WO2022083687A1 - Composés hétérocycliques de sélénium et leur application - Google Patents

Composés hétérocycliques de sélénium et leur application Download PDF

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WO2022083687A1
WO2022083687A1 PCT/CN2021/125264 CN2021125264W WO2022083687A1 WO 2022083687 A1 WO2022083687 A1 WO 2022083687A1 CN 2021125264 W CN2021125264 W CN 2021125264W WO 2022083687 A1 WO2022083687 A1 WO 2022083687A1
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compound
added
μmol
mmol
ethyl acetate
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PCT/CN2021/125264
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English (en)
Chinese (zh)
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毛魏魏
钱文远
韦昌青
余柱
胡国平
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 CN202180071258.9A priority Critical patent/CN116390922A/zh
Publication of WO2022083687A1 publication Critical patent/WO2022083687A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
    • 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
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • 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
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to selenium heterocyclic compounds and applications thereof. Specifically, it relates to compounds represented by formula (II) and pharmaceutically acceptable salts thereof.
  • IBD Inflammatory bowel disease
  • CD Crohn's disease
  • UC ulcerative colitis
  • Common symptoms include diarrhea, bloody stools, and abdominal pain.
  • the clinical course is intermittent, alternating cycles of exacerbations and remissions, and patients with ulcerative colitis have an increased risk of colorectal cancer (Dennis et al. N Engl J Med, 2011, 365, 1713-1725).
  • Excessive inflammatory responses in the gastrointestinal tract are mediated by inflammatory cytokines such as TNF ⁇ , IFN- ⁇ , IL-1, IL-6, IL-12, IL-21 and IL-23, and are Cells of the adaptive immune system act, including on T and B lymphocytes, epithelial cells, macrophages and dendritic cells (Neurath, M.F. Nat. Rev. Immunol. 2014, 14, 329).
  • the Janus kinase (JAK) family: JAK1, JAK2, JAK3, and Tyk2 are non-receptor tyrosine kinases that play key roles in the transduction of many of the above-mentioned cytokines.
  • cytokines When cytokines bind to receptors, the associated JAK homo- or heterodimers are phosphorylated and activated, allowing subsequent recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT) family transcription factors .
  • Phosphorylated STATs pSTATs are transported to the nucleus and induce gene transcription of several chemokines, cytokines and proteases associated with the pathogenesis of IBD.
  • Tovatinib is also in clinical development for CD, and further trials for this indication were discontinued due to the failure of patients with moderate to severe CD to achieve significant efficacy in a 4-week phase II clinical trial, despite biomarker-based There is conclusive evidence for the involvement of the target of the biological analysis, but it is unclear whether the efficacy of tovatinib is related to clinical study design, mechanistic differences between UC and CD, or dose-limiting systemic dose-limiting that prevents adequate exposure of the drug to intestinal tissue adverse events (AEs).
  • AEs intestinal tissue adverse events
  • AEs Common systemic adverse events (AEs) in Phase 2 and 3 clinical trials of tovatinib in IBD included decreased hemoglobin, decreased absolute neutrophil count (ANC), increased total cholesterol (low-density and high-density lipids), and Infection (Sandborn, W.J. et al., N. Engl. J. Med. 2012, 367, 616).
  • ANC absolute neutrophil count
  • TPO JAK2-dependent inhibition of EPO
  • JAK1-selective inhibitors such as filgotinib and Upadacitinib
  • filgotinib and Upadacitinib are currently being used in Phase 3 clinical trials in CD and UC.
  • the recently approved 15 mg twice-daily dose of upadacitinib for rheumatoid arthritis also has a boxed warning from the FDA about the risk of thrombosis (Upadacitinib Instructions for Use) ).
  • Another approach is to maximize intestinal tissue exposure to JAK inhibitors while avoiding possible systemic exposure.
  • JAK inhibitors may have adverse systemic immunosuppressive effects due to the regulatory effects of the JAK/STAT pathway on the immune system. There is thus a need to provide new JAK inhibitors that have their effects at the focal site without significant systemic effects. Specifically, it has advantages for the treatment of gastrointestinal inflammatory diseases such as UC and CD.
  • the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • T 1 is N or CH
  • T 2 is N or CH
  • T3 is N or CH
  • R 1 is H, CN, C 1-3 alkyl, -NH-C 1-3 alkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the C 1-3 alkyl , -NH-C 1-3 alkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, each independently optionally substituted with 1, 2 or 3 R a ;
  • R2 is R21 or
  • D 1 is O, NH or CH 2 ;
  • D 2 is CH or N
  • E 1 and E 2 are each independently a single bond or CH 2 ;
  • R 3 is H or C 1-3 alkyl
  • R 4 is H or C 1-3 alkyl
  • q 1 or 2;
  • n 0, 1 or 2;
  • n 1 or 2;
  • Ra and Rb are each independently F, Cl, Br, I, OH, NH2 , CN or COOH;
  • Said "4-6-membered heterocycloalkyl” and "5-6-membered heteroaryl” each independently contain 1, 2 or 3 independently -O-, -NH-, -S-, -Se- or A heteroatom or heteroatom group of N.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is N or CH
  • T 2 is N or CH
  • R 1 is H, CN, C 1-3 alkyl, -NH-C 1-3 alkyl or 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, -NH-C 1-3 Alkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R a ;
  • R2 is R21 or
  • D 1 is O or CH 2 ;
  • R 21 is H, C 1-3 alkyl, -NH-C 1-3 alkyl or -N(C 1-3 alkyl) 2 , wherein the C 1-3 alkyl, -NH-C 1- 3 alkyl and -N(C 1-3 alkyl) 2 are optionally substituted by 1, 2 or 3 R b ;
  • R 3 is H or C 1-3 alkyl
  • q 1 or 2;
  • n 0, 1 or 2;
  • Ra and Rb are each independently F, Cl, Br, I, OH, NH2 , CN or COOH.
  • the "4-6 membered heterocycloalkyl” contains 1, 2 or 3 heteroatoms or heteroatomic groups that are independently -O-, -NH-, -S-, -Se- or N.
  • R 1 is H, CN, CH 3 , -NH-CH 3 , wherein the CH 3 , -NH-CH 3 , Each independently is optionally substituted with 1, 2 or 3 R a , R a and other variables as defined herein.
  • R 1 is H, CN, CH 3 , -NH-CH 3 or wherein the CH 3 , -NH-CH 3 and Optionally substituted with 1, 2 or 3 Ra , Ra and other variables as defined herein.
  • R 1 is H, CN, CF 3 , -NH-CH 3 , Other variables are as defined in the present invention.
  • R 1 is H, CN, CF 3 , -NH-CH 3 or Other variables are as defined in the present invention.
  • R 21 is H, CN, NH 2 , CH 3 , wherein the CH 3 , Each independently is optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
  • R 21 is H, CN, NH 2 , CH 3 ,
  • R 2 is H, CN, NH 2 , CH 3 ,
  • R 2 is H, CH 3 , the CH 3 , Optionally substituted with 1, 2 or 3 R b , other variables are as defined in the present invention.
  • R 2 is H, CH 3 , Other variables are as defined in the present invention.
  • R 3 is H or CH 3 , and other variables are as defined in the present invention.
  • R 4 is H or CH 3 , and other variables are as defined in the present invention.
  • R 1 , R 2 , R 3 , L 1 , T 3 , T 2 and q are as defined in the present invention.
  • R 1 , R 2 , R 3 , L 1 , T 2 and q are as defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention provides the application of the above compounds or their pharmaceutically acceptable salts in the preparation of medicines for treating JAK-related diseases.
  • the present invention provides use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pan-JAK-related diseases limited to the intestinal tract.
  • the present invention also provides a method for treating intestinal-limited pan-JAK-related diseases in a subject in need thereof, comprising providing the subject with an effective dose of a compound as defined in any of the above technical solutions or a pharmaceutically acceptable salts or pharmaceutical compositions.
  • pan-JAK-related disease limited to the intestine is inflammatory bowel disease.
  • the compounds of the present invention show good inhibition in the in vitro activity test of two isoforms of kinases, JAK1 and JAK2.
  • the compounds of the present invention exhibited good inhibitory properties in the in vitro activity test of cell (THP1 and HT29) functional assays.
  • the compounds of the present invention show good drug exposure levels in the small intestine and colon of rats, and the compounds have high small intestine/plasma and colon/plasma ratios, showing good tissue selectivity.
  • the compounds of the present invention show good drug exposure levels in the small intestine and colon of mice, and the small intestine/plasma and colon/plasma ratios of the compounds are high, showing good tissue selectivity.
  • the compounds of the present invention can alleviate the weight loss induced by OXA, significantly improve the disease activity index (DAI) score and the end point colon weight-length ratio, and exhibit a good therapeutic effect.
  • DAI disease activity index
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in 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, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; 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 both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • 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 thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, 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 one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content 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 Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of 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 enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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 deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only 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 does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting 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 (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, -Se-, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O ) p , where p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • 4-6 membered heterocycloalkyl examples 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-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any one range from n to n+m, eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, 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, 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 groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg 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 the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • 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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments 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. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • the following abbreviations are used herein: aq stands for water; TFA stands for trifluoroacetic acid; ACN stands for acetonitrile; DMSO stands for dimethyl sulfoxide.
  • Step 1 Compound 1-1 (2 g, 11.56 mmol) was dissolved in dimethyl sulfoxide (10 mL) at 25 °C, 1-2 (2.88 g, 12.72 mmol) and N,N-diisopropyl were added Ethylamine (2.99 g, 23.12 mmol) was stirred at 100° C.
  • Step 1' at 0 °C, compound 1-4a (10 g, 78.68 mmol) was dissolved in dichloromethane (100 mL), and N,N-diisopropylethylamine (12.20 g, 94.41 mmol, 16.45 mL) was added.
  • Step 2' Dissolve compound 1-4c (11g, 42.74mmol) in methanol (100mL), under nitrogen protection, add palladium carbon (0.1g, palladium content 10%), then replace with hydrogen three times, at 25 °C Stir for 16 hours, filter through celite and concentrate under reduced pressure to give crude 1-4.
  • 1H NMR 400MHz, DMSO-d6) ⁇ -0.05--0.03(s, 9H), 0.77-0.86(t, 2H), 1.95 -1.97(s, 3H), 3.47-3.53(t, 2H), 5.06-5.08(s, 1H), 5.08-5.11(s, 2H), 5.16(s, 2H).
  • Step 2 Compound 1-3 (2.5 g, 6.89 mmol) was dissolved in dioxane (30 mL), compound 1-4 (1.64 g, 7.23 mmol), cesium carbonate (4.49 g, 13.78 mmol) and [ (2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino -1,1'-biphenyl)]palladium(II) methanesulfonate (312.28 mg, 344.49 ⁇ mol), was replaced with nitrogen three times and then heated to 100° C., and stirred for 16 hours under nitrogen protection.
