WO2022253333A1 - Amide compounds and application thereof - Google Patents

Amide compounds and application thereof Download PDF

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Publication number
WO2022253333A1
WO2022253333A1 PCT/CN2022/096978 CN2022096978W WO2022253333A1 WO 2022253333 A1 WO2022253333 A1 WO 2022253333A1 CN 2022096978 W CN2022096978 W CN 2022096978W WO 2022253333 A1 WO2022253333 A1 WO 2022253333A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
added
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PCT/CN2022/096978
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French (fr)
Chinese (zh)
Inventor
王建非
杨广文
奥志华
孙继奎
胡世尘
张杨
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022253333A1 publication Critical patent/WO2022253333A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a class of amide compounds and applications thereof, in particular to compounds represented by formula (P) and pharmaceutically acceptable salts thereof.
  • JAK is a class of non-receptor tyrosine kinases with four subtypes, JAK1, JAK2, JAK3, and TYK2.
  • the JAK-STAT signaling pathway mediated by them is related to cell proliferation, differentiation, apoptosis, and immune regulation.
  • JAK-STAT is an essential pathway for immune response, and when inflammation occurs, overactivation of JAK will in turn promote disease progression.
  • JAK1, JAK2 and TYK2 widely exist in various tissues and cells in the body, and JAK3 mainly exists in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes.
  • JAK1 has become a target for diseases such as immunity, inflammation, and cancer
  • JAK2 has become a target for blood system-related diseases
  • JAK3 has become a target for autoimmune diseases.
  • Popular target TYK2 has also become a target in diseases such as autoimmunity and inflammation.
  • the four members of the JAK family have different functions. If they lack selectivity, they may interfere with a variety of normal signal transduction and cause a variety of toxic and side effects, which also limits the first generation of non-selective JAK inhibitors (such as ruxolitinib). , Tofacitinib, etc.) clinical application range.
  • non-selective JAK inhibitors such as ruxolitinib. , Tofacitinib, etc.
  • the five JAK inhibitors approved by the FDA all carry a black-box warning. In addition to target-related toxicity, many of them may be caused by off-target.
  • JAK2 a member of the JAK family, plays an important role in mediating the signaling of pro-inflammatory cytokines, including IL-12, IL-23 and type I interferons. Th17 and Th1 cells are differentiated and formed under the activation of IL-12 and IL-23, and drive the release of a series of pro-inflammatory factors, further aggravating the inflammatory response.
  • BMS-986165 an oral allosteric inhibitor of TYK2 developed by BMS, has a unique mechanism of action. Unlike other JAK inhibitors, it acts on the pseudokinase region of TYK2 JH2, achieving high kinase selectivity (>1000 times). It beat the oral standard drug Apremilast in the Phase III clinical trial of psoriasis, and it was safe and well tolerated. This reflects that highly selective TYK2 inhibitors have great potential for clinical application in the treatment of psoriasis and other targets, and have great clinical application value.
  • the present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
  • T, Y, Y 1 , Y 2 and Y 3 are selected from N and CH, said CH is optionally substituted by 1 halogen, C 1-3 alkyl and C 1-3 alkoxy;
  • R 11 is selected from C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN, and the C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN are optionally replaced by 1, 2 or 3 Halogen substitution;
  • R 12 is selected from N(R 2 ) 2 and C(R 2 ) 3 ;
  • R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from H, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R b ;
  • Ring B does not exist
  • Ring B is selected from C 5-10 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 5-10 cycloalkyl, 5- 10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 R c ;
  • s 0, 1 or 2;
  • n and m are independently selected from 0, 1, 2 and 3;
  • R 3 are independently selected from H and C 1-3 alkyl
  • R is selected from F, Cl, Br, I and OH
  • R and R are independently selected from H, D, F, Cl, Br and I;
  • Each R c is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
  • Hetero in the 3-6 membered heterocycloalkane, 5-10 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-10 membered heteroaryl means that 1, 2 or 3 are independently selected from Atoms or atomic groups of N, O, S and NH.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T is selected from N and CH optionally substituted by 1 halogen
  • R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R ;
  • Ring B does not exist
  • ring B is selected from 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R c ;
  • n and m are independently selected from 0, 1, 2 and 3;
  • R 3 are independently selected from H and C 1-3 alkyl
  • R is selected from F, Cl, Br, I and OH
  • R and R are independently selected from H, D, F, Cl, Br and I;
  • Each R c is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
  • Hetero in the 5-6 membered heteroaryl represents 1, 2 or 3 atoms or atomic groups independently selected from N, O, S and NH.
  • T is selected from N and CH, and other variables are as defined in the present invention.
  • T is selected from N, and other variables are as defined in the present invention.
  • n is selected from 0 and 1, and other variables are as defined in the present invention.
  • each of the above-mentioned R c is independently selected from H, F, Cl, Br, I and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 halogens, and other variables are as in this invention defined.
  • each R c mentioned above is independently selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 and CF 3 , and other variables are as defined in the present invention.
  • each of the above R 1 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • R 1 is selected from OCH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from H, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 is selected from H, CH 3 and CD 3 , and other variables are as defined in the present invention.
  • the aforementioned Y, Y 1 , Y 2 and Y 3 are selected from CH, and other variables are as defined in the present invention.
  • R 12 is selected from NH 2 , NHCH 3 , NHCD 3 , CH 2 CH 3 and CH 2 CD 3 , and other variables are as defined in the present invention.
  • the above ring B is selected from said Optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
  • the above ring B is selected from Other variables are as defined herein.
  • the above-mentioned E is selected from NH, -(CH 2 )-NH-, -(CH 2 )-N(CH 3 )-, Other variables are as defined herein.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T is selected from N and CH optionally substituted by 1 halogen
  • R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R ;
  • Ring B does not exist
  • Ring B is selected from a 5-membered heteroaryl optionally substituted by 1, 2 or 3 R ;
  • n and m are independently selected from 0, 1 and 2;
  • R 3 are independently selected from H and C 1-3 alkyl
  • R and R are independently selected from H, D, F, Cl, Br and I;
  • R c is independently selected from H, F, Cl, Br and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • each R is selected from F, Cl, Br and I;
  • the 5-membered heteroaryl group contains 1, 2 or 3 atoms or atom groups independently selected from N, O, S and NH.
  • R c is independently selected from H, F, Cl, Br and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R c is independently selected from H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 and CF 3 , and other variables are as defined in the present invention.
  • R 1 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • R 1 is selected from OCH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 is selected from CD 3 , and other variables are as defined in the present invention.
  • the above ring B is selected from said Optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
  • the above ring B is selected from Other variables are as defined herein.
  • the above-mentioned E is selected from -(CH 2 )-NH-, -(CH 2 )-N(CH 3 )-, Other variables are as defined herein.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from:
  • T1 is selected from N and CH;
  • R 1 , R 2 , E, T and R c are as defined in the present invention.
  • the present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the above compound or a pharmaceutically acceptable salt thereof is selected from:
  • the present invention also provides following experimental method:
  • Adenosine Tri-Phosphate is a common energy carrier in various life activities in nature, and is the smallest unit of energy storage and transfer.
  • CellTiter-Glo TM Live Cell Detection Kit uses luciferase as the detection substance, and luciferase needs the participation of ATP in the process of luminescence.
  • Add CellTiter-Glo TM reagent to the cell culture medium measure the luminescence value, the light signal is directly proportional to the amount of ATP in the system, and ATP is positively correlated with the number of living cells. Therefore, by using the CellTiter-Glo kit to detect the ATP content, the cell proliferation can be detected.
  • the cell lines were Ba/F3-FL-TYK2-E957D and Ba/F3-TEL-TYK2.
  • Ba/F3-FL-TYK2-E957D cells can stably express exogenously introduced human TYK2-E957D gene, and the TYK2-E957D gene sequence contains JH1 and JH2 domains;
  • Ba/F3-TEL-TYK2 cells can stably express exogenous
  • the introduced human TEL-TYK2 gene, the TEL-TYK2 gene sequence only includes the JH1 domain of TYK2.
  • Cell lines were cultured in an incubator with culture conditions of 37 °C, 5% CO2 . Passage regularly, and take cells in logarithmic growth phase for plating.
  • the cell viability rate should be over 90%.
  • Adding drugs to the compound detection cell plate Take 5 ⁇ L of 20 ⁇ compound working solution and add it to the cell culture plate as shown in Table 1. Add 5 ⁇ L of DMSO-cell culture medium mixture to the Max control. The final concentration of DMSO was 0.1%.
  • the SpectraMax Paradigm readout yields the corresponding RLU of fluorescence per well.
  • Inhibition Rate (Inh%) 100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%.
  • the inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the data were analyzed with GraphPad Prism software, and the nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated accordingly.
  • the purpose of this experiment is to detect the inhibitory effect of compounds on cytokine-activated JAK-STAT signaling pathway in human peripheral blood mononuclear cells (PBMC).
  • PBMC peripheral blood mononuclear cells
  • the TYK2 signaling pathway is activated by IFN ⁇ stimulation, and the inhibitory activity of the compound on its downstream STAT1 phosphorylation can be detected, and the half inhibitory concentration IC 50 of the compound on the activity of the TYK2 signaling pathway can be obtained; while for the JAK1 signaling pathway, JAK1 is activated by IL-6 stimulation Signaling pathway, detecting the inhibitory activity of the compound on its downstream STAT1 phosphorylation, the half inhibitory concentration IC 50 of the compound on the activity of the JAK1 signaling pathway can be obtained; The inhibitory activity of the downstream STAT5 phosphorylation can be used to obtain the half inhibitory concentration IC 50 of the compound on the activity of the JAK2 signaling pathway; for the JAK3 signaling pathway, the JAK3 signaling
  • PBMC Human Peripheral Blood Mononuclear Cells
  • Culture medium 1640 culture medium + 10% fetal bovine serum + 1% double antibody + 1% non-essential amino acids (percentages are volume ratios)
  • PBMCs frozen in liquid nitrogen were thawed in a water bath at 37° C., culture medium was added, and centrifuged at 320 g for 3 min.
  • the cells were centrifuged at 320 g for 3 min, and 200 ⁇ L of staining solution was added to each well to wash once.
  • pSTAT1 (stimulated by IL-6 and IFN ⁇ ) or pSTAT5 (stimulated by IL-2) in CD4 positive cells by flow cytometry; detect the fluorescence intensity of pSTAT5 (stimulated by GM-CSF) in CD33 positive cells.
  • the compound of the present invention has good inhibitory effect on TYK2 JH2 pseudokinase.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to the salts of the compounds of the present invention, which are prepared from the compounds with specific substituents found in 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, either neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • 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 both.
  • the compounds of the invention may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 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%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture 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, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. 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 compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • 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.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations 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.
  • a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting 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 to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight solid line bond in -OCH3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • 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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C2-4alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
  • the C 2-4 alkenyl includes C 2-3 , C 4 , C 3 and C 2 alkenyl, etc.; the C 2-4 alkenyl can be monovalent, divalent or multivalent. Examples of C alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.
  • C2-4 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, the carbon-carbon triple bond can be located anywhere in the group.
  • the C 2-4 alkynyl includes C 2-3 , C 4 , C 3 and C 2 alkynyl and the like. It may be monovalent, divalent or polyvalent. Examples of C alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 5-10 cycloalkyl means a saturated cyclic hydrocarbon group composed of 5 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include Spiral, parallel and bridged rings.
  • the C 5-10 cycloalkyl group includes C 5-8 or C 5-6 and the like; it may be monovalent, divalent or multivalent.
  • Examples of C 5-10 cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0] dicyclodecane Wait.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-6-membered heterocycloalkyl group includes 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolid
  • the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings.
  • the 5-10 membered heterocycloalkyl group includes 5-8 membered, 5-6 membered, 5-membered, 6-membered and 8-membered heterocycloalkyl groups and the like.
  • Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl,
  • C 6-10 aromatic ring and “C 6-10 aryl” in the present invention can be used interchangeably, and the term “C 6-10 aromatic ring” or “C 6-10 aryl” means that the A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ -electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It can be monovalent, divalent or multivalent, and the C 6-10 aryl group includes C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 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 , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl 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-triazolyl, etc.
  • 5-10 membered heteroaryl ring and “5-10 membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10 membered heteroaryl” means that there are 5 to 10 rings
  • the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-10 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5-membered and 6-membered heteroaryl groups and the like.
  • Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl 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-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the solvent used in the present invention is commercially available.
  • G-1-2 (0.25g, 1.32mmol, 1eq) was dissolved in MeOH (7.5mL), methylamine (410.78mg, 3.97mmol, 30% purity, 3eq), sodium cyanoborohydride (249.36mg, 3.97mmol, 3eq), acetic acid (262.12mg, 4.36mmol, 249.64 ⁇ L, 3.3eq) were stirred at room temperature 25°C for 1.5 hours.
  • the phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was passed through SFC (column: DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m; mobile phase: CO 2 -isopropanol containing 0.1% ammonia; gradient: containing 0.1 % ammonia water isopropanol 52%-52%, 9min) separation and purification to obtain WX-002A and WX-002B.
  • SFC column: DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m
  • mobile phase CO 2 -isopropanol containing 0.1% ammonia
  • gradient containing 0.1 % ammonia water isopropanol 52%-52%, 9min
  • Example 6 Referring to the synthesis steps of Example 6, replace 6-2 in Step 2 with the fragment G-1 in the table below to synthesize the compounds in Table 4 below.
  • Dissolve compound 7-1 (15g, 125.92mmol, 1eq) in acetic acid (30mL), add fuming nitric acid (8.73g, 138.52mmol, 6.23mL, 1.1eq) dropwise at 50°C, the temperature should not be higher than 70°C, stir 4hr.
  • the reaction solution was slowly added to ice water (90 mL), solids were precipitated and filtered.
  • Trifluoroacetic acid salt 35mg, 71.35 ⁇ mol, 1eq
  • triethylamine 28.88mg, 285.38 ⁇ mol, 39.72 ⁇ L, 4eq
  • dichloromethane 1.5mL
  • - Acryloyl chloride 7.75 mg, 85.61 ⁇ mol, 6.98 ⁇ L, 1.2 eq
  • reaction solution was added to aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was separated by preparative high-performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: A (water, ammonium bicarbonate) and B (acetonitrile; gradient: B%: 20%-55%, 8min), Compound WX-008 was obtained.
  • TR-FRET fluorescence resonance energy transfer
  • HEPES pH7.5 the final concentration is 20mM
  • MgCl 2 the final concentration is 10mM
  • Brij-35 the final concentration is 0.015%
  • DTT the final concentration is 2mM
  • BSA the final concentration is 50 ⁇ g/mL.
  • WX-003A 0.51 WX-004B 0.39 WX-005 0.27 WX-006 0.43 WX-007 0.12 WX-008 0.16 WX-009 0.49
  • the compound of the present invention has good inhibitory effect on TYK2 JH2 pseudokinase.

Abstract

A class of amide compounds and an application thereof. Specifically disclosed are compounds represented by formula (P) and a pharmaceutically acceptable salt thereof.

Description

酰胺类化合物及其应用Amide compounds and their applications
本申请主张如下优先权：This application claims the following priority:
CN202110615081.6，申请日：2021年06月02日。CN202110615081.6, application date: June 02, 2021.
技术领域technical field
本发明涉及一类酰胺类化合物及其应用，具体涉及式(P)所示化合物及其药学上可接受的盐。The present invention relates to a class of amide compounds and applications thereof, in particular to compounds represented by formula (P) and pharmaceutically acceptable salts thereof.
背景技术Background technique
JAK是一类非受体酪氨酸激酶，共有JAK1、JAK2、JAK3、TYK2四种亚型，它们介导的JAK-STAT信号通路与细胞的增殖、分化、凋亡以及免疫调节有关。JAK-STAT是免疫反应所必需的通路，而在炎症发生时，JAK被过度激活又会反过来促进疾病进展。JAK1、JAK2和TYK2广泛存在于体内各种组织和细胞中，JAK3主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。基于JAK激酶家族中各亚型的功能特点和特殊的组织分布，JAK1已成为免疫、炎症和癌症等疾病的靶点；JAK2已成为血液***相关疾病的靶点；JAK3已成为自身免疫性疾病的热门靶点；TYK2也成为自身免疫和炎症等疾病的靶点。JAK is a class of non-receptor tyrosine kinases with four subtypes, JAK1, JAK2, JAK3, and TYK2. The JAK-STAT signaling pathway mediated by them is related to cell proliferation, differentiation, apoptosis, and immune regulation. JAK-STAT is an essential pathway for immune response, and when inflammation occurs, overactivation of JAK will in turn promote disease progression. JAK1, JAK2 and TYK2 widely exist in various tissues and cells in the body, and JAK3 mainly exists in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes. Based on the functional characteristics and special tissue distribution of each subtype in the JAK kinase family, JAK1 has become a target for diseases such as immunity, inflammation, and cancer; JAK2 has become a target for blood system-related diseases; JAK3 has become a target for autoimmune diseases. Popular target; TYK2 has also become a target in diseases such as autoimmunity and inflammation.
JAK家族4个成员功能各不相同，如果缺乏选择性，很可能会干扰多种正常信号传导，引起多种毒副作用，这也限制了第一代非选择性JAK抑制剂(例卢可替尼、托法替尼等)的临床应用范围。FDA批准的5款JAK抑制剂，全部带有黑框警告，除靶点相关毒性外，很多可能是由脱靶造成。The four members of the JAK family have different functions. If they lack selectivity, they may interfere with a variety of normal signal transduction and cause a variety of toxic and side effects, which also limits the first generation of non-selective JAK inhibitors (such as ruxolitinib). , Tofacitinib, etc.) clinical application range. The five JAK inhibitors approved by the FDA all carry a black-box warning. In addition to target-related toxicity, many of them may be caused by off-target.
开发高选择性JAK抑制剂是降低毒副作用的重要手段，但是JAK家族四个亚型同源性高达40％～70％，开发高选择性的JAK抑制剂难度大，暂无高选择性的JAK抑制剂上市。TYK2是JAK家族一员，在介导促炎性细胞因子(包括IL-12，IL-23和I型干扰素)的信号传导中起重要作用。Th17及Th1细胞在IL-12及IL-23激活下分化形成，并驱动一系列促炎因子的释放，进一步加剧炎症反应。这些细胞因子与银屑病、炎症性肠病(IBD)和***性红斑狼疮(SLE)等多种炎症和自身免疫性疾病的发病机制有关。BMS公司开发的口服TYK2别构抑制剂BMS-986165作用机制独特，与其它JAK抑制剂不一样的是，它作用于TYK2 JH2假激酶区域，实现了激酶高选择性(＞1000倍)。它在银屑病临床三期实验中击败口服标准药物阿普斯特(Apremilast)，而且安全耐受性较好。这体现了高选择性TYK2抑制剂在治疗银屑病等靶点方面具有巨大的临床应用潜力，具有重大的临床应用价值。The development of highly selective JAK inhibitors is an important means to reduce toxic and side effects, but the homology of the four subtypes of the JAK family is as high as 40% to 70%. It is difficult to develop highly selective JAK inhibitors, and there is no highly selective JAK yet Inhibitors are on the market. TYK2, a member of the JAK family, plays an important role in mediating the signaling of pro-inflammatory cytokines, including IL-12, IL-23 and type I interferons. Th17 and Th1 cells are differentiated and formed under the activation of IL-12 and IL-23, and drive the release of a series of pro-inflammatory factors, further aggravating the inflammatory response. These cytokines have been implicated in the pathogenesis of several inflammatory and autoimmune diseases such as psoriasis, inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). BMS-986165, an oral allosteric inhibitor of TYK2 developed by BMS, has a unique mechanism of action. Unlike other JAK inhibitors, it acts on the pseudokinase region of TYK2 JH2, achieving high kinase selectivity (>1000 times). It beat the oral standard drug Apremilast in the Phase III clinical trial of psoriasis, and it was safe and well tolerated. This reflects that highly selective TYK2 inhibitors have great potential for clinical application in the treatment of psoriasis and other targets, and have great clinical application value.
