WO2020259626A1 - 作为irak4抑制剂的咪唑并吡啶类化合物 - Google Patents

作为irak4抑制剂的咪唑并吡啶类化合物 Download PDF

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WO2020259626A1
WO2020259626A1 PCT/CN2020/098259 CN2020098259W WO2020259626A1 WO 2020259626 A1 WO2020259626 A1 WO 2020259626A1 CN 2020098259 W CN2020098259 W CN 2020098259W WO 2020259626 A1 WO2020259626 A1 WO 2020259626A1
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compound
group
alkyl
pharmaceutically acceptable
isomers
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PCT/CN2020/098259
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English (en)
French (fr)
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王建非
李婕
谭海忠
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 CN202080036574.8A priority Critical patent/CN113825755B/zh
Priority to US17/597,126 priority patent/US20220227758A1/en
Publication of WO2020259626A1 publication Critical patent/WO2020259626A1/zh

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 IRAK4 inhibitors and their application in the preparation of drugs for treating diseases related to IRAK4. 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 NF-kB signaling pathway, which ultimately leads to the expression of pro-inflammatory cytokines.
  • Clinicopathological studies have shown that individuals with IRAK4 mutations have protective effects against chronic lung disease and inflammatory bowel disease. IRAK4 defect itself is not lethal, individuals can survive to adulthood, and the risk of infection decreases with age. Therefore, IRAK4 has become an important therapeutic target, attracting extensive research and development interest.
  • TLR/IL-1R pathway mediated by IRAK4 has been shown to be closely related to the development and progression of some diseases, such as atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, sepsis, inflammatory Enteritis, asthma, metabolic syndrome, etc.
  • IRAK4 inhibitors can effectively block the production of pro-inflammatory cytokine tumor necrosis factor TNF-alpha; in collagen-induced mouse arthritis models, IRAK4 inhibits The agent can effectively block the production of TNF-alpha and effectively inhibit the joint swelling of mice; in the mouse OCI-ly10 xenograft tumor model, IRAK4 inhibitors can effectively block the activation of the signaling pathway caused by abnormal MyD88-L265P, thereby inhibiting BTK
  • the combined use of inhibitors, PI3K inhibitors, etc. significantly enhances the efficacy of these inhibitors in DLBCL and promotes tumor cell apoptosis.
  • IRAK4 inhibitors can be widely used in the treatment of inflammatory diseases, immune diseases, tumor diseases and other diseases, and are an important target.
  • the development of IRAK4 inhibitors has significant clinical value.
  • BAY-1830839 and BAY-1834845 are small-molecule IRAK4 inhibitors developed by Bayer, and are currently undergoing clinical trials for immune diseases.
  • the present invention provides a compound represented by formula (II), its isomers or a pharmaceutically acceptable salt thereof,
  • R 1 is C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from C 1-6 alkyl, C 1-6 alkoxy, cyclopropyl, azetidinyl, The C 1-6 alkyl, C 1-6 alkoxy, cyclopropyl, azetidinyl, Optionally substituted by 1, 2 or 3 R b ;
  • R 3 is a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally substituted with 1, 2 or 3 R c ;
  • T 1 is selected from CH 2 , NH and O;
  • T 2 is selected from CH 2 , NH and O;
  • R a is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • the group is optionally substituted with 1, 2 or 3 R;
  • R is each independently selected from H, OH, and NH 2 .
  • the R 1 is CF 3 , and other variables are as defined in the present invention.
  • the R b is independently selected from H, F, Cl, OH, NH 2 , CN, CH 3 , CH 2 OH, CH 2 NH 2 , And -COOH, other variables are as defined in the present invention.
  • the R 2 is selected from C 1-3 alkyl, C 1-3 alkoxy, The C 1-3 alkyl group, C 1-3 alkoxy group, 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 3 is selected from Other variables are as defined in the present invention.
  • the compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 3 , R b , T 1 and T 2 are as defined in the present invention.
  • n is selected from 1, 2 and 3.
  • the present invention provides a compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 alkyl and C 1-6 alkoxy, said C 3-8 cycloalkyl, 3 to 8-membered Heterocycloalkyl, C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with 1, 2 or 3 R b ;
  • 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 H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • hetero of the 3- to 8-membered heterocycloalkyl group is independently selected from N, O, and NH, and the number of the aforementioned heteroatoms or heteroatom groups is independently selected from 1, 2, and 3, respectively.
  • the R 1 is CF 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 , And -COOH, other variables are as defined in the present invention.
  • the R 2 is selected from piperidinyl, piperazinyl, tetrahydropyrrolyl, tetrahydropyranyl, cyclopropyl, C 1-3 alkyl, and C 2-4 alkoxy
  • the piperidinyl group, piperazinyl group, tetrahydropyrrolyl group, tetrahydropyranyl group, cyclopropyl group, C 1-3 alkyl group and C 2-4 alkoxy group are optionally selected by 1, 2 or 3 R b is substituted, 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 compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • L 1 , R 1 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 above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • 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 use of the above-mentioned compound, its isomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a medicine for treating IRAK4-related diseases.
  • the compounds of the present invention generally exhibit good inhibitory activity against IRAK4.
  • the compound of the present invention generally exhibits a good activity of inhibiting cell TNF- ⁇ production in THP-1 cell activity experiments, and exhibits a good anti-inflammatory effect on a collagen-induced mouse arthritis model.