  • Step 3 Add selenium powder (4.39g, 54.17mmol) to ethanol (30mL) at 0-5°C, then slowly add sodium borohydride (2.38g, 62.91mmol), stir at room temperature until solid particles Completely disappeared, pyridine (8.57 g, 108.35 mmol) and compound 1-5 (3 g, 5.42 mmol) were added to the reaction solution, and the temperature was raised to 80 ° C and stirred for half an hour, and then slowly added 2M aqueous hydrochloric acid (32.50 mL), Continue stirring for half an hour, LC-MS showed that the raw materials were completely consumed, 50 mL of ammonium chloride aqueous solution was added to the reaction solution, and extracted with ethyl acetate (50 mL ⁇ 3), and the combined organic phases were washed with saturated brine (50 mL).
  • Step 4 Compound 1-6 (1.4 g, 2.21 mmol) was dissolved in ethanol (15 mL) at 25 °C, 1-7 (204.07 mg, 2.21 mmol) was added, and the mixture was stirred at 80 °C for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain crude product 1-8.
  • Step 5 Compound 1-8 (1.4 g, 2.08 mmol) was dissolved in ethyl acetate (2 mL), ethyl acetate solution of hydrochloric acid (4 M, 14 mL) was added, and the mixture was stirred at 25° C. for 1 hour. The reaction solution was directly filtered to obtain the crude hydrochloride of compound 1-9 as the filter cake. MS ESI calcd for C20H25N7Se [ M +H] + 444, found 444.
  • Step 6 The crude hydrochloride of 1-9 (0.85 g, 1.65 mmol) was dissolved in methanol (10 mL), N,N-diisopropylethylamine (639.52 mg, 4.95 mmol, 862 ⁇ L) was added, and the mixture was After stirring at 25°C for 10 minutes, compound 1-10 (0.290 g, 5.47 mmol, 363 ⁇ L) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step 1 To a solution of 2-1 (10 mg, 81.23 ⁇ mol) in DMF (0.5 mL) at 25 °C was added N,N-diisopropylethylamine (21.0 mg, 162.46 ⁇ mol) and O-(7- Nitrobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (34.0mg, 89.35 ⁇ mol), stirred at 25°C for 0.5h, and then added 1- A solution of 9's hydrochloride (41.86 mg, 81.23 ⁇ mol) and N,N-diisopropylethylamine (21.00 mg, 162.46 ⁇ mol, 28.30 ⁇ L) in DMF (0.5 mL) and stirred at 0-5 °C for 1 h .
  • N,N-diisopropylethylamine 21.0 mg, 162.46 ⁇ mol
  • Step 1 The hydrochloride of compound 1-9 (50 mg, 97.02 ⁇ mol) was dissolved in methylpyrrolidone (1 mL) at 20 °C, triethylamine (49.09 mg, 485.10 ⁇ mol, 67.52 ⁇ L) was added, and the solution was heated at 20 °C. After stirring for 0.5 h, methylpyrrolidone (0.5 mL) was added to the reaction solution, the reaction solution was cooled to 0 °C, stirred for more than 0.5 h, 3-1 (21.03 mg, 116.42 ⁇ mol) was slowly added, the mixture was warmed to 20 °C and Stir for 3h.
  • Step 1 At 20°C, the hydrochloride salt of compound 1-9 (60 mg, 116.43 ⁇ mol) was dissolved in DMF (1 mL), potassium carbonate (32.18 mg, 232.86 ⁇ mol) and 4-1 (26.08 mg, 116.43 ⁇ mol) were added ⁇ mol), the mixture was stirred at 50° C. for 16 hours. 20 mL of water was added to the reaction solution, extracted with dichloromethane (10 mL ⁇ 3), the combined organic phase was washed with saturated brine (5 mL ⁇ 3), and finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, Get crude.
  • Step 1 Compound 5-1 (33.38 mg, 176.41 ⁇ mol) was dissolved in DMF (1 mL) at 20°C, hydroxybenzotriazole (47.67 mg, 352.81 ⁇ mol) and 1-(3-dimethylamino) were added propyl)-3-ethylcarbodiimide hydrochloride (67.63 mg, 352.81 ⁇ mol), and the mixture was stirred at 20° C. for 0.5 h.
  • Step 2 Compound 5-2 (150 mg, 244.45 ⁇ mol) was dissolved in dichloromethane (3 mL) at 20 °C, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated and spin-dried to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% TFA)-ACN]; ACN%: 13%-43%, 10 minutes) to obtain compound 5 -3's trifluoroacetate salt.
  • Step 1 Compound 1-1 (200 mg, 1.16 mmol) and compound 6-1 (305.64 mg, 1.27 mmol) were dissolved in DMSO (2 mL) at 25 °C, and N,N-diisopropylethylamine ( 298.83 mg, 2.31 mmol), stirred at 100 °C for 2 hours, 10 mL of ethyl acetate was added to the reaction solution, washed with saturated brine (10 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure , to obtain crude 6-2.
  • MS ESI calculated: C19H25ClN4O2 [M + H] + 377 , found 377 .
  • Step 2 Compound 6-2 (300 mg, 796.01 ⁇ mol), compound 1-4 (217.19 mg, 955.21 mmol), cesium carbonate (518.71 mg, 1.59 mmol) and [(2-di-cyclohexylphosphino-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methane
  • Palladium(II) sulfonate methanesulfonate 72.16 mg, 89.60 ⁇ mol
  • dioxane 3 mL
  • Step 3 At 0-5°C, add selenium powder (285.23 mg, 3.52 mmol) to ethanol (4 mL), then slowly add sodium borohydride (159.91 mg, 4.23 mmol) in batches, and stir at room temperature until The solid particles disappeared completely. Pyridine (557.24 mg, 7.04 mmol) and compound 6-3 (200 mg, 352.24 ⁇ mol) were added to the reaction solution, and the temperature was raised to 80 °C and stirred for 0.5 hours, and then 2M aqueous hydrochloric acid (2.11 mL) was slowly added.
  • Step 4 Compound 6-4 (140 mg, 159.69 ⁇ mol) was dissolved in ethanol (1 mL) at 25° C., compound 6-5 (17.73 mg, 196.62 ⁇ mol) was added, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain crude product 6-6. MS ESI calculated: C 32 H 49 N 7 O 3 SeSi[M+H] + 687, found 687.
  • Step 5 Compound 6-6 (110 mg, 160.16 ⁇ mol) was dissolved in ethyl acetate (1 mL), ethyl acetate solution of hydrochloric acid (4 M, 1.11 mL) was added, and the mixture was stirred at 25° C. for 12 hours. The reaction solution was directly filtered to obtain the crude hydrochloride of compound 6-7 as the filter cake. MS ESI calcd for C21H27N7Se [M+H] + 456, found 456.
  • Step 6 The crude hydrochloride of 6-7 (45 mg, 76.51 ⁇ mol) was dissolved in methanol (1 mL), N,N-diisopropylethylamine (49.44 mg, 382.53 ⁇ mol) was added, and the mixture was stirred at 25°C After 5 minutes, acrylonitrile (1-10) (12.18 mg, 229.52 ⁇ mol, 363 ⁇ L) was added, and the mixture was stirred at 25° C. for 16 hours.
  • N,N-diisopropylethylamine 49.44 mg, 382.53 ⁇ mol
  • Step 1 The crude hydrochloride salt of compound 6-7 (45 mg, 76.51 ⁇ mol) was dissolved in methanol (1 mL), triethylamine (38.71 mg, 382.53 ⁇ mol) was added, and then compound 3-1 ( 16.58 mg, 91.81 ⁇ mol), stirred at 25°C for 16 hours. LC-MS showed that the starting material was completely consumed and the main peak was the product peak.
  • Step 1 Compound 8-1 (15 g, 78.13 mmol) was dissolved in dichloromethane (200 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.97 g) was added , 93.75 mmol) and 1-hydroxybenzotriazole (12.67 g, 93.75 mmol), were mixed and stirred at 20 °C for 1 hour, and then N,O-dimethylhydroxylamine hydrochloride (11.43 g, 117.19 mmol) and trimethylamine were added. Ethylamine (23.72 g, 234.38 mmol, 32.62 mL) was reacted at 20°C for 3 hours.
  • 1 H NMR 400 MHz, CDCl 3
  • Step 2 Compound 8-2 (14.54 g, 61.85 mmol) was dissolved in tetrahydrofuran (200 mL), methylmagnesium bromide ether solution (3M, 24.74 mL) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 1 hour after the dropwise addition. . The reaction was quenched by adding 200 mL of saturated aqueous ammonium chloride solution, diluted with 200 mL of water, and extracted with 400 mL of ethyl acetate (200 mL ⁇ 2).
  • Step 3 Compound 8-3 (11.65 g, 61.31 mmol) and ammonium chloride (327.94 mg, 6.13 mmol) were mixed, dichloromethane (200 mL) was added, and bromine (10.29 g, 64.37 mmol, 3.32 mL) was added dropwise , the reaction solution was reacted at 30-40 °C for 4 hours. 200 mL of saturated aqueous sodium bicarbonate solution was added, then diluted with 200 mL of water, extracted with dichloromethane 400 mL (200 mL ⁇ 2), the combined organic layers were washed with brine 150 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 8-4 .
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 4.36 (s, 2H), 7.73 (s, 2H)
  • Step 4 elemental selenium (2.89g, 35.67mmol, 2.83mL) was added to ethanol (30mL), sodium borohydride (1.83g, 48.37mmol) was added in batches at 0-5°C, and the reaction was performed at 20°C for 1 hour after the addition. Then 4-morpholinecarbonitrile (2 g, 17.84 mmol) was slowly added, then pyridine hydrochloride (8.24 g, 71.35 mmol) was slowly added, and the mixture was reacted at 20° C. for 16 hours.
  • Step 5 Compound 8-4 (278.52 mg, 1.04 mmol) was added to methanol (6 mL) and water (2 mL), sodium fluoride (21.74 mg, 517.85 ⁇ mol) and 8-6 (0.2 g, 1.04 mmol) were added, The reaction was carried out at 20°C for 1 hour. 20 mL of water was added, the solid was precipitated, filtered, and the filter cake was vacuum-dried to obtain compound 8-7.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 3.51-3.59 (m, 4H), 3.82-3.88 (m, 4H), 7.67 (s, 2H), 7.68 (s, 1H).
  • Step 6 Compounds 8-7 (1.71 g, 4.71 mmol), 1-2 (1.17 g, 5.18 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4 ',6'-Triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate ( 213.45 mg, 235.50 ⁇ mol) and cesium carbonate (3.07 g, 9.42 mmol) were added to dioxane (35 mL) and reacted at 80° C. for 16 hours under nitrogen atmosphere.
  • MS ESI calculated: C24H32ClN5O3Se [ M +H] + 554, found 554.
  • Step 7 Compounds 8-8 (680 mg, 1.12 mmol) and 8-9 (264.86 mg, 1.34 mmol) were added to toluene (15 mL) followed by [(2-di-cyclohexylphosphino-3,6-di Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II) Mesylate (101.44 mg, 111.91 ⁇ mol) and cesium carbonate (729.24 mg, 2.24 mmol) were reacted at 80° C. under nitrogen atmosphere for 16 hours.
  • MS ESI calculated: C33H46N8O5Se [M+H] +715 , found 715 .