发明内容Contents of the invention
本发明提供了式(P)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022096978-appb-000001
Figure PCTCN2022096978-appb-000001
其中，in,
T、Y、Y 1、Y 2和Y 3选自N和CH，所述CH任选被1个卤素、C 1-3烷基和C 1-3烷氧基取代； T, Y, Y 1 , Y 2 and Y 3 are selected from N and CH, said CH is optionally substituted by 1 halogen, C 1-3 alkyl and C 1-3 alkoxy;
R 11选自C 2-4烯基、C 2-4炔基和CH 2CN，所述C 2-4烯基、C 2-4炔基和CH 2CN任选被1、2或3个卤素取代；R 12选自N(R 2) 2和C(R 2) 3； R 11 is selected from C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN, and the C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN are optionally replaced by 1, 2 or 3 Halogen substitution; R 12 is selected from N(R 2 ) 2 and C(R 2 ) 3 ;
R 13选自C 3-6环烷基、3-6元杂环烷基、苯基、5-6元杂芳基、NHC(＝O)-C 3-6环烷基、NHC(＝O)-3-6元杂环烷基、NHC(＝O)-苯基和NHC(＝O)-5-6元杂芳基，所述C 3-6环烷基、3-6元杂环烷基、苯基、5-6元杂芳基、NHC(＝O)C 3-6环烷基、NHC(＝O)-3-6元杂环烷基、NHC(＝O)-苯基和NHC(＝O)-5-6元杂芳基任选被1、2或3个卤素、C 1-3烷基和C 1-3烷氧基取代； R 13 is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, NHC(=O)-C 3-6 cycloalkyl, NHC(=O )-3-6 membered heterocycloalkyl, NHC(=O)-phenyl and NHC(=O)-5-6 membered heteroaryl, the C 3-6 cycloalkyl, 3-6 membered heterocyclic Alkyl, phenyl, 5-6 membered heteroaryl, NHC(=O)C 3-6 cycloalkyl, NHC(=O)-3-6 membered heterocycloalkyl, NHC(=O)-phenyl and NHC(=O)-5-6 membered heteroaryl optionally substituted by 1, 2 or 3 halogens, C 1-3 alkyl and C 1-3 alkoxy;
R 1选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
R 2选自H、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代； R 2 is selected from H, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R b ;
环B不存在；Ring B does not exist;
或者，环B选自C 5-10环烷基、5-10元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 5-10环烷基、5-10元杂环烷基、C 6-10芳基和5-10元杂芳基任选被1、2或3个R c取代； Alternatively, Ring B is selected from C 5-10 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 5-10 cycloalkyl, 5- 10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 R c ;
E选自-(CH 2) s-NR 3-、
Figure PCTCN2022096978-appb-000002
和-C(＝O)NR 3-C 3-6环烷基-NR 3-； E is selected from -(CH 2 ) s -NR 3 -,
Figure PCTCN2022096978-appb-000002
and -C(=O)NR 3 -C 3-6 cycloalkyl-NR 3 -;
s为0、1或2；s is 0, 1 or 2;
n和m分别独立地选自0、1、2和3；n and m are independently selected from 0, 1, 2 and 3;
R 3分别独立地选自H和C 1-3烷基； R 3 are independently selected from H and C 1-3 alkyl;
R 4选自F、Cl、Br、I和OH； R is selected from F, Cl, Br, I and OH;
R a和R b分别独立地选自H、D、F、Cl、Br和I； R and R are independently selected from H, D, F, Cl, Br and I;
各R c分别独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； Each R c is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
所述3-6元杂环烷、5-10元杂环烷基、5-6元杂芳基和5-10元杂芳基中“杂”表示1、2或3个分别独立地选自N、O、S和NH的原子或原子团。"Hetero" in the 3-6 membered heterocycloalkane, 5-10 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-10 membered heteroaryl means that 1, 2 or 3 are independently selected from Atoms or atomic groups of N, O, S and NH.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022096978-appb-000003
Figure PCTCN2022096978-appb-000003
其中，in,
T选自N和CH，所述CH任选被1个卤素取代；T is selected from N and CH optionally substituted by 1 halogen;
R 1选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
R 2选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代； R 2 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R ;
环B不存在；Ring B does not exist;
或者，环B选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个R c取代； Alternatively, ring B is selected from 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R c ;
E选自-(CH 2)-NR 3-、
Figure PCTCN2022096978-appb-000004
和-C(＝O)NR 3-C 3-6环烷基-NR 3-； E is selected from -(CH 2 )-NR 3 -,
Figure PCTCN2022096978-appb-000004
and -C(=O)NR 3 -C 3-6 cycloalkyl-NR 3 -;
n和m分别独立地选自0、1、2和3；n and m are independently selected from 0, 1, 2 and 3;
R 3分别独立地选自H和C 1-3烷基； R 3 are independently selected from H and C 1-3 alkyl;
R 4选自F、Cl、Br、I和OH； R is selected from F, Cl, Br, I and OH;
R a和R b分别独立地选自H、D、F、Cl、Br和I； R and R are independently selected from H, D, F, Cl, Br and I;
各R c分别独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； Each R c is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
所述5-6元杂芳基中“杂”表示1、2或3个分别独立地选自N、O、S和NH的原子或原子团。"Hetero" in the 5-6 membered heteroaryl represents 1, 2 or 3 atoms or atomic groups independently selected from N, O, S and NH.
在本发明的一些方案中，上述T选自N和CH，其他变量如本发明所定义。In some aspects of the present invention, the above T is selected from N and CH, and other variables are as defined in the present invention.
在本发明的一些方案中，上述T选自N，其他变量如本发明所定义。In some solutions of the present invention, the above T is selected from N, and other variables are as defined in the present invention.
在本发明的一些方案中，上述n选自0和1，其他变量如本发明所定义。In some solutions of the present invention, the above n is selected from 0 and 1, and other variables are as defined in the present invention.
在本发明的一些方案中，上述各R c分别独立地选自H、F、Cl、Br、I和CH 3，所述CH 3任选被1、2或3个卤素取代，其他变量如本发明所定义。 In some schemes of the present invention, each of the above-mentioned R c is independently selected from H, F, Cl, Br, I and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 halogens, and other variables are as in this invention defined.
在本发明的一些方案中，上述各R c分别独立地选自H、F、Cl、Br、I、CH 3、CH 2F、CHF 2和CF 3，其他变量如本发明所定义。 In some solutions of the present invention, each R c mentioned above is independently selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 and CF 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述各R 1选自CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some embodiments of the present invention, each of the above R 1 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 1选自OCH 3，其他变量如本发明所定义。 In some solutions of the present invention, the above R 1 is selected from OCH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2选自H、CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from H, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2选自H、CH 3和CD 3，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from H, CH 3 and CD 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述Y、Y 1、Y 2和Y 3选自CH，其他变量如本发明所定义。 In some solutions of the present invention, the aforementioned Y, Y 1 , Y 2 and Y 3 are selected from CH, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 11选自CH 2＝CH 2和CH 2CN，其他变量如本发明所定义。 In some solutions of the present invention, the above R 11 is selected from CH 2 =CH 2 and CH 2 CN, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 12选自NH 2、NHCH 3、NHCD 3、CH 2CH 3和CH 2CD 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 12 is selected from NH 2 , NHCH 3 , NHCD 3 , CH 2 CH 3 and CH 2 CD 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 13选自NHC(＝O)-环丙基，其他变量如本发明所定义。 In some aspects of the present invention, the above R 13 is selected from NHC(=O)-cyclopropyl, and other variables are as defined in the present invention.
在本发明的一些方案中，上述环B选自
Figure PCTCN2022096978-appb-000005
所述
Figure PCTCN2022096978-appb-000006
任选被1、2或3个R c取代，其他变量如本发明所定义。 In some aspects of the present invention, the above ring B is selected from
Figure PCTCN2022096978-appb-000005
said
Figure PCTCN2022096978-appb-000006
Optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
在本发明的一些方案中，上述环B选自
Figure PCTCN2022096978-appb-000007
其他变量如本发明所定义。 In some aspects of the present invention, the above ring B is selected from
Figure PCTCN2022096978-appb-000007
Other variables are as defined herein.
在本发明的一些方案中，上述E选自NH、-(CH 2)-NH-、-(CH 2)-N(CH 3)-、
Figure PCTCN2022096978-appb-000008
Figure PCTCN2022096978-appb-000009
其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned E is selected from NH, -(CH 2 )-NH-, -(CH 2 )-N(CH 3 )-,
Figure PCTCN2022096978-appb-000008
Figure PCTCN2022096978-appb-000009
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022096978-appb-000010
选自
Figure PCTCN2022096978-appb-000011
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022096978-appb-000010
selected from
Figure PCTCN2022096978-appb-000011
Other variables are as defined herein.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022096978-appb-000012
Figure PCTCN2022096978-appb-000012
其中，in,
T选自N和CH，所述CH任选被1个卤素取代；T is selected from N and CH optionally substituted by 1 halogen;
R 1选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
R 2选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代； R 2 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R ;
环B不存在；Ring B does not exist;
或者，环B选自5元杂芳基，所述5元杂芳基任选被1、2或3个R c取代； Alternatively, Ring B is selected from a 5-membered heteroaryl optionally substituted by 1, 2 or 3 R ;
E选自-(CH 2)-NR 3-、
Figure PCTCN2022096978-appb-000013
和-C(＝O)NR 3-C 3-5环烷基-NR 3-； E is selected from -(CH 2 )-NR 3 -,
Figure PCTCN2022096978-appb-000013
and -C(=O)NR 3 -C 3-5 cycloalkyl-NR 3 -;
n和m分别独立地选自0、1和2；n and m are independently selected from 0, 1 and 2;
R 3分别独立地选自H和C 1-3烷基； R 3 are independently selected from H and C 1-3 alkyl;
R a和R b分别独立地选自H、D、F、Cl、Br和I； R and R are independently selected from H, D, F, Cl, Br and I;
R c独立地选自H、F、Cl、Br和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代； R c is independently selected from H, F, Cl, Br and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
各R选自F、Cl、Br和I；each R is selected from F, Cl, Br and I;
所述5元杂芳基包含1、2或3个分别独立地选自N、O、S和NH的原子或原子团。The 5-membered heteroaryl group contains 1, 2 or 3 atoms or atom groups independently selected from N, O, S and NH.
在本发明的一些方案中，上述R c独立地选自H、F、Cl、Br和CH 3，所述CH 3任选被1、2或3个R取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R c is independently selected from H, F, Cl, Br and CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R c独立地选自H、F、Cl、Br、CH 3、CH 2F、CHF 2和CF 3，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R c is independently selected from H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 and CF 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 1选自CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 1选自OCH 3，其他变量如本发明所定义。 In some solutions of the present invention, the above R 1 is selected from OCH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2选自CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2选自CD 3，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from CD 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述环B选自
Figure PCTCN2022096978-appb-000014
所述
Figure PCTCN2022096978-appb-000015
Figure PCTCN2022096978-appb-000016
任选被1、2或3个R c取代，其他变量如本发明所定义。 In some aspects of the present invention, the above ring B is selected from
Figure PCTCN2022096978-appb-000014
said
Figure PCTCN2022096978-appb-000015
Figure PCTCN2022096978-appb-000016
Optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
在本发明的一些方案中，上述环B选自
Figure PCTCN2022096978-appb-000017
其他变量如本发明所定义。 In some aspects of the present invention, the above ring B is selected from
Figure PCTCN2022096978-appb-000017
Other variables are as defined herein.
在本发明的一些方案中，上述E选自-(CH 2)-NH-、-(CH 2)-N(CH 3)-、
Figure PCTCN2022096978-appb-000018
Figure PCTCN2022096978-appb-000019
其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned E is selected from -(CH 2 )-NH-, -(CH 2 )-N(CH 3 )-,
Figure PCTCN2022096978-appb-000018
Figure PCTCN2022096978-appb-000019
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022096978-appb-000020
选自
Figure PCTCN2022096978-appb-000021
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022096978-appb-000020
selected from
Figure PCTCN2022096978-appb-000021
Other variables are as defined herein.
本发明还有一些方案由上述变量任意组合而来。Some solutions of the present invention are formed by any combination of the above variables.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：In some aspects of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:
Figure PCTCN2022096978-appb-000022
Figure PCTCN2022096978-appb-000022
其中，in,
T 1选自N和CH； T1 is selected from N and CH;
R 1、R 2、E、T和R c如本发明所定义。 R 1 , R 2 , E, T and R c are as defined in the present invention.
本发明提供了下式所示化合物或其药学上可接受的盐，The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022096978-appb-000023
Figure PCTCN2022096978-appb-000023
Figure PCTCN2022096978-appb-000024
Figure PCTCN2022096978-appb-000024
Figure PCTCN2022096978-appb-000025
Figure PCTCN2022096978-appb-000025
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：In some aspects of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:
Figure PCTCN2022096978-appb-000026
Figure PCTCN2022096978-appb-000026
Figure PCTCN2022096978-appb-000027
Figure PCTCN2022096978-appb-000027
本发明还提供了下述实验方法：The present invention also provides following experimental method:
实验例：化合物对Ba/F3-FL-TYK2-E957D和Ba/F3-TEL-TYK2细胞增殖的抑制活性Experimental example: Inhibitory activity of the compound on the proliferation of Ba/F3-FL-TYK2-E957D and Ba/F3-TEL-TYK2 cells
三磷酸腺苷(Adenosine Tri-Phosphate，ATP)是自然界中各种生命活动中共用的能量载体，是能量储存和转移的最小单位。CellTiter-Glo TM活细胞检测试剂盒采用萤光素酶作检测物，发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-Glo TM试剂，测量发光值，光信号和体系中ATP量成正比，而ATP又和活细胞数正相关。因此通过使用CellTiter-Glo试剂盒检测ATP含量，可以检测出细胞的增殖情况。本测试中，细胞系为Ba/F3-FL-TYK2-E957D和Ba/F3-TEL-TYK2。其中Ba/F3-FL-TYK2-E957D细胞能够稳定表达外源导入的人TYK2-E957D基因，TYK2-E957D基因序列包含有JH1和JH2结构域；Ba/F3-TEL-TYK2细胞能够稳定表达外源导入的人TEL-TYK2基因，TEL-TYK2基因序列仅包含TYK2的JH1结构域。 Adenosine Tri-Phosphate (ATP) is a common energy carrier in various life activities in nature, and is the smallest unit of energy storage and transfer. CellTiter-Glo TM Live Cell Detection Kit uses luciferase as the detection substance, and luciferase needs the participation of ATP in the process of luminescence. Add CellTiter-Glo TM reagent to the cell culture medium, measure the luminescence value, the light signal is directly proportional to the amount of ATP in the system, and ATP is positively correlated with the number of living cells. Therefore, by using the CellTiter-Glo kit to detect the ATP content, the cell proliferation can be detected. In this test, the cell lines were Ba/F3-FL-TYK2-E957D and Ba/F3-TEL-TYK2. Among them, Ba/F3-FL-TYK2-E957D cells can stably express exogenously introduced human TYK2-E957D gene, and the TYK2-E957D gene sequence contains JH1 and JH2 domains; Ba/F3-TEL-TYK2 cells can stably express exogenous The introduced human TEL-TYK2 gene, the TEL-TYK2 gene sequence only includes the JH1 domain of TYK2.
IC 50测定过程： IC50 determination process:
1)细胞培养1) Cell culture
将细胞系在培养条件37℃，5％CO 2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。 Cell lines were cultured in an incubator with culture conditions of 37 °C, 5% CO2 . Passage regularly, and take cells in logarithmic growth phase for plating.
2)化合物存储板制备2) Compound storage plate preparation
a)用DMSO将待测化合物配置成10mM溶液，再用DMSO将待测化合物稀释至0.3或1mM。a) Prepare the test compound into a 10 mM solution with DMSO, and then dilute the test compound to 0.3 or 1 mM with DMSO.
b)制备1000×化合物存储板(管)：用DMSO从最高浓度3倍梯度稀释至最低浓度，9个浓度(Ba/F3-FL-TYK2-E957D细胞系最高浓度为1μM或300nM；Ba/F3-TEL-TYK2细胞系最高浓度为10μM)。b) Prepare 1000× compound storage plate (tube): use DMSO to serially dilute from the highest concentration 3 times to the lowest concentration, 9 concentrations (Ba/F3-FL-TYK2-E957D cell line highest concentration is 1μM or 300nM; Ba/F3 - TEL-TYK2 cell line at a maximum concentration of 10 μM).
c)20×化合物工作液的配制：在平底的96孔透明药板中加入49μL细胞培养液，从1000×化合物存储板中吸取1μL化合物加入96孔透明药板的细胞培养液中。在溶媒对照中加入1μL DMSO。加入化合物或DMSO后用排枪吹打混匀。c) Preparation of 20×compound working solution: Add 49 μL of cell culture medium to a flat-bottomed 96-well transparent drug plate, and pipette 1 μL of compound from the 1000× compound storage plate into the cell culture medium of the 96-well transparent drug plate. Add 1 µL of DMSO to the vehicle control. After adding the compound or DMSO, pipette and mix with an exhaust gun.
3)细胞铺板与给药3) Cell plating and administration
a)用台盼兰进行细胞染色并计数活细胞，要求细胞活率90％以上。a) Cell staining with trypan blue and counting live cells, the cell viability rate should be over 90%.
b)在化合物检测细胞板中每孔加入95μL细胞悬液(2000cells/well)，在Min对照孔中加入不含细胞(含0.1％DMSO)的培养液。b) 95 μL of cell suspension (2000 cells/well) was added to each well of the compound detection cell plate, and culture solution without cells (containing 0.1% DMSO) was added to the Min control well.
c)化合物检测细胞板加药：取5μL的20×化合物工作液按表1所示加入到细胞培养板中。在Max对照中加入5μL DMSO-细胞培养液混合液。DMSO终浓度为0.1％。c) Adding drugs to the compound detection cell plate: Take 5 μL of 20×compound working solution and add it to the cell culture plate as shown in Table 1. Add 5 μL of DMSO-cell culture medium mixture to the Max control. The final concentration of DMSO was 0.1%.
d)将培养板在37℃，5％CO2培养箱中培养72小时。d) Incubate the culture plate for 72 hours in a 37°C, 5% CO2 incubator.
