WO2023016530A1 - 一类3,4-二氢-2H-苯并[b][1,4]噁嗪类化合物及其制备方法 - Google Patents

一类3,4-二氢-2H-苯并[b][1,4]噁嗪类化合物及其制备方法 Download PDF

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WO2023016530A1
WO2023016530A1 PCT/CN2022/111904 CN2022111904W WO2023016530A1 WO 2023016530 A1 WO2023016530 A1 WO 2023016530A1 CN 2022111904 W CN2022111904 W CN 2022111904W WO 2023016530 A1 WO2023016530 A1 WO 2023016530A1
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compound
reaction solution
ethyl acetate
added
stirred
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PCT/CN2022/111904
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English (en)
French (fr)
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吴凌云
赵乐乐
孙建军
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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a class of 3,4-dihydro-2H-benzo[b][1,4]oxazine compounds and their preparation methods, as well as the application of such compounds in the preparation of drugs for the treatment of related diseases, in particular to the formula (I) Compounds and pharmaceutically acceptable salts thereof.
  • Tumor immunotherapy is a therapeutic area that has attracted much attention in recent years.
  • the main mechanism is to enhance the anti-tumor ability of the immune microenvironment by mobilizing the body's immune system.
  • monoclonal antibody drugs for tumor immunotherapy such as Keytruda and OPDIVO, have been used for the treatment of various cancers such as non-small cell lung cancer and melanoma.
  • RORs Retinoic acid-related orphan receptors
  • RORs Retinoic acid-related orphan receptors
  • RORs belong to the nuclear receptor superfamily and are a member of intracellular transcription factors, which can regulate a variety of physiological processes, including reproductive development, metabolism, and immune system regulation.
  • ROR has three family members: ROR- ⁇ , - ⁇ and - ⁇ , which are encoded by RORA, RORB and RORC genes, respectively.
  • ROR ⁇ includes two subtypes, ROR ⁇ 1 and ROR ⁇ t (ROR ⁇ 2).
  • ROR ⁇ 1 is expressed in various tissues and organs such as thymus, muscle, pancreas, prostate, and liver, while the short-chain subtype ROR ⁇ t of ROR ⁇ is mainly distributed in the thymus and promotes the differentiation of initial T cells into Th17 and Tc17 cells.
  • Th17 and Tc17 cells promote inflammatory and autoimmune responses by secreting IL-17, IL-22, GM-CSF and other cytokines and inflammatory factors.
  • IL-17 can promote the recruitment and infiltration of CTLs and NK cells in the tumor microenvironment, and enhance the anti-tumor effect of effector T cells.
  • ROR ⁇ agonists currently have no drugs approved for marketing, and Lycera Corp’s
  • ROR ⁇ agonist LYC-55716 monotherapy for the treatment of advanced solid tumors is in phase II clinical research, and it is combined with PD-1 monoclonal antibody pembrolizumab in the treatment of advanced non-small cell lung cancer The treatment is in a phase 1b clinical study.
  • this field still needs candidate compounds with better activity and better pharmacokinetic parameters to advance to clinical trials to meet the therapeutic needs.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from N and C (R 12 );
  • T 2 is selected from N and C (R 15 );
  • Ring A is selected from 5 membered heteroaryls
  • R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 Alkoxy and C 1-3 alkylamino, wherein said C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R b are independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and -COOH;
  • R is independently selected from F, Cl, Br, I, -OH and -NH 2 ;
  • Hetero in the 5-membered heteroaryl represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N, respectively.
  • T 1 is selected from C(R 12 ), and other variables are as defined in the present invention.
  • T1 is selected from N, and other variables are as defined in the present invention.
  • T 2 is selected from C(R 15 ), and other variables are as defined in the present invention.
  • T 2 is selected from N, and other variables are as defined in the present invention.
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CH 3 , and other variables are as defined in the present invention.
  • the aforementioned R a are independently selected from -CH 3 , and other variables are as defined in the present invention.
  • R a are independently selected from F, and other variables are as defined in the present invention.