  • Step 8 To compound 8-10 (160.67 mg, 225.11 ⁇ mol) was added ethyl acetate hydrochloride (4 M, 3 mL), and the reaction was carried out at 20° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 8-11. MS ESI calculated: C 23 H 30 N 8 OSe [M+H]+515, found 515.
  • Step 9 Compound 8-11 (120 mg, 218.20 ⁇ mol) was dissolved in methanol (3 mL), diisopropylethylamine (141.00 mg, 1.09 mmol, 190.03 ⁇ L) and acrylonitrile (0.11 g, 2.07 mmol, 137.50 ⁇ L) were added ⁇ L), react at 20°C for 16 hours.
  • reaction solution was added with 30 mL of water, extracted with 40 mL (20 mL ⁇ 2) of ethyl acetate, the combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column type: Phenomenex Synergi C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 16%-46%, 10 minutes) to obtain the trifluoroacetic acid salt of compound 8-12.
  • MS ESI calculated: C 26 H 33 N 9 OSe [M+H]+568, found 568.
  • Step 1 Compound 9-1 (15.36 mg, 105.84 ⁇ mol) was dissolved in DMF (0.5 mL) at 20°C, 1-hydroxybenzotriazole (28.60 mg, 211.69 ⁇ mol) and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40.58 mg, 211.69 ⁇ mol), and the mixture was stirred at 20° C. for 0.5 hr.
  • the crude product was separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; ACN%: 23%-53%, 8 minutes) to obtain the compound 9-2.
  • Step 1 Compound 1-6 (80 mg, 126.03 ⁇ mol) was dissolved in ethanol (1 mL) at 20 °C, 10-1 (13.43 mg, 126.03 ⁇ mol, 12.79 ⁇ L) was added, and the mixture was stirred at 80 °C for 7 hours . The reaction solution was concentrated under reduced pressure to obtain crude product 10-2. MS ESI calculated: C32H49N7O3SeSi [ M +H] + 688 , found 688.
  • Step 2 Compound 10-2 (90 mg, 131.04 ⁇ mol) was dissolved in methanol (0.5 mL) at 20 °C, hydrochloric acid/ethyl acetate (4 M, 2 mL) was added, and the mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain crude 10-3 hydrochloride. MS ESI calculated: C 21 H 27 N 7 Se[M+H] + 458, found 458.
  • Step 3 Compound 10-3 hydrochloride (80 mg, 162.30 ⁇ mol, HCl) was dissolved in methanol (1 mL) at 20°C, diisopropylethylamine (62.93 mg, 486.91 ⁇ mol, 84.81 ⁇ L) was added and Acrylonitrile (1-10) (120 mg, 2.26 mmol, 150.00 ⁇ L), and the mixture was stirred at 20° C. for 2 hours.
  • Step 1 Elemental selenium (4.62g, 57.07mmol) was added to ethanol (40mL), sodium borohydride (2.19g, 57.89mmol) was added in batches at 0-5°C, reacted at 20°C for 1 hour after the addition, and then slowly added Dimethylcyanamide (11-1) (2 g, 28.53 mmol), then pyridine hydrochloride (13.19 g, 114.13 mmol) was slowly added, and the mixture was reacted at 20° C. for 16 hours.
  • Step 2 Compound 8-4 (1 g, 3.72 mmol) was added to methanol (30 mL), compound 11-2 (561.76 mg, 3.72 mmol) was added, and the mixture was reacted at 20° C. for 1 hour.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 3.17(s, 6H), 7.58(s, 1H), 7.69(s, 2H)
  • Step 3 Compound 11-3 (0.8 g, 2.49 mmol), 1-2 (563.91 mg, 2.49 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (155.15 mg, 249.17 ⁇ mol), palladium acetate (55.94 mg, 249.17 ⁇ mol) and cesium carbonate (1.62 g, 4.98 mmol) were added to dioxane (20 mL) and reacted at 90° C. for 5 hours under nitrogen atmosphere.
  • MS ESI calculated: C22H30ClN5O2Se [M + H] + 512 , found 512.
  • Step 4 Compound 11-4 (300 mg, 587.18 ⁇ mol), 8-9 (127.39 mg, 645.90 ⁇ mol) were added to dioxane (10 mL), followed by [(2-di-cyclohexylphosphino-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methane Palladium(II) sulfonate mesylate (53.23 mg, 58.72 ⁇ mol) and cesium carbonate (382.63 mg, 1.17 mmol) were reacted at 90° C. for 5 hours under nitrogen atmosphere.
  • Step 5 Compound 11-5 (150 mg, 223.32 ⁇ mol) was dissolved in ethyl acetate (3 mL), ethyl acetate hydrochloride (4 M, 3 mL) was added, and the reaction was carried out at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 11-6. MS ESI calculated: C21H28N8Se [M+H] + 473 , found 473.
  • Step 6 Compound 11-6 (150 mg, 295.32 ⁇ mol) was dissolved in methanol (5 mL), diisopropylethylamine (190.84 mg, 1.48 mmol, 257.20 ⁇ L) and acrylonitrile (0.1 g, 1.88 mmol, 125.00 were added) ⁇ L), react at 20°C for 16 hours.
  • reaction solution was added with 30 mL of water, extracted with 40 mL (20 mL ⁇ 2) of ethyl acetate, the combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column type: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 15%-45%, 10 minutes) to obtain the trifluoroacetate salt of compound 11-7.
  • MS ESI calculated: C21H28N8Se [M+H] + 473 , found 473.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 2.39(s,3H),9.72-10.09(m,1H),10.23(s,1H)
  • Step 2 Compound 8-4 (3 g, 12.16 mmol) was added to methanol (120 mL), compound 12-2 (1.80 g, 12.27 mmol) was added, and the reaction was carried out at 20° C. for 2 hours.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 2.82(s, 3H), 7.75(s, 2H), 8.30(s, 1H)
  • Step 3 Compound 12-3 (0.5 g, 1.71 mmol), 1-2 (387.49 mg, 1.71 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (106.61 mg, 171.22 ⁇ mol), palladium acetate (38.44 mg, 171.22 ⁇ mol) and cesium carbonate (1.12 g, 3.42 mmol) were added to dioxane (10 mL) and reacted at 90° C. for 5 hours under nitrogen atmosphere.
  • MS ESI calculated: C21H27ClN4O2Se [M + H] + 483 , found 483 .
  • Step 4 Compounds 12-4 (590 mg, 1.22 mmol) and 8-9 (241.49 mg, 1.22 mmol) were added to dioxane (15 mL) followed by [(2-di-cyclohexylphosphino-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methane Palladium(II) sulfonate methanesulfonate (120.99 mg, 122.44 ⁇ mol) and cesium carbonate (797.85 mg, 2.45 mmol) were reacted at 90° C. for 5 hours under nitrogen atmosphere.
  • MS ESI calculated: C30H41N7O4Se [M + H] + 644 , found 644.
  • Step 5 Compound 12-5 (150 mg, 210.07 ⁇ mol) was dissolved in ethyl acetate (3 mL), ethyl acetate hydrochloride (4 M, 2.70 mL) was added, and the reaction was carried out at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 12-6. MS ESI calculated: C20H25N7Se [ M +H] + 444, found 444.
  • Step 6 Compound 12-6 (100 mg, 226.03 ⁇ mol) was dissolved in methanol (3 mL), diisopropylethylamine (146.06 mg, 1.13 mmol, 196.85 ⁇ L) and acrylonitrile (0.12 g, 2.26 mmol, 150.00 were added) ⁇ L), react at 15°C for 2 hours.
  • reaction solution was added with 30 mL of water, extracted with 40 mL (20 mL ⁇ 2) of ethyl acetate, the combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column type: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 13%-43%, 10 minutes) to obtain the trifluoroacetate salt of compound 12-7.
  • MS ESI calculated: C23H28N8Se [M+H] +497 , found 497 .
  • Step 1 Dissolve the crude hydrochloride of 6-7 (55 mg, 96.41 ⁇ mol) in DMF (1 mL), add N,N-diisopropylethylamine (37.38 mg, 289.24 ⁇ mol), and stir at 0°C 0.5 h, then compound 5-1 (16.58 mg, 91.81 ⁇ mol) and 1-hydroxybenzotriazole (23.69 mg, 175.29 ⁇ mol) and 1-(3-dimethylaminopropyl)-3- were added at 0 °C A solution of ethylcarbodiimide hydrochloride (36.96 mg, 192.82 ⁇ mol) in DMF (1 mL) was stirred at 25° C. for 15.5 hours.
  • Step 2 Dissolve 13-1 (20 mg, 31.87 ⁇ mol) in dichloromethane (1 mL), add trifluoroacetic acid (616 mg, 5.4 mmol), stir at 0°C for 16 hours, LC-MS shows that the starting material is basically consumed The main peak is the product peak.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product, which was prepared and separated by high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% TFA)-ACN]; B(ACN)%: 17 %-47%, 10 min) to give compound 13-2 as the trifluoroacetate salt.
  • Step 1 The crude hydrochloride of 6-7 (55 mg, 96.41 ⁇ mol) was dissolved in DMF (2 mL), potassium carbonate (53.30 mg, 385.65 ⁇ mol) and compound 4-1 (43.19 mg, 192.82 ⁇ mol) were added at 120 Stir at °C for 3 hours.
  • the reaction solution was diluted with 10 mL of water and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
  • the crude product was prepared and separated by high performance liquid chromatography (column: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (0.1%TFA)-ACN]; B(ACN)%: 40%-70%, 8 minutes) then (column: Phenomenex Synergi C18 150*25mm *10 ⁇ m; mobile phase: [water (0.1% TFA)-ACN]; B(ACN) %: 15%-45%, 10 minutes) to give the trifluoroacetate salt of compound 14-1.
  • Step 1 Compound 15-1 (2 g, 13.23 mmol) and diisopropylethylamine (2.56 g, 19.84 mmol) were added to tetrahydrofuran (30 mL), nitrile bromide (1.78 g, 16.80 mmol) was added at 0°C, 1.24 mL), reacted at 20°C for 16 hours.
  • the reaction solution was diluted with 100 mL of water, extracted with 120 mL of ethyl acetate (40 mL ⁇ 3), the combined organic layers were washed with 50 mL of brine, and dried over sodium sulfate to obtain compound 15-2.
  • Step 2 Elemental selenium (2.10g, 25.99mmol) was added to ethanol (50mL), sodium borohydride (983.24mg, 25.99mmol) was added in batches at 0-5°C, reacted at 20°C for 1 hour after the addition, and then slowly added Compound 15-2 (2.29 g, 13.00 mmol) was then slowly added with pyridine hydrochloride (6.01 g, 51.98 mmol), and the mixture was reacted at 20° C. for 16 hours.
  • Step 3 Compound 8-4 (0.6 g, 2.23 mmol, ) was added to methanol (40 mL), compound 15-3 (631.21 mg, 2.45 mmol) was added, and the reaction was carried out at 20° C. for 1 hour. After completion of the reaction, filter and vacuum dry the filter cake to obtain compound 15-4. MS ESI calculated: C17H15Cl2N3OSe [ M + H] + 428 , found 428.