4)CellTiter-Glo发光法细胞活性检测4) CellTiter-Glo Luminescent Cell Viability Detection
以下步骤按照Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573)的说明书来进行。The following steps were performed according to the instructions of the Promega CellTiter-Glo Luminescent Cell Viability Detection Kit (Promega-G7573).
a)将CellTiter-Glo缓冲液融化并放置至室温。a) Thaw CellTiter-Glo Buffer and let it cool to room temperature.
b)将CellTiter-Glo底物放置至室温。b) Bring CellTiter-Glo Substrate to room temperature.
c)在一瓶CellTiter-Glo底物中加入CellTiter-Glo缓冲液以溶解底物，从而配制CellTiter-Glo工作液。c) Add CellTiter-Glo Buffer to a vial of CellTiter-Glo Substrate to dissolve the substrate to prepare CellTiter-Glo Working Solution.
d)缓慢涡旋震荡使充分溶解。d) Slowly vortex to fully dissolve.
e)取出细胞培养板放置10分钟使其平衡至室温。e) Take out the cell culture plate and let it equilibrate to room temperature for 10 minutes.
f)在每孔中加入50μL(等于每孔中细胞培养液一半体积)的CellTiter-Glo工作液。f) Add 50 μL (equal to half the volume of the cell culture medium in each well) of CellTiter-Glo working solution to each well.
g)将培养板在轨道摇床上振摇2分钟以诱导细胞裂解。g) Shake the plate on an orbital shaker for 2 minutes to induce cell lysis.
h)培养板在室温放置10分钟以稳定发光信号。h) The culture plate was left at room temperature for 10 minutes to stabilize the luminescent signal.
i)在SpectraMax Paradigm读板器上检测发光信号。i) Detection of luminescent signal on SpectraMax Paradigm plate reader.
5)数据处理5) Data processing
SpectraMax Paradigm读数得出对应的每孔荧光值RLU。The SpectraMax Paradigm readout yields the corresponding RLU of fluorescence per well.
细胞增殖抑制率(Inhibition Rate)数据采用下列公式来处理：Cell proliferation inhibition rate (Inhibition Rate) data is processed by the following formula:
Inhibition Rate(Inh％)＝100-(RLU Drug-RLU Min)/(RLU Max-RLU Min)*100％。在EXCEL中计算不同浓度化合物对应的抑制率，然后用GraphPad Prism软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。 Inhibition Rate (Inh%)=100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%. The inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the data were analyzed with GraphPad Prism software, and the nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated accordingly.
实验例：化合物对人PBMC细胞TYK2、JAK1、JAK2和JAK3信号通路的抑制活性Experimental example: Inhibitory activity of compounds on TYK2, JAK1, JAK2 and JAK3 signaling pathways in human PBMC cells
本实验目的是在人外周血单个核细胞(PBMC)中检测化合物对细胞因子激活的JAK-STAT信号通路的抑制作用。其中通过IFNα刺激激活TYK2信号通路，检测化合物对其下游STAT1磷酸化的抑制活性，可得出化合物对TYK2信号通路活性的半数抑制浓度IC 50；而对于JAK1信号通路，通过IL-6刺激激活JAK1信号通路，检测化合物对其下游STAT1磷酸化的抑制活性，可得出化合物对JAK1信号通路活性的半数抑制浓度IC 50；对于JAK2信号通路，通过GM-CSF刺激激活JAK2信号通路，检测化合物对其下游 STAT5磷酸化的抑制活性，可得出化合物对JAK2信号通路活性的半数抑制浓度IC 50；对于JAK3信号通路，通过IL-2刺激激活JAK3信号通路，检测化合物对其下游STAT5磷酸化的抑制活性，可得出化合物对JAK3信号通路活性的半数抑制浓度IC 50。 The purpose of this experiment is to detect the inhibitory effect of compounds on cytokine-activated JAK-STAT signaling pathway in human peripheral blood mononuclear cells (PBMC). Among them, the TYK2 signaling pathway is activated by IFNα stimulation, and the inhibitory activity of the compound on its downstream STAT1 phosphorylation can be detected, and the half inhibitory concentration IC 50 of the compound on the activity of the TYK2 signaling pathway can be obtained; while for the JAK1 signaling pathway, JAK1 is activated by IL-6 stimulation Signaling pathway, detecting the inhibitory activity of the compound on its downstream STAT1 phosphorylation, the half inhibitory concentration IC 50 of the compound on the activity of the JAK1 signaling pathway can be obtained; The inhibitory activity of the downstream STAT5 phosphorylation can be used to obtain the half inhibitory concentration IC 50 of the compound on the activity of the JAK2 signaling pathway; for the JAK3 signaling pathway, the JAK3 signaling pathway can be activated by IL-2 stimulation, and the inhibitory activity of the compound on its downstream STAT5 phosphorylation can be detected , the half inhibitory concentration IC 50 of the compound on JAK3 signaling pathway activity can be obtained.
1主要试剂及仪器1 Main reagents and instruments
1)细胞：人外周血单个核细胞(PBMC)(供应商：赛笠生物)1) Cells: Human Peripheral Blood Mononuclear Cells (PBMC) (Supplier: Saili Biological)
2)试剂2) Reagent
表1试剂信息Table 1 Reagent information
Figure PCTCN2022096978-appb-000028
Figure PCTCN2022096978-appb-000028
3)仪器3) Instrument
流式细胞仪：品牌：BD；型号：FortessaFlow cytometer: Brand: BD; Model: Fortessa
2试剂配制2 reagent preparation
培养液：1640培养液+10％胎牛血清+1％双抗+1％非必需氨基酸(百分比均为体积比)Culture medium: 1640 culture medium + 10% fetal bovine serum + 1% double antibody + 1% non-essential amino acids (percentages are volume ratios)
3实验步骤3 experimental steps
a)将于液氮中冻存的PBMC在37℃水浴中解冻，加入培养液，320g离心3min。a) PBMCs frozen in liquid nitrogen were thawed in a water bath at 37° C., culture medium was added, and centrifuged at 320 g for 3 min.
b)培养液重悬细胞后计数，用培养液将细胞浓度调整为5×10 5个/mL，然后将细胞悬液接种至两个96孔圆底板，每孔200μL。37℃、5％CO 2条件下孵育90min。 b) Count the cells after resuspending them in the culture medium, adjust the cell concentration to 5×10 5 cells/mL with the culture medium, and then inoculate the cell suspension into two 96-well round-bottom plates, 200 μL per well. Incubate for 90 min at 37°C and 5% CO 2 .
c)加入不同浓度的待测化合物(2μM起始，5倍梯度稀释，共8个浓度)，37℃、5％CO 2孵育30min。 c) Add different concentrations of the compound to be tested (starting at 2 μM, 5-fold serial dilution, 8 concentrations in total), and incubate at 37° C., 5% CO 2 for 30 min.
d)在第一个圆底板中加入IL-6(终浓度20ng/mL)，37℃、5％CO 2孵育15min。 d) Add IL-6 (final concentration: 20 ng/mL) to the first round bottom plate, and incubate at 37° C., 5% CO 2 for 15 min.
e)在第二个圆底板中加入IFNα(终浓度1000U/mL)，37℃、5％CO 2孵育15min。 e) Add IFNα (final concentration: 1000 U/mL) to the second round bottom plate, and incubate at 37° C., 5% CO 2 for 15 minutes.
f)在第三个圆底板中加入IL-2(终浓度4ng/mL)，37℃、5％CO 2孵育15min。 f) Add IL-2 (final concentration: 4 ng/mL) to the third round bottom plate, and incubate at 37° C., 5% CO 2 for 15 min.
g)在第四个圆底板中加入GM-CSF(终浓度20pg/mL)，37℃、5％CO 2孵育15min。 g) Add GM-CSF (final concentration: 20 pg/mL) to the fourth round bottom plate, and incubate at 37° C., 5% CO 2 for 15 minutes.
h)细胞320g离心3min，每孔加入200μL染色液洗一次。h) The cells were centrifuged at 320 g for 3 min, and 200 μL of staining solution was added to each well to wash once.
i)在GM-CSF刺激的培养板中每孔加入50μL含有人CD33抗体的染色液，其余三个培养板中加入50μL含有CD4抗体的染色液，4℃染色30min。染色液洗两次。i) Add 50 μL of staining solution containing human CD33 antibody to each well of the GM-CSF-stimulated culture plate, add 50 μL of staining solution containing CD4 antibody to the remaining three culture plates, and stain at 4° C. for 30 min. Wash twice in staining solution.
j)每孔加入100μL固定液，4℃固定15min。染色液洗一次。j) Add 100 μL of fixative solution to each well and fix at 4°C for 15 minutes. Wash once with staining solution.
k)每孔加入100μL破膜液，4℃破膜20min。染色液洗两次。k) Add 100 μL permeation solution to each well, and permeate the membrane at 4°C for 20 minutes. Wash twice in staining solution.
1)在IL-6、IFNα刺激的培养板中每孔加入50μL含有人pSTAT1抗体的染色液；在IL-2、GM-CSF刺激的培养板中每孔加入50μL含有人pSTAT5抗体的染色液，室温染色15min。染色液洗两次。1) Add 50 μL of staining solution containing human pSTAT1 antibody to each well of the culture plate stimulated by IL-6 and IFNα; add 50 μL of staining solution containing human pSTAT5 antibody to each well of the culture plate stimulated by IL-2 and GM-CSF, Stain at room temperature for 15 minutes. Wash twice in staining solution.
m)150μL染色液重悬细胞。m) Resuspend the cells in 150 μL staining solution.
n)用流式细胞仪检测CD4阳性细胞中pSTAT1(IL-6和IFNα刺激)或pSTAT5(IL-2刺激)的荧光强度；检测CD33阳性细胞中pSTAT5(GM-CSF刺激)的荧光强度。n) Detect the fluorescence intensity of pSTAT1 (stimulated by IL-6 and IFNα) or pSTAT5 (stimulated by IL-2) in CD4 positive cells by flow cytometry; detect the fluorescence intensity of pSTAT5 (stimulated by GM-CSF) in CD33 positive cells.
技术效果technical effect
本发明化合物对TYK2 JH2假激酶具有良好的抑制作用。The compound of the present invention has good inhibitory effect on TYK2 JH2 pseudokinase.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无 毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to the salts of the compounds of the present invention, which are prepared from the compounds with specific substituents found in the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, 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 both.
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereoisomers and interconversions isomer.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotation, "(-)" means levorotation, and "(±)" means racemization.
除非另有说明，用楔形实线键
Figure PCTCN2022096978-appb-000029
和楔形虚线键
Figure PCTCN2022096978-appb-000030
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022096978-appb-000031
和直形虚线键
Figure PCTCN2022096978-appb-000032
表示立体中心的相对构型，用波浪线
Figure PCTCN2022096978-appb-000033
表示楔形实线键
Figure PCTCN2022096978-appb-000034
或楔形虚线键
Figure PCTCN2022096978-appb-000035
或用波浪线
Figure PCTCN2022096978-appb-000036
表示直形实线键
Figure PCTCN2022096978-appb-000037
或直形虚线键
Figure PCTCN2022096978-appb-000038
Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022096978-appb-000029
and dotted wedge keys
Figure PCTCN2022096978-appb-000030
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2022096978-appb-000031
and straight dashed keys
Figure PCTCN2022096978-appb-000032
Indicates the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022096978-appb-000033
Indicates wedge-shaped solid-line bond
Figure PCTCN2022096978-appb-000034
or dotted wedge key
Figure PCTCN2022096978-appb-000035
or with tilde
Figure PCTCN2022096978-appb-000036
Indicates a straight solid line key
Figure PCTCN2022096978-appb-000037
or straight dotted key
Figure PCTCN2022096978-appb-000038
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 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%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。 例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise stated, the terms "isomer excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. from amines to amino groups formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond 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. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。The term "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. When a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "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 realizable basis.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。 When the number of a substituent is 0, it means that the substituent does not exist, such as -A-(R) 0 means that the structure is actually -A.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。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.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2022096978-appb-000039
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。 A substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit
Figure PCTCN2022096978-appb-000039
It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022096978-appb-000040
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022096978-appb-000041
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022096978-appb-000042
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the linking group listed does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure PCTCN2022096978-appb-000040
The connecting 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 to form
Figure PCTCN2022096978-appb-000041
It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
Figure PCTCN2022096978-appb-000042
Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022096978-appb-000043
直形虚线键
Figure PCTCN2022096978-appb-000044
或波浪线
Figure PCTCN2022096978-appb-000045
表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022096978-appb-000046
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2022096978-appb-000047
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2022096978-appb-000048
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022096978-appb-000049
Figure PCTCN2022096978-appb-000050
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022096978-appb-000051
仍包括
Figure PCTCN2022096978-appb-000052
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。 Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group. The chemical bonds that the site connects with other groups can use straight solid line bonds
Figure PCTCN2022096978-appb-000043
Straight dotted key
Figure PCTCN2022096978-appb-000044
or tilde
Figure PCTCN2022096978-appb-000045
express. For example, the straight solid line bond in -OCH3 means that it is connected to other groups through the oxygen atom in the group;
Figure PCTCN2022096978-appb-000046
The straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
Figure PCTCN2022096978-appb-000047
The wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
Figure PCTCN2022096978-appb-000048
Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2022096978-appb-000049
Figure PCTCN2022096978-appb-000050
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2022096978-appb-000051
still include
Figure PCTCN2022096978-appb-000052
For groups with this connection method, only when a chemical bond is connected, the H at this site will be reduced by one to become the corresponding monovalent piperidinyl group.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring" means a "ring" with 5-7 atoms arranged around it.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term "C 1-3 alkoxy" denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，“C 2-4烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至4个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C 2-4烯基包括C 2-3、C 4、C 3和C 2烯基等；所述C 2-4烯基可以是一价、二价或者多价。C 2-4烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、丁间二烯基等。 Unless otherwise specified, " C2-4alkenyl " is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group. The C 2-4 alkenyl includes C 2-3 , C 4 , C 3 and C 2 alkenyl, etc.; the C 2-4 alkenyl can be monovalent, divalent or multivalent. Examples of C alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.
除非另有规定，“C 2-4炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至4个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C 2-4炔基包括C 2-3、C 4、C 3和C 2炔基等。其可以是一价、二价或者多价。C 2-4炔基的实例包括但不限于乙炔基、丙炔基、丁炔基等。 Unless otherwise specified, " C2-4 alkynyl" is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, the carbon-carbon triple bond can be located anywhere in the group. The C 2-4 alkynyl includes C 2-3 , C 4 , C 3 and C 2 alkynyl and the like. It may be monovalent, divalent or polyvalent. Examples of C alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
除非另有规定，“C 5-10环烷基”表示由5至10个碳原子组成的饱和环状碳氢基团，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。所述C 5-10环烷基包括C 5-8或C 5-6等；其可以是一价、二价或者多价。C 5-10环烷基的实例包括，但不限于，环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。 Unless otherwise specified, "C 5-10 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 5 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include Spiral, parallel and bridged rings. The C 5-10 cycloalkyl group includes C 5-8 or C 5-6 and the like; it may be monovalent, divalent or multivalent. Examples of C 5-10 cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0] dicyclodecane Wait.
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1，2-噁嗪基、1，2-噻嗪基、六氢哒嗪基、高哌嗪 基或高哌啶基等。 Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 3-6-membered heterocycloalkyl group includes 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl pyridyl, etc.
除非另有规定，术语“5-10元杂环烷基”本身或者与其他术语联合分别表示由5至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“5-10元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-10元杂环烷基包括5-8元、5-6元、5元、6元和8元杂环烷基等。5-10元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1，2-噁嗪基、1，2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。 Unless otherwise specified, the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings. In addition, as for the "5-10 membered heterocycloalkyl group", a heteroatom may occupy the attachment position of the heterocycloalkyl group to the rest of the molecule. The 5-10 membered heterocycloalkyl group includes 5-8 membered, 5-6 membered, 5-membered, 6-membered and 8-membered heterocycloalkyl groups and the like. Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.
除非另有规定，本发明术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。 Unless otherwise specified, the terms "C 6-10 aromatic ring" and "C 6-10 aryl" in the present invention can be used interchangeably, and the term "C 6-10 aromatic ring" or "C 6-10 aryl" means that the A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated π-electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It can be monovalent, divalent or multivalent, and the C 6-10 aryl group includes C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1，2，3-***基、2H-1，2，3-***基、1H-1，2，4-***基和4H-1，2，4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the terms "5-6-membered heteroaryl ring" and "5-6-membered heteroaryl" in the present invention can be used interchangeably, and the term "5-6-membered heteroaryl" means that there are 5 to 6 ring atoms A monocyclic group with a conjugated π-electron system, 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 , where p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl 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-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidyl (including 2-pyrimidyl and 4-pyrimidyl, etc.).
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-10元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-10元杂芳基包括5-8元、5-7元、5-6元、5元和6 元杂芳基等。所述5-10元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1，2，3-***基、2H-1，2，3-***基、1H-1，2，4-***基和4H-1，2，4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。 Unless otherwise specified, the terms "5-10 membered heteroaryl ring" and "5-10 membered heteroaryl" can be used interchangeably in the present invention, and the term "5-10 membered heteroaryl" means that there are 5 to 10 rings A cyclic group with a conjugated π-electron system composed of atoms, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system in which each ring is aromatic. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2). The 5-10 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5-membered and 6-membered heteroaryl groups and the like. Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl 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-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.) , purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.) .