  • 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. In general, 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 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.
  • 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.
  • 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 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 3-5 alkyl is used to mean a linear or branched saturated hydrocarbon group composed of 3 to 5 carbon atoms.
  • the C 3-5 alkyl group includes C 3-4 and C 5 alkyl groups, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C 3-5 alkyl groups include, but are not limited to, 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 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy 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 3 and C 2 alkoxy groups 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 structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • ACN stands for acetonitrile
  • H 2 O stands for water
  • DMSO dimethyl sulfoxide
  • MeOH stands for methanol
  • NH 4 HCO 3 stands for ammonium bicarbonate
  • LAH stands for tetrahydrolithium aluminum
  • BOC stands for tert-butyl Oxycarbonyl is an amine protecting group
  • Ms stands for methylsulfonyl, which is a protective group
  • TBS stands for tert-butyldimethylsilyl, which is a protective group
  • LDA stands for lithium diisopropylamine
  • M stands for mol/L
  • N/A stands for detection
  • 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 in SD rats induced by lipopolycollagen (LPS).
  • Figure 2 is a graph showing the changes in body weight of mice of different groups in the in vivo pharmacodynamic study of the compound of the present invention in a mouse model of human B-cell lymphoma OCI-LY10 subcutaneous xenograft tumor.
  • Figure 3 is a graph showing the relative body weight change (%) in the in vivo pharmacodynamic study of the compound of the present invention in a mouse model of human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor.
  • Figure 4 is a graph of the tumor growth curve in the in vivo pharmacodynamic study of the compound of the present invention in a mouse model of human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor.
  • Figure 5 is a graph showing the changes in body weight of mice of different groups in the study of the in vivo efficacy of the compound of the present invention in collagen-induced arthritis in mice.
  • Figure 6 shows the changes in clinical scores of different groups in the study of the efficacy of the compound of the present invention in collagen-induced arthritis in mice.
  • Figure 7 is the area under the clinical score curve of different groups in the study of the efficacy of the compound of the present invention in collagen-induced arthritis in mice.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was subjected to high pressure liquid chromatography HPLC (column: Boston Green ODS 150*30 5 ⁇ m; mobile phase: A: water containing 0.1% trifluoroacetic acid, B: acetonitrile; gradient: B%: 25%-55%, 8 minutes) Separate with supercritical liquid chromatography SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: A: ethanol with 0.1% ammonia, B: liquid carbon dioxide; gradient: B%: 50%-50%) Compound WX001 was obtained.
  • Example 2 Refer to the synthesis steps of Example 1, the difference is that the B3 (morpholine) of step 1 in Example 1 is replaced with the corresponding B fragment in fragment 1.
  • the synthesis step may undergo de-Boc, hydrolysis or hydrogenation operations. , The final synthesis of each embodiment in Table 2 below.
  • Step 1 Refer to the synthesis method of compound WX001 to synthesize WX018-1
  • Step 1 Use fragment B5 as a raw material to refer to the synthesis method of compound WX001.
  • the hydroxyl group is protected by TBSCl to obtain intermediate WX023-1.
  • each of the examples in the following table was synthesized using fragment 1 in the following table 4 as a raw material.
  • Test Example 1 Evaluation of in vitro enzyme activity
  • 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 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
  • WX001 2.2 WX002 0.4 WX003 1.2 WX004 4.6 WX005 1.3 WX006 3.8 WX007 0.9 WX008 1.5 WX010 4.6 WX013 3.6 WX014 1.7 WX015 0.7 WX016 1.2 WX017 1.3 WX018 9.8 WX019 19.4 WX020 20.5 WX021 7.1 WX023 1.3 WX025 0.5
  • the compound of the present invention generally exhibits good inhibitory activity against IRAK4.
  • 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-a Elisa kit was used to detect the content of TNF-a in cell culture supernatant samples.
  • TNF-a is produced by stimulating THP-1 cells with 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 TNF-a Elisa kit to detect the content of TNF-a. 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+(IC 50 /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 3 In vivo pharmacodynamic study of TNF-a 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-a in the plasma was detected according to the ELISA kit instructions.
  • Test Example 4 In vivo pharmacodynamic study of WX005 on human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor mouse model
  • the purpose of this experiment is to study the efficacy of WX005 test drug on human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor in CB17 SCID 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 measuring tumor volume (TV), calculating 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 weight change of human B-cell lymphoma OCI-LY10 cell subcutaneous xenograft tumor model tumor-bearing mice after administration of WX005 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 WX005 compound. Data points represent the average tumor volume within the group, and error bars represent standard errors (SEM).
  • the T/C value of the ibrutinib (10mpk) group was 39%, the TGI value was 85%, and the p value was ⁇ 0.001.
  • the T/C value of the WX005 (50mpk) group was 53%, the TGI value was 66%, and the p value was ⁇ 0.01.
  • the WX005+Ibrutinib (50+10mpk) group has a T/C value of 27%, a TGI value of 102%, and p ⁇ 0.001. Compared with the solvent control group, it has a significant anti-tumor effect and is significantly better than 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.
  • the purpose of this experiment is to investigate the therapeutic effect of compound WX005 on collagen-induced arthritis in mice.
  • LPS Sigma; Item No.: L2630;
  • Acetic acid Sigma (St. Louis, MO, USA), article number: A8976;
  • Bovine Type II Collagen Sichuan University; Catalog Number: 20181016;
  • mice 39 were randomly selected as the normal control group, and the other 34 were immunized. The day of the first immunization was recorded as day 0.