  • Step 4 Compound 15-4 (560 mg, 1.31 mmol), 1-2 (296.68 mg, 1.31 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (29.43 mg, 131.09 ⁇ mol ), palladium acetate (29.43 mg, 131.09 ⁇ mol) and cesium carbonate (854.24 mg, 2.62 mmol) were added to dioxane (15 mL) and reacted at 90° C. for 16 hours under nitrogen atmosphere.
  • MS ESI calculated: C29H36ClN5O3Se [ M +H] + 618 , found 618.
  • Step 5 Compound 15-5 (440 mg, 648.91 ⁇ mol), 8-9 (127.99 mg, 648.91 ⁇ mol) were added to dioxane (15 mL), followed by [(2-di-cyclohexylphosphino-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methane Palladium (II) sulfonate methanesulfonate (58.82 mg, 64.89 ⁇ mol), cesium carbonate (422.85 mg, 1.30 mmol), reacted at 90° C. for 5 hours under nitrogen atmosphere.
  • MS ESI calculated: C38H50N8O5Se [M+ H ] + 779 , found 779.
  • Step 6 Compound 15-6 (150 mg, 223.32 ⁇ mol) was dissolved in trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL) and reacted at 70° C. for 20 hours. The reaction solution was concentrated under reduced pressure to obtain compound 15-7. MS ESI calculated: C20H26N8Se [ M +H] +459 , found 459.
  • Step 7 Compound 15-7 (90 mg, 157.49 ⁇ mol) was dissolved in methanol (3 mL), diisopropylethylamine (101.77 mg, 787.46 ⁇ mol, 137.16 ⁇ L) and acrylonitrile (0.15 g, 2.07 mmol, 137.50 ⁇ L) were added ⁇ L), react at 15°C for 2 hours.
  • reaction solution was added with 30 mL of water, extracted with 40 mL (20 mL ⁇ 2) of ethyl acetate, the combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column type: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; % acetonitrile: 10%-40%, 10 minutes) to obtain the trifluoroacetate salt of compound 15-8.
  • MS ESI calculated: C23H29N9Se [M+H] + 512 , found 512.
  • Step 1 Compound 16-1 (11.88 mg, 139.71 ⁇ mol) was dissolved in DMF (0.5 mL) at 20°C, O-(7-azabenzotriazole-1-yl)-N was added, N,N,N-tetramethylurea hexafluorophosphonium salt (88.54 mg, 232.86 ⁇ mol, 34.62 ⁇ L), and the mixture was stirred at 20° C. for 0.5 hr.
  • Step 1 Compound 1-3 (2 g, 5.51 mmol) was dissolved in tetrahydrofuran (20 mL) at 0°C, sodium hydrogen (330.71 mg, 8.27 mmol, 60% purity) was added, and the mixture was stirred at 0°C for 0.5 hours. Iodomethane (0.17 g, 8.27 mmol, 514.70 ⁇ L) was added to the reaction solution, and the mixture was stirred at 20° C. for 1 hour.
  • Step 2 Compound 17-1 (1.86 g, 4.94 mmol) was dissolved in dioxane (20 mL), compound 1-4 (1.18 g, 5.18 mmol), cesium carbonate (3.22 g, 9.87 mmol) and [ (2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino -1,1'-biphenyl)]palladium(II) methanesulfonate methanesulfonate (223.69 mg, 246.76 ⁇ mol), replaced with nitrogen three times and then heated to 100° C., and stirred for 16 hours under nitrogen protection.
  • Step 3 Add selenium powder (885.68mg, 10.94mmol) to ethanol (20mL) at 0-5°C, then add sodium borohydride (413.75mg, 10.94mmol) slowly, stir at room temperature for half an hour , until the solid particles completely disappeared, pyridine hydrochloride (1.69g, 14.58mmol) and compound 17-2 (2.07g, 3.65mmol) were added to the reaction solution, and the temperature was raised to 80 ° C and stirred for 2 hours, and added to the reaction solution.
  • Step 4 Compound 17-3 (300 mg, 462.41 ⁇ mol) was dissolved in ethanol (3 mL) at 25° C., 6-5 (300 mg, 3.24 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain crude product 17-4. MS ESI calcd for C32H49N7O3SeSi [ M +H] + 688 , found 688.
  • Step 5 Compound 17-4 (200 mg, 359.35 ⁇ mol) was dissolved in methanol (0.5 mL), ethyl acetate solution of hydrochloric acid (4 M, 3 mL) was added, and the mixture was stirred at 20° C. for 16 hours. The reaction solution was directly spin-dried to obtain the crude hydrochloride of compound 17-5. MS ESI calcd for C21H27N7Se [M+H] + 458, found 458.
  • Step 6 Dissolve the crude hydrochloride of 17-5 (160 mg, 324.61 ⁇ mol) in methanol (1 mL), add N,N-diisopropylethylamine (125.86 mg, 973.82 ⁇ mol, 169.62 ⁇ L), then add Acrylonitrile (1-10) (120 mg, 2.26 mmol, 150.00 ⁇ L) was stirred at 20° C. for 2 hours.
  • Step 2 Compound 18-2 (0.6 g, 1.65 mmol) was dissolved in dioxane (10 mL), 1-4 (412.46 mg, 1.81 mmol), cesium carbonate (1.07 g, 3.30 mmol) and [( 2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino- 1,1'-biphenyl)] palladium(II) mesylate (74.74 mg, 82.45 ⁇ mol) was replaced with nitrogen three times and then heated to 100° C. and stirred under nitrogen protection for 16 hours.
  • Step 3 Compound 18-3 (0.35 g, 630.91 ⁇ mol) was dissolved in DMF (10 mL) at 25° C., water (0.5 mL), triethylamine (363.50 mg, 3.59 mmol, 0.5 mL) and Selenium powder (150 mg, 1.85 mmol) was replaced with carbon monoxide three times and reacted at 90 ° C under 15 psi pressure for 1.5 hours, 50 mL of ammonium chloride aqueous solution was added to the reaction solution, and extracted with dichloromethane (50 mL ⁇ 3), the combined organic The phase was washed with saturated brine (50 mL), and finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 18-4.
  • Step 4 Compound 18-4 (0.4 g, 629.19 ⁇ mol) was dissolved in ethanol (4 mL) at 25° C., 6-5 (58.22 mg, 629.19 ⁇ mol) was added, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain crude product 18-5. MS ESI calcd for C30H46N8O3SeSi [ M +H] + 675, found 675.
  • Step 5 Compound 18-5 (350 mg, 519.46 ⁇ mol) was dissolved in ethyl acetate solution of hydrochloric acid (4 M, 5 mL) and stirred at 25° C. for 2 hours. The reaction solution was directly filtered to obtain the crude hydrochloride of compound 18-6 as the filter cake. MS ESI calcd for C19H24N8Se [ M +H] + 445, found 445.
  • Step 6 The crude hydrochloride of 18-6 (100 mg, 193.68 ⁇ mol) was dissolved in methanol (10 mL), N,N-diisopropylethylamine (75.1 mg, 581.0 ⁇ mol, 101.20 ⁇ L) was added, and the mixture was After stirring at 25°C for 10 minutes, acrylonitrile (1-10) (20.55 mg, 387.35 ⁇ mol, 25.69 ⁇ L) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step 1 The crude hydrochloride of 18-6 (30 mg, 44.68 ⁇ mol) was dissolved in DMF (0.5 mL), triethylamine (22.61 mg, 223.40 ⁇ mol, 31.09 ⁇ L) was added, the mixture was stirred for 0.5 hours, and then added to the reaction DMF (0.5 mL) was added to the liquid and cooled to 0 °C, stirred over 0.5 h, 3-1 (9.68 mg, 53.62 ⁇ mol) was added slowly, the mixture was warmed to 20 °C and stirred for 3 h. LC-MS showed that the starting material was consumed and the main peak was the product peak.
  • Step 1 At 20°C, diisopropylethylamine (2.50 g, 19.32 mmol) and compound 20-1 (2 g, 9.66 mmol) were added to tetrahydrofuran (40 mL), 1-2 (2.19 g, 9.66 mmol) It was dissolved in tetrahydrofuran (10 mL), dropped into the former system at 0°C, and reacted at 20°C for 18 hours.
  • Step 2 Compound 20-2 (2.15 g, 5.42 mmol) was dissolved in methanol (20 mL) and water (6 mL), lithium hydroxide (454.63 mg, 10.83 mmol) was added, and the reaction was carried out at 20°C for 2 hours.
  • the pH of the reaction solution was adjusted to 4 with 0.5M aqueous hydrochloric acid solution, the reaction solution was diluted with 100 mL of water, extracted with 120 mL of ethyl acetate (40 mL ⁇ 3), the combined organic layers were washed with brine 40 mL, dried over sodium sulfate, filtered and reduced in pressure Concentration gave compound 20-3.
  • MS ESI calculated: C17H23ClN4O4 [M + H] +383 , found 383 .
  • Step 3 Compound 20-3 (1.9 g, 4.96 mmol) was dissolved in dichloromethane (40 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.14 g, 5.96 mmol) and 1-hydroxybenzotriazole (804.70 mg, 5.96 mmol), reacted at 20° C. for 0.5 hour. Then, methoxymethylamine hydrochloride (726.12 mg, 7.44 mmol) and triethylamine (2.01 g, 19.85 mmol) were added, and the reaction solution was reacted at 20° C. for 16 hours.
  • MS ESI calculated: C19H28ClN5O4 [M + H] +426 , found 426 .
  • Step 4 Compound 20-4 (1.80 g, 4.24 mmol) was dissolved in tetrahydrofuran (30 mL), methylmagnesium bromide ether solution (3M, 3.11 mL,) was added dropwise at 0°C, and the reaction was carried out at 0°C for 1 hour. 20 mL of saturated ammonium chloride solution was added to quench the reaction, the reaction solution was diluted with 60 mL of water, extracted with 60 mL of ethyl acetate (30 mL ⁇ 2), the combined organic layers were washed with 30 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 5 Compound 20-5 (660 mg, 1.73 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.05 g, 10.40 mmol) was added, and tert-butyldimethylsilyltrifluoromethyl was added dropwise Sulfonate (1.37 g, 5.20 mmol) was reacted at 15°C for 1 hour.
  • the reaction solution was diluted with dichloromethane 60 mL, and was diluted with saturated aqueous sodium bicarbonate solution 60 mL (30 mL ⁇ 2), water (20 mL) and brine 30 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 20-6.
  • MS ESI calculated: C30H53ClN4O3Si [ M + H] +609 , found 609.
  • Step 6 Compound 20-6 (1.14 g, 1.87 mmol) was dissolved in tetrahydrofuran (30 mL) and water (5 mL), bromosuccinimide (332.95 mg, 1.87 mmol) was added, and the reaction was carried out at 15°C for 2 hours. The reaction solution was diluted with 100 mL of water, extracted with 100 mL of ethyl acetate (50 mL ⁇ 2), the combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 20-7. MS ESI calculated: C18H24BrClN4O3 [ M + H] + 459, found 459.