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022096978-appb-000053
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method is:
Figure PCTCN2022096978-appb-000053
After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：aq代表水；eq代表当量、等量；DCM代表二氯甲烷；PE代表石油醚；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；DMF代表N，N-二甲基甲酰胺；Boc代表叔丁氧羰基是一种胺保护基团；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；HCl代表盐酸；mp代表熔点；Pd(dppf)Cl代表[1，1′-双(二苯膦基)二茂铁]二氯化钯；Pd(dppf)Cl 2.CH 2Cl 2代表[1，1′-双(二苯膦基)二茂铁]二氯化钯二氯甲烷复合物；TEA代表三乙胺；Xantphos代表4，5-双二苯基膦-9，9-二甲基氧杂蒽；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；HOBt代表1-羟基苯并***；NMP代表N-甲基吡咯烷酮；DIPEA代表N，N-二异丙基乙胺；SEM代表2-(三甲硅烷基)乙氧甲基；SFC代表超临界流体色谱法；Rt代表保留时间；e.e.％代表对映体过量百分率。 The present invention adopts the following abbreviations: aq stands for water; eq stands for equivalent, equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for Methanol; DMF stands for N,N-dimethylformamide; Boc stands for tert-butoxycarbonyl, which is an amine protecting group; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl Dicarbonate; TFA stands for trifluoroacetic acid; HCl stands for hydrochloric acid; mp stands for melting point; Pd(dppf)Cl stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(dppf) Cl 2 .CH 2 Cl 2 stands for [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; TEA stands for triethylamine; Xantphos stands for 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene; Pd 2 (dba) 3 represents tris(dibenzylideneacetone) dipalladium; EDCI represents 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride; HOBt stands for 1-hydroxybenzotriazole; NMP stands for N-methylpyrrolidone; DIPEA stands for N,N-diisopropylethylamine; SEM stands for 2-(trimethylsilyl)ethoxy Methyl; SFC stands for supercritical fluid chromatography; Rt stands for retention time; ee% stands for enantiomeric excess.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022096978-appb-000054
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to the conventional naming principles in this field or using
Figure PCTCN2022096978-appb-000054
The software is named, and the commercially available compounds adopt the supplier catalog name.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情 况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
参考例1Reference example 1
Figure PCTCN2022096978-appb-000055
Figure PCTCN2022096978-appb-000055
步骤1：化合物A-1的合成Step 1: Synthesis of Compound A-1
将化合物A-1-1(10g，49.49mmol，1eq)，双联频哪醇硼酸酯(18.85g，74.24mmol，1.5eq)，乙酸钾(14.57g，148.48mmol，3eq)溶于1，4-二氧六环(200mL)中，置换氮气三次后加入Pd(dppf)Cl 2.CH 2Cl 2(2.02g，2.47mmol，0.05eq)，在100℃搅拌2hr。向反应液中加入水(200mL)，用乙酸乙酯(100mL*2)萃取，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～25％，)，得到化合物A-1。 Compound A-1-1 (10g, 49.49mmol, 1eq), double pinacol borate (18.85g, 74.24mmol, 1.5eq), potassium acetate (14.57g, 148.48mmol, 3eq) were dissolved in 1, To 4-dioxane (200 mL), Pd(dppf)Cl 2 .CH 2 Cl 2 (2.02 g, 2.47 mmol, 0.05 eq) was added after replacing nitrogen three times, and stirred at 100° C. for 2 hr. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL*2), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-25%) to obtain compound A-1.
1HNMR(400MHz，CDCl 3)δ：7.13-7.11(m，1H)，6.93(t，J＝15.2，7.6Hz，1H)，6.88-6.85(m，1H)，3.81(s，3H)，1.36(s，12H)；LCMS m/z＝250.1[M+H] +。 1 HNMR (400MHz, CDCl 3 ) δ: 7.13-7.11 (m, 1H), 6.93 (t, J=15.2, 7.6Hz, 1H), 6.88-6.85 (m, 1H), 3.81 (s, 3H), 1.36 (s, 12H); LCMS m/z = 250.1 [M+H] + .
参考例2Reference example 2
Figure PCTCN2022096978-appb-000056
Figure PCTCN2022096978-appb-000056
步骤1：化合物B-1-2的合成Step 1: Synthesis of Compound B-1-2
将化合物B-1-1(20g，135.17mmol，1eq)溶于NMP(200mL)中，0℃加入钠氢(6.49g，162.20mmol，60％纯度，1.2eq)，搅拌0.5小时后，加入2-(三甲硅烷基)乙氧甲基氯(27.04g，162.20mmol，28.71mL，1.2eq)，自然升至15℃搅拌16hr。向反应液中加入饱和氯化铵水溶液(50mL)后加入乙酸乙酯(200mL*2)和水(200mL*2)萃取，有机相用饱和食盐水(200mL*2)清洗后用无水硫酸钠干燥后过滤，滤液减压浓缩得到化合物B-1-2。 1HNMR(400MHz，CDCl 3)δ：8.13(s，1H)，5.44(s，2H)，3.66-3.62(m，2H)，0.94-0.90(m，2H)，-0.02(s，9H)；LCMS m/z＝278.0[M+H] +。 Compound B-1-1 (20g, 135.17mmol, 1eq) was dissolved in NMP (200mL), and sodium hydrogen (6.49g, 162.20mmol, 60% purity, 1.2eq) was added at 0°C. After stirring for 0.5 hours, 2 -(Trimethylsilyl)ethoxymethyl chloride (27.04g, 162.20mmol, 28.71mL, 1.2eq), naturally raised to 15°C and stirred for 16hr. Add saturated ammonium chloride aqueous solution (50mL) to the reaction solution, then add ethyl acetate (200mL*2) and water (200mL*2) for extraction, the organic phase is washed with saturated brine (200mL*2) and then washed with anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure to obtain compound B-1-2. 1 HNMR (400MHz, CDCl 3 ) δ: 8.13(s, 1H), 5.44(s, 2H), 3.66-3.62(m, 2H), 0.94-0.90(m, 2H), -0.02(s, 9H); LCMS m/z = 278.0 [M+H] + .
步骤2：化合物B-1的合成Step 2: Synthesis of Compound B-1
将化合物B-1-2(5g，17.97mmol，1eq)，化合物A-1(4.48g，17.97mmol，1eq)，碳酸钾(4.97g，35.94mmol，2eq)溶于1，4-二氧六环(50mL)和水(30mL)中，置换氮气三次后加入Pd(dppf)Cl 2(1.31g，1.80mmol，0.1eq)，90℃搅拌14hr。向反应液中加入水(100mL)，用乙酸乙酯(50mL*2)萃取，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0～50％)得到化合物B-1。 1HNMR(400MHz，CDCl 3)δ：8.31(s，1H)，7.38-7.36(m，1H)，7.01(t，J＝15.2，7.6Hz，1H)，6.87-6.83(m，1H)，5.58(s，2H)，3.78(s，3H)，3.74-3.69(m，2H)，0.98-0.94(m，2H)，-0.01(s，9H)；LCMS m/z＝321.1[M+H] +。 Compound B-1-2 (5g, 17.97mmol, 1eq), compound A-1 (4.48g, 17.97mmol, 1eq), potassium carbonate (4.97g, 35.94mmol, 2eq) were dissolved in 1,4-dioxane Pd(dppf)Cl 2 (1.31g, 1.80mmol, 0.1eq) was added to the ring (50mL) and water (30mL), after nitrogen was replaced three times, and stirred at 90°C for 14hr. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL*2), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain compound B-1. 1 HNMR (400MHz, CDCl 3 ) δ: 8.31(s, 1H), 7.38-7.36(m, 1H), 7.01(t, J=15.2, 7.6Hz, 1H), 6.87-6.83(m, 1H), 5.58 (s, 2H), 3.78(s, 3H), 3.74-3.69(m, 2H), 0.98-0.94(m, 2H), -0.01(s, 9H); LCMS m/z=321.1[M+H] + .
参考例3Reference example 3
Figure PCTCN2022096978-appb-000057
Figure PCTCN2022096978-appb-000057
步骤1：化合物C-1的合成Step 1: Synthesis of Compound C-1
将化合物C-1-1(2g，11.55mmol，1eq)和对甲苯磺酰氯(2.42g，12.70mmol，1.1eq)加入到二氯甲烷(20mL)中，然后加入4-二甲氨基吡啶(116.20mg，951.10μmol，0.0824eq)，置换氮气后，降温至0℃，然后滴加入三乙胺(2.34g，23.09mmol，3.21mL，2eq)，在20℃反应12hr。加入水(20mL)，用二氯甲烷(20mL)萃取，有机相用饱和氯化钠水溶液洗涤一次，有机相用无水硫酸钠干燥，浓缩得粗品。粗品使用正庚烷(20mL)搅拌1hr，过滤，滤饼用正庚烷淋洗，干燥得到化合物C-1。 1HNMR(400MHz，CDCl 3)δ：7.78(d，J＝8.0Hz，2H)，7.37(d，J＝8.4Hz，2H)，5.04-4.98(m，1H)，4.10-3.94(m，2H)，3.90-3.86(m，2H)，2.57(s，3H)，2.43(s，9H)；LCMS m/z＝272[M-55] +。 Compound C-1-1 (2g, 11.55mmol, 1eq) and p-toluenesulfonyl chloride (2.42g, 12.70mmol, 1.1eq) were added to dichloromethane (20mL), and then 4-dimethylaminopyridine (116.20 mg, 951.10μmol, 0.0824eq), after nitrogen replacement, the temperature was lowered to 0°C, then triethylamine (2.34g, 23.09mmol, 3.21mL, 2eq) was added dropwise, and reacted at 20°C for 12hr. Add water (20 mL), extract with dichloromethane (20 mL), wash the organic phase once with saturated aqueous sodium chloride solution, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product was stirred with n-heptane (20 mL) for 1 hr, filtered, the filter cake was rinsed with n-heptane, and dried to obtain compound C-1. 1 HNMR (400MHz, CDCl 3 ) δ: 7.78(d, J=8.0Hz, 2H), 7.37(d, J=8.4Hz, 2H), 5.04-4.98(m, 1H), 4.10-3.94(m, 2H ), 3.90-3.86 (m, 2H), 2.57 (s, 3H), 2.43 (s, 9H); LCMS m/z=272[M-55] + .
参考例4Reference example 4
Figure PCTCN2022096978-appb-000058
Figure PCTCN2022096978-appb-000058
步骤1：化合物D-1的合成Step 1: Synthesis of Compound D-1
将D-1-1(2g，9.94mmol，1eq)和对甲苯磺酰氯(2.08g，10.93mmol，1.1eq)加入到二氯甲烷(20mL)中，然后加入4-二甲氨基吡啶(100.00mg，818.53μmol，0.0824eq)，置换氮气后，降温至0℃，然后滴加入三乙胺(2.01g，19.87mmol，2.77mL，2eq)，在20℃反应12hr。反应完成后，加入水(20mL)，用二氯甲烷(20mL)萃取，有机相用饱和氯化钠水溶液洗涤一次，有机相用无水硫酸钠干燥，浓缩得粗品。粗品使用正庚烷(20mL)搅拌1hr，过滤，滤饼用正庚烷淋洗，干燥得到化合物D-1。 1HNMR(400MHz，CDCl 3) δ：7.82(d，J＝8.0Hz，2H)，7.36(d，J＝8.0Hz，2H)，4.46(s，1H)，3.58-3.55(m，1H)，3.41-3.35(m，2H)，3.33-3.20(m，1H)，2.45(s，3H)，1.94-1.82(m，1H)，1.81-1.70(m，2H)，1.50-1.47(m，1H)，1.43(s，9H)；LCMS m/z＝378[M+23] +。 Add D-1-1 (2g, 9.94mmol, 1eq) and p-toluenesulfonyl chloride (2.08g, 10.93mmol, 1.1eq) into dichloromethane (20mL), then add 4-dimethylaminopyridine (100.00mg , 818.53μmol, 0.0824eq), after nitrogen replacement, the temperature was lowered to 0°C, then triethylamine (2.01g, 19.87mmol, 2.77mL, 2eq) was added dropwise, and reacted at 20°C for 12hr. After the reaction was complete, water (20 mL) was added, extracted with dichloromethane (20 mL), the organic phase was washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was stirred with n-heptane (20 mL) for 1 hr, filtered, the filter cake was rinsed with n-heptane, and dried to obtain compound D-1. 1 HNMR (400MHz, CDCl 3 ) δ: 7.82(d, J=8.0Hz, 2H), 7.36(d, J=8.0Hz, 2H), 4.46(s, 1H), 3.58-3.55(m, 1H), 3.41-3.35(m, 2H), 3.33-3.20(m, 1H), 2.45(s, 3H), 1.94-1.82(m, 1H), 1.81-1.70(m, 2H), 1.50-1.47(m, 1H) ), 1.43 (s, 9H); LCMS m/z=378[M+23] + .
参照参考例4的合成，将步骤1中D-1-1分别替换为下表中的片段，合成下表2中的化合物。Referring to the synthesis of Reference Example 4, replace D-1-1 in Step 1 with the fragments in the table below to synthesize the compounds in Table 2 below.
表2Table 2
Figure PCTCN2022096978-appb-000059
Figure PCTCN2022096978-appb-000059
参考例7Reference example 7
Figure PCTCN2022096978-appb-000060
Figure PCTCN2022096978-appb-000060
步骤1：化合物D-4的合成Step 1: Synthesis of Compound D-4
将化合物D-4-1(2g，9.94mmol，1eq)溶于二氯甲烷(20mL)中，加入三乙胺(4.02g，39.75mmol，5.53mL，4eq)，对甲苯磺酰氯(3.79g，19.87mmol，2eq)，二甲氨基吡啶(121.40mg，993.73μmol，0.1eq)，在15℃下搅拌20hr。向反应液中加入水(20mL)静置分液，有机相用无水硫酸钠干燥后过滤，滤液浓缩得到粗品。向粗品中加入正庚烷(30mL)有固体析出，搅拌0.5小时，过滤，滤饼即为化合物D-4。Compound D-4-1 (2g, 9.94mmol, 1eq) was dissolved in dichloromethane (20mL), triethylamine (4.02g, 39.75mmol, 5.53mL, 4eq), p-toluenesulfonyl chloride (3.79g, 19.87mmol, 2eq), dimethylaminopyridine (121.40mg, 993.73μmol, 0.1eq), stirred at 15°C for 20hr. Water (20 mL) was added to the reaction solution and allowed to stand for liquid separation, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. Add n-heptane (30 mL) to the crude product and a solid precipitates out. Stir for 0.5 hour and filter. The filter cake is compound D-4.
参考例8Reference example 8
Figure PCTCN2022096978-appb-000061
Figure PCTCN2022096978-appb-000061
步骤1：化合物E-1的合成Step 1: Synthesis of Compound E-1
将化合物1-2(10g，50.27mmol，1eq)溶于二氯甲烷(150mL)中，然后加入草酰氯(8.93g，70.38mmol，6.16mL，1.4eq)，然后加入N，N-二甲基甲酰胺(183.72mg，2.51mmol，193.39μL，0.05eq)，在20℃下反应4hr。将反应体系浓缩，再加入二氯甲烷(30mL)，再浓缩，然后加入二氯甲烷(150mL)，加入氘代甲胺盐酸盐(3.37g，47.76mmol，0.95eq)，然后降温至0℃后，加入DIPEA(19.49g，150.83mmol，26.27mL，3eq)，在20℃下反应16hr。反应完成后，向体系中加入水(150mL)，萃取分液，然后水相再用二氯甲烷(150mL)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0～20％)，得到化合物E-1。LCMS m/z＝209.0[M+1] +。 Compound 1-2 (10g, 50.27mmol, 1eq) was dissolved in dichloromethane (150mL), then oxalyl chloride (8.93g, 70.38mmol, 6.16mL, 1.4eq) was added, followed by N,N-dimethyl Formamide (183.72 mg, 2.51 mmol, 193.39 μL, 0.05 eq) was reacted at 20° C. for 4 hr. Concentrate the reaction system, then add dichloromethane (30mL), concentrate again, then add dichloromethane (150mL), add deuterated methylamine hydrochloride (3.37g, 47.76mmol, 0.95eq), then cool to 0°C After that, DIPEA (19.49g, 150.83mmol, 26.27mL, 3eq) was added and reacted at 20°C for 16hr. After the reaction is complete, add water (150mL) to the system, extract and separate the liquids, then extract the aqueous phase with dichloromethane (150mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain Crude. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-20%) to obtain compound E-1. LCMS m/z = 209.0 [M+1] + .
参考例9Reference example 9
Figure PCTCN2022096978-appb-000062
Figure PCTCN2022096978-appb-000062
步骤1：化合物F-1-2的合成Step 1: Synthesis of Compound F-1-2
将化合物F-1-1(18.5g，96.35mmol，1eq)溶于二氯甲烷(200mL)中，然后加入草酰氯(15.90g，125.26mmol，10.96mL，1.3eq)，然后加入N，N-二甲基甲酰胺(352.15mg，4.82mmol，370.68μL，0.05eq)，在25℃下反应16hr。然后将反应体系浓缩，再加入二氯甲烷(50mL)，再次浓缩，直接用于下一步，得到化合物F-1-2。Compound F-1-1 (18.5g, 96.35mmol, 1eq) was dissolved in dichloromethane (200mL), then oxalyl chloride (15.90g, 125.26mmol, 10.96mL, 1.3eq) was added, then N,N- Dimethylformamide (352.15mg, 4.82mmol, 370.68μL, 0.05eq) was reacted at 25°C for 16hr. Then the reaction system was concentrated, then dichloromethane (50 mL) was added, concentrated again, and directly used in the next step to obtain compound F-1-2.
步骤2：化合物F-1的合成Step 2: Synthesis of Compound F-1
将化合物F-1-2(20g，95.04mmol，1eq)，然后加入二氯甲烷(300mL)中，加入氘代甲胺盐酸盐(5.36g，76.03mmol，0.8eq)，然后降温至0℃后，加入DIPEA(36.85g，285.11mmol，49.66mL，3eq)，在20℃下反应16hr。反应完成后，向体系中加入饱和氯化铵水溶液(100mL)，萃取分液，然后水相再用二氯甲烷(60mL)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。向粗品中加入甲基叔丁基醚(100mL)，搅拌2hr后，过滤，滤饼减压浓缩得到化合物F-1。 1H NMR(400MHz，DMSO-d 6)δ：8.59(s，1H)，8.48(s，1H)，7.91(s，1H)；LCMS m/z＝208.1[M+1] +。 Compound F-1-2 (20g, 95.04mmol, 1eq) was then added to dichloromethane (300mL), and deuterated methylamine hydrochloride (5.36g, 76.03mmol, 0.8eq) was added, then cooled to 0°C After that, DIPEA (36.85g, 285.11mmol, 49.66mL, 3eq) was added and reacted at 20°C for 16hr. After the reaction was complete, add saturated aqueous ammonium chloride (100 mL) to the system, extract and separate the liquids, then extract the aqueous phase with dichloromethane (60 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain crude product. Add methyl tert-butyl ether (100 mL) to the crude product, stir for 2 hrs, filter, and concentrate the filter cake under reduced pressure to obtain compound F-1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.59 (s, 1H), 8.48 (s, 1H), 7.91 (s, 1H); LCMS m/z = 208.1 [M+1] + .
参考例10Reference example 10
Figure PCTCN2022096978-appb-000063
步骤1：化合物G-1-2的合成
Figure PCTCN2022096978-appb-000063
Step 1: Synthesis of compound G-1-2
将化合物G-1-1(1g，4.17mmol，1eq)溶于THF(30mL)中，氮气保护，降温至-78℃，滴加加入n-BuLi(2.5M，1.83mL，1.1eq)，于-78℃继续搅拌30min，然后加入DMF(380.86mg，5.21mmol，400.91μL，1.25eq)，升至室温25℃搅拌10小时。往反应液中加入水(50mL)，用乙酸乙脂(50mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，40℃真空浓缩得到粗品。粗品经硅胶柱层析纯化(石油醚∶乙酸乙酯＝20∶1-5∶1)得到化合物G-1-2。 1H NMR(400MHz，CDCl 3)δ：9.83(s，1H)，6.90(s，1H)，74.17(s，3H)。 Compound G-1-1 (1g, 4.17mmol, 1eq) was dissolved in THF (30mL), under nitrogen protection, the temperature was lowered to -78°C, n-BuLi (2.5M, 1.83mL, 1.1eq) was added dropwise, and in Continue stirring at -78°C for 30 min, then add DMF (380.86 mg, 5.21 mmol, 400.91 μL, 1.25 eq), warm to room temperature and stir at 25°C for 10 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo at 40°C to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-5:1) to obtain compound G-1-2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.83 (s, 1H), 6.90 (s, 1H), 74.17 (s, 3H).