  • DBA/1 mice were anesthetized with isoflurane, and then injected 50 microliters of the prepared collagen emulsion (containing 200 micrograms of CII) subcutaneously (2-3 cm from the base of the tail) to sensitize them. On day 23, 100 microliters of 0.3 mg/mL LPS solution (containing 30 micrograms of LPS) was injected intraperitoneally. Mice in the normal group do not need to be immunized.
  • mice with a clinical score of 0 to 1 were selected, and re-randomized into 3 treatment groups according to body weight and score, with 8 mice in each group.
  • the first group (normal group) were normal mice without any treatment; the second group (vehicle control group) was given vehicle; the third group (WX005 group) was given WX005 at a dose of 100 mg/kg, twice a day, It lasted 14 days in total.
  • the volume of intragastric administration was 10 mL/kg (Table 7).
  • NA no administration

Abstract

一类IRAK4抑制剂，及其在制备治疗与IRAK4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抑制剂的咪唑并吡啶类化合物
本申请主张如下优先权：
CN201910562164.6，申请日2019.06.26；
CN201910619604.7，申请日2019.07.10；
CN201911240851.2，申请日2019.12.06；
CN202010466005.9，申请日2020.05.28。
技术领域
本发明涉及一类IRAK4抑制剂，及其在制备治疗与IRAK4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-kB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，吸引了广泛的研发兴趣。
IRAK4介导的TLR/IL-1R通路的异常激活已经被证实与一些疾病的发展与进程密切相关，如动脉粥样硬化、类风湿性关节炎、***性红斑狼疮、脓毒血症、炎症性肠炎、哮喘、代谢综合症等。相关文献表明：在LPS或者CpG诱导的PMBC或者THP细胞中，IRAK4抑制剂可以有效阻断促炎症细胞因子肿瘤坏死因子TNF-alpha的产生；在胶原蛋白诱导的小鼠关节炎模型中，IRAK4抑制剂可以有效阻断TNF-alpha的产生，有效抑制小鼠关节肿胀；在小鼠OCI-ly10移植瘤模型中，IRAK4抑制剂可以有效阻断MyD88-L265P异常导致的信号通路激活，从而与BTK抑制剂、PI3K抑制剂等联用，显著增强这些抑制剂在弥漫性大B细胞淋巴瘤DLBCL中的药效，促进肿瘤细胞的凋亡。因此，IRAK4抑制剂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，是一个重要的靶点，开发IRAK4抑制剂具有显著的临床价值。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，目前已经开展免疫类疾病的临床。
Figure PCTCN2020098259-appb-000001
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 PCTCN2020098259-appb-000002
其中，
R 1为C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2选自C 1-6烷基、C 1-6烷氧基、环丙基、氮杂环丁基、
Figure PCTCN2020098259-appb-000003
所述C 1-6烷基、C 1-6烷氧基、环丙基、氮杂环丁基、
Figure PCTCN2020098259-appb-000004
任选被1、2或3个R b取代；
R 3为C 1-6烷基，所述C 1-6烷基任选被1、2或3个R c取代；
T 1选自CH 2、NH和O；
T 2选自CH 2、NH和O；
R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
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、-C(＝O)-C 1-3烷氧基、-C(＝O)NH 2和-COOH，所述CH 3、-C(＝O)-C 1-3烷基和-C(＝O)-C 1-3烷氧基任选被1、2或3个R取代；
R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、COOH和-S(＝O) 2-C 1-3烷基；
R分别独立地选自H、OH和NH 2。
在本发明的一些方案中，所述R 1为CF 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分别独立地选自H、F、Cl、OH、NH 2、CN、CH 3、CH 2OH、CH 2NH 2、
Figure PCTCN2020098259-appb-000005
和-COOH，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 1-3烷基、C 1-3烷氧基、
Figure PCTCN2020098259-appb-000006
Figure PCTCN2020098259-appb-000007
所述C 1-3烷基、C 1-3烷氧基、
Figure PCTCN2020098259-appb-000008
Figure PCTCN2020098259-appb-000009
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 PCTCN2020098259-appb-000010
Figure PCTCN2020098259-appb-000011
Figure PCTCN2020098259-appb-000012
其他变量如本发明所定义。
在本发明的一些方案中，所述R c分别独立地选自H、F、Cl、OH、NH 2、COOH和-S(＝O) 2CH 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 3选自
Figure PCTCN2020098259-appb-000013
其他变量如本发明所定义。
在本发明的一些方案中，所述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020098259-appb-000014
Figure PCTCN2020098259-appb-000015
其中，R 3、R b、T 1和T 2如本发明所定义；
m选自1、2和3。
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020098259-appb-000016
其中，
R 1为C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2选自C 3-8环烷基、3～8元杂环烷基、C 1-6烷基和C 1-6烷氧基，所述C 3～8环烷基、3～8元杂环烷基、C 1-6烷基和C 1-6烷氧基任选被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H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
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、-C(＝O)-C 1-3烷氧基和-COOH；
R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
所述3～8元杂环烷基之“杂”分别独立地选自：N、O、NH，上述杂原子或杂原子团的数目分别独立地选自1、2和3。
在本发明的一些方案中，所述R 1为CF 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 PCTCN2020098259-appb-000017
和-COOH，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选自哌啶基、哌嗪基、四氢吡咯基、四氢吡喃基、环丙基、C 1-3烷基和C 2-4烷氧基，所述哌啶基、哌嗪基、四氢吡咯基、四氢吡喃基、环丙基、C 1-3烷基和C 2-4烷氧基任选被 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 PCTCN2020098259-appb-000018
Figure PCTCN2020098259-appb-000019
Figure PCTCN2020098259-appb-000020
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 PCTCN2020098259-appb-000021
其他变量如本发明所定义。
在本发明的一些方案中，所述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020098259-appb-000022
其中，L 1、R 1和R b如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
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 PCTCN2020098259-appb-000023
Figure PCTCN2020098259-appb-000024