  • Step 7 Compound 20-7 (650 mg, 1.13 mmol) was dissolved in methanol (25 mL), compound 12-2 (138.18 mg, 1.13 mmol) was added at 0-5 °C, and the reaction was carried out at 15 °C for 0.5 hour. Then BOC acid anhydride (296.56 mg, 1.36 mmol), 2,6-lutidine (13.83 mg, 113.24 ⁇ mol) and triethylamine (458.33 mg, 4.53 mmol) were added, and the reaction was carried out at 15° C. for 16 hours.
  • MS ESI calculated: C20H26ClN5O2Se [ M + H] + 484, found 484.
  • Step 8 Compound 20-8 (100 mg, 205.03 ⁇ mol), 8-9 (48.53 mg, 246.03 ⁇ mol) were added to dioxane (3 mL), followed by [(2-di-cyclohexylphosphino-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methane Palladium(II) sulfonate methanesulfonate (18.59 mg, 20.50 ⁇ mol), cesium carbonate (133.60 mg, 410.05 ⁇ mol), reacted at 80° C. under nitrogen atmosphere for 3 hours.
  • MS ESI calculated: C29H40N8O4Se [M + H] +645 , found 645 .
  • Step 9 Compound 20-9 (65 mg, 100.99 ⁇ mol) was dissolved in methanol (1 mL), ethyl acetate hydrochloride (4 M, 2 mL) was added, and the reaction was carried out at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 20-10. MS ESI calculated: C19H24N8Se [ M +H] + 444, found 444.
  • Step 10 Compound 20-10 (50 mg, 104.20 ⁇ mol) was dissolved in methanol (2 mL), diisopropylethylamine (67.33 mg, 520.98 ⁇ mol) and acrylonitrile (0.22 g, 4.15 mmol) were added at 15° C. React for 2 hours. The reaction solution was added with 5 mL of water and 5 mL of methanol, stirred for 15 minutes, and filtered to obtain a filter cake. The filter cake was slurried by adding 5 mL of methanol, and filtered to obtain compound 20-11. MS ESI calculated: C22H27N9Se [M+H] +498 , found 498.
  • Step 1 Compound 20-7 (600 mg, 1.05 mmol) was dissolved in methanol (25 mL), compound 8-6 (201.84 mg, 1.05 mmol) was added at 0-5 °C, and the reaction was carried out at 15 °C for 0.5 hour. Then (Boc) 2 O (273.75 mg, 1.25 mmol), 2,6-lutidine (12.77 mg, 104.53 ⁇ mol) and triethylamine (423.07 mg, 4.18 mmol) were added, and the reaction was carried out at 15° C. for 16 hours.
  • MS ESI calculated: C23H31ClN6O3Se [ M +H] + 555 , found 555.
  • Step 2 Compound 21-1 (250 mg, 451.31 ⁇ mol), 8-9 (106.82 mg, 541.57 ⁇ mol) were added to dioxane (8 mL), followed by [(2-di-cyclohexylphosphino-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methane Palladium(II) sulfonate mesylate (40.91 mg, 45.13 ⁇ mol) and cesium carbonate (294.09 mg, 902.62 ⁇ mol) were reacted at 80° C. under nitrogen atmosphere for 3 hours.
  • MS ESI calculated: C32H45N9O5Se [M+ H ] + 716 , found 716.
  • Step 3 Compound 21-2 (220 mg, 270.88 ⁇ mol,) was dissolved in methanol (2 mL), ethyl acetate hydrochloride (4 M, 6 mL) was added, and the reaction was carried out at 40° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 21-3. MS ESI calculated: C22H29N9Se [M+H] + 516 , found 516.
  • Step 4 Compound 21-3 (150 mg, 272.26 ⁇ mol) was dissolved in methanol (5 mL), diisopropylethylamine (175.93 mg, 1.36 mmol) and acrylonitrile (28.89 mg, 544.52 ⁇ mol) were added at 15° C. React for 2 hours. The reaction solution was added with 10 mL of water and 10 mL of methanol, stirred for 15 minutes, and filtered to obtain a filter cake, which was slurried by adding 10 mL of methanol, and filtered to obtain compound 21-4. MS ESI calculated: C 25 H 32 N 10 OSe[M+H] + 569, found 569.
  • Step 1 22-1 (1.2 g, 2.48 mmol) was dissolved in ethanol (50 mL), 22-2 (580.83 mg, 2.98 mmol) was added, and the mixture was stirred at 80° C. for 1 hour.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product, which was diluted with 50 mL of tetrahydrofuran, triethylamine (502.31 mg, 4.96 mmol) and di-tert-butyl dicarbonate (541.70 mg, 2.48 mmol) were added, and the mixture was stirred at 80° C. for 1 hour.
  • Step 2 Dissolve 22-3 (280 mg, 518.60 ⁇ mol) in tetrahydrofuran (6 mL), add a solution of lithium hydroxide monohydrate (65.29 mg, 1.56 mmol) in water (2 mL), and stir at 35° C. for 16 hours.
  • the crude product was soaked in tetrahydrofuran (10 mL) and methanol (5 mL), filtered, and the filtrate was concentrated to obtain compound 22-4.
  • MS ESI calcd for C21H25ClN4O4Se [M + H] + 512, found 512 .
  • Step 3 22-4 (160 mg, 312.59 ⁇ mol) was dissolved in acetonitrile (4 mL), 22-5 (35.69 mg, 625.17 ⁇ mol) and N,N-diisopropylethylamine (161.59 mg, 1.25 mmol) were added 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (130.74mg, 343.84 ⁇ mol) was added at 30°C under stirring for 16 hours.
  • Step 4 Compound 22-6 (150 mg, 272.26 ⁇ mol), 8-9 (64.44 mg, 326.71 ⁇ mol), cesium carbonate (177.42 mg, 544.52 ⁇ mol) and [(2-di-cyclohexylphosphino-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonic acid
  • Palladium (II) methanesulfonate 24.68 mg, 27.23 ⁇ mol
  • dioxane 5 mL
  • Step 5 Compound 22-7 (100 mg, 140.51 ⁇ mol) was dissolved in ethyl acetate (2 mL), ethyl acetate solution of hydrochloric acid (4 M, 2 mL) was added, and the mixture was stirred at 30° C. for 16 hours. The reaction solution was directly filtered to obtain the crude hydrochloride of compound 22-8 as the filter cake. MS ESI calculated for C23H28N8OSe [M+H] + 512 , found 512.
  • Step 6 The crude hydrochloride of 22-8 (70 mg, 136.86 ⁇ mol, HCl) was dissolved in methanol (5 mL), N,N-diisopropylethylamine (88.44 mg, 684.29 ⁇ mol), and acrylonitrile were added. (1-10) (21.79 mg, 410.57 ⁇ mol), stirred at 25° C. for 16 hours. LC-MS showed that the starting material was completely consumed and the main peak was the product peak.
  • Step 1 Dissolve 22-3 (80 mg, 156.29 ⁇ mol) in acetonitrile (4 mL), add 23-1 (32.50 mg, 312.59 ⁇ mol) and N,N-diisopropylethylamine (80.80 mg, 625.17 ⁇ mol) 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (65.37mg, 171.92 ⁇ mol) was added at 50°C under stirring for 16 hours.
  • MS ESI calcd for C22H28ClN5O3Se [ M +H] + 525, found 525.
  • Step 2 Compound 23-2 (60 mg, 114.31 ⁇ mol), 8-9 (27.05 mg, 137.17 ⁇ mol), cesium carbonate (74.49 mg, 228.61 ⁇ mol) and [(2-di-cyclohexylphosphino-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonic acid
  • Palladium(II) methanesulfonate (20.72 mg, 22.86 ⁇ mol) was dissolved in dioxane (5 mL), replaced with nitrogen three times, then heated to 100° C., and stirred under nitrogen protection for 16 hours.
  • Step 3 Compound 23-3 (40 mg, 58.34 ⁇ mol) was dissolved in ethyl acetate (2 mL), ethyl acetate solution of hydrochloric acid (4 M, 2 mL) was added, and the mixture was stirred at 30° C. for 3 hours. The reaction solution was directly filtered to obtain the crude hydrochloride of compound 23-4 as the filter cake. MS ESI calculated for C21H26N8OSe [M+H] + 485 , found 485.
  • Step 4 The crude hydrochloride of 23-4 (60 mg, 123.60 ⁇ mol) was dissolved in methanol (5 mL), N,N-diisopropylethylamine (79.87 mg, 617.99 ⁇ mol), and acrylonitrile (1 -10) (19.68 mg, 370.80 ⁇ mol), stirred at 25° C. for 1 hour.
  • Step 1 Dissolve 22-3 (200 mg, 370.43 ⁇ mol) in tetrahydrofuran (5 mL), add a solution of diisobutylaluminum hydride in toluene (1 M, 1.18 mL) at -65 °C, and stir at 0 °C for 2 hours .
  • Step 2 Dissolve 24-1 (180 mg, 361.54 ⁇ mol) in dichloromethane (5 mL), add Dess Martin Periodane (230.01 mg, 542.30 ⁇ mol l), and stir at 20° C. for 1 hour. Saturated sodium sulfite (5 mL) and saturated sodium bicarbonate (5 mL) were added to the reaction solution, stirred at 20° C.
  • Step 3 Dissolve 24-2 (170 mg, 310.20 ⁇ mol) in tetrahydrofuran (5 mL), add elemental iodine (393.66 mg, 1.55 mmol) and ammonia water (434.85 mg, 3.10 mmol, 25%), stir at 30° C. for 16 Hour. Saturated sodium sulfite (5 mL) and saturated sodium bicarbonate (5 mL) were added to the reaction solution, stirred at 20° C.
  • Step 4 Compound 24-3 (100 mg, 198.84 ⁇ mol), 8-9 (43.14 mg, 218.72 ⁇ mol), cesium carbonate (194.36 mg, 596.52 ⁇ mol) and [(2-di-cyclohexylphosphino-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonic acid
  • Palladium (II) methanesulfonate (18.02 mg, 19.88 ⁇ mol) was dissolved in dioxane (4 mL), replaced with nitrogen three times, then heated to 90° C., and stirred for 2 hours under nitrogen protection.
  • Step 5 Compound 24-4 (100 mg, 151.00 ⁇ mol) was dissolved in ethyl acetate (2 mL), ethyl acetate solution of hydrochloric acid (4 M, 2 mL) was added, and the mixture was stirred at 45° C. for 2 hours. The reaction solution was directly concentrated to obtain the crude hydrochloride of compound 24-5. MS ESI calculated for C20H22N8Se [ M +H] + 453, found 453.
  • Step 6 The crude hydrochloride of 24-5 (70 mg, 154.39 ⁇ mol) was dissolved in methanol (2 mL), N,N-diisopropylethylamine (99.77 mg, 771.94 ⁇ mol) was added, and acrylonitrile (1 -10) (24.58 mg, 463.17 ⁇ mol), stirred at 20° C. for 1 hour. LC-MS showed that the starting material was consumed and the main peak was the product peak.