  • R b are independently selected from -COOH, and other variables are as defined in the present invention.
  • R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -O-CH 3 , -NH-CH 3 and -N-(CH 3 ) 2 , wherein the -CH 3 , -O-CH 3 , -NH-CH 3 and -N-(CH 3 ) 2 are respectively Independently optionally substituted with 1, 2 or 3 R a , R a and other variables are as defined herein.
  • R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -O-CH 3 and -NH-CH 3 , wherein said -CH 3 , -O-CH 3 and -NH-CH 3 are independently optionally substituted by 1, 2 or 3 R a , R a and Other variables are as defined herein.
  • R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CF 3 , -O-CH 3 , -O-CH 2 F, -O-CHF 2 , -O-CF 3 and -N-(CH 3 ) 2 , other variables are as defined in the present invention.
  • R 11 is selected from H and F, and other variables are as defined in the present invention.
  • R 12 is selected from H and F, and other variables are as defined in the present invention.
  • R 13 is selected from H, and other variables are as defined in the present invention.
  • R 14 is selected from H, F, Cl, -CH 3 and -O-CH 3 , wherein the -CH 3 and -O-CH 3 are independently optionally replaced by 1, 2 or 3 R a substitutions, R a and other variables are as defined herein.
  • R 14 is selected from H, F, Cl, -CF 3 , -O-CH 3 and -O-CF 3 , and other variables are as defined in the present invention.
  • R 15 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -O-CH 3 and -NH-CH 3 described in -CH 3 , -O-CH 3 and -NH-CH 3 are independently optionally substituted by 1, 2 or 3 R a , and R a and other variables are as defined in the present invention.
  • R 15 is selected from H, F, Cl, CN, -CH 3 , -CF 3 , -O-CH 3 , -O-CH 2 F, -O-CHF 2 , -O- CF 3 and -N-(CH 3 ) 2 , other variables are as defined in the present invention.
  • R 2 is selected from -CH 2 -CH 3 , wherein the -CH 2 -CH 3 is optionally substituted by 1, 2 or 3 R b , and R b and other variables are as described in the present invention definition.
  • the above-mentioned ring A is selected from 5-membered nitrogen-containing heteroaryl groups, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from 1,2,4-oxadiazole, 1,3,4-oxadiazole, oxazole, pyrazole and 1,2,4-triazole, other variables such as defined in the present invention.
  • the above-mentioned ring A is selected from Wherein, D 1 is selected from O or NH; T 3 , T 4 , T 5 and T 6 are independently selected from N and CH; other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined herein.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • D 1 , T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , R 11 , R 12 , R 13 , R 14 , R 15 and R 2 are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • D 1 , T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , R 11 , R 12 , R 13 , R 14 , R 15 and R 2 are as defined in the present invention;
  • Carbon atoms with "*" are chiral carbon atoms and exist as (R) or (S) single enantiomer or enrichment of one enantiomer.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • D 1 , T 3 , T 4 , T 5 , T 6 , R 11 , R 12 , R 13 , R 14 , R 15 and R 2 are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • D 1 , T 3 , T 4 , T 5 , T 6 , R 11 , R 12 , R 13 , R 14 , R 15 and R 2 are as defined in the present invention
  • Carbon atoms with "*" are chiral carbon atoms and exist as (R) or (S) single enantiomer or enrichment of one enantiomer.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the compound of the present invention As a class of 3,4-dihydro-2H-benzo[b][1,4]oxazine compounds with ROR ⁇ agonistic activity or inverse agonistic activity, the compound of the present invention has remarkable in vitro activity and good pharmacokinetic properties. Kinetic properties, and in the MC38 mouse colon cancer xenograft model, combined with PD-1 monoclonal antibody has excellent tumor inhibitory effect.
  • 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 a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • 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.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into
  • 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 and straight dashed keys
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • 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 diastereoisomeric 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. 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.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the 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-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond 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.
  • 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.
  • C 1-3 alkylamino denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 etc.
  • the term "5-membered heteroaryl” and “5-membered heteroaryl ring” in the present invention can be used interchangeably.