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 PCTCN2020098259-appb-000025
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相关疾病的药物中的应用。
技术效果
本发明化合物对IRAK4普遍展现出较好的抑制活性。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，在胶原诱导的小鼠关节炎模型上的展现很好的抗炎效果。
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 PCTCN2020098259-appb-000026
和楔形虚线键
Figure PCTCN2020098259-appb-000027
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020098259-appb-000028
和直形虚线键
Figure PCTCN2020098259-appb-000029
表示立体中心的相对构型，用波浪线
Figure PCTCN2020098259-appb-000030
表示楔形实线键
Figure PCTCN2020098259-appb-000031
或楔形虚线键
Figure PCTCN2020098259-appb-000032
或用波浪线
Figure PCTCN2020098259-appb-000033
表示直形实线键
Figure PCTCN2020098259-appb-000034
和直形虚线键
Figure PCTCN2020098259-appb-000035
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 PCTCN2020098259-appb-000036
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 PCTCN2020098259-appb-000037
Figure PCTCN2020098259-appb-000038
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。“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。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
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 PCTCN2020098259-appb-000039
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 PCTCN2020098259-appb-000040
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 PCTCN2020098259-appb-000041
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 PCTCN2020098259-appb-000042
直形虚线键
Figure PCTCN2020098259-appb-000043
或波浪线
Figure PCTCN2020098259-appb-000044
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 PCTCN2020098259-appb-000045
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 PCTCN2020098259-appb-000046
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 PCTCN2020098259-appb-000047
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 PCTCN2020098259-appb-000048
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2020098259-appb-000049
仍包括
Figure PCTCN2020098259-appb-000050
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 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 3-5烷基”用于表示直链或支链的由3至5个碳原子组成的饱和碳氢基团。所述C 3-5烷基包括C 3-4和C 5烷基等；其可以是一价、二价或者多价。C 3-5烷基的实例包括但不限于丙基(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 1-6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6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6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)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
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 3和C 2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。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2020098259-appb-000051
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
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：ACN代表乙腈；H 2O代表水；DMSO代 表二甲亚砜；MeOH代表甲醇；NH 4HCO 3代表碳酸氢铵；LAH代表四氢锂铝；BOC代表叔丁氧羰基是一种胺保护基团；Ms代表甲磺酰基，是一种保护基团；TBS代表叔丁基二甲基硅烷基，是一种保护基团；LDA代表二异丙基胺基锂；M代表mol/L；N/A代表为检测；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 PCTCN2020098259-appb-000052
软件命名，市售化合物采用供应商目录名称。
附图说明
图1为脂多胶原(LPS)诱导的SD大鼠血浆TNF-α浓度图。
图2为本发明化合物在人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中不同组别的老鼠体重变化曲线图。
图3为本发明化合物在人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中相对体重变化(％)曲线图。
图4为本发明化合物在人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中肿瘤生长曲线图。
图5为本发明化合物在胶原诱导的小鼠关节炎体内药效研究中不同组别的老鼠体重变化曲线图。
图6为本发明化合物在胶原诱导的小鼠关节炎体内药效研究中不同组别的临床评分变化。
图7为本发明化合物在胶原诱导的小鼠关节炎体内药效研究中不同组别的临床评分曲线下面积。
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。
中间体A1
Figure PCTCN2020098259-appb-000053
合成路线：
Figure PCTCN2020098259-appb-000054
步骤1：化合物A1的合成
将琥珀酸单乙酯酰氯(50g)加到乙腈(500mL)中，并搅拌均匀。将三甲基硅重氮甲烷(2M,227.84mL)滴加到上述混合物中，并在25℃搅拌0.5小时。将反应体系冷却到0℃后，将氢溴酸醋酸溶液(93.10g,33％含量)滴加到反应体系中，恢复至25℃并搅拌0.5小时。停止反应，减压浓缩掉乙腈，将剩余液体倒入500mL乙酸乙酯中，用饱和碳酸氢钠洗涤三次，每次100mL。分出有机相，加适量无水硫酸钠干燥。过滤除去干 燥剂，滤液减压浓缩得到粗产品。粗产品经过柱纯化(石油醚～石油醚:乙酸乙酯＝10:1)得到中间体A1。如下表1中的各个中间体均为商业市售试剂。
表1
Figure PCTCN2020098259-appb-000055
Figure PCTCN2020098259-appb-000056
实施例1：化合物WX001的合成
Figure PCTCN2020098259-appb-000057
合成路线：
Figure PCTCN2020098259-appb-000058
步骤1：化合物WX001-1的合成
将4-氯-5-硝基-吡啶-2-胺(0.2g)加入B3(1.0g)中，所得混合物在14℃下搅拌16小时。将反应液减压浓缩至干，向残余物中加入10mL的乙酸乙酯，继续搅拌10分钟。过滤除去不溶物，滤液减压浓缩得到WX001-1。LCMS(ESI)m/z:＝225.8[M+H] +， 1H NMR(400MHz,CD 3OD)δ＝8.55(s,1H),5.97(s,1H),3.85-3.80(m,4H),3.12-3.06(m,4H)。
步骤2：化合物WX001-2的合成
将化合物WX001-1(0.1g)加到中间体A1(129.33mg)中，所得混合物在100℃下搅拌16小时。反应液冷却至室温后，向反应液中加入10mL的乙酸乙酯和5mL的饱和碳酸氢钠水溶液，搅拌使其完全溶解。静置分出有机相，水相用乙酸乙酯萃取两次，每次10mL。合并有机相，用适量无水硫酸钠干燥。过滤除去干燥剂，滤液减压浓缩得到粗品。粗品经过柱纯化(洗脱剂：甲醇/乙酸乙酯＝0-10％)得到化合物WX001-2。LCMS(ESI)m/z:＝349.1[M+H] +， 1H NMR(400MHz,MeOD-d 4)δ＝9.27(s,1H),7.63(s,1H),6.98(s,1H),4.14(q,J＝6.8Hz,2H),3.87-3.83(m,4H),3.20-3.07(m,4H),2.75-2.60(m,2H),2.35-2.20(m,2H),1.27-1.22(m,3H).