  • Step 1 25-1 (10g, 109.73mmol) was added to absolute ethanol (30mL), then methyl iodide (18.38g, 129.48mmol) was added, stirred at 80°C for 4 hours in a stuffy tank, the solid was precipitated and directly filtered to obtain the compound The hydriodate of 25-2.
  • Step 2 at 25 ° C, add selenium powder (6.95g, 85.81mmol) to ethanol (140mL), then add sodium borohydride (3.57g, 94.39mmol) in batches, after the black selenium powder disappears completely, add Sodium carbonate (4.55 g, 42.90 mmol) and the hydroiodide salt of 25-2 (10 g, 42.90 mmol), and warmed to 25 °C and stirred for 16 hours. The reaction solution was quenched by adding 20 mL of glacial acetic acid, and concentrated under reduced pressure to obtain the crude product.
  • Step 3 25-3 (4 g, 28.98 mmol) and 1-1 (4.01 g, 23.18 mmol) were added to trifluoroacetic acid (50 mL), and the temperature was raised to 80°C and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with ethyl acetate (100 mL), the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL ⁇ 3), and the organic phase was diluted with saturated brine (50 mL).
  • Step 4 25-4 (1 g, 2.99 mmol) was added to DMF (20 mL) followed by triethylamine (605.76 mg, 5.99 mmol), 4-dimethylaminopyridine (73.13 mg, 598.64 ⁇ mol) and dicarbonic acid Di-tert-butyl ester (979.88 mg, 4.49 mmol) was stirred at 25°C for 1 hour.
  • Step 5 Compound 25-5 (1.2 g, 3.04 mmol), 1-2 (826.90 mg, 3.65 mmol), tris(dibenzylideneacetone)dipalladium (278.82 mg, 304.48 ⁇ mol), 4,5-bis (Diphenylphosphorus)-9,9-dimethylxanthene (352.35 mg, 608.96 ⁇ mol) and cesium carbonate (1.98 g, 6.09 mmol) were added to dioxane (40 mL), and the temperature was raised to Stir at 100°C for 16 hours under nitrogen protection.
  • MS ESI calculated: C24H33ClN6O4Se [ M + H] + 584, found 584.
  • Step 6 Compound 25-6 (120 mg, 182.89 ⁇ mol), 8-9 (43.29 mg, 219.46 ⁇ mol), cesium carbonate (178.76 mg, 548.66 ⁇ mol) and [(2-di-cyclohexylphosphino-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonic acid
  • Palladium (II) methanesulfonate (16.58 mg, 18.29 ⁇ mol) was added to dioxane (5 mL), replaced with nitrogen three times and then heated to 90° C.
  • Step 7 Compound 25-7 (80 mg, 107.42 ⁇ mol) was dissolved in ethyl acetate (2 mL), ethyl acetate solution of hydrochloric acid (4 M, 2 mL) was added, and the mixture was stirred at 45° C. for 2 hours. The reaction solution was directly concentrated to obtain the crude hydrochloride of compound 25-8. MS ESI calcd for C18H23N9Se [M+H] + 444, found 444.
  • Step 8 The crude hydrochloride of 25-8 (50 mg, 103.98 ⁇ mol) was dissolved in methanol (2 mL), N,N-diisopropylethylamine (67.19 mg, 519.91 ⁇ mol) was added, and acrylonitrile (1 -10) (16.55 mg, 311.94 ⁇ mol), stirred at 20° C. for 1 hour.
  • Step 1 At 20°C, the hydrochloride salt of compound 18-6 (60 mg, 89.36 ⁇ mol) was dissolved in DMF (0.5 mL), potassium carbonate (24.70 mg, 178.72 ⁇ mol) and 4-1 (24.02 mg, 107.23 ⁇ mol, 12.57 ⁇ L), and the mixture was stirred at 50° C. for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product.
  • Step 1 Compound 27-1 (1.8 g, 12.28 mmol) was dissolved in tetrahydrofuran (10 mL) and saturated sodium bicarbonate solution (10 mL) at 0 °C, CbzCl (2.30 g, 13.50 mmol, 1.92 mL) was added, and Stir at 20°C for 16 hours. 10 mL of water was added to the reaction solution, and extracted with dichloromethane (20 mL ⁇ 3). The combined organic phases were washed with 0.5 M aqueous hydrochloric acid (5 mL ⁇ 3) and saturated brine (5 mL ⁇ 3) in turn.
  • Step 2 Compound 27-2 (950 mg, 3.89 mmol), selenium (629.80 mg, 7.78 mmol, 617.45 ⁇ L) were dissolved in N,N-DMF (10 mL) and water (1 mL), the mixture was vented under vacuum , and the gas was replaced three times with carbon monoxide, and the reaction mixture was stirred at 80° C. for 16 hours under carbon monoxide gas (50 psi).
  • Step 4 Compound 27-4 (500 mg, 1.01 mmol), 1-2 (228.58 mg, 1.01 mmol), ( ⁇ )-2,2-bis(diphenylphosphino)-11-binaphthyl (62.89 mg, 101.00 ⁇ mol), palladium acetate (22.68 mg, 101.00 ⁇ mol) and cesium carbonate (658.15 mg, 2.02 mmol) were dissolved in dioxane (12 mL), the mixture was purged with nitrogen three times, and stirred at 90° C. for 16 hours.
  • Step 5 Compound 27-5 (500 mg, 729.81 ⁇ mol), 8-9 (158.34 mg, 802.79 ⁇ mol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2', 4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3) (66.16mg, 72.98 ⁇ mol) and cesium carbonate (475.57 mg, 1.46 mmol) were dissolved in dioxane (12 mL), the mixture was purged with nitrogen three times, and stirred at 90° C.
  • methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2', 4',6'-Triisopropyl-1,1'-biphenyl)(2'
  • Step 6 Compound 27-6 (380 mg, 449.23 ⁇ mol) was dissolved in methanol (1 mL), ethyl acetate solution of hydrochloric acid (4 M, 4 mL) was added, and the mixture was stirred at 20° C. for 16 hours. The reaction solution was directly spin-dried to obtain the crude hydrochloride of compound 27-7. MS ESI calcd for C32H38N8O2Se [M + H] + 647 , found 647.
  • Step 7 The crude hydrochloride of 27-7 (300 mg, 417.49 ⁇ mol) was dissolved in methanol (3 mL), N,N-diisopropylethylamine (161.87 mg, 1.25 mmol, 218.16 ⁇ L) was added, followed by Compound acrylonitrile (1-10) (33.23 mg, 626.24 ⁇ mol, 41.54 ⁇ L) was stirred at 20° C. for 2 hours. LC-MS showed that the starting material was consumed and the main peak was the product peak.
  • Step 8 The trifluoroacetate salt of 27-8 (90 mg, 128.81 ⁇ mol) was dissolved in hydrobromic acid (0.3 mL) and stirred at 15° C. for 16 hours. The reaction solution was filtered to obtain a crude product, which was prepared and separated by high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% TFA)-ACN]; ACN%: 8%-38% , 10 min) to obtain the trifluoroacetate salt of compound 27-9. MS ESI calcd for C27H35N9Se [M+H] + 566, found 566.
  • column chromatography SiO 2
  • Step 2 Compound 28-1 (0.6 g, 1.59 mmol) was dissolved in dioxane (10 mL), 1-4 (397.15 mg, 1.75 mmol), cesium carbonate (1.03 g, 3.18 mmol) and [( 2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino- 1,1'-biphenyl)]palladium(II) methanesulfonate (143.94 mg, 158.79 ⁇ mol) was replaced with nitrogen three times and then heated to 100° C. and stirred for 4 hours under nitrogen protection.
  • Step 3 Compound 28-2 (500 mg, 879.07 ⁇ mol) was dissolved in DMF (10 mL) at 25°C, followed by adding water (0.5 mL), triethylamine (363.50 mg, 3.59 mmol, 0.5 mL) and selenium Powder (213.55 mg, 2.64 mmol), replaced with carbon monoxide three times and reacted at 90 ° C under 15 psi pressure for 1.5 hours, 50 mL of ammonium chloride aqueous solution was added to the reaction solution, and extracted with dichloromethane (50 mL ⁇ 3), the combined organic The phase was washed with saturated brine (50 mL), and finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 28-3.
  • Step 4 Compound 28-3 (600 mg, 923.42 ⁇ mol) was dissolved in ethanol (5 mL) at 25° C., 6-5 (85.44 mg, 923.42 ⁇ mol) was added, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain crude product 28-4. MS ESI calcd for C31H48N8O3SeSi [ M +H] + 689 , found 689.
  • Step 5 Compound 28-4 (600 mg, 872.34 ⁇ mol,) was dissolved in an ethyl acetate solution of hydrochloric acid (4 M, 5 mL) and stirred at 25° C. for 2 hours. The reaction solution was directly filtered to obtain the crude hydrochloride of compound 28-5 as the filter cake. MS ESI calculated for C20H26N8Se [ M +H] + 459, found 459.
  • Step 6 The crude hydrochloride of 28-5 (100 mg, 202.47 ⁇ mol) was dissolved in methanol (2 mL), N,N-diisopropylethylamine (52.34 mg, 404.95 ⁇ mol, 70.53 ⁇ L) was added, and the mixture was After stirring at 25°C for 10 minutes, compound acrylonitrile (1-10) (10.74 mg, 202.47 ⁇ mol, 13.43 ⁇ L) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step 1 Compound 29-1 (0.5 g, 4.50 mmol) was dissolved in DMF (10 mL) at 25° C., water (1 mL) and selenium powder (728.58 mg, 9.00 mmol) were added successively, and the solution was replaced with carbon monoxide three times. Under the pressure of 50 psi, the reaction was carried out at 80 °C for 16 hours. After TLC monitoring the consumption of the raw materials, 50 mL of ammonium chloride aqueous solution was added to the reaction solution, and extracted with dichloromethane (50 mL ⁇ 3), and the combined organic phase was then saturated brine.
  • Step 2 Compound 29-2 (0.4 g, 1.49 mmol) was added to methanol (10 mL), compound 8-4 (285.76 mg, 1.49 mmol) was added, and the reaction was carried out at 20° C. for 1 hour. TLC showed that the starting material was completely consumed.
  • Step 3 Compound 29-3 (350 mg, 966.55 ⁇ mol), Compound 1-2 (262.49 mg, 1.16 mmol), ( ⁇ )-2,2-bis(diphenylphosphino)-1,1-binaphthyl (120.37 mg, 193.31 ⁇ mol), palladium acetate (21.70 mg, 96.65 ⁇ mol), and cesium carbonate (629.84 mg, 1.93 mmol) were added to dioxane (5 mL) and reacted at 80° C. for 3 hours under nitrogen atmosphere.
  • Step 4 Compound 29-4 (250 mg, 452.93 ⁇ mol) was dissolved in dioxane (5 mL), compound 8-9 (98.27 mg, 498.22 ⁇ mol), cesium carbonate (295.14 mg, 905.85 ⁇ mol) and [( 2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino- 1,1'-biphenyl)]palladium(II) methanesulfonate (41.06 mg, 45.29 ⁇ mol) was replaced with nitrogen three times and then heated to 90° C. and stirred for 4 hours under nitrogen protection.