步骤2：化合物G-1的合成Step 2: Synthesis of Compound G-1
将G-1-2(0.25g，1.32mmol，1eq)加入MeOH(7.5mL)中溶解，加入甲胺(410.78mg，3.97mmol，30％纯度，3eq)，氰基硼氢化钠(249.36mg，3.97mmol，3eq)，乙酸(262.12mg，4.36mmol，249.64μL，3.3eq)在室温25℃搅拌1.5小时。反应结束后，反应液加入水20mL，6N盐酸调节pH＝3-4，继续搅拌30min加入NaOH(4N)溶液，调节至pH为10，用乙酸乙酯(20mL)萃取后，无水硫酸钠干燥，真空浓缩。粗品用二氯甲烷(3mL)溶解加入碳酸酐二叔丁酯(1.44g，6.61mmol，1.52mL，5eq)，搅拌30min。在40℃真空浓缩后加水(30mL)，加乙酸乙酯(30ml)萃取，无水硫酸钠干燥，40℃真空浓缩。粗品经硅胶柱层析(石油醚∶乙酸乙酯＝10％-50％)纯化得到化合物G-1。LCMS m/z＝305.9[M+1] +。 G-1-2 (0.25g, 1.32mmol, 1eq) was dissolved in MeOH (7.5mL), methylamine (410.78mg, 3.97mmol, 30% purity, 3eq), sodium cyanoborohydride (249.36mg, 3.97mmol, 3eq), acetic acid (262.12mg, 4.36mmol, 249.64μL, 3.3eq) were stirred at room temperature 25°C for 1.5 hours. After the reaction, add 20 mL of water to the reaction solution, adjust the pH to 3-4 with 6N hydrochloric acid, continue stirring for 30 min, add NaOH (4N) solution, adjust the pH to 10, extract with ethyl acetate (20 mL), and dry over anhydrous sodium sulfate , concentrated in vacuo. The crude product was dissolved in dichloromethane (3 mL) and di-tert-butyl carbonic anhydride (1.44 g, 6.61 mmol, 1.52 mL, 5 eq) was added, and stirred for 30 min. Concentrate in vacuo at 40°C, add water (30 mL), extract with ethyl acetate (30 ml), dry over anhydrous sodium sulfate, and concentrate in vacuo at 40°C. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10%-50%) to obtain compound G-1. LCMS m/z = 305.9 [M+1] + .
实施例1Example 1
Figure PCTCN2022096978-appb-000064
Figure PCTCN2022096978-appb-000064
步骤1：化合物1-2的合成Step 1: Synthesis of Compound 1-2
将化合物1-1(20g，96.61mmol，1eq)溶于乙腈(100mL)和水(15mL)中，加入溴化锂(25.17g，289.84mmol，7.28mL，3eq)和DIPEA(37.46g，289.84mmol，50.48mL，3eq)，在20℃搅拌反应3hr。将体系过滤，滤饼用乙腈(50mL)淋洗，得到滤饼化合物1-2。LCMS m/z＝192.9[COOH+1] +。 Compound 1-1 (20g, 96.61mmol, 1eq) was dissolved in acetonitrile (100mL) and water (15mL), and lithium bromide (25.17g, 289.84mmol, 7.28mL, 3eq) and DIPEA (37.46g, 289.84mmol, 50.48 mL, 3eq), the reaction was stirred at 20°C for 3hr. The system was filtered, and the filter cake was rinsed with acetonitrile (50 mL) to obtain filter cake compound 1-2. LCMS m/z = 192.9 [COOH+1] + .
步骤2：化合物1-3的合成Step 2: Synthesis of compounds 1-3
将化合物B-1(0.15g，468.08μmol，1eq)溶于异丙醇(1.5mL)中，加入醋酸锌(171.76mg，936.15μmol，2eq)，化合物1-2(108.40mg，561.69μmol，1.2eq)，水(0.5mL)，在65℃搅拌15hr。向反应液中加入水2mL，搅拌，过滤，收集滤饼，得到化合物1-3。 1HNMR(400MHz，DMSO-d 6)δ：12.11(s，1H)，8.83(s，1H)， 7.75(d，J＝7.2Hz，1H)，7.68(d，J＝8.4Hz，1H)，7.34-7.30(m，2H)，5.59(s，2H)，3.72(s，3H)，3.69-3.65(m，3H)，0.88(t，J＝16.0，8.0Hz，2H)，-0.05(s，9H)；LCMS m/z＝477.1[M+H] +。 Dissolve compound B-1 (0.15g, 468.08μmol, 1eq) in isopropanol (1.5mL), add zinc acetate (171.76mg, 936.15μmol, 2eq), compound 1-2 (108.40mg, 561.69μmol, 1.2 eq), water (0.5 mL), stirred at 65 °C for 15 hr. Add 2 mL of water to the reaction solution, stir, filter, and collect the filter cake to obtain compound 1-3. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 12.11 (s, 1H), 8.83 (s, 1H), 7.75 (d, J=7.2Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.34-7.30(m, 2H), 5.59(s, 2H), 3.72(s, 3H), 3.69-3.65(m, 3H), 0.88(t, J=16.0, 8.0Hz, 2H), -0.05(s , 9H); LCMS m/z = 477.1 [M+H] + .
步骤3：化合物1-4的合成Step 3: Synthesis of Compounds 1-4
将化合物1-3(3.76g，7.38mmol，1eq，0.5Zn)，环丙基甲酰胺(6.28g，73.77mmol，10eq)，碳酸铯(7.21g，22.13mmol，3eq)，Xantphos(426.86mg，737.71μmol，0.1eq)溶于1，4-二氧六环(75.2mL)中，氮气置换三次后加入Pd 2(dba) 3(675.54mg，737.71μmol，0.1eq)，120℃搅拌2hr。与另一批次(500mg)一起后处理，向反应液中加入3mol/L稀盐酸调至pH＝3，加入二氯甲烷(50mL*2)和水(50mL*2)萃取，用无水硫酸钠干燥后过滤，滤液减压浓缩，得到化合物1-4。LCMS m/z＝526.2[M+H] +。 Compound 1-3 (3.76g, 7.38mmol, 1eq, 0.5Zn), cyclopropylformamide (6.28g, 73.77mmol, 10eq), cesium carbonate (7.21g, 22.13mmol, 3eq), Xantphos (426.86mg, 737.71μmol, 0.1eq) was dissolved in 1,4-dioxane (75.2mL), replaced with nitrogen three times, and Pd 2 (dba) 3 (675.54mg, 737.71μmol, 0.1eq) was added, and stirred at 120°C for 2hr. After treatment with another batch (500mg), add 3mol/L dilute hydrochloric acid to the reaction solution to adjust to pH = 3, add dichloromethane (50mL*2) and water (50mL*2) for extraction, and use anhydrous sulfuric acid After drying over sodium, it was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-4. LCMS m/z = 526.2 [M+H] + .
步骤4：化合物1-5的合成Step 4: Synthesis of Compounds 1-5
将化合物1-4(5g，4.76mmol，纯度：50％，1eq)溶于NMP(50mL)和乙腈(25mL)中，加入N-甲基咪唑(1.17g，14.27mmol，1.14mL，3eq)，EDCI(1.28g，6.66mmol，1.4eq)，HOBt(321.34mg，2.38mmol，0.5eq)，氘代甲胺盐酸盐(335.48mg，4.76mmol，1eq，HCl)，65℃下搅拌1hr。向反应液中加入水(100mL*2)和乙酸乙酯(100mL*2)萃取后，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析纯化(梯度洗脱：乙酸乙酯/石油醚＝0～100％)，得到化合物1-5。 1HNMR(400MHz，CDCl 3)δ：11.19(s，1H)，9.45(s，1H)，8.32(s，1H)，8.23(s，1H)，8.02(s，1H)，7.86(dd，J＝8.0，1.6Hz，1H)，7.53(d，J＝8.0Hz，1H)，7.31-7.29(m，1H)，5.58(s，2H)，3.83(s，3H)，3.74-3.70(m，2H)，1.13-1.09(m，2H)，1.01-0.90(m，5H)，0.08(s，9H)；LCMS m/z＝542.3[M+H] +。 Compound 1-4 (5g, 4.76mmol, purity: 50%, 1eq) was dissolved in NMP (50mL) and acetonitrile (25mL), N-methylimidazole (1.17g, 14.27mmol, 1.14mL, 3eq) was added, EDCI (1.28g, 6.66mmol, 1.4eq), HOBt (321.34mg, 2.38mmol, 0.5eq), deuterated methylamine hydrochloride (335.48mg, 4.76mmol, 1eq, HCl), stirred at 65°C for 1 hr. After adding water (100mL*2) and ethyl acetate (100mL*2) to the reaction solution for extraction, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: ethyl acetate/petroleum ether=0-100%) to obtain compound 1-5. 1 H NMR (400 MHz, CDCl 3 ) δ: 11.19 (s, 1H), 9.45 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.86 (dd, J =8.0, 1.6Hz, 1H), 7.53(d, J=8.0Hz, 1H), 7.31-7.29(m, 1H), 5.58(s, 2H), 3.83(s, 3H), 3.74-3.70(m, 2H), 1.13-1.09 (m, 2H), 1.01-0.90 (m, 5H), 0.08 (s, 9H); LCMS m/z = 542.3 [M+H] + .
步骤5：化合物1-6的合成Step 5: Synthesis of Compounds 1-6
将化合物1-5(1.2g，2.22mmol，1eq)溶于三氟乙酸(24mL)中，15℃搅拌1hr。向反应液中加入饱和碳酸氢钠水溶液500mL调至pH＝8后加入水200mL和二氯甲烷(1000mL*5)和乙醇(300mL*5)萃取，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩得到化合物1-6。 1HNMR(400MHz，DMSO-d 6)δ：14.19-14.02(m，1H)，11.35-11.32(m，1H)，11.00(s，1H)，9.15(d，J＝14.8Hz，1H)，8.16-8.09(m，2H)，7.81-7.68(m，1H)，7.59-7.50(m，1H)，7.37-7.27(m，1H)，3.72(s，3H)，1.40-1.23(m，1H)，0.87-0.81(m，4H)；LCMS m/z＝412.2[M+H] +。 Compound 1-5 (1.2 g, 2.22 mmol, 1 eq) was dissolved in trifluoroacetic acid (24 mL), stirred at 15°C for 1 hr. Add 500 mL of saturated aqueous sodium bicarbonate solution to the reaction solution to adjust to pH=8, then add 200 mL of water, dichloromethane (1000 mL*5) and ethanol (300 mL*5) for extraction, the organic phase is dried with anhydrous sodium sulfate and filtered, and the filtrate Concentration under reduced pressure afforded compound 1-6. 1 H NMR (400MHz, DMSO-d 6 ) δ: 14.19-14.02 (m, 1H), 11.35-11.32 (m, 1H), 11.00 (s, 1H), 9.15 (d, J=14.8Hz, 1H), 8.16 -8.09(m, 2H), 7.81-7.68(m, 1H), 7.59-7.50(m, 1H), 7.37-7.27(m, 1H), 3.72(s, 3H), 1.40-1.23(m, 1H) , 0.87-0.81 (m, 4H); LCMS m/z = 412.2 [M+H] + .
步骤6：化合物1-7的合成Step 6: Synthesis of Compounds 1-7
将化合物1-6(100mg，243.05μmol，1eq)和化合物C-1(159.15mg，486.11μmol，2eq)加入到N，N-二甲基甲酰胺(3mL)中，然后加入Cs 2CO 3(158.38mg，486.11μmol，2eq)，置换N 2后，在90℃下反应12hr。反应完成后，加入水(10mL)和EtOAc(10mL)萃取，有机相用饱和氯化钠水溶液洗涤一次，有机相用无水硫酸钠干燥，浓缩得粗品。粗品未纯化，直接用于下一步。得到化合物1-7。LCMS m/z＝567.3[M+H] +。 Compound 1-6 (100 mg, 243.05 μmol, 1 eq) and compound C-1 (159.15 mg, 486.11 μmol, 2 eq) were added to N,N-dimethylformamide (3 mL), and then Cs 2 CO 3 ( 158.38mg, 486.11μmol, 2eq), after replacing N 2 , react at 90°C for 12hr. After the reaction was completed, water (10 mL) and EtOAc (10 mL) were added for extraction, the organic phase was washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was used directly in the next step without purification. Compounds 1-7 were obtained. LCMS m/z = 567.3 [M+H] + .
步骤7：化合物1-8的盐酸盐的合成Step 7: Synthesis of the hydrochloride salt of compound 1-8
化合物1-7(137mg，241.78μmol，1eq)加入到EtOAc(1mL)中，然后加入HCl/EtOAc(4M，630.60μL，10eq)，在20℃下搅拌1hr。反应完成后，将体系过滤，滤饼使用EtOAc淋洗，收集滤饼，干燥得到化合物1-8的盐酸盐。 1HNMR(400MHz，DMSO-d 6)δ：11.44(s，1H)，11.11(s，1H)，9.38(s，2H)，9.16(s，1H)，8.74(s，1H)，8.14(s，1H)，7.72(d，J＝4.0Hz，1H)，7.57-7.55(m，1H)，7.34-7.30(m，1H)，5.64-5.60(m，1H)，4.44-4.38(m，4H)，3.79(s，3H)，2.11-2.04(m，1H)，0.85-0.82(m，4H)；LCMS m/z＝467.2[M+H] +。 Compound 1-7 (137 mg, 241.78 μmol, 1 eq) was added to EtOAc (1 mL), then HCl/EtOAc (4M, 630.60 μL, 10 eq) was added, and stirred at 20° C. for 1 hr. After the reaction was completed, the system was filtered, the filter cake was rinsed with EtOAc, the filter cake was collected, and dried to obtain the hydrochloride of compound 1-8. 1 H NMR (400MHz, DMSO-d 6 ) δ: 11.44(s, 1H), 11.11(s, 1H), 9.38(s, 2H), 9.16(s, 1H), 8.74(s, 1H), 8.14(s , 1H), 7.72(d, J=4.0Hz, 1H), 7.57-7.55(m, 1H), 7.34-7.30(m, 1H), 5.64-5.60(m, 1H), 4.44-4.38(m, 4H ), 3.79(s, 3H), 2.11-2.04(m, 1H), 0.85-0.82(m, 4H); LCMS m/z=467.2[M+H] + .
步骤8：化合物WX-001的合成Step 8: Synthesis of Compound WX-001
化合物1-8的盐酸盐(170mg，337.99μmol，1eq)加入到DCM(4mL)和NMP(0.5mL)中，然后加入DIPEA(174.73mg，1.35mmol，235.48μL，4eq)，置换N 2后，降温至-60℃，然后滴加入丙烯酰氯(30.59mg，337.99μmol，27.56μL，1eq)，在-60℃下搅拌2hr。反应完成后，向反应液中加入二氯甲烷(50mL)和水(50mL)，萃取分液，水相再用二氯甲烷(50mL)萃取，用无水硫酸钠干燥有机相后浓缩。粗品使用制备薄层色谱硅胶板(DCM∶MeOH＝10∶1)纯化得到化合物WX-001。 1HNMR(400MHz，CDCl 3)δ：11.06(s，1H)，9.39(s，1H)，8.25(s，2H)，8.09(s，1H)，7.81(d，J＝4.0Hz，1H)，7.55(d，J＝4.0Hz，1H)，7.31-7.29(m，1H)，6.43-6.39(m，1H)，6.27-6.20(m，1H)，5.76(d，J＝12.0Hz，1H)，5.31-5.27(m，1H)，4.76-4.71(m，2H)，4.63-4.57(m，2H)，3.784(s，3H)，1.81-1.78(m，1H)，1.12-1.08(m，2H)，0.92-0.88(m，2H)；LCMS m/z＝521.2[M+H] +。 The hydrochloride salt of compound 1-8 (170mg, 337.99μmol, 1eq) was added to DCM (4mL) and NMP (0.5mL), then DIPEA (174.73mg, 1.35mmol, 235.48μL, 4eq) was added, after replacing N2 , cooled to -60°C, then added dropwise acryloyl chloride (30.59mg, 337.99μmol, 27.56μL, 1eq), and stirred at -60°C for 2hr. After the reaction was complete, dichloromethane (50mL) and water (50mL) were added to the reaction solution for extraction and separation, the aqueous phase was extracted with dichloromethane (50mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative thin-layer chromatography on a silica gel plate (DCM:MeOH=10:1) to obtain compound WX-001. 1 HNMR (400MHz, CDCl 3 ) δ: 11.06(s, 1H), 9.39(s, 1H), 8.25(s, 2H), 8.09(s, 1H), 7.81(d, J=4.0Hz, 1H), 7.55(d, J=4.0Hz, 1H), 7.31-7.29(m, 1H), 6.43-6.39(m, 1H), 6.27-6.20(m, 1H), 5.76(d, J=12.0Hz, 1H) , 5.31-5.27(m, 1H), 4.76-4.71(m, 2H), 4.63-4.57(m, 2H), 3.784(s, 3H), 1.81-1.78(m, 1H), 1.12-1.08(m, 2H), 0.92-0.88 (m, 2H); LCMS m/z = 521.2 [M+H] + .
实施例2Example 2
Figure PCTCN2022096978-appb-000065
Figure PCTCN2022096978-appb-000065
步骤1：化合物2-1的合成Step 1: Synthesis of Compound 2-1
将化合物1-6(100mg，243.05μmol，1eq)和化合物D-1(172.79mg，486.11μmol，2eq)加入到N，N-二甲基甲酰胺(3mL)中，然后加入碳酸铯(158.38mg，486.11μmol，2eq)，置换氮气后，在90℃下反应12hr。反应完成后，加入水(5mL)和乙酸乙酯(5mL)萃取分液，水相再用乙酸乙酯(5mL)萃取，有机相用饱和氯化钠水溶液洗涤一次，有机相用无水硫酸钠干燥，浓缩得化合物2-1，粗品直接用于下一步。LCMS m/z＝595.3[M+H] +。 Compound 1-6 (100 mg, 243.05 μmol, 1 eq) and compound D-1 (172.79 mg, 486.11 μmol, 2 eq) were added to N,N-dimethylformamide (3 mL), then cesium carbonate (158.38 mg , 486.11μmol, 2eq), after replacing nitrogen, react at 90°C for 12hr. After the reaction is complete, add water (5mL) and ethyl acetate (5mL) to extract and separate the liquids, then extract the aqueous phase with ethyl acetate (5mL), wash the organic phase once with saturated aqueous sodium chloride solution, and wash the organic phase with anhydrous sodium sulfate After drying and concentration, compound 2-1 was obtained, and the crude product was directly used in the next step. LCMS m/z = 595.3 [M+H] + .