步骤3：化合物WX001-3的合成
将化合物WX001-2(0.82g)溶解在乙醇(10mL)中，在氩气保护下加入雷尼镍(605.02mg)。置换三次氩气后，再置换三次氢气，最后在氢气50Psi，温度50℃下搅拌16小时。反应液冷却至室温后，垫硅藻土过滤除去催化剂，滤液减压浓缩得到化合物WX001-3。LCMS(ESI)m/z:＝319.0[M+H] +， 1H NMR(400MHz,DMSO-d 6)δ＝7.68(s,1H),7.35(s,1H),6.82(s,1H),4.51(s,2H),4.06(q,J＝8.0Hz,2H),3.80-3.76(m,4H),2.91-2.75(m,6H),2.68-2.63(m,2H),1.18(t,J＝7.0Hz,3H).
步骤4：化合物WX001-4的合成
将化合物WX001-3(0.05g)溶解在无水二氯甲烷(5mL)中，然后加入6-(三氟甲基)吡啶-2-羧酸(36.02mg,)，O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(89.57mg)，N,N-二异丙基乙基胺(40.59mg)，所得反应液在10℃下搅拌3小时。将反应液用10mL的二氯甲烷稀释，然后用水洗涤三次，每次10mL。合并有机相，用饱和食盐水10mL洗涤。有机相用适量无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩得到化合物WX001-4。LCMS(ESI)m/z:＝492.1[M+H] +。
步骤5：化合物WX001的合成
将化合物WX001-4(48.42mg)溶解在无水四氢呋喃(5mL)中，在10℃下加入甲基溴化镁***溶液(3M,164.22微升)，并在10℃下搅拌10分钟。向反应液中加入2mL的饱和氯化铵水溶液和5mL水淬灭反应。分出四氢呋喃层，水相用乙酸乙酯萃取三次，每次10mL。合并有机相，用适量无水硫酸钠干燥。过滤除去干燥剂，滤液减压浓缩得到粗品。粗品经过高压液相色谱HPLC(柱子：Boston Green ODS 150*30 5μm；流动相：A:含0.1％三氟醋酸的水,B:乙腈；梯度：B％:25％-55％，8分钟)和超临界液相色谱SFC(柱子：DAICEL CHIRALPAK IC(250mm*30mm,10um)；流动相：A:含0.1％氨水的乙醇，B:液态二氧化碳；梯度：B％:50％-50％)分离得到化合物WX001。LCMS(ESI)m/z＝478.1[M+H] +， 1H NMR(400MHz,DMSO-d 6)δ＝10.81(br s,1H),9.71(s,1H),8.62-8.52(m,2H),8.45(d,J＝6.8Hz,1H),7.95(s,1H),7.52(s,1H),4.62(s,1H),4.13-3.94(m,4H),3.20-3.02(m,4H),2.90-2.98(m,2H),2.01-1.90(m,2H),1.34(s,6H).
实施例2：化合物WX002的合成
Figure PCTCN2020098259-appb-000059
合成路线：
Figure PCTCN2020098259-appb-000060
步骤1：化合物WX002-1的合成
将2-丁酮(510mL)和2-氨基-4-氯-5-硝基吡啶(30g)搅拌均匀，然后将碘化钠(77.73g)和氢碘酸(29.14g)加入反应体系中，将温度升至84℃反应24小时。反应液冷却至室温后，减压浓缩至约250mL，向其中加入500mL水，并搅拌15分钟。反应液过滤得到粗产品。将6g硫代硫酸钠溶于120mL水后，加入上述粗产品，并搅拌30分钟。过滤，滤饼用水淋洗3次，每次60mL。滤饼干燥后得到化合物WX002-1。LCMS(ESI)m/z＝265.9[M+H] +.