  • Step 5 Compound 29-5 (200 mg, 280.61 ⁇ mol) was dissolved in an ethyl acetate solution of hydrochloric acid (4 M, 2 mL) and stirred at 25° C. for 2 hours. The reaction solution was directly filtered to obtain the crude hydrochloride of compound 29-6 as the filter cake. MS ESI calcd for C24H31N7OSe [ M +H] + 514, found 514.
  • Step 6 The crude hydrochloride of 29-6 (150 mg, 273.24 ⁇ mol) was dissolved in methanol (1 mL), N,N-diisopropylethylamine (70.63 mg, 546.48 ⁇ mol, 95.19 ⁇ L) was added, and the mixture was After stirring at 25°C for 10 minutes, compound acrylonitrile (1-10) (29.00 mg, 546.48 ⁇ mol, 36.25 ⁇ L) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step 1 Compound 30-1 (0.5 g, 8.76 mmol, 591.02 ⁇ L) was added to dichloromethane (5 mL) at 0°C, followed by triethylamine (2.66 g, 26.27 mmol, 3.66 mL) and 30-2 (1.11 g, 10.51 mmol, 773.00 ⁇ L), reacted at 20° C. for 2 hours. TLC showed that the starting material was completely consumed.
  • Step 2 Elemental selenium (1.58g, 19.49mmol) was added to ethanol (30mL), sodium borohydride (737.26mg, 19.49mmol) was added in batches at 0-5°C, after the addition, the reaction was performed at 20°C for 1 hour, and 30- 3 (0.8 g, 9.74 mmol), then pyridine hydrochloride (4.50 g, 38.98 mmol) was slowly added, and the mixture was reacted at 80° C. for 1 hour.
  • Step 3 Compound 30-4 (0.45 g, 1.67 mmol) was added to methanol (2 mL), Compound 8-4 (272.89 mg, 1.67 mmol) and sodium fluoride (35.13 mg, 836.67 ⁇ mol) were added, and the reaction was carried out at 20°C for 0.5 hour .
  • Step 4 Compound 30-5 (600 mg, 1.80 mmol), Compound 1-2 (407.68 mg, 1.80 mmol), ( ⁇ )-2,2-bis(diphenylphosphino)-1,1-binaphthyl (224.34 mg, 360.28 ⁇ mol), palladium acetate (40.44 mg, 180.14 ⁇ mol), and cesium carbonate (1.17 g, 3.60 mmol) were added to dioxane (4 mL) and reacted at 80° C. for 3 hours under nitrogen atmosphere.
  • Step 5 Compound 30-6 (400 mg, 764.92 ⁇ mol) was dissolved in dioxane (4 mL), compound 8-9 (165.96 mg, 841.42 ⁇ mol), cesium carbonate (498.45 mg, 1.53 mmol) and [( 2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino- 1,1'-biphenyl)]palladium(II) methanesulfonate methanesulfonate (69.34 mg, 76.49 ⁇ mol), replaced with nitrogen three times, then heated to 100° C., and stirred for 4 hours under nitrogen protection.
  • Step 6 Compound 30-7 (350 mg, 397.31 ⁇ mol) was dissolved in an ethyl acetate solution of hydrochloric acid (4 M, 4 mL) and stirred at 25° C. for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude hydrochloride of compound 30-8. MS ESI calcd for C22H28N8Se [M+H] + 485, found 485.
  • Step 7 The crude hydrochloride of 30-8 (250 mg, 480.83 ⁇ mol) was dissolved in methanol (5 mL), N,N-diisopropylethylamine (186.43 mg, 1.44 mmol, 251.26 ⁇ L) was added, and the mixture was After stirring at 25°C for 10 minutes, compound acrylonitrile (1-10) (51.03 mg, 961.66 ⁇ mol, 63.79 ⁇ L) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step 2 Compound 33-1 (0.7 g, 1.85 mmol) was dissolved in tetrahydrofuran (10 mL) at 0 °C, sodium hydride (110 mg, 2.75 mmol, 60% purity) was added, stirred at 0 °C for 0.5 hours, and then Iodomethane (525.8 mg, 3.71 mmol, 230.6 ⁇ L, ) was slowly added to the system, and then the whole system was stirred at 35° C. for 3 hours.
  • sodium hydride 110 mg, 2.75 mmol, 60% purity
  • Step 3 Compound 31-2 (600 mg, 1.53 mmol) was dissolved in dioxane (5 mL), compound 1-4 (382.9 mg, 1.68 mmol), cesium carbonate (997.6 mg, 3.06 mmol) and [( 2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino- 1,1'-biphenyl)] palladium(II) methanesulfonate (138.8 mg, 153.10 ⁇ mol) methanesulfonate (138.8 mg, 153.10 ⁇ mol) was replaced with nitrogen three times and then heated to 100° C., and stirred for 4 hours under nitrogen protection.
  • Step 4 At 25°C, compound 31-3 (250 mg, 428.9 ⁇ mol, ) was dissolved in DMF (5 mL), followed by adding water (0.3 mL), triethylamine (218.1 mg, 2.16 mmol, 0.3 mL) and Selenium powder (104.2 mg, 1.29 mmol) was replaced with carbon monoxide three times and reacted at 90 ° C under 15 psi pressure for 2 hours, 50 mL of ammonium chloride aqueous solution was added to the reaction solution, and extracted with dichloromethane (50 mL ⁇ 3), the combined The organic phase was washed with saturated brine (50 mL), and finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 31-4.
  • Step 5 Compound 31-4 (300 mg, 451.95 ⁇ mol) was dissolved in ethanol (5 mL) at 25° C., 6-5 (50.2 mg, 542.34 ⁇ mol) was added, and the mixture was stirred at 80° C. for 3 hours. The reaction solution was directly concentrated under reduced pressure to obtain crude product 31-5. MS ESI calculated for C32H50N8O3SeSi [ M +H] + 703 , found 703.
  • Step 6 Compound 31-5 (0.3 g, 427.45 ⁇ mol) was dissolved in methanolic hydrochloric acid solution (4 M, 4 mL) and stirred at 30° C. for 1 hour. LCMS showed that the reaction of the starting materials was basically complete, and the main peak was the product peak. The reaction solution was directly concentrated under reduced pressure to obtain the crude hydrochloride of compound 31-6. MS ESI calcd for C21H28N8Se [M+H] + 473 , found 473.
  • Step 7 The crude hydrochloride of 31-6 (200 mg, 393.76 ⁇ mol) was dissolved in methanol (2 mL), N,N-diisopropylethylamine (152.7 mg, 1.18 mmol, 205.8 ⁇ L) was added, and the mixture was After stirring at 25°C for 10 minutes, acrylonitrile (1-10) (41.8 mg, 787.52 ⁇ mol, 52.2 ⁇ L,) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step 1 Compound 18-1 (0.6 g, 3.45 mmol) was dissolved in tetrahydrofuran (15 mL) at 20°C, and diisopropylethylamine (891.37 mg, 6.90 mmol) was added. Then 1-2 (780.45 mg, 3.45 mmol) was added dropwise at 0°C, reacted at 0°C for 2 hours, and then at 20°C for 16 hours. The reaction solution was diluted with 15 mL of water and extracted with 120 mL (40 mL ⁇ 3) of ethyl acetate.
  • Step 2 Compound 32-2 (740 mg, 1.98 mmol) was dissolved in DMF (15 mL), and sodium hydride (103.00 mg, 2.58 mmol) was added in batches at 0°C. After the addition, the reaction was carried out at this temperature for 30 minutes, and then 0 Iodomethane (309.29 mg, 2.18 mmol) was added dropwise at °C, and the mixture was reacted at 15 °C for 2 hours. 10 mL of saturated aqueous ammonium chloride solution was added, then 50 mL of water was added, and extracted with 40 mL of ethyl acetate (20 mL ⁇ 2).
  • Step 3 Compound 32-3 (0.6 g, 1.59 mmol), 8-9 (344.50 mg, 1.75 mmol) were added to dioxane (15 mL) followed by [(2-di-cyclohexylphosphino-3 ,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] Palladium(II) methanesulfonate methanesulfonate (143.94 mg, 158.79 ⁇ mol), cesium carbonate (1.03 g, 3.18 mmol) were reacted at 80° C. for 3 hours under nitrogen atmosphere.
  • Step 4 DMF (5mL) and water (0.5mL) were added to the single-neck flask, followed by compound 32-4 (350mg, 630.29 ⁇ mol), selenium powder (153.12mg, 1.89mmol) and triethylamine (352.59mg, 3.48mmol) ), replaced 3 times with carbon monoxide, and reacted at 90° C. for 1 hour under a carbon monoxide (15 psi) atmosphere.
  • the reaction solution was diluted with 50 mL of water and extracted with 120 mL (40 mL ⁇ 3) of ethyl acetate. The combined organic layers were washed with brine 50 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 32-5.
  • MS ESI calculated: C27H40N8O4Se [M + H] + 621 , found 621.
  • Step 6 Compound 32-6 (50 mg, 76.03 ⁇ mol) was added to a single-neck flask, ethyl acetate hydrochloride (4 M, 3 mL) was added, and the reaction was carried out at 50° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 32-7 hydrochloride. MS ESI calculated: C20H26N8Se [ M +H] +459 , found 459.
  • Step 7 Compound 32-7 hydrochloride (50 mg, 101.24 ⁇ mol) was dissolved in methanol (2 mL), diisopropylethylamine (65.42 mg, 506.20 ⁇ mol) and acrylonitrile (1-10) (10.74 mg were added) , 202.48 ⁇ mol), and reacted at 15 °C for 2 hours.
  • reaction solution was added with 30 mL of water, extracted with 40 mL (20 mL ⁇ 2) of ethyl acetate, the combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column type: Phenomenex Luna C18 75 ⁇ 30 mm ⁇ 3 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 15%-45%, 7 minutes) to obtain the trifluoroacetic acid salt of compound 32-8.
  • MS ESI calculated: C23H29N9Se [M+H] + 512 , found 512.
  • Step 1 The hydrochloride of 32-7 (60 mg, 104.99 ⁇ mol) was dissolved in methylpyrrolidone (1 mL), triethylamine (53.1 mg, 524.9 ⁇ mol, 73.0 ⁇ L) was added, and the mixture was stirred at 20° C. for 30 minutes, Then, the reaction system was cooled to 0°C, compound 3-1 (20.86 mg, 115.49 ⁇ mol) was added, and the mixture was stirred at 20°C for 2 hours.
  • Step 1 At 20°C, diisopropylethylamine (6.24g, 48.31mmol) and compound 20-1 (5g, 24.15mmol) were added to tetrahydrofuran (80mL), compound 1-2 (5.47g, 24.15mmol) ) was dissolved in tetrahydrofuran (20 mL), dropped into the former system at 0°C, and reacted at 20°C for 16 hours.
  • MS ESI calculated: C18H25ClN4O4 [M + H] + 397 , found 397 .