  • the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • a 5-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • Examples of the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole base, 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 -thiazo
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxyl protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxy group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and 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 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
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • m-CPBA 3-chloroperoxybenzoic acid
  • eq represents equivalent, equivalent
  • CDI represents Carbonyldiimidazole
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DIAD stands for diisopropyl azodicarboxylate
  • DMF stands for N,N-dimethylformamide
  • DMSO stands for dimethylsulfoxide
  • EtOAc stands for ethyl acetate EtOH is ethanol
  • MeOH is methanol
  • CBz benzyloxycarbonyl
  • reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (200mL), washed with water (200mL x 1) and saturated brine (200mL x 1) successively, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed After concentration, the residue was separated and purified by silica gel column chromatography (4:1 petroleum ether/ethyl acetate) to obtain compound 1-6.
  • reaction solution was filtered through celite, the filter residue was washed with ethyl acetate (100 mL), the filtrate was washed with water (100 mL x 3) and saturated brine (100 mL x 1) successively, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to After concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate) to obtain compound 1-9.
  • reaction solution was concentrated under reduced pressure to remove ethanol, the aqueous phase was extracted with ethyl acetate (50mL x 2), the organic phases were combined, washed with saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed After concentration, the residue was separated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to obtain compound 1-10. MS-ESI calculated [M+H] + 488, found 488.
  • reaction solution was concentrated under reduced pressure, water (10mL) was added, the pH value was adjusted to 4 with hydrochloric acid (1M), and then extracted with ethyl acetate (20mL x 3), the combined organic phases were washed with saturated brine (50mL x 2), and then It was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography (neutral, ammonium bicarbonate system) to obtain compound 1.
  • compound 2-1 (1.39g, 7.94mmol) was dissolved in dry dichloromethane (20mL), and then 2-(7-azobenzotriazole)-N,N,N,N -Tetramethylurea hexafluorophosphate (3.45g, 9.08mmol) and diisopropylethylamine (1.47g, 11.4mmol), then add tert-butyl carbazate (1.00g, 7.57mmol), and the reaction solution was After stirring at 25°C for 12 hours, water (20 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL x 1).
  • compound 2-5 (1.80g, 3.80mmol) was dissolved in anhydrous N,N-dimethylformamide (20mL), compound 2-3 (860mg, 4.56mmol), diisopropyl Ethylamine (2.46g, 19.0mmol), 50% propylphosphoric acid tricyclic acid anhydride solution (7.26g, 11.4mmol), the reaction solution was stirred at 130°C for 12 hours, water (40mL) was added to the reaction solution, and ethyl acetate Esters (40 mL x 1) were extracted. The organic phase was washed with saturated brine (40mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (2:1 petroleum ether/ethyl acetate) to obtain compound 2- 6. MS-ESI calculated value [M+H] + 626, found value 626.
  • compound 9-1 (2.20g, 10.6mmol) was dissolved in anhydrous methanol (20mL), potassium carbonate (2.92g, 21.1mmol) and (1-diazo-2-oxopropyl) were added Dimethyl phosphonate (2.43g, 12.7mmol), the reaction solution was stirred at 25°C for 12 hours, water (40mL) was added to the reaction solution, and extracted with ethyl acetate (50mL x 1).
  • compound 2-5 (300mg, 0.634mmol) was dissolved in dry tetrahydrofuran (10mL), and borane tetrahydrofuran solution (1M, 1.9mL, 1.90mmol) was added dropwise at zero temperature, and the reaction solution was stirred at 0°C for 1 After 1 hour, ice water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 1).
  • compound 11-2 (320mg, 0.697mmol) was dissolved in anhydrous dichloromethane (5mL), Dess Martin periodinane (443mg, 1.04mmol) was added, and the reaction solution was stirred at 25°C for 12 hours , adding saturated sodium carbonate aqueous solution (20mL) to the reaction solution, extracted with ethyl acetate (20mL x 1). The organic phase was washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the remaining The compound was separated and purified by silica gel column chromatography (2:1 petroleum ether/ethyl acetate) to obtain compound 11-3. MS-ESI calculated value [M+H] + 458, observed value 458.