步骤2：化合物WX002-2的合成
将化合物WX002-1(25g)加到中间体A1(29.46g)中，所得混合物在100℃下搅拌12小时。反应液冷却至室温后，向反应体系中加入适量甲醇，搅拌使其完全溶解。将上述甲醇溶液减压浓缩至干，得到棕色粘稠固体。将上述棕色粘稠固体与50mL乙酸乙酯混合搅拌30分钟。过滤，将滤饼与50mL乙酸乙酯混合搅拌30分钟。再次过滤，滤饼干燥后得到化合物WX002-2。LCMS(ESI)m/z＝390.0[M+H] +。
步骤3：化合物WX002-3的合成
将化合物WX002-2(6g)加到乙醇(100mL)中并搅拌均匀。将氯化铵的水溶液(4M,30.00mL)和铁粉(2.15g)加入反应体系中，将温度升至90℃搅拌反应1小时。趁热过滤，滤饼用甲醇充分洗涤3次，每次50mL。合并滤液，减压浓缩得到粗产品。粗产品经过柱纯化(二氯甲烷:甲醇＝100:0～70:30)得到化合物WX002-3。LCMS(ESI)m/z＝360.0[M+H] +。
步骤4：化合物WX002-4的合成
将化合物WX002-3(1.4g)加入N,N-二甲基甲酰胺(14mL)中，并搅拌均匀。然后加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(2.22g)，6-三氟甲基吡啶-2-羧酸(819.42mg)和N,N-二异丙基乙胺(1.51g)，所得反应液在室温15℃反应2小时。反应液过滤，滤饼用N,N-二甲基甲酰胺(2mL)充分洗涤， 干燥后得到化合物WX002-4。LCMS(ESI)m/z＝533.1[M+H] +。
步骤5：化合物WX002-5的合成
将化合物WX002-4(500mg)加入甲醇(20mL)中，然后依次加入2-二环己基磷-2,4,6-三异丙基联苯(463.80mg)，醋酸钯(42.18mg)和三乙胺(285.17mg)。所得反应液在一氧化碳50Psi，温度80℃下反应13小时。将反应液体冷却至室温，在硅藻土上过滤，滤饼用甲醇洗涤2次，每次10mL。合并滤液，滤液减压浓缩至干，得到粗产品WX002-5，未继续纯化。
步骤6：化合物WX002的合成
将粗产品WX002-5(250mg)溶于无水四氢呋喃(2.5mL)中，降温至0℃后，缓慢滴加甲基溴化镁***溶液(3M,1.44mL)并搅拌2小时。向反应液中加入1M的稀盐酸2mL淬灭反应。分出有机相，水相用乙酸乙酯萃取三次，每次2mL。合并有机相，用饱和食盐水3mL洗涤，再用无水硫酸钠干燥。过滤除去干燥剂，滤液减压浓缩得粗品。粗品经过高压液相色谱HPLC(柱子：Welch Xtimate C18 150*25mm*5μm；流动相：A:含10mM NH 4HCO 3的水，B:甲醇；梯度：B％:52％-72％,10.5分钟)分离，得到化合物WX002。LCMS(ESI)m/z＝451.3[M+H] +，1H NMR(400MHz,CDCl 3)δ＝12.18(s,1H),9.56(s,1H),8.46-8.51(m,1H),8.13(t,J＝7.84,1H),7.87(d,J＝8.0,1H),7.45(s,1H),7.35(s,1H),3.92(s,1H),2.87-2.98(m,2H),2.64(s,1H),1.96(t,J＝7.60,2H),1.75(s,6H),1.33(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B3(***啉)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、水解或氢化等操作，最终合成如下表2中各实施例。
表2
Figure PCTCN2020098259-appb-000061
Figure PCTCN2020098259-appb-000062
Figure PCTCN2020098259-appb-000063
Figure PCTCN2020098259-appb-000064
实施例18：化合物WX018的合成
Figure PCTCN2020098259-appb-000065
合成路线：
Figure PCTCN2020098259-appb-000066
步骤1：参考化合物WX001的合成方法合成WX018-1
步骤2：化合物WX018的合成
将化合物WX018-1(550mg)加入四氢呋喃(10.0mL)和水(10.0mL)的混合溶液中，再加入氢氧化钠(254.06mg)，所得混合液在30℃下搅拌16小时。减压浓缩除去四氢呋喃，边搅拌边滴加1M的稀盐酸，使溶液pH＝3左右，有固体析出。过滤，收集滤饼。将滤饼送高效液相色谱HPLC机分纯化[柱子:YMC Triart C18 150*25mm*5um；mobile phase:[H 2O(10mM NH 4HCO 3)-ACN]；B％梯度:21％-51％,9.5分钟]，冻干后得到化合物WX018。
1H NMR(400MHz,DMSO-d 6)δ＝10.59(s,1H),9.49(s,1H),8.54-8.34(m,2H),8.23(d,J＝7.8Hz,1H),7.73(s,1H),7.23(s,1H),4.40(br s,1H),3.03(br t,J＝10.8Hz,2H),2.92-2.76(m,5H),2.63(brt,J＝7.6Hz,2H),1.90-1.75(m,2H),1.65(brd,J＝12.4Hz,2H),1.23(s,3H)。
LCMS(ESI)m/z＝492.1[M+H] +
参考实施例1和实施例18的合成步骤，以下表中片段1中相应的B片段为原料合成如下表3的各实施例。
表3
Figure PCTCN2020098259-appb-000067
Figure PCTCN2020098259-appb-000068
实施例23：化合物WX023的合成
Figure PCTCN2020098259-appb-000069
合成路线：
Figure PCTCN2020098259-appb-000070
步骤1：以片段B5为原料参考化合物WX001的合成方法，合成步骤经过TBSCl保护羟基得到中间体WX023-1。
步骤2：化合物WX023-2的合成
将四氢呋喃(30.0mL)加入四氢锂铝(106.5mg)中，在氮气保护下，冷却至0℃.再将化合物WX023-1(1.7g)溶于四氢呋喃(30.0mL)的混合液慢慢滴入。所得混合液在-20℃～0℃下搅拌1小时。在0℃下，将反应液边搅拌边缓慢倒入50.0mL的饱和氯化铵水溶液中淬灭。分液，水相用二氯甲烷萃取(100mL×2)。合并有机相，干燥，过滤并减压浓缩。得到化合物WX023-2。
步骤3：化合物WX023-3的合成
将三氯甲烷(15.0mL)加入化合物WX023-2(1.2g)中，再加入三乙胺(646.2mg)所得混合液在氮气保护，0℃下搅拌10分钟。然后滴入甲烷磺酰氯(1.2g)溶于三氯甲烷(15.0mL)的混合溶液。自然升温至25℃，继续搅拌20分钟。尾气用用饱和碳酸氢钠水溶液吸收。原料反应完全，低温浓缩后，得到化合物WX023-3。
步骤4：化合物WX023的合成