  • Step 2 Compound 34-1 (5.23 g, 13.18 mmol) was dissolved in tetrahydrofuran (80 mL), and sodium hydride (632.49 mg, 15.81 mmol) was added in portions at 0°C. After the addition, the reaction was carried out at 0°C for 30 minutes. Iodomethane (2.06 g, 14.50 mmol) was dissolved in tetrahydrofuran (20 mL), added dropwise to the above reaction system at 0°C, and then reacted at 15°C for 16 hours.
  • MS ESI calculated: C19H27ClN4O4 [M + H] + 411 , found 411 .
  • Step 3 Compound 34-2 (2.4 g, 5.84 mmol) was dissolved in tetrahydrofuran (50 mL), methylmagnesium bromide ether solution (3M, 3.11 mL,) was added dropwise at 0°C, and the reaction was carried out at -78°C for 1 hour. 5 mL of saturated ammonium chloride solution was added to quench the reaction, the reaction solution was diluted with 60 mL of water, extracted with 60 mL of ethyl acetate (30 mL ⁇ 2), the combined organic layers were washed with 30 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • methylmagnesium bromide ether solution 3M, 3.11 mL,
  • Step 4 Compound 34-3 (800 mg, 2.03 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.23 g, 12.16 mmol) was added, and tert-butyldimethylsilyl trifluoromethyl was added dropwise Sulfonate (1.61 g, 6.08 mmol, ) was reacted at 15°C for 16 hours.
  • the reaction solution was diluted with dichloromethane 60 mL, and was diluted with saturated aqueous sodium bicarbonate solution 60 mL (30 mL ⁇ 2), water (20 mL) and brine 30 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 34-4.
  • MS ESI calculated: C25H41ClN4O3Si [ M + H] + 509 , found 509.
  • Step 5 Compound 34-4 (1.15 g, 2.03 mmol) was dissolved in tetrahydrofuran (30 mL) and water (5 mL), bromosuccinimide (721.57 mg, 4.05 mmol) was added, and the reaction was carried out at 15° C. for 2 hours.
  • the reaction solution was diluted with 100 mL of water, extracted with 100 mL of ethyl acetate (50 mL ⁇ 2), the combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 34-5.
  • MS ESI calculated: C19H26BrClN4O3 [ M + H] + 473 , found 473.
  • Step 6 Compound 34-5 (800 mg, 2.14 mmol) was dissolved in methanol (25 mL), methylselenamide (12-2) (261.25 mg, 2.14 mmol) was added at 0-5 °C, and the reaction was carried out at 15 °C for 2 hours . Then BOC acid anhydride (560.70 mg, 2.57 mmol), 2,6-lutidine (26.16 mg, 214.09 ⁇ mol) and triethylamine (866.55 mg, 8.56 mmol) were added, and the reaction was carried out at 15° C. for 2 hours.
  • BOC acid anhydride 560.70 mg, 2.57 mmol
  • 2,6-lutidine 26.16 mg, 214.09 ⁇ mol
  • triethylamine 866.55 mg, 8.56 mmol
  • MS ESI calculated: C21H28ClN5O2Se [ M + H] + 498 , found 498.
  • Step 7 Compound 34-6 (120 mg, 241.50 ⁇ mol), tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (57.16 mg, 289.80 ⁇ mol) was added to dioxane (4 mL) Add [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2- (2'-Amino-1,1'-biphenyl)]palladium(II) mesylate (21.89 mg, 24.15 ⁇ mol) mesylate and cesium carbonate (157.37 mg, 483.00 ⁇ mol) at 80°C under nitrogen atmosphere The reaction was carried out for 3 hours.
  • Step 8 Compound 34-7 (60 mg, 91.23 ⁇ mol) was added to hydrochloric acid methanol (4 M, 3 mL), and the reaction was carried out at 40° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of compound 34-8. MS ESI calculated: C 20 H 26 N 8 Se[M+H] + 459, found 459.
  • Step 9 The hydrochloride salt of compound 34-8 (55 mg, 120.24 ⁇ mol) was dissolved in methanol (2 mL), diisopropylethylamine (62.16 mg, 480.94 ⁇ mol) and acrylonitrile (1-10) (12.76 ⁇ g) were added mg, 240.47 ⁇ mol), reacted at 15°C for 2 hours.
  • reaction solution was added with 30 mL of water, extracted with 40 mL (20 mL ⁇ 2) of ethyl acetate, the combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column type: 3- 100 C18 ultra 150*50mm*3 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 5%-35%, 10 minutes) to obtain the formate salt of compound 34-9.
  • MS ESI calculated: C23H29N9Se [M+H] +512 , found 512.
  • Step 1 The hydrochloride salt of compound 34-8 (110 mg, 222.72 ⁇ mol) was dissolved in tetrahydrofuran (2 mL), triethylamine (112.68 mg, 1.11 mmol, ) and compound 3-1 (40.23 mg, 222.72 ⁇ mol) were added, The reaction was carried out at 15°C for 1 hour.
  • reaction solution was added with 30 mL of water, extracted with 40 mL (20 mL ⁇ 2) of ethyl acetate, the combined organic layers were washed with 20 mL of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column type: Phenomenex luna C18 150*25mm*10 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 16%-46%, 10 minutes) to obtain the formate salt of compound 35-1.
  • MS ESI calculated: C 24 H 30 N 10 O 2 SSe[M+H] + 603, found 603.
  • Step 1 Compound 5-1 (7.69 mg, 40.62 ⁇ mol) was dissolved in DMF (0.3 mL) at 20°C, 1-hydroxybenzotriazole (10.98 mg, 81.24 ⁇ mol) and 1-(3- Dimethylaminopropyl)-3-acetaldehyde hydrochloride (15.57 mg, 81.24 ⁇ mol), and the mixture was stirred at 20° C. for 0.5 hr. A solution of compound 18-6 hydrochloride (30 mg, 44.68 ⁇ mol) and diisopropylethylamine (15.75 mg, 121.85 umol) in dimethylformamide (0.3 mL) was added to the mixture, and stirred at 20° C. for 16 Hour.
  • Step 2 Compound 36-1 (60 mg, 97.62 ⁇ mol) was dissolved in dichloromethane (3 mL) at 20°C, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material was consumed and the main peak was the product peak. The reaction solution was concentrated and spin-dried to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% TFA)-ACN]; ACN%: 13%-43%, 10 minutes) to obtain compound 36 -2's trifluoroacetate.
  • JAK1, 2, 3 and TYK2 were used in this experiment method for activity detection.
  • the enzyme, ULight-labeled polypeptide substrate, ATP, and detection compound are mixed and the reaction incubated.
  • EDTA was added to stop the reaction, and Eu-labeled antibody was added at the same time.
  • kinase assays the binding of europium-labeled anti-phosphorylated substrate antibodies to phosphorylated ULight-labeled substrates enables donor and acceptor molecules to approach each other. After irradiation with 320nm wavelength light, the kinase reacts, the energy of the europium donor is transferred to the ULight acceptor dye, and the 665nm wavelength light is generated. The emission intensity of light is proportional to the phosphorylation level of the ULight matrix.
  • the final test concentration of the compound is from 1 ⁇ M to 0.017 nM, 3-fold serial dilution, 11 concentrations.
  • the content of DMSO in the detection reaction was 1%.
  • kinase assay Preparation of buffers including: 50 mM HEPES (pH 7.5), 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EDTA, 1 mM DTT.
  • test compound of the present invention exhibits a good inhibitory effect on the in vitro activity test of two subtypes of kinases, JAK1 and JAK2.
  • IL-13 final concentration 6ng/mL was added to HT29 cells and incubated at 37°C for 30min; IL-6 (final concentration 30ng/mL) was added to THP1 cells and incubated at 37°C for 15min (the negative control group did not add Cytokine stimulation, positive control group added the same concentration of cytokines).
  • the pSTAT3 antibody or pSTAT6 antibody was added to the staining buffer at a ratio of 2:48, and 50 ⁇ L/well was added to THP1 or HT29 cells, respectively, and stained at 4°C for 30 min.
  • the cells were resuspended in 150 ⁇ L of staining buffer, and the mean fluorescence intensity (MFI) of PE channel (pSTAT) was detected by flow cytometry.
  • MFI mean fluorescence intensity
  • test compounds of the present invention exhibited good inhibitory activity in the in vitro activity test of cell (THP1 and HT29) functional experiments.
  • the rats were sacrificed by CO 2 at 1, 3, 6, and 12 hours.
  • About 200 ⁇ L of blood was collected from the jugular vein, placed in an EDTA-K2 test tube, and centrifuged at 4°C, 3,200 g for 10 min to obtain plasma.
  • Store at ⁇ 10°C; take the small intestine and colon at each time point, squeeze out the contents of the colon and small intestine, rinse with normal saline, weigh and homogenize (the homogenate solution is methanol:15mM PBS 1:2), and the homogenate ratio is 1:4 (1g tissue 4ml homogenate), stored at -70 ⁇ 10°C.
  • Protein precipitation add 200 ⁇ L of acetonitrile containing internal standard to 20 ⁇ L of plasma sample, after mixing, centrifuge at 12,000 g at 4 °C, take 50 ⁇ L of the supernatant after treatment, add 50 ⁇ L of the supernatant to the 96-well plate, centrifuge at 3,220 g at 4 °C, and perform LC- MS/MS analysis.
  • the compounds of the present invention show good drug exposure levels in the small intestine and colon of rats, and the small intestine/plasma and colon/plasma ratios of the compounds are high, showing good tissue selectivity.
  • mice There were 2 male C57BL/6J mice at each time point, 4 time points, 8 mice in total; after an overnight fast, they were administered p.o. at a dose of 3 mg/kg, and the administration volume was 3 mL/kg.
  • Protein precipitation 60 ⁇ L of acetonitrile containing internal standard was added to 3 ⁇ L of plasma sample, mixed and centrifuged at 12,000g at 4°C. After treatment, 50 ⁇ L of supernatant was added to a 96-well plate, centrifuged at 3,220g at 4°C, and the supernatant was directly subjected to LC-MS. /MS analysis.
  • the compounds of the present invention show good drug exposure levels in the small intestine and colon of mice, and the small intestine/plasma and colon/plasma ratios of the compounds are high, showing good tissue selectivity.
  • the solvent is 0.5% CMC-Na
  • the body weight and Disease Activity Index (DAI) scores of the animals were recorded every day, which were used to evaluate the morbidity of each group of animals and the effect of the test compound on the disease.
  • the DAI score consists of 3 parts, and the specific criteria refer to Table 4 below.
  • the compounds of the present invention can alleviate the OXA-induced weight loss, significantly improve the disease activity index (DAI) score and the end point colon weight-length ratio in the oxazolone (OXA)-induced mouse enteritis model, showing good performance. treatment effect.
  • DAI disease activity index
  • OXA oxazolone

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Abstract

L'invention concerne une classe de composés hétérocycliques de sélénium et leur application. Sont spécifiquement divulgués un composé représenté par la formule (II) et et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2021/125264 2020-10-21 2021-10-21 Composés hétérocycliques de sélénium et leur application WO2022083687A1 (fr)

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WO2023202706A1 (fr) * 2022-04-21 2023-10-26 南京明德新药研发有限公司 Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application

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