  • compound 11-5 (82.0 mg, 0.162 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 11-1 (49.6 mg, 0.243 mmol), cuprous iodide (6.2 mg, 0.324 mmol) were added , potassium carbonate (44.7mg, 0.324mmol), the reaction solution was stirred at 30°C for 12 hours, water (20mL) was added to the reaction solution, and extracted with ethyl acetate (20mL x 1).
  • compound 12-1 (70.2mg, 0.369mmol) was dissolved in anhydrous N,N-dimethylformamide (16mL), N,N-carbonyldiimidazole (64.9mg, 0.400mmol) was added, and the reaction The solution was stirred at 30°C for 2 hours, then compound 1-10 (150mg, 0.308mmol) was added, the reaction solution was stirred at 110°C for 10 hours, water (30mL) was added to the reaction solution, and ethyl acetate (20mL x 1 ) extraction, the organic phase was washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by thin-layer chromatography (1:1 petroleum ether/ethyl acetate) to obtain Compound 12-2. MS-ESI calculated [M+Na] + 664, found 664.
  • compound 15-2 (195mg, 1.23mmol) was dissolved in anhydrous methanol (20mL), potassium carbonate (443mg, 1.04mmol) and (1-diazo-2-oxopropyl)phosphonic acid were added Dimethyl ester (284mg, 1.48mmol), the reaction solution was stirred at 25°C for 12 hours, water (40mL) was added to the reaction solution, and extracted with ethyl acetate (50mL x 1).
  • Compound 19-2 was obtained by referring to the first step method in Example 18. MS-ESI calculated value [M+H] + 660, found value 660.
  • compound 1-8 (800mg, 0.634mmol) was dissolved in dry 1,4-dioxane (10mL), and diboronic acid pinacol ester (440mg, 1.73mmol), potassium acetate (463mg, 4.72mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (129mg, 0.157mmol), the reaction solution was stirred at 90°C for 12 hours , water (40 mL) was added to the reaction solution, and extracted with ethyl acetate (40 mL x 1).
  • ROR ⁇ ligand-binding domain LBD
  • TR-FRET time-resolved fluorescence energy transfer
  • the compound to be tested was diluted in DMSO and further diluted in assay buffer (50mM Tris pH 7.0, 50mM KCl, 1mM Na-EDTA, 0.1mM DTT, 0.01% BSA) (4-fold dilution, 10 concentrations, highest concentration 5000 nM), the final DMSO concentration was 1%.
  • the hROR ⁇ -LBD protein was diluted in assay buffer to give a final hROR ⁇ -LBD concentration of 15 nM in 384-well plates.
  • a stock solution of biotin-SRC1 polypeptide Biotin-SPSSHSSLTERHKILHRLLQEGSP
  • SA-eu (1 nM final concentration) and SA-APC 50 nM final concentration
  • the final assay mixture was incubated overnight at 4°C, equilibrated at room temperature for 1 hour, and centrifuged at 1000 rpm for 1 minute. Fluorescence readings were detected on the Envision microplate detector, and the logarithmic curve of the ratio of the fluorescence signal of emission wavelength 665nM/615nM to the compound concentration was drawn by GraphPad Prism software, and the 50% effective concentration (EC 50 ) and 50% inhibition of the compound were calculated Concentration ( IC50 ). The maximum response (Emax) was the upper peak peak of the signal determined by GraphPad Prism fit.
  • the compound of the present invention has obvious agonistic or inverse agonistic activity on the in vitro activity of ROR ⁇ .
  • Non-essential amino acids (Gibco)
  • the CD3 antibody was diluted to 5 ⁇ g/mL in DPBS, added to a 96-well U-bottom plate, 50 ⁇ L of liquid per well, and coated overnight at 4°C.
