人B细胞淋巴瘤细胞，培养在37℃,5％CO 2培养箱中。培养基成分为IMDM(GIBCO,Cat#12440053)；补加成分为20％FBS(Hyclone,Cat#SH30084.03)；1％PenStrep(Thermo,Cat#SV30010)。
3.实验方法
OCI-LY10肿瘤细胞培养传代，将0.2mL(1×10 7个)OCI-LY10细胞皮下接种于每只裸小鼠的右后背(加基质胶，体积比为1:1)，肿瘤平均体积达到167mm 3时开始分组给药。每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动，摄食摄水量，体重变化(每周测量两次体重)，肿瘤大小(每周测量两次肿瘤体积)，外观体征或其它不正常情况。
4.数据分析
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。包括测量肿瘤体积(TV)，计算化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)。
TV＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
TGI(％)＝(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积))×100％。
T/C％＝T RTV/C RTV×100％(T RTV：治疗组RTV；C RTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即d 0)测量所得平均肿瘤体积，V t为某一次测量时的平均肿瘤体积，T RTV与C RTV取同一天数据。
5.实验结果
5.1.死亡率、发病率及体重变化情况
实验动物的体重作为间接测定药物毒性的参考指标。给药18天(PG-D1-D18)，所有实验组小鼠无异常，表现出良好的药物耐受性。
WX001化合物对人B细胞淋巴瘤OCI-LY10细胞皮下异种移植肿瘤雌性CB17SCID小鼠模型的体重影响如图2和图3所示。图2表示人B细胞淋巴瘤OCI-LY10细胞皮下异种移植瘤模型荷瘤鼠在给予WX化合物后的体重变化。数据点代表组内平均体重，误差线代表标准误(SEM)。图3所示相对体重变化基于开始给药时动物体重计算得出。数据点代表组内平均体重变化百分比，误差线代表标准误(SEM)。
5.2.肿瘤生长曲线
图4表示人B细胞淋巴瘤OCI-LY10细胞皮下异种移植瘤模型荷瘤鼠在给予WX001化合物后的肿瘤生长曲线。数据点代表组内平均肿瘤体积，误差线代表标准误(SEM)。
6.实验结果及讨论
在本实验中，我们评价了WX001化合物在人B细胞淋巴瘤OCI-LY10细胞皮下异种移植瘤模型中的体内药效。各组在不同时间点的瘤体积图4所示。
开始给药后18天，Ibrutinib(10mpk)组T/C值为39％，TGI值为85％，p值<0.001。WX001(50mpk)组T/C值为22％,TGI值为109％,p<0.001，与溶剂对照组相比具有显著的抑瘤作用，并且显著优于Ibrutinib(10mpk)组。
OCI-LY10细胞系，是同时高度依赖于MyD88-L265P和BCR(CD79A/B)双突变的ABC-DLBCL细胞系。IRAK4和BTK双靶点抑制剂WX001(50mpk)单药展现显著抑瘤效果(TGI＝109％)，显著优于Ibrutinib(10mpk)的单药药效(TGI＝85％)，展现了IRAK4/BTK双通路同时抑制的显著作用，并且动物耐受性良好。

Claims (15)

  1. 式(II)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020101369-appb-100001
    其中，
    R 1为H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基、环丙基和-C(＝O)-NH 2，所述C 1-6烷基、环丙基和-C(＝O)-NH 2任选被1、2或3个R a取代；
    R 2选自噻吩基、苯基、吡啶基、环丙基、环己基和
    Figure PCTCN2020101369-appb-100002
    所述噻吩基、苯基、吡啶基、环丙基、环己基和
    Figure PCTCN2020101369-appb-100003
    任选被1、2、3、4或5个R b取代；
    T 1选自CH 2、NH和O；
    R 3选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R c取代；
    R a分别独立地选自F、OH、NH 2和CN；
    R b分别独立地选自H、D、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、COOH、-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基和-C(＝O)-NH 2，所述OH、NH 2、C 1-3烷基、COOH、-C(＝O)-C 1-3烷基、-C(＝O)-O-C 1-3烷基和-C(＝O)-NH 2任选被1、2或3个R取代；
    R c分别独立地选自F、OH、NH 2、CN、CH 3、COOH和-SO 2CH 3；
    R分别独立地选自F、OH、NH 2和CH 3。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、环丙基和-C(＝O)-NH 2，所述C 1-3烷基、环丙基和-C(＝O)-NH 2任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自CN、CH 3、CF 3、
    Figure PCTCN2020101369-appb-100004
    Figure PCTCN2020101369-appb-100005
    和-C(＝O)-NH 2。
  4. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R b分别独立地选自H、 D、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、COOH、
    Figure PCTCN2020101369-appb-100006
    Figure PCTCN2020101369-appb-100007
    所述OH、NH 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、
    Figure PCTCN2020101369-appb-100008
    任选被1、2或3个R取代。
  5. 根据权利要求4所述化合物、其异构体或其药学上可接受的盐，其中，R b分别独立地选自H、D、F、Cl、OH、OCH 3、CN、CH 3、CH 2OH、CH 2NH 2、COOH、
    Figure PCTCN2020101369-appb-100009
  6. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 2选自噻吩基、苯基、吡啶基、环丙基、环己基、
    Figure PCTCN2020101369-appb-100010
    所述噻吩基、苯基、吡啶基、环丙基、环己基、
    Figure PCTCN2020101369-appb-100011
    任选被1、2、3、4或5个R b取代。
  7. 根据权利要求6所述化合物、其异构体或其药学上可接受的盐，其中，R 2选自
    Figure PCTCN2020101369-appb-100012
    Figure PCTCN2020101369-appb-100013
  8. 根据权利要求1或7所述化合物、其异构体或其药学上可接受的盐，其中，R 2选自
    Figure PCTCN2020101369-appb-100014
    Figure PCTCN2020101369-appb-100015
    Figure PCTCN2020101369-appb-100016
  9. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 3选自C 2-5烷基，所述C 2-5烷基任选被1、2或3个R c取代。
  10. 根据权利要求9所述化合物、其异构体或其药学上可接受的盐，其中，R 3选自CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、CH 2CH 2CH 2CH 3、CH 2CH(CH 3) 2和CH 2CH 2CH(CH 3) 2，所述CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、CH 2CH 2CH 2CH 3、CH 2CH(CH 3) 2和CH 2CH 2CH(CH 3) 2任选被1、2或3个R c取代。
  11. 根据权利要求10所述化合物、其异构体或其药学上可接受的盐，其中，R 3选自
    Figure PCTCN2020101369-appb-100017
    Figure PCTCN2020101369-appb-100018
  12. 根据权利要求1～11任意一项所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020101369-appb-100019
    Figure PCTCN2020101369-appb-100020
    其中，L 1选自C 2-5烷基，R 1、R 3和R b如权利要求1～11任意一项所定义。
  13. 下式所示化合物、其异构体或其药学上可接受的盐
    Figure PCTCN2020101369-appb-100021
    Figure PCTCN2020101369-appb-100022
    Figure PCTCN2020101369-appb-100023
  14. 一种药物组合物，包括治疗有效量的根据权利要求1～13任意一项所述的化合物、其异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  15. 根据权利要求1～13任意一项所述的化合物、其异构体或其药学上可接受的盐或根据权利要求14所述的药物组合物在制备治疗与IRAK4和BTK相关疾病的药物中的应用。
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