步骤2：化合物2-2的盐酸盐的合成Step 2: Synthesis of the hydrochloride salt of compound 2-2
将化合物2-1(150mg，252.24μmol，1eq)加入到乙酸乙酯(0.2mL)中，然后加入氯化氢/乙酸乙酯溶液(4M，630.59μL，10eq)，在20℃下搅拌1hr。将反应体系过滤，滤饼使用乙酸乙酯淋洗，收集滤饼，得到化合物2-2的盐酸盐。LCMS m/z＝495.2[M+H] +。 Compound 2-1 (150mg, 252.24μmol, 1eq) was added to ethyl acetate (0.2mL), then hydrogen chloride/ethyl acetate solution (4M, 630.59μL, 10eq) was added, and stirred at 20°C for 1hr. The reaction system was filtered, the filter cake was rinsed with ethyl acetate, and the filter cake was collected to obtain the hydrochloride of compound 2-2. LCMS m/z = 495.2 [M+H] + .
步骤3：化合物WX-002A和WX-002B的合成Step 3: Synthesis of Compounds WX-002A and WX-002B
化合物2-2的盐酸盐(60mg，112.99μmol，1eq)加入到二氯甲烷(2mL)和NMP(2mL)中，然后加入DIPEA(58.41mg，451.96μmol，78.72μL，4eq)，置换N 2后，降温至-60℃，然后滴加入丙烯酰氯(10.23mg，112.99μmol，9.21μL，1eq)，在-60℃下搅拌1hr。反应完成后，向体系中加入水(10mL)和二氯甲烷(10mL)萃取分液，然后水相再用二氯甲烷(10mL)萃取，合并有机相，用饱和氯化钠水溶液洗涤一次，有机 相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经过SFC(色谱柱：DAICEL CHIRALPAK AD 250mm*30mm，10μm；流动相：CO 2-含0.1％氨水的异丙醇；梯度：含0.1％氨水的异丙醇52％-52％，9min)分离纯化得到WX-002A和WX-002B。后再经SFC(色谱柱：ChiralpakAD-3，3μm，0.46cm id×15cm L；流动相：CO 2-含0.05％二乙胺的iPrOH；梯度：含0.05％二乙胺的iPrOH，10～40％，6min；流速：2.5mL/min；波长：220nm；压力：1500psi)测e.e.％值。 Compound 2-2 hydrochloride (60mg, 112.99μmol, 1eq) was added to dichloromethane (2mL) and NMP (2mL), then DIPEA (58.41mg, 451.96μmol, 78.72μL, 4eq) was added to replace N2 Afterwards, the temperature was lowered to -60°C, and then acryloyl chloride (10.23 mg, 112.99 μmol, 9.21 μL, 1 eq) was added dropwise, and stirred at -60°C for 1 hr. After the reaction was complete, add water (10mL) and dichloromethane (10mL) to the system for extraction and separation, then extract the aqueous phase with dichloromethane (10mL), combine the organic phases, and wash once with saturated aqueous sodium chloride solution. The phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was passed through SFC (column: DAICEL CHIRALPAK AD 250mm*30mm, 10μm; mobile phase: CO 2 -isopropanol containing 0.1% ammonia; gradient: containing 0.1 % ammonia water isopropanol 52%-52%, 9min) separation and purification to obtain WX-002A and WX-002B. After SFC (chromatographic column: ChiralpakAD-3, 3 μm, 0.46cm id × 15cm L; mobile phase: CO 2 - iPrOH containing 0.05% diethylamine; gradient: iPrOH containing 0.05% diethylamine, 10-40 %, 6min; flow rate: 2.5mL/min; wavelength: 220nm; pressure: 1500psi) to measure ee% value.
WX-002A： 1H NMR(400MHz，CDCl 3)δ：11.05(s，1H)，9.40(s，1H)，8.25(s，1H)，8.09(s，1H)，7.79(d，J＝8.0Hz，1H)，7.53(d，J＝8.0Hz，1H)，7.29-7.25(m，1H)，6.65-6.58(m，1H)，6.36-6.32(m，1H)，5.76-5.74(m，1H)，4.70-4.49(m，1H)，4.38-4.31(m，1H)，3.92-3.89(m，1H)，3.82(s，3H)，3.63-3.56(m，1H)，3.33-3.29(m，1H)，2.38-2.24(m，2H)，1.98-1.89(m，1H)，1.78-1.70(m，2H)，1.12-1.10(m，2H)，0.92-0.90(m，2H)；LCMS m/z＝549.3[M+H] +。SFC(色谱柱：Chiralpak AD-3，3μm，0.46cm id×15cm L；流动相：CO 2-含0.05％二乙胺的iPrOH；梯度：含0.05％二乙胺的iPrOH，10～40％，6min；流速：2.5mL/min；波长：220nm；压力：1500psi。Rt＝1.099min，e.e.％＝99.94％。 WX-002A: 1 H NMR (400MHz, CDCl 3 ) δ: 11.05(s, 1H), 9.40(s, 1H), 8.25(s, 1H), 8.09(s, 1H), 7.79(d, J=8.0 Hz, 1H), 7.53(d, J=8.0Hz, 1H), 7.29-7.25(m, 1H), 6.65-6.58(m, 1H), 6.36-6.32(m, 1H), 5.76-5.74(m, 1H), 4.70-4.49(m, 1H), 4.38-4.31(m, 1H), 3.92-3.89(m, 1H), 3.82(s, 3H), 3.63-3.56(m, 1H), 3.33-3.29( m, 1H), 2.38-2.24(m, 2H), 1.98-1.89(m, 1H), 1.78-1.70(m, 2H), 1.12-1.10(m, 2H), 0.92-0.90(m, 2H); LCMS m/z = 549.3 [M+H] + . SFC (chromatographic column: Chiralpak AD-3, 3 μm, 0.46cm id × 15cm L; mobile phase: CO 2 -iPrOH containing 0.05% diethylamine; gradient: iPrOH containing 0.05% diethylamine, 10～40%, 6min; flow rate: 2.5mL/min; wavelength: 220nm; pressure: 1500psi. Rt = 1.099min, ee% = 99.94%.
WX-002B： 1H NMR(400MHz，CDCl 3)δ：11.05(s，1H)，9.40(s，1H)，8.25(s，1H)，8.09(s，1H)，7.79(d，J＝8.0Hz，1H)，7.53(d，J＝8.0Hz，1H)，7.29-7.25(m，1H)，6.65-6.58(m，1H)，6.36-6.32(m，1H)，5.76-5.74(m，1H)，4.70-4.49(m，1H)，4.38-4.31(m，1H)，3.92-3.89(m，1H)，3.82(s，3H)，3.63-3.56(m，1H)，3.33-3.29(m，1H)，2.38-2.24(m，2H)，1.98-1.89(m，1H)，1.78-1.70(m，2H)，1.12-1.10(m，2H)，0.92-0.90(m，2H)；LCMS m/z＝549.3[M+H] +。SFC(色谱柱：Chiralpak AD-3，3μm，0.46cm id×15cm L；流动相：CO 2-含0.05％二乙胺的iPrOH；梯度：含0.05％二乙胺的iPrOH，10～40％，6min；流速：2.5mL/min；波长：220nm；压力：1500psi。Rt＝1.316min，e.e.％＝97.94％。 WX-002B: 1 H NMR (400MHz, CDCl 3 ) δ: 11.05(s, 1H), 9.40(s, 1H), 8.25(s, 1H), 8.09(s, 1H), 7.79(d, J=8.0 Hz, 1H), 7.53(d, J=8.0Hz, 1H), 7.29-7.25(m, 1H), 6.65-6.58(m, 1H), 6.36-6.32(m, 1H), 5.76-5.74(m, 1H), 4.70-4.49(m, 1H), 4.38-4.31(m, 1H), 3.92-3.89(m, 1H), 3.82(s, 3H), 3.63-3.56(m, 1H), 3.33-3.29( m, 1H), 2.38-2.24(m, 2H), 1.98-1.89(m, 1H), 1.78-1.70(m, 2H), 1.12-1.10(m, 2H), 0.92-0.90(m, 2H); LCMS m/z = 549.3 [M+H] + . SFC (chromatographic column: Chiralpak AD-3, 3 μm, 0.46cm id × 15cm L; mobile phase: CO 2 -iPrOH containing 0.05% diethylamine; gradient: iPrOH containing 0.05% diethylamine, 10～40%, 6min; flow rate: 2.5mL/min; wavelength: 220nm; pressure: 1500psi. Rt = 1.316min, ee% = 97.94%.
参照实施例2的合成步骤，将步骤1中D-1分别替换为下表中的片段，合成下表3中的化合物。Referring to the synthesis steps in Example 2, replace D-1 in Step 1 with the fragments in the table below to synthesize the compounds in Table 3 below.
表3table 3
Figure PCTCN2022096978-appb-000066
Figure PCTCN2022096978-appb-000066
Figure PCTCN2022096978-appb-000067
Figure PCTCN2022096978-appb-000067
Figure PCTCN2022096978-appb-000068
Figure PCTCN2022096978-appb-000068
Figure PCTCN2022096978-appb-000069
Figure PCTCN2022096978-appb-000069
实施例6Example 6
Figure PCTCN2022096978-appb-000070
Figure PCTCN2022096978-appb-000070
步骤1：化合物6-2的合成Step 1: Synthesis of Compound 6-2
将化合物6-1(5g，25.78mmol，1eq)和1-Boc-3-碘氮杂环丁烷(9.49g，33.51mmol，1.30eq)溶于DMF(50mL)中，然后加入叔丁醇钾(5.78g，51.56mmol，2eq)，在20℃下，反应18hr。反应完成后，向体系中加入水(100mL)和甲基叔丁基醚(100mL)萃取，水相再用甲基叔丁基醚(100mL)萃取，合并有机相，然后用饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，浓缩得粗品。粗品经硅胶柱层析柱纯化(乙酸乙酯/石油醚＝0～15％)，得化合物6-2。 1H NMR(400MHz，CDCl 3)δ：7.91(s，1H)，7.18(s，1H)，4.98-4.93(m，1H)，4.50-4.43(m，2H)，4.20-4.12(m，2H)，1.47(s，9H)；LCMS m/z＝350.0[M+H] +。 Compound 6-1 (5g, 25.78mmol, 1eq) and 1-Boc-3-iodoazetidine (9.49g, 33.51mmol, 1.30eq) were dissolved in DMF (50mL), and then potassium tert-butoxide was added (5.78g, 51.56mmol, 2eq), reacted at 20°C for 18hr. After the reaction was complete, add water (100mL) and methyl tert-butyl ether (100mL) to the system for extraction, then extract the aqueous phase with methyl tert-butyl ether (100mL), combine the organic phases, and then use saturated aqueous sodium chloride After washing, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-15%) to obtain compound 6-2. 1 H NMR (400MHz, CDCl 3 ) δ: 7.91(s, 1H), 7.18(s, 1H), 4.98-4.93(m, 1H), 4.50-4.43(m, 2H), 4.20-4.12(m, 2H ), 1.47 (s, 9H); LCMS m/z = 350.0 [M+H] + .
步骤2：化合物6-3的合成Step 2: Synthesis of Compound 6-3
将化合物6-2(3.4g，9.74mmol，1eq)，A-1(2.43g，9.74mmol，1eq)，碳酸铯(6.35g，19.47mmol，2eq)溶于二氧六环(56.5mL)和水(11.4mL)中，氮气置换三次后加入Pd(dppf)Cl 2(712.49mg，973.75μmol，0.1eq)，在100℃搅拌2hr。反应完成后，向反应液中加入水(50mL)和乙酸乙酯(100mL)萃取分液，水相再用乙酸乙酯(100mL)萃取，合并有机相，有机相用无水硫酸钠干燥后浓缩得粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0～100％)，得到化合物6-3。LCMS m/z＝345.1[M+H] +。 Compound 6-2 (3.4g, 9.74mmol, 1eq), A-1 (2.43g, 9.74mmol, 1eq), cesium carbonate (6.35g, 19.47mmol, 2eq) were dissolved in dioxane (56.5mL) and In water (11.4 mL), Pd(dppf)Cl 2 (712.49 mg, 973.75 μmol, 0.1 eq) was added after nitrogen replacement three times, and stirred at 100° C. for 2 hr. After completion of the reaction, add water (50mL) and ethyl acetate (100mL) to the reaction solution for extraction and separation, then extract the aqueous phase with ethyl acetate (100mL), combine the organic phases, dry the organic phases with anhydrous sodium sulfate and concentrate Get crude products. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-100%) to obtain compound 6-3. LCMS m/z = 345.1 [M+H] + .
步骤3：化合物6-4的合成Step 3: Synthesis of compound 6-4
将化合物6-3(1.1g，3.19mmol，1eq)和化合物E-1(667.68mg，3.19mmol，1eq)加入到NMP(15mL)、水 (5mL)中，然后加入醋酸锌(2.34g，12.78mmol，4eq)，在120℃下反应12hr。反应完成后，加入水(50mL)和乙酸乙酯(50mL)萃取，水相再用乙酸乙酯(50mL)萃取，合并有机相，然后用饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，浓缩得粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0～20％)，得到化合物6-4。 1H NMR(400MHz，CDCl 3)δ：10.98(s，1H)，8.25(s，1H)，8.07(d，J＝8.0Hz，1H)，7.81(s，1H)，7.69(s，1H)，7.25-7.20(m，2H)，7.03(s，1H)，4.99-4.93(m，1H)，4.52-4.48(m，2H)，4.17-4.10(m，2H)，3.73(s，3H)，1.50(s，9H)；LCMS m/z＝517.2[M+H] +。 Compound 6-3 (1.1g, 3.19mmol, 1eq) and compound E-1 (667.68mg, 3.19mmol, 1eq) were added to NMP (15mL), water (5mL), and then zinc acetate (2.34g, 12.78 mmol, 4eq), reacted at 120°C for 12hr. After the reaction was complete, add water (50mL) and ethyl acetate (50mL) for extraction, and then extract the aqueous phase with ethyl acetate (50mL), combine the organic phases, then wash with saturated aqueous sodium chloride solution, and wash the organic phase with anhydrous sodium sulfate Dry and concentrate to give crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-20%) to obtain compound 6-4. 1 H NMR (400MHz, CDCl 3 ) δ: 10.98(s, 1H), 8.25(s, 1H), 8.07(d, J=8.0Hz, 1H), 7.81(s, 1H), 7.69(s, 1H) , 7.25-7.20(m, 2H), 7.03(s, 1H), 4.99-4.93(m, 1H), 4.52-4.48(m, 2H), 4.17-4.10(m, 2H), 3.73(s, 3H) , 1.50 (s, 9H); LCMS m/z = 517.2 [M+H] + .
步骤4：化合物6-5的合成Step 4: Synthesis of compound 6-5
将化合物6-4(0.15g，290.14μmol，1eq)和环丙基甲酰胺(493.84mg，5.80mmol，20eq)加入到1，4-二氧六环(6mL)和NMP(1.2mL)中，然后加入碳酸铯(283.60mg，870.42μmol，3eq)，Xantphos(25.18mg，43.52μmol，0.15eq)，氮气置换三次后加入Pd 2(dba) 3(39.85mg，43.52μmol，0.15eq)，在120℃反应6hr。反应完成后，加入水(10mL)和EtOAc(10mL)萃取，有机相用饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，浓缩得到化合物6-5。LCMS m/z＝566.3[M+H] +。 Compound 6-4 (0.15 g, 290.14 μmol, 1 eq) and cyclopropylformamide (493.84 mg, 5.80 mmol, 20 eq) were added to 1,4-dioxane (6 mL) and NMP (1.2 mL), Then add cesium carbonate (283.60mg, 870.42μmol, 3eq), Xantphos (25.18mg, 43.52μmol, 0.15eq), add Pd 2 (dba) 3 (39.85mg, 43.52μmol, 0.15eq) after nitrogen replacement three times, at 120 ℃ reaction 6hr. After the reaction was completed, water (10 mL) and EtOAc (10 mL) were added for extraction, the organic phase was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, and concentrated to obtain compound 6-5. LCMS m/z = 566.3 [M+H] + .
步骤5：化合物6-6的盐酸盐的合成Step 5: Synthesis of the hydrochloride salt of compound 6-6
将化合物6-5(300mg，530.38μmol，1eq)溶于乙酸乙酯(0.6mL)，然后加入盐酸/乙酸乙酯(4M，2.65mL，20eq)，在20℃下反应2hr。反应完成后，将体系过滤，得到化合物6-6的盐酸盐。LCMS m/z＝466.2[M+H] +。 Compound 6-5 (300mg, 530.38μmol, 1eq) was dissolved in ethyl acetate (0.6mL), then hydrochloric acid/ethyl acetate (4M, 2.65mL, 20eq) was added, and reacted at 20°C for 2hr. After the reaction was completed, the system was filtered to obtain the hydrochloride of compound 6-6. LCMS m/z = 466.2 [M+H] + .
步骤6：化合物WX-006的合成Step 6: Synthesis of Compound WX-006
将化合物6-6的盐酸盐(40mg，79.68μmol，1eq)加入到二氯甲烷(2mL)中，然后加入DIPEA(41.19mg，318.74μmol，55.52μL，4eq)，置换N 2后，降温至-60℃，然后滴加入丙烯酰氯(7.21mg，79.68μmol，6.50μL，1eq)，在-60℃下搅拌2hr。反应完成后，向体系中加入水(10mL)和二氯甲烷(10mL)萃取分液，然后水相再用二氯甲烷(10mL)萃取，合并有机相，用饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，粗品使用制备薄层色谱硅胶板(EtOA C∶MeOH＝10∶1)纯化得到化合物WX-006。 1H NMR(400MHz，CDCl 3)δ：11.12(s，1H)，9.31(s，1H)，8.25(s，1H)，8.12(s，1H)，7.94(d，J＝8.0Hz，1H)，7.84(s，1H)，7.69(s，1H)，7.37(d，J＝8.0Hz，1H)，7.29-7.23(m，1H)，6.46-6.42(m，1H)，6.27-6.20(m，1H)，5.80-5.78(m，1H)，5.10-5.07(m，1H)，4.77-4.67(m，2H)，4.46-4.37(m，2H)，3.73(s，3H)，1.80-1.74(m，1H)，1.13-1.08(m，2H)，0.95-0.91(m，2H)；LCMS m/z＝520.2[M+H] +。 The hydrochloride (40mg, 79.68μmol, 1eq) of compound 6-6 was added in dichloromethane (2mL), then DIPEA (41.19mg, 318.74μmol, 55.52μL, 4eq) was added, and after N2 was replaced, the temperature was lowered to -60°C, then acryloyl chloride (7.21 mg, 79.68 μmol, 6.50 μL, 1 eq) was added dropwise, and stirred at -60°C for 2 hr. After the completion of the reaction, add water (10mL) and methylene chloride (10mL) to the system for extraction and separation, then extract the aqueous phase with methylene chloride (10mL), combine the organic phases, and wash with saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by preparative thin-layer chromatography on a silica gel plate ( EtOAc: MeOH=10:1) to obtain compound WX-006. 1 H NMR (400MHz, CDCl 3 ) δ: 11.12(s, 1H), 9.31(s, 1H), 8.25(s, 1H), 8.12(s, 1H), 7.94(d, J=8.0Hz, 1H) , 7.84(s, 1H), 7.69(s, 1H), 7.37(d, J=8.0Hz, 1H), 7.29-7.23(m, 1H), 6.46-6.42(m, 1H), 6.27-6.20(m , 1H), 5.80-5.78(m, 1H), 5.10-5.07(m, 1H), 4.77-4.67(m, 2H), 4.46-4.37(m, 2H), 3.73(s, 3H), 1.80-1.74 (m, 1H), 1.13-1.08 (m, 2H), 0.95-0.91 (m, 2H); LCMS m/z = 520.2 [M+H] + .