  • C57BL/6 mouse spleen in culture medium (RPMI 1640+10% fetal bovine serum+1% penicillin+streptomycin+1% non-essential amino acid+0.05mM ⁇ -mercaptoethanol), pass through a 70 ⁇ m filter to prepare a single cell suspension , centrifuge at 300g for 3min. Add erythrocyte lysate to lyse at room temperature for 3 min. CD4 + cells were isolated using the Mouse CD4 + T cell isolation kit.
  • CD4 + cells obtained above at a density of 5*10 5 /mL into the coated wells , 200 ⁇ L cell suspension per well; then add CD28 antibody (3 ⁇ g/mL), TGF ⁇ (3ng/mL), IL-6 (30ng/mL), IL-23 (10ng/mL), IL-1 ⁇ (10ng/mL ), IFN ⁇ antibody (10 ⁇ g/mL) and IL-4 antibody (10 ⁇ g/mL); then the compound of the present invention was added to the well, and cultured at 37° C. under 5% CO 2 for 3 days.
  • the U-bottom plate was centrifuged at 300g for 3min, the supernatant was discarded, and washed twice with staining buffer r.
  • the IL-17A antibody was diluted 1:200 in permeabilization buffer, 50 ⁇ L of dye solution was added to each well, stained at room temperature for 30 min, and then washed twice with staining buffer. Finally, the cells were resuspended with 150 ⁇ L staining buffer, and the ratio of IL-17A was detected by flow cytometry.
  • Table 3 The compounds of the present invention promote the ability of CD4 + cells to differentiate into Th17 cells to measure results
  • the compounds of the present invention can significantly promote the differentiation of CD4 + cells into Th17 cells, thereby increasing the ratio of IL-17A.
  • the pharmacokinetic characteristics of the compounds were tested in rodents after intravenous injection (IV) and oral administration (PO) according to the standard protocol.
  • IV intravenous injection
  • PO oral administration
  • the solvent for intravenous injection is a mixed solvent made up of 5% dimethyl sulfoxide, 30% PEG400, and 65% hydroxypropyl beta cyclodextrin (10%).
  • the oral vehicle is a mixed vehicle made of 0.5% hypromellose and 0.2% Tween.
  • the project used four female Balb/c mice, two mice were administered intravenously, the dose was 0.5mg/kg, and the collection 0h (before administration) and after administration were 0.0833, 0.25, 0.5, 1, Plasma samples at 2, 4, 8, and 24 hours were administered orally to the other two mice at a dose of 1 mg/kg, collected at 0 h (before administration) and at 0.25, 0.5, 1, 2, and 4 hours after administration , 8, 24h plasma samples, collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate supernatant to obtain plasma samples, add 4 times volume of acetonitrile solution containing internal standard to precipitate protein, centrifuge to take supernatant and add equal volume The water was then centrifuged to take the supernatant sample, and the blood drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters were calculated, such as peak concentration (C max ), clearance rate (CL), half-life (T 1 / 2 ), tissue distribution (V
  • the compounds of this invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • the purpose of this experiment is to study the evaluation of the compound of the present invention on the MC38 mouse colon cancer xenograft tumor model in vivo.
  • the culture medium is 1640 medium containing 10% fetal bovine serum, and the culture conditions are 37°C and 5% carbon dioxide.
  • the subculture ratio was 1:2 ⁇ 1:3, and subcultured 2 ⁇ 3 times a week.
  • 0.1 mL (2 ⁇ 10 5 ) cells were inoculated subcutaneously on the right back of each mouse. On the same day, animals were randomized into groups based on body weight.
  • the experimental vehicle was 5% DMSO/95% (20% hydroxypropyl beta cyclodextrin).
  • the test substance was dissolved in a solvent, prepared into a uniform solution with a certain concentration, and stored at 4°C.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week with vernier calipers.
  • T/C Relative tumor proliferation rate
  • PD-1 monoclonal antibody BioXcell. PD-1 monoclonal antibody was administered on the 7th day after grouping, and compound 24 was administered on the day of grouping.
  • the combination of the compound of the present invention and PD-1 monoclonal antibody has an excellent tumor-inhibiting effect on the transplanted tumor model of MC38 mouse colon cancer.