向化合物WX023-3(1.0g)中加入N,N二-甲基甲酰胺(5.0mL)，再加入化合物甲基亚磺酸钠(286.3mg)和碘化钾(776.0mg)，所得混合液在80℃微波反应1小时，将四批同样规格的反应液合并。加入乙腈20mL 后减压抽滤，滤液减压浓缩。粗品经过柱分离纯化[甲醇＝0～40％,二氯甲烷:甲醇]得到化合物WX023。
1H NMR(400MHz,DMSO-d 6)δ＝10.55(s,1H),9.59(s,1H),8.55-8.38(m,2H),8.25(d,J＝7.6Hz,1H),7.94(s,1H),7.33(s,1H),4.79(br s,1H),4.85-4.67(m,1H),3.76(br s,1H),3.57-3.46(m,2H),3.21-3.07(m,5H),3.03(s,3H),1.98-1.89(m,2H),1.80-1.64(m,2H).
LCMS(ESI)m/z＝512.1[M+H] +
参考实施例1和实施例23的合成步骤，以如下表4中片段1为原料合成下表中的各实施例。
表4
Figure PCTCN2020098259-appb-000071
试验例1：体外酶活性评价
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5所示。
表5：本发明化合物体外激酶活性筛选试验结果
化合物 IRAK4/IC 50(nM)
WX001 2.2
WX002 0.4
WX003 1.2
WX004 4.6
WX005 1.3
WX006 3.8
WX007 0.9
WX008 1.5
WX010 4.6
WX013 3.6
WX014 1.7
WX015 0.7
WX016 1.2
WX017 1.3
WX018 9.8
WX019 19.4
WX020 20.5
WX021 7.1
WX023 1.3
WX025 0.5
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：体外细胞活性评价
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-a Elisa试剂盒检测细胞培养上清样品中TNF-a的含量。TNF-a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-a Elisa试剂盒可以检测TNF-a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+(IC 50/X)^HillSlope)。
测试结果汇总如表6所示。
表6：本发明化合物体外筛选试验结果
化合物 THP-1/IC 50(nM)
WX002 54
WX005 114
WX015 201
WX016 181
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3：脂多胶原(LPS)诱导的SD大鼠TNF-a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***(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-a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-a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-a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-a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WX005后对脂多胶原(LPS)诱导的TNF-a分泌展现了显著的抑制作用。剂量从3mpk到10mpk再到30mpk时，WX005显示出明显的量效关系，同时本实验中WX005在30mpk剂量下的药效等同于0.5mpk剂量下***(DEX)的药效。
试验例4：WX005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WX005受试药对人B细胞淋巴瘤OCI-LY10细胞皮下异种移植瘤在CB17 SCID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。
WX005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CB17 SCID小鼠模型的体重影响图2和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WX005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WX005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WX005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如图4所示。
开始给药后18天，伊鲁替尼(10mpk)组T/C值为39％，TGI值为85％，p值<0.001。WX005(50mpk)组T/C值为53％，TGI值为66％，p值<0.01。WX005+伊鲁替尼(50+10mpk)组T/C值为27％,TGI值为102％,p<0.001，与溶剂对照组相比具有显著的抑瘤作用，且显著优于伊鲁替尼(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抑制剂WX005(50mpk)单药展现一定抑瘤效果(TGI＝66％)，动物耐受性良好；BTK抑制剂伊鲁替尼(10mpk)单药也展现一定抑瘤效果的药效(TGI＝85％)；WX005(50mpk)与伊鲁替尼(10mpk)联用时，显著增加了伊鲁替尼(10mpk)单药的抑瘤效果，TGI达到102％，展现了BCR通路和MyD88通路双重抑制的协同效应，并且动物耐受性良好。
试验例5：胶原诱导的小鼠关节炎体内药效研究
1.实验目的
本次实验目的是考察化合物WX005在胶原诱导的小鼠关节炎模型上的治疗效果。
2.实验材料
动物：6-8周雄性DBA/1小鼠；供应商：维通利华。
3.实验试剂
LPS：Sigma；货号：L2630；
乙酸：Sigma(St.Louis,MO,USA)，货号：A8976；
完全弗氏佐剂：Sigma，货号：F5881；
牛二型胶原：四川大学；货号：20181016；
溶媒：5％DMSO+10％SOLUTOL+85％H 2O。
4.实验仪器
麻醉机：瑞曼仪器，iR3TM HSIV-u
高速匀浆机：IKA，T10 basic,37140,827825
5.实验过程
实验分组：39只DBA/1小鼠，随机挑出5只作为正常对照组，另外34只进行免疫。第一次免疫当天记为第0天。建模时，DBA/1小鼠经异氟烷麻醉后，在尾部皮下(距尾根部2-3厘米)注射50微升的制备好的胶原乳剂(包含200微克CII)致敏。第23天，腹腔注射100微升0.3mg/mL的LPS溶液(含有30微克LPS)。正常组的小鼠无需免疫。