参照实施例6的合成步骤，将步骤2中6-2分别替换为下表中的片段G-1，合成下表4中的化合物。Referring to the synthesis steps of Example 6, replace 6-2 in Step 2 with the fragment G-1 in the table below to synthesize the compounds in Table 4 below.
表4Table 4
Figure PCTCN2022096978-appb-000071
Figure PCTCN2022096978-appb-000071
Figure PCTCN2022096978-appb-000072
Figure PCTCN2022096978-appb-000072
实施例7Example 7
Figure PCTCN2022096978-appb-000073
Figure PCTCN2022096978-appb-000073
步骤1：化合物7-2的合成Step 1: Synthesis of compound 7-2
将化合物7-1(15g，125.92mmol，1eq)溶于醋酸(30mL)中，50℃滴加入发烟硝酸(8.73g，138.52mmol，6.23mL，1.1eq)，温度不能高于70℃，搅拌4hr。将反应液缓慢的加入到冰水(90mL)中，有固体析出，过滤。滤饼通过硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～25％)，得到化合物7-2。 1HNMR(400MHz，C 3D 6O) δ：8.47(dd，J＝8.4，1.6Hz，1H)，8.15(dd，J＝7.6，1.6Hz，1H)，7.31(dd，J＝8.4，7.6Hz，1H)。 Dissolve compound 7-1 (15g, 125.92mmol, 1eq) in acetic acid (30mL), add fuming nitric acid (8.73g, 138.52mmol, 6.23mL, 1.1eq) dropwise at 50°C, the temperature should not be higher than 70°C, stir 4hr. The reaction solution was slowly added to ice water (90 mL), solids were precipitated and filtered. The filter cake was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-25%) to obtain compound 7-2. 1 HNMR (400MHz, C 3 D 6 O) δ: 8.47 (dd, J=8.4, 1.6Hz, 1H), 8.15 (dd, J=7.6, 1.6Hz, 1H), 7.31 (dd, J=8.4, 7.6 Hz, 1H).
步骤2：化合物7-3的合成Step 2: Synthesis of compound 7-3
将化合物7-2(4.5g，27.42mmol，1eq)溶于N，N-二甲基甲酰胺(45mL)中，加入碳酸钾(11.37g，82.26mmol，3eq)，碘甲烷(7.78g，54.84mmol，3.41mL，2eq)，在15℃下搅拌40hr。向反应液中加入水(50mL)和甲叔醚(50mL*3)萃取，有机相用无水硫酸钠干燥，滤液减压浓缩得到化合物7-3。Compound 7-2 (4.5g, 27.42mmol, 1eq) was dissolved in N,N-dimethylformamide (45mL), potassium carbonate (11.37g, 82.26mmol, 3eq), iodomethane (7.78g, 54.84 mmol, 3.41 mL, 2 eq), stirred at 15 °C for 40 hr. Water (50 mL) and tertiary methyl ether (50 mL*3) were added to the reaction solution for extraction, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 7-3.
步骤3：化合物7-4的合成Step 3: Synthesis of compound 7-4
将化合物7-3(5.5g，30.87mmol，1eq)溶于乙醇(55mL)中，加入碳酸氢钠(7.78g，92.62mmol，3.60mL，3eq)，盐酸羟胺(6.44g，92.62mmol，3eq)，在90℃搅拌1hr。将反应液过滤，滤液浓缩，得到化合物7-4。LCMS m/z＝212.0[M+H] +。 Compound 7-3 (5.5g, 30.87mmol, 1eq) was dissolved in ethanol (55mL), sodium bicarbonate (7.78g, 92.62mmol, 3.60mL, 3eq), hydroxylamine hydrochloride (6.44g, 92.62mmol, 3eq) were added , stirred at 90 °C for 1 hr. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 7-4. LCMS m/z = 212.0 [M+H] + .
步骤4：化合物7-5的合成Step 4: Synthesis of compound 7-5
将化合物7-4(7.5g，35.52mmol，1eq)，N，N-二异丙基碳二亚胺(10.76g，85.24mmol，13.20mL，2.4eq)，化合物BOC-甘氨酸(12.44g，71.03mmol，2eq)溶于N，N-二甲基甲酰胺(75mL)中，在15℃下搅拌1.5hr，然后加入四丁基氟化胺(1M，163.37mL，4.6eq)，继续搅拌1hr。向反应液中加入水(100mL)，加入乙酸乙酯(200mL*2)萃取，有机相用无水硫酸钠干燥，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物7-5。LCMS m/z＝295.0[M+H-55] +。 Compound 7-4 (7.5g, 35.52mmol, 1eq), N, N-diisopropylcarbodiimide (10.76g, 85.24mmol, 13.20mL, 2.4eq), compound BOC-glycine (12.44g, 71.03 mmol, 2eq) was dissolved in N,N-dimethylformamide (75mL), stirred at 15°C for 1.5hr, then tetrabutylammonium fluoride (1M, 163.37mL, 4.6eq) was added, and stirring was continued for 1hr. Water (100 mL) was added to the reaction solution, followed by ethyl acetate (200 mL*2) for extraction, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain compound 7-5. LCMS m/z = 295.0 [M+H-55] + .
步骤5：化合物7-6的合成Step 5: Synthesis of Compound 7-6
将化合物7-5(7.78g，22.21mmol，1eq)溶于乙酸乙酯(150mL)中，加入二水合二氯化锡(10.55g，88.83mmol，1.44mL，4eq)，在70℃搅拌1hr。向反应液中加入水(100mL)，有固体析出，过滤，滤液静置分液，有机相用无水硫酸钠干燥，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物7-6。 1HNMR(400MHz，CDCl 3)δ：7.35(dd，J＝8.0，1.6Hz，1H)，7.04(t，J＝8.0，4.0Hz，1H)，6.91(dd，J＝8.0，1.6Hz，1H)，5.24-5.19(m，1H)，4.71-4.62(m，2H)，4.02-3.95(m，2H)，3.83(s，3H)，1.49(s，9H)；LCMS m/z＝321.0[M+H] +。 Compound 7-5 (7.78g, 22.21mmol, 1eq) was dissolved in ethyl acetate (150mL), tin dichloride dihydrate (10.55g, 88.83mmol, 1.44mL, 4eq) was added, and stirred at 70°C for 1hr. Water (100 mL) was added to the reaction solution, solids were precipitated, filtered, the filtrate was left to separate liquids, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain compound 7-6. 1 HNMR (400MHz, CDCl 3 ) δ: 7.35(dd, J=8.0, 1.6Hz, 1H), 7.04(t, J=8.0, 4.0Hz, 1H), 6.91(dd, J=8.0, 1.6Hz, 1H ), 5.24-5.19(m, 1H), 4.71-4.62(m, 2H), 4.02-3.95(m, 2H), 3.83(s, 3H), 1.49(s, 9H); LCMS m/z=321.0[ M+H] + .
步骤6：化合物7-7的合成Step 6: Synthesis of Compound 7-7
将化合物E-1(391.55mg，1.87mmol，1.2eq)，化合物7-6(0.5g，1.56mmol，1eq)溶于四氢呋喃(25mL)中，在0℃下滴加(双三甲基硅基)胺基锂(1M，4.68mL，3eq)，自然升至15℃搅拌2hr。向反应液中加入水(10mL)，加入乙酸乙酯(10mL*2)萃取，有机相用无水硫酸钠干燥，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物7-7。 1HNMR(400MHz，CDCl 3)δ：10.98(s，1H)，8.25-8.24(m，1H)，7.92-7.90(m，1H)，7.49-7.47(m，1H)，7.32(t，J＝8.0，4.0Hz，1H)，6.95(s，1H)，5.24-5.21(m，1H)，4.69-4.66(m，2H)，3.83(s，3H)，1.49(s，9H)；LCMS m/z＝493.1[M+H] +。 Compound E-1 (391.55mg, 1.87mmol, 1.2eq), compound 7-6 (0.5g, 1.56mmol, 1eq) was dissolved in tetrahydrofuran (25mL), and added dropwise at 0°C (bistrimethylsilyl ) Lithium amide (1M, 4.68mL, 3eq), naturally raised to 15°C and stirred for 2hr. Water (10 mL) was added to the reaction solution, ethyl acetate (10 mL*2) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain compound 7-7. 1 HNMR (400MHz, CDCl 3 ) δ: 10.98(s, 1H), 8.25-8.24(m, 1H), 7.92-7.90(m, 1H), 7.49-7.47(m, 1H), 7.32(t, J= 8.0, 4.0Hz, 1H), 6.95(s, 1H), 5.24-5.21(m, 1H), 4.69-4.66(m, 2H), 3.83(s, 3H), 1.49(s, 9H); LCMS m/ z = 493.1 [M+H] + .
步骤7：化合物7-8的合成Step 7: Synthesis of compounds 7-8
将化合物7-7(80mg，162.29μmol，1eq)，化合物2，4-二甲氧基苄胺(203.52mg，1.22mmol，183.35μL，7.5eq)溶于二甲基亚砜(4mL)中，在120℃下搅拌4hr。向反应液中加入水(5mL)和乙酸乙酯(10mL*2)萃取，有机相用无水硫酸钠干燥，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～66％)，得到化合物7-8。LCMS m/z＝624.2[M+H] +。 Compound 7-7 (80 mg, 162.29 μmol, 1 eq), compound 2,4-dimethoxybenzylamine (203.52 mg, 1.22 mmol, 183.35 μL, 7.5 eq) were dissolved in dimethylsulfoxide (4 mL), Stir at 120 °C for 4 hrs. Water (5 mL) and ethyl acetate (10 mL*2) were added to the reaction solution for extraction, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-66%) to obtain compound 7-8. LCMS m/z = 624.2 [M+H] + .
步骤8：化合物7-9的合成Step 8: Synthesis of compounds 7-9
将化合物7-8(70mg，112.24μmol，1eq)溶于二氯甲烷(1.4mL)中，在0℃加入三氟乙酸(3.02g，26.47mmol，1.96mL，235.85eq)，自然升温至15℃搅拌2hr。向反应液中加入饱和碳酸氢钠水溶液(30mL)，调至pH＝8，加入二氯甲烷(50mL)萃取，有机相用无水硫酸钠干燥，滤液减压浓缩得到化合物7-9。LCMS m/z＝374.1[M+H] +。 Compound 7-8 (70mg, 112.24μmol, 1eq) was dissolved in dichloromethane (1.4mL), trifluoroacetic acid (3.02g, 26.47mmol, 1.96mL, 235.85eq) was added at 0°C, and the temperature was naturally raised to 15°C Stir for 2hr. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution to adjust the pH to 8, dichloromethane (50 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 7-9. LCMS m/z = 374.1 [M+H] + .
步骤9：化合物7-10的合成Step 9: Synthesis of Compounds 7-10
将化合物7-9(55mg，147.30μmol，1eq)溶于四氢呋喃(5.5mL)中，在0℃加入DIPEA(19.04mg，147.30μmol，25.66μL，1eq)，化合物丙烯酰氯(6.67mg，73.65μmol，6.01μL，0.5eq)，搅拌0.5hr。向反应液中加入水(3mL)，加入乙酸乙酯(5mL*3)萃取，有机相用无水硫酸钠干燥，滤液减压浓缩得到化合物7-10。LCMS m/z＝428.1[M+H] +。 Compound 7-9 (55mg, 147.30μmol, 1eq) was dissolved in tetrahydrofuran (5.5mL), DIPEA (19.04mg, 147.30μmol, 25.66μL, 1eq), compound acryloyl chloride (6.67mg, 73.65μmol, 6.01 μL, 0.5eq), stirred for 0.5hr. Water (3 mL) was added to the reaction solution, ethyl acetate (5 mL*3) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 7-10. LCMS m/z = 428.1 [M+H] + .
步骤10：化合物WX-007的合成Step 10: Synthesis of Compound WX-007
将化合物7-10(50mg，116.98μmol，1eq)溶于二氯甲烷(5mL)中，加入吡啶(39.79mg，503.01μmol，40.60μL，4.3eq)，化合物环丙甲酰氯(12.23mg，116.98μmol，10.63μL，1eq)，在15℃搅拌1hr。向反应液加入水(5mL)后静置分液，有机相用无水硫酸钠干燥，滤液减压浓缩得粗品。粗品经薄层制备板纯化(展开剂：二氯甲烷∶甲醇＝10∶1)，得到的化合物再次经制备高效液相色谱分离(色谱柱：Waters Xbridge BEH C18 100*30mm*10μm；流动相：A(水，碳酸氢铵)和B(乙腈；梯度：B％：30％-60％，8min)，得到WX-007。 1H NMR(400MHz，CDCl 3)δ：11.43(s，1H)，8.22(s，1H)，7.96-7.95(m，1H)，7.85(d，J＝7.6Hz，1H)，7.62(d，J＝8.0Hz，1H)，7.35(t，J＝8.0，4.0Hz，1H)，6.44-6.39(m，2H)，6.29-6.22(m，1H)，5.79(d，J＝10.8Hz，1H)，4.90-4.88(m，2H)，3.85(s，3H)，2.05(s，1H)，1.27-1.25(m，1H)，1.13-1.11(m，2H)，1.00-0.97(m，2H)；LCMS m/z＝496.1[M+H] +。 Compound 7-10 (50mg, 116.98μmol, 1eq) was dissolved in dichloromethane (5mL), pyridine (39.79mg, 503.01μmol, 40.60μL, 4.3eq), compound cyclopropanoyl chloride (12.23mg, 116.98μmol , 10.63 μL, 1 eq), stirred at 15° C. for 1 hr. Water (5 mL) was added to the reaction liquid, and the liquid was separated by standing. The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer preparative plate (developing solvent: dichloromethane:methanol=10:1), and the obtained compound was separated by preparative high-performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: A (water, ammonium bicarbonate) and B (acetonitrile; gradient: B%: 30%-60%, 8min), to obtain WX-007. 1 H NMR (400MHz, CDCl 3 ) δ: 11.43 (s, 1H), 8.22(s, 1H), 7.96-7.95(m, 1H), 7.85(d, J=7.6Hz, 1H), 7.62(d, J=8.0Hz, 1H), 7.35(t, J=8.0, 4.0Hz , 1H), 6.44-6.39(m, 2H), 6.29-6.22(m, 1H), 5.79(d, J=10.8Hz, 1H), 4.90-4.88(m, 2H), 3.85(s, 3H), 2.05 (s, 1H), 1.27-1.25 (m, 1H), 1.13-1.11 (m, 2H), 1.00-0.97 (m, 2H); LCMS m/z = 496.1 [M+H] + .
实施例8Example 8
Figure PCTCN2022096978-appb-000074
Figure PCTCN2022096978-appb-000074
步骤1：化合物8-2的合成Step 1: Synthesis of compound 8-2
将化合物8-1(1.05g，5.43mmol，1eq)，化合物1-Boc-2，5-二氢吡咯-3-硼酸频哪醇酯(1.92g，6.51mmol，1.2eq)加入到二氧六环(20mL)和水(5mL)中，之后加入磷酸钾(3.46g，16.29mmol，3eq)，Pd(dppf)Cl 2.CH 2Cl 2(265.98mg，325.70μmol，0.06eq)，在100℃反应16hr。将反应液过滤后，滤液加入水(50mL)，用乙酸乙酯(30mL*4)萃取，合并有机相，无水硫酸钠干燥过滤，滤液减压浓缩，柱纯化：粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～15％)，得到化合物8-2。LCMS m/z＝282.2[M+H] +。 Compound 8-1 (1.05g, 5.43mmol, 1eq), compound 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester (1.92g, 6.51mmol, 1.2eq) was added to dioxane ring (20mL) and water (5mL), then added potassium phosphate (3.46g, 16.29mmol, 3eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (265.98mg, 325.70μmol, 0.06eq), at 100°C Reaction 16hr. After filtering the reaction solution, add water (50mL) to the filtrate, extract with ethyl acetate (30mL*4), combine the organic phases, dry and filter over anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and column purification: the crude product is separated by silica gel column chromatography Purification (ethyl acetate/petroleum ether=0-15%) gave compound 8-2. LCMS m/z = 282.2 [M+H] + .
步骤2：化合物8-3的合成Step 2: Synthesis of compound 8-3
将化合物8-2(0.8g，2.84mmol，1eq)，化合物A-1(848.83mg，3.41mmol，1.2eq)加入到二氧六环(20mL)，水(5mL)中，之后加入磷酸钾(1.81g，8.52mmol，3eq)，Pd(dppf)Cl 2.CH 2Cl 2(231.89mg，283.95μmol，0.1eq)，在100℃反应16hr。将反应液过滤后，滤液倒入水(30mL)中，乙酸乙酯(30mL*3)萃取后，合并有机相。无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物8-3。LCMS m/z＝369.3[M+H] +。 Compound 8-2 (0.8g, 2.84mmol, 1eq), compound A-1 (848.83mg, 3.41mmol, 1.2eq) were added to dioxane (20mL), water (5mL), and then potassium phosphate ( 1.81g, 8.52mmol, 3eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (231.89mg, 283.95μmol, 0.1eq), react at 100°C for 16hr. After the reaction solution was filtered, the filtrate was poured into water (30 mL), extracted with ethyl acetate (30 mL*3), and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain compound 8-3. LCMS m/z = 369.3 [M+H] + .
步骤3：化合物8-4的合成Step 3: Synthesis of Compound 8-4
将湿钯碳(0.2g，10％含量)加入到乙酸乙酯(20mL)中，之后加入化合物8-3(0.5g，1.36mmol，1eq)，H 2(15psi)氛围，25℃反应2hr。将反应液过滤，滤液减压浓缩。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物8-4。LCMS m/z＝371.3[M+H] +。 Wet palladium on carbon (0.2g, 10% content) was added to ethyl acetate (20mL), and then compound 8-3 (0.5g, 1.36mmol, 1eq) was added under H 2 (15psi) atmosphere, and reacted at 25°C for 2hr. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain compound 8-4. LCMS m/z = 371.3 [M+H] + .