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Abstract

公开了一类3,4-二氢-2H-苯并[b][1,4]噁嗪类化合物及其制备方法，以及该类化合物在制备治疗相关疾病药物中的应用。具体公开了式(Ⅰ)所示化合物及其药学上可接受的盐。

Description

一类3,4-二氢-2H-苯并[b][1,4]噁嗪类化合物及其制备方法
本申请主张如下优先权：
CN202110933020.4，2021年08月13日。
技术领域
本发明涉及一类3,4-二氢-2H-苯并[b][1,4]噁嗪类化合物及其制备方法，以及该类化合物在制备治疗相关疾病药物中的应用，具体涉及式(Ⅰ)所示化合物及其药学上可接受的盐。
背景技术
肿瘤免疫疗法是近年来备受关注的治疗领域，主要机理是通过调动机体的免疫系统，增强免疫微环境的抗肿瘤能力。目前已有肿瘤免疫治疗的单抗药物如Keytruda和OPDIVO等用于非小细胞肺癌和黑色素瘤等多种癌症的治疗。
维甲酸相关孤儿受体(RAR-related orphan receptor，RORs)属于核受体超家族，是细胞内转录因子的一员，能够调控多种生理过程，包括生殖发育、新陈代谢、免疫系统调节等。ROR有三个家族成员：ROR-α、-β和-γ，分别由RORA、RORB、RORC基因编码。RORγ又包括RORγ1和RORγt(RORγ2)两种亚型。RORγ1在胸腺、肌肉、胰腺、前列腺和肝脏等多种组织和器官中表达，而RORγ的短链亚型RORγt主要分布于胸腺，促进初始T细胞向Th17和Tc17细胞分化。Th17和Tc17细胞通过分泌IL-17，IL-22，GM-CSF等细胞因子和炎症因子，促进炎症反应和自身免疫应答。IL-17可以促进肿瘤微环境中CTLs和NK细胞的招募和浸润，提升效应T细胞的抗肿瘤作用。
RORγ激动剂目前没有药物获批上市，Lycera Corp公司的RORγ激动剂LYC-55716单药用于晚期实体瘤的治疗处于临床二期研究，与PD-1单抗pembrolizumab联用治疗晚期非小细胞肺癌的治疗处于临床1b期研究。面对巨大的未满足市场，该领域仍然需要活性更好，药代动力学参数更优的候选化合物推进临床试验，以满足治疗需求。
发明内容
本发明提供了式(Ⅰ)化合物或其药学上可接受的盐，
Figure PCTCN2022111904-appb-000001
其中，
T 1选自N和C(R 12)；
T 2选自N和C(R 15)；
环A选自5元杂芳基；
R 11、R 12、R 13、R 14和R 15分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R a取代；
R 2选自C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
R a分别独立地选自F、Cl、Br、I、-OH、-NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代；
R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN和-COOH；
R分别独立地选自F、Cl、Br、I、-OH和-NH 2；
所述5元杂芳基中的“杂”表示1、2、3或4个分别独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述T 1选自C(R 12)，其他变量如本发明所定义。
本发明的一些方案中，上述T 1选自N，其他变量如本发明所定义。
本发明的一些方案中，上述T 2选自C(R 15)，其他变量如本发明所定义。
本发明的一些方案中，上述T 2选自N，其他变量如本发明所定义。
本发明的一些方案中，上述R a分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R a分别独立地选自-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R a分别独立地选自F，其他变量如本发明所定义。
本发明的一些方案中，上述R b分别独立地选自-COOH，其他变量如本发明所定义。
本发明的一些方案中，上述R 11、R 12、R 13、R 14和R 15分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-O-CH 3、-NH-CH 3和-N-(CH 3) 2，其中所述-CH 3、-O-CH 3、-NH-CH 3和-N-(CH 3) 2分别独立地任选被1、2或3个R a取代，R a及其他变量如本发明所定义。
本发明的一些方案中，上述R 11、R 12、R 13、R 14和R 15分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-O-CH 3和-NH-CH 3，其中所述-CH 3、-O-CH 3和-NH-CH 3分别独立地任选被1、2或3个R a取代，R a及其他变量如本发明所定义。
本发明的一些方案中，上述R 11、R 12、R 13、R 14和R 15分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-CF 3、-O-CH 3、-O-CH 2F、-O-CHF 2、-O-CF 3和-N-(CH 3) 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 11选自H和F，其他变量如本发明所定义。
本发明的一些方案中，上述R 12选自H和F，其他变量如本发明所定义。
本发明的一些方案中，上述R 13选自H，其他变量如本发明所定义。
本发明的一些方案中，上述R 14选自H、F、Cl、-CH 3和-O-CH 3，其中所述-CH 3和-O-CH 3分别独立地 任选被1、2或3个R a取代，R a及其他变量如本发明所定义。
本发明的一些方案中，上述R 14选自H、F、Cl、-CF 3、-O-CH 3和-O-CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 15选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-O-CH 3和-NH-CH 3其中所述-CH 3、-O-CH 3和-NH-CH 3分别独立地任选被1、2或3个R a取代，R a及其他变量如本发明所定义。