第26天，当平均临床评分达到0.8分左右时，挑选临床评分为0～1分小鼠24只，按照体重和评分，重新随机分组到3个治疗组，每组8只小鼠。
第一组(正常组)为正常小鼠，不做任何处理；第二组(溶媒对照组)给予溶媒；第三组(WX005组)给予WX005，剂量为100mg/kg，每天给药2次，共持续14天。灌胃给药体积为10mL/kg(表7)。
表7：实验分组情况
分组 动物数 给药化合物 给药方式 剂量及频率
正常组 5 NA NA NA
溶媒对照组 8 NA 灌胃 每天1次
WX005组 8 WX005 灌胃 100mpk,每天2次
注：NA代表不给药。
临床观察：从免疫前7天至免疫后第23天，每日观察DBA/1小鼠的基本健康状况及体重变化(一周记录一次)。第23天之后，每日观察小鼠健康状况，发病情况，及体重变化(一周至少记录三次)，直至实验结束。根据病变的不同程度(红肿，关节变形)按照0-4分的标准进行评分，每个肢体的最高评分为4分，每只动物最高评分为16分。评分标准如表8。
表8：关节炎临床评分标准
分值 临床症状
0 无红斑和红肿
1 近跗骨附近或踝关节或跖骨出现红斑或轻度红肿，1个脚趾红肿
2 踝关节和跖骨轻微红斑和肿胀，或超过两个脚趾红肿
3 踝、腕关节和跖骨中度红斑和肿胀
4 踝、腕关节，跖骨和脚趾全部严重红肿
6.实验结果及讨论
如图5数据显示，正常组小鼠的体重未见明显增长，溶媒对照组和WX005组小鼠的体重稳定增长。从如图6和图7中，溶媒对照组和WX005组小鼠临床评分结果汇总可以看出，WX005组能体现很好的药效。

Claims (11)

  1. 式(II)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020098259-appb-100001
    其中，
    R 1为C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
    R 2选自C 1-6烷基、C 1-6烷氧基、环丙基、氮杂环丁基、
    Figure PCTCN2020098259-appb-100002
    所述C 1-6烷基、C 1-6烷氧基、环丙基、氮杂环丁基、
    Figure PCTCN2020098259-appb-100003
    任选被1、2或3个R b取代；
    R 3为C 1-6烷基，所述C 1-6烷基任选被1、2或3个R c取代；
    T 1选自CH 2、NH和O；
    T 2选自CH 2、NH和O；
    R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
    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、-C(＝O)-C 1-3烷氧基、-C(＝O)NH 2和-COOH，所述CH 3、-C(＝O)-C 1-3烷基和-C(＝O)-C 1-3烷氧基任选被1、2或3个R取代；
    R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、COOH和-S(＝O) 2-C 1-3烷基；
    R分别独立地选自H、OH和NH 2。
  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为CF 3。
  3. 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 b分别独立地选自H、F、Cl、OH、NH 2、CN、CH 3、CH 2OH、CH 2NH 2、
    Figure PCTCN2020098259-appb-100004
    和-COOH。
  4. 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 2选自C 1-3烷基、C 1-3烷氧基、
    Figure PCTCN2020098259-appb-100005
    所述C 1-3烷基、C 1-3烷氧基、
    Figure PCTCN2020098259-appb-100006
    任选被1、2或3个R b取代。
  5. 根据权利要求3或4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 PCTCN2020098259-appb-100007
    Figure PCTCN2020098259-appb-100008
  6. 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 c分别独立地选自H、F、Cl、OH、NH 2、COOH和-S(＝O) 2CH 3。
  7. 根据权利要求1或6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 PCTCN2020098259-appb-100009
    Figure PCTCN2020098259-appb-100010
  8. 根据权利要求1～7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 PCTCN2020098259-appb-100011
    其中，R 3如权利要求1或7所定义；
    R b如权利要求1或3所定义；
    T 1和T 2如权利要求1所定义；
    m选自1、2和3。
  9. 下列所示化合物、其异构体或其药学上可接受的盐
    Figure PCTCN2020098259-appb-100012
    Figure PCTCN2020098259-appb-100013
  10. 一种药物组合物，包括治疗有效量的根据权利要求1～9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。
  11. 根据权利要求1～9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10所述的药物组合物在制备治疗与IRAK4相关疾病的药物中的应用。
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WO2023283372A1 (en) * 2021-07-07 2023-01-12 Biogen Ma Inc. Compounds for targeting degradation of irak4 proteins
WO2023098857A1 (zh) * 2021-12-03 2023-06-08 武汉人福创新药物研发中心有限公司 Irak4抑制剂及其用途

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