步骤4：化合物8-5的合成Step 4: Synthesis of compound 8-5
将化合物8-4(0.3g，809.84μmol，1eq)，化合物F-1(168.49mg，809.84μmol，1eq)加入到四氢呋喃(10mL)中，之后0℃加入双(三甲硅基)氨基锂(1M，1.62mL，2eq)，在25℃下反应0.5hr。将反应液加入到饱和氯化铵水溶液(15mL)中，用乙酸乙酯(20mL*3)萃取。合并有机相，无水硫酸钠干燥过滤，滤液减压浓缩。粗品薄层制备板纯化(二氯甲烷/甲醇＝20∶1)，得到化合物8-5。LCMS m/z＝542.3[M+H] +。 Add compound 8-4 (0.3g, 809.84μmol, 1eq), compound F-1 (168.49mg, 809.84μmol, 1eq) into tetrahydrofuran (10mL), then add bis(trimethylsilyl)amide lithium (1M , 1.62mL, 2eq), reacted at 25°C for 0.5hr. The reaction liquid was added to saturated aqueous ammonium chloride solution (15 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried and filtered over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by TLC (dichloromethane/methanol=20:1) to obtain compound 8-5. LCMS m/z = 542.3 [M+H] + .
步骤5：化合物8-6的合成Step 5: Synthesis of compound 8-6
将化合物8-5(50mg，92.24μmol，1eq)，环丙基甲酰胺(78.50mg，922.44μmol，10eq)加入到二氧六环(2mL)中之后加入碳酸铯(90.16mg，276.73μmol，3eq)，Xantphos(5.34mg，9.22μmol，0.1eq)，Pd 2(dba) 3(8.45mg，9.22μmol，0.1eq)，在120℃下反应16hr。将反应液加入到水(30mL)中，用乙酸乙酯(30mL*3)萃取。合并有机相无水硫酸钠干燥过滤，滤液减压浓缩。粗品薄层制备板纯化(二氯甲烷/甲醇＝20∶1)，得到化合物8-6。LCMS m/z＝591.4[M+H] +。 Compound 8-5 (50 mg, 92.24 μmol, 1 eq), cyclopropylformamide (78.50 mg, 922.44 μmol, 10 eq) were added to dioxane (2 mL) followed by cesium carbonate (90.16 mg, 276.73 μmol, 3 eq ), Xantphos (5.34mg, 9.22μmol, 0.1eq), Pd 2 (dba) 3 (8.45mg, 9.22μmol, 0.1eq), react at 120°C for 16hr. The reaction liquid was added to water (30 mL), and extracted with ethyl acetate (30 mL*3). The combined organic phases were dried and filtered over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by TLC (dichloromethane/methanol=20:1) to obtain compound 8-6. LCMS m/z = 591.4 [M+H] + .
步骤6：化合物8-7的三氟乙酸盐的合成Step 6: Synthesis of Trifluoroacetate Salt of Compound 8-7
将化合物8-6(40mg，67.72μmol，1eq)加入到二氯甲烷(0.5mL)中，之后加入三氟乙酸(0.5mL)，25℃反应2hr。将反应液减压浓缩得到化合物8-7的三氟乙酸盐。LCMS m/z＝491.3[M+H] +。 Compound 8-6 (40 mg, 67.72 μmol, 1 eq) was added into dichloromethane (0.5 mL), followed by trifluoroacetic acid (0.5 mL), and reacted at 25° C. for 2 hr. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 8-7. LCMS m/z = 491.3 [M+H] + .
步骤7：化合物WX-008的合成Step 7: Synthesis of Compound WX-008
将化合物8-7的三氟乙酸盐(35mg，71.35μmol，1eq)，三乙胺(28.88mg，285.38μmol，39.72μL，4eq)加入到二氯甲烷(1.5mL)中，然后降温至-78℃后加入丙烯酰氯(7.75mg，85.61μmol，6.98μL，1.2eq)。在-78℃下反应2hr。将反应液加入到氯化铵水溶液(10mL)中，用二氯甲烷(10mL*3)萃取后，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经制备高效液相色谱分离(色谱柱：Phenomenex C18 80*40mm*3μm；流动相：A(水，碳酸氢铵)和B(乙腈；梯度：B％：20％-55％，8min)，得到化合物WX-008。 1HNMR(400MHz，DMSO-d 6)δ：10.79(s，1H)，10.66(s，1H)，8.95-8.92(m，2H)，8.60(s，1H)，8.53(s，1H)，8.07(s，1H)，7.56-7.54(m，1H)，7.45-7.43(m，1H)，7.29-7.27(m，1H)，6.69-6.62(m，1H)，5.72(d，J＝5.2Hz，1H)，5.69(s，1H)，4.16(m，3H)，3.86-3.70(m，1H)，3.46-3.32(m，3H)，2.46-2.44(m，2H)，2.00-1.97(m，2H)，0.79(s，4H)；LCMS m/z＝545.4[M+H] +。 Trifluoroacetic acid salt (35mg, 71.35μmol, 1eq) of compound 8-7, triethylamine (28.88mg, 285.38μmol, 39.72μL, 4eq) were added in dichloromethane (1.5mL), then cooled to - Acryloyl chloride (7.75 mg, 85.61 μmol, 6.98 μL, 1.2 eq) was added after 78°C. React at -78°C for 2 hrs. The reaction solution was added to aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by preparative high-performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3μm; mobile phase: A (water, ammonium bicarbonate) and B (acetonitrile; gradient: B%: 20%-55%, 8min), Compound WX-008 was obtained. 1 HNMR (400 MHz, DMSO-d 6 ) δ: 10.79 (s, 1H), 10.66 (s, 1H), 8.95-8.92 (m, 2H), 8.60 (s, 1H), 8.53 ( s, 1H), 8.07(s, 1H), 7.56-7.54(m, 1H), 7.45-7.43(m, 1H), 7.29-7.27(m, 1H), 6.69-6.62(m, 1H), 5.72( d, J=5.2Hz, 1H), 5.69(s, 1H), 4.16(m, 3H), 3.86-3.70(m, 1H), 3.46-3.32(m, 3H), 2.46-2.44(m, 2H) , 2.00-1.97 (m, 2H), 0.79 (s, 4H); LCMS m/z = 545.4 [M+H] + .
生物测试数据biological test data
实验例1：化合物对TYK2 JH2假激酶抑制活性Experimental Example 1: Compounds have inhibitory activity against TYK2 JH2 pseudokinase
本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对TYK2 JH2假激酶的抑制作用。In this experiment, the method of fluorescence resonance energy transfer (TR-FRET) was used to test the inhibitory effect of compounds on TYK2 JH2 pseudokinase.
1实验试剂1 experimental reagent
表5试剂信息Table 5 Reagent information
试剂名称Reagent name 供应商supplier 存储条件storage conditions
TYK2/JAK1TYK2/JAK1 BioduroBioduro -80℃-80°C
TracerTracer BioduroBioduro -80℃-80°C
Tb antibodyTb antibody CisbioCisbio -80℃-80°C
HEPESHEPES InvitrogenInvitrogen 4℃4°C
MgCl2 1MMgCl2 1M SigmaSigma 常温room temperature
Brij L23 solution(Brij-35)Brij L23 solution(Brij-35) SigmaSigma 常温room temperature
DTTDTT SigmaSigma -20℃-20°C
BSABSA SigmaSigma 4℃4°C
2实验方法2 Experimental methods
1)准备1X实验工作液1) Prepare 1X experimental working solution
HEPES pH7.5，终浓度为20mM；MgCl 2，终浓度为10mM；Brij-35，终浓度为0.015％；DTT，终浓度为2mM；BSA，终浓度为50μg/mL。 HEPES pH7.5, the final concentration is 20mM; MgCl 2 , the final concentration is 10mM; Brij-35, the final concentration is 0.015%; DTT, the final concentration is 2mM; BSA, the final concentration is 50μg/mL.
2)实验操作步骤：2) Experimental operation steps:
a)用DMSO溶解化合物到10mM的存储浓度。a) Compounds were dissolved in DMSO to a stock concentration of 10 mM.
b)在化合物稀释板子中配备200倍于终浓度的化合物浓度，按照27倍倍比稀释法，从最高浓度点稀释，共4个浓度点，并转移到Echo板中。b) Prepare a compound concentration of 200 times the final concentration in the compound dilution plate, dilute from the highest concentration point according to the 27-fold dilution method, and transfer it to the Echo plate.
c)用Echo仪器将化合物从Echo板脉冲到384实验板，使得化合物变成3倍倍比稀释矩阵，11个浓度点。c) Pulse the compound from the Echo plate to the 384 assay plate with the Echo instrument, so that the compound becomes a 3-fold dilution matrix with 11 concentration points.
d)加5μL 3X TYK2 JH2激酶到384实验板中。d) Add 5 μL of 3X TYK2 JH2 kinase to the 384 assay plate.
e)加5μL 3X Tb到384实验板中。e) Add 5 μL 3X Tb to the 384 assay plate.
f)加5μL 3X Tracer到384孔实验板中。f) Add 5μL 3X Tracer to the 384-well experimental plate.
g)离心30秒，室温孵育60分钟。g) Centrifuge for 30 seconds and incubate at room temperature for 60 minutes.
h)Envision酶标仪(PerkinElmer)495/520荧光信号值。h) Envision microplate reader (PerkinElmer) 495/520 fluorescence signal value.
3)数据分析3) Data analysis
使用XL-Fit软件进行数据分析，得出化合物IC 50。结果如表6： Data analysis was performed using XL-Fit software to obtain compound IC 50 . The results are shown in Table 6:
表6：激酶半数抑制浓度IC 50(nM) Table 6: Kinase half inhibitory concentration IC 50 (nM)
受试品Test article TYK2 JH2TYK2 JH2
WX-001WX-001 0.400.40
WX-002AWX-002A 0.630.63
WX-002BWX-002B 0.530.53
WX-003AWX-003A 0.510.51
WX-004BWX-004B 0.390.39
WX-005WX-005 0.270.27
WX-006WX-006 0.430.43
WX-007WX-007 0.120.12
WX-008WX-008 0.160.16
WX-009WX-009 0.490.49
结论：本发明化合物对TYK2 JH2假激酶具有良好的抑制作用。Conclusion: the compound of the present invention has good inhibitory effect on TYK2 JH2 pseudokinase.

Claims (18)

  1. 式(P)所示化合物或其药学上可接受的盐，A compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022096978-appb-100001
    Figure PCTCN2022096978-appb-100001
    其中，in,
    T、Y、Y 1、Y 2和Y 3选自N和CH，所述CH任选被1个卤素、C 1-3烷基和C 1-3烷氧基取代； T, Y, Y 1 , Y 2 and Y 3 are selected from N and CH, said CH is optionally substituted by 1 halogen, C 1-3 alkyl and C 1-3 alkoxy;
    R 11选自C 2-4烯基、C 2-4炔基和CH 2CN，所述C 2-4烯基、C 2-4炔基和CH 2CN任选被1、2或3个卤素取代； R 11 is selected from C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN, and the C 2-4 alkenyl, C 2-4 alkynyl and CH 2 CN are optionally replaced by 1, 2 or 3 halogen substitution;
    R 12选自N(R 2) 2和C(R 2) 3； R 12 is selected from N(R 2 ) 2 and C(R 2 ) 3 ;
    R 13选自C 3-6环烷基、3-6杂环烷基、苯基、5-6杂芳基、NHC(＝O)-C 3-6环烷基、NHC(＝O)-3-6杂环烷基、NHC(＝O)-苯基和NHC(＝O)-5-6元杂芳基，所述C 3-6环烷基、3-6杂环烷基、苯基、5-6杂芳基、NHC(＝O)-C 3-6环烷基、NHC(＝O)-3-6杂环烷基、NHC(＝O)-苯基和NHC(＝O)-5-6元杂芳基任选被1、2或3个卤素、C 1-3烷基和C 1-3烷氧基取代； R 13 is selected from C 3-6 cycloalkyl, 3-6 heterocycloalkyl, phenyl, 5-6 heteroaryl, NHC (=O)-C 3-6 cycloalkyl, NHC (=O)- 3-6 heterocycloalkyl, NHC(=O)-phenyl and NHC(=O)-5-6 membered heteroaryl, the C 3-6 cycloalkyl, 3-6 heterocycloalkyl, benzene base, 5-6 heteroaryl, NHC(=O)-C 3-6 cycloalkyl, NHC(=O)-3-6 heterocycloalkyl, NHC(=O)-phenyl and NHC(=O )-5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 halogens, C 1-3 alkyl and C 1-3 alkoxy;
    R 1选自C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 is selected from C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R a ;
    R 2选自H、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代； R 2 is selected from H, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R b ;
    环B不存在；Ring B does not exist;
    或者，环B选自C 5-10环烷基、5-10元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 5-10环烷基、5-10元杂环烷基、C 6-10芳基和5-10元杂芳基任选被1、2或3个R c取代； Alternatively, Ring B is selected from C 5-10 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 5-10 cycloalkyl, 5- 10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by 1, 2 or 3 R c ;
    E选自-(CH 2) s-NR 3-、
    Figure PCTCN2022096978-appb-100002
    和-C(＝O)NR 3-C 3-6环烷基-NR 3-；     E is selected from -(CH 2 ) s -NR 3 -,
    Figure PCTCN2022096978-appb-100002
    and -C(=O)NR 3 -C 3-6 cycloalkyl-NR 3 -;
    s为0、1或2；s is 0, 1 or 2;
    n和m分别独立地选自0、1、2和3；n and m are independently selected from 0, 1, 2 and 3;
    R 3分别独立地选自H和C 1-3烷基； R 3 are independently selected from H and C 1-3 alkyl;
    R 4选自F、Cl、Br、I和OH； R is selected from F, Cl, Br, I and OH;
    R a和R b分别独立地选自H、D、F、Cl、Br和I； R and R are independently selected from H, D, F, Cl, Br and I;
    各R c分别独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代； Each R c is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
    所述3-6元杂环烷、5-10元杂环烷基、5-6元杂芳基和5-10元杂芳基中“杂”表示1、2或3个分别独立地选自N、O、S和NH的原子或原子团。"Hetero" in the 3-6 membered heterocycloalkane, 5-10 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-10 membered heteroaryl means that 1, 2 or 3 are independently selected from Atoms or atomic groups of N, O, S and NH.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，各R c分别独立地选自H、F、Cl、Br、I和CH 3，所述CH 3任选被1、2或3个卤素取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R c is independently selected from H, F, Cl, Br, I and CH 3 , and the CH 3 is optionally replaced by 1, 2 or 3 halogen substitutions.
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，各R c分别独立地选自H、F、Cl、Br、I、CH 3、CH 2F、CHF 2和CF 3。 The compound or the pharmaceutically acceptable salt thereof according to claim 2, wherein each R c is independently selected from H, F, Cl, Br, I, CH 3 , CH 2 F, CHF 2 and CF 3 .
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自CH 3和OCH 3，所述CH 3和OCH 3任选被1、2或3个R a取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 and OCH 3 , and said CH 3 and OCH 3 are optionally substituted by 1, 2 or 3 R a .
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R 1选自OCH 3。 The compound or the pharmaceutically acceptable salt thereof according to claim 4, wherein R 1 is selected from OCH 3 .
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2选自H、CH 3和OCH 3，所述CH 3和OCH 3分别独立地任选被1、2或3个R b取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, CH 3 and OCH 3 , and said CH 3 and OCH 3 are independently optionally replaced by 1, 2 or 3 R b replaces.
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，R 2选自H、CH 3和CD 3。 The compound or the pharmaceutically acceptable salt thereof according to claim 6, wherein R 2 is selected from H, CH 3 and CD 3 .
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，Y、Y 1、Y 2和Y 3选自CH。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y, Y 1 , Y 2 and Y 3 are selected from CH.
  9. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 11选自CH 2＝CH 2和CH 2CN。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from CH 2 =CH 2 and CH 2 CN.
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 12选自NH 2、NHCH 3、NHCD 3、CH 2CH 3和CH 2CD 3。 The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R 12 is selected from NH 2 , NHCH 3 , NHCD 3 , CH 2 CH 3 and CH 2 CD 3 .
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 13选自NHC(＝O)-环丙基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 13 is selected from NHC(=O)-cyclopropyl.
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2022096978-appb-100003
    Figure PCTCN2022096978-appb-100004
    所述
    Figure PCTCN2022096978-appb-100005
    任选被1、2或3个R c取代。     The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from
    Figure PCTCN2022096978-appb-100003
    Figure PCTCN2022096978-appb-100004
    said
    Figure PCTCN2022096978-appb-100005
    Optionally substituted with 1, 2 or 3 Rc .
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2022096978-appb-100006
    Figure PCTCN2022096978-appb-100007
    The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein Ring B is selected from
    Figure PCTCN2022096978-appb-100006
    Figure PCTCN2022096978-appb-100007
  14. 根据权利要求1所述化合物或其药学上可接受的盐，其中，E选自NH、-(CH 2)-NH-、-(CH 2)-N(CH 3)-、
    Figure PCTCN2022096978-appb-100008
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein E is selected from NH, -(CH 2 )-NH-, -(CH 2 )-N(CH 3 )-,
    Figure PCTCN2022096978-appb-100008
  15. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022096978-appb-100009
    选自
    Figure PCTCN2022096978-appb-100010
    Figure PCTCN2022096978-appb-100011
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022096978-appb-100009
    selected from
    Figure PCTCN2022096978-appb-100010
    Figure PCTCN2022096978-appb-100011
  16. 根据权利要求1～15任意一项所述化合物或其药学上可接受的盐，其选自：The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-15, which is selected from:
    Figure PCTCN2022096978-appb-100012
    Figure PCTCN2022096978-appb-100012
    Figure PCTCN2022096978-appb-100013
    Figure PCTCN2022096978-appb-100013
    其中，in,
    T 1选自N和CH； T1 is selected from N and CH;
    R 1、R 2、E、T和R c如权利要求1～15任意一项所定义。 R 1 , R 2 , E, T and R c are as defined in any one of claims 1-15.
  17. 下式所示化合物或其药学上可接受的盐，A compound represented by the following formula or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022096978-appb-100014
    Figure PCTCN2022096978-appb-100014
    Figure PCTCN2022096978-appb-100015
    Figure PCTCN2022096978-appb-100015
    Figure PCTCN2022096978-appb-100016
    Figure PCTCN2022096978-appb-100016
  18. 根据权利要求17所述化合物或其药学上可接受的盐，其选自：The compound or pharmaceutically acceptable salt thereof according to claim 17, which is selected from:
    Figure PCTCN2022096978-appb-100017
    Figure PCTCN2022096978-appb-100017
    Figure PCTCN2022096978-appb-100018
    Figure PCTCN2022096978-appb-100018
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