本发明的一些方案中，上述R 15选自H、F、Cl、CN、-CH 3、-CF 3、-O-CH 3、-O-CH 2F、-O-CHF 2、-O-CF 3和-N-(CH 3) 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自-CH 2-CH 3，其中所述-CH 2-CH 3任选被1、2或3个R b取代，R b及其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自
Figure PCTCN2022111904-appb-000002
其他变量如本发明所定义。
本发明的一些方案中，上述环A选自5元含氮杂芳基，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自1,2,4-恶二唑、1,3,4-恶二唑、恶唑、吡唑和1,2,4-三唑，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2022111904-appb-000003
其中，D 1选自O或NH；T 3、T 4、T 5和T 6分别独立地选自N和CH；其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2022111904-appb-000004
其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
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
Figure PCTCN2022111904-appb-000005
其中，D 1、T 1、T 2、T 3、T 4、T 5、T 6、R 11、R 12、R 13、R 14、R 15和R 2如本发明所定义。
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
Figure PCTCN2022111904-appb-000006
其中，D 1、T 1、T 2、T 3、T 4、T 5、T 6、R 11、R 12、R 13、R 14、R 15和R 2如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
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
Figure PCTCN2022111904-appb-000007
其中，D 1、T 3、T 4、T 5、T 6、R 11、R 12、R 13、R 14、R 15和R 2如本发明所定义。
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
Figure PCTCN2022111904-appb-000008
其中，D 1、T 3、T 4、T 5、T 6、R 11、R 12、R 13、R 14、R 15和R 2如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明还提供了下列所示化合物或其药学上可接受的盐，
Figure PCTCN2022111904-appb-000009
Figure PCTCN2022111904-appb-000010
本发明还提供了下列所示化合物或其药学上可接受的盐，
Figure PCTCN2022111904-appb-000011
Figure PCTCN2022111904-appb-000012
Figure PCTCN2022111904-appb-000013
Figure PCTCN2022111904-appb-000014
技术效果
作为一类具有RORγ激动活性或反向激动活性的3,4-二氢-2H-苯并[b][1,4]噁嗪类化合物，本发明的化合物体外活性显著，具有良好的药代动力学性质，并且在MC38小鼠结肠癌移植瘤模型中与PD-1单抗联用具有优异的抑瘤效果。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠 檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022111904-appb-000015
和楔形虚线键
Figure PCTCN2022111904-appb-000016
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022111904-appb-000017
和直形虚线键
Figure PCTCN2022111904-appb-000018
表示立体中心的相对构型，用波浪线
Figure PCTCN2022111904-appb-000019
表示楔形实线键
Figure PCTCN2022111904-appb-000020
或楔形虚线键
Figure PCTCN2022111904-appb-000021
或用波浪线
Figure PCTCN2022111904-appb-000022
表示直形实线键
Figure PCTCN2022111904-appb-000023
和直形虚线键
Figure PCTCN2022111904-appb-000024
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，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。
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原 子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022111904-appb-000025
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 PCTCN2022111904-appb-000026
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 PCTCN2022111904-appb-000027
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022111904-appb-000028
直形虚线键
Figure PCTCN2022111904-appb-000029
或波浪线
Figure PCTCN2022111904-appb-000030
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022111904-appb-000031
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 PCTCN2022111904-appb-000032
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 PCTCN2022111904-appb-000033
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 PCTCN2022111904-appb-000034
Figure PCTCN2022111904-appb-000035
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022111904-appb-000036
仍包括
Figure PCTCN2022111904-appb-000037
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。
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”。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲 氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基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烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，本发明术语“5元杂芳基”与“5元杂芳环”可以互换使用，术语“5元杂芳基”表示由5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元杂芳基的实例包括但不限吡咯基(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)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、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)。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022111904-appb-000038
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基，是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；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；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022111904-appb-000039
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
合成路线：
Figure PCTCN2022111904-appb-000040
第一步
将化合物1-1(50.0g,0.384mol)溶于甲醇(500mL)中,向其中加入浓盐酸(1mL),反应液在70℃下搅拌12小时。反应液冷至室温后向其中加入固体碳酸氢钠(3.00g),室温下搅拌0.5小时后过滤,滤液浓缩得到化合物1-2。 1H NMR(400MHz,CDCl 3)δ4.28-4.25(m,1H),3.81(s,3H),3.70(s,3H),2.93(br s,1H),2.53-2.46(m,2H),2.22-2.17(m,1H),1.99-1.91(m,1H)。
第二步
将化合物1-2(33.8g,0.192mol),化合物1-3(50.2g,0.230mol)和三苯基膦(60.4g,0.230mol)溶于二氯甲烷(300mL)中,反应液冷至0℃,向其中缓慢滴加偶氮二甲酸二异丙酯(46.6g,0.230mol)的二氯甲烷(50mL)溶液,滴完后反应液在0℃下搅拌0.5小时,然后在20℃下搅拌12小时,减压浓缩除去溶剂,粗产物经过柱层析法分离用二氯甲烷为洗脱剂以除去三苯基氧膦,洗脱液浓缩后所得剩余物溶于乙酸乙酯(500mL),再依次用氢氧化钠水溶液(1M,500mL x 4)和饱和食盐水(500mL x 1)洗涤,有机相用无水硫酸钠 干燥,过滤,滤液减压浓缩得到化合物1-4。 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝2.4Hz,1H),7.61(dd,J＝8.8,2.4Hz,1H),6.84(d,J＝8.8Hz,1H),4.94-4.91(m,1H),3.79(s,3H),3.71(s,3H),2.71-2.61(m,2H),2.43-2.30(m,2H)。MS-ESI计算值[M+Na] +398和400,实测值398和400。
第三步
将化合物1-4(35.8g,0.952mol)溶于醋酸(284mL)中,再加入铁粉(26.6g,0.476mol)。60℃条件下,搅拌反应2小时。将反应液趁热用硅藻土过滤,滤渣用乙酸乙酯(500mL)洗涤,滤液依次用水(500mL x 3)和饱和食盐水(500mL x 1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物1-5。 1H NMR(400MHz,CDCl 3)δ8.50(br s,1H),7.03-7.00(m,1H),6.89(d,J＝2.4Hz,1H),6.77(d,J＝8.4Hz,1H),4.55(dd,J＝8.4,4.4Hz,1H),3.63(s,3H),2.54-2.50(m,2H),2.32-2.24(m,1H),2.18-2.09(m,1H)。MS-ESI计算值[M+H] +314和316,实测值314和316。
第四步
将化合物1-5(20.0g,63.7mmol)溶于四氢呋喃(200mL)中,在0℃下向其中缓慢滴加硼烷二甲硫醚络合物(10M,15.9mL,0.159mol),滴加完后反应液在50℃下搅拌1小时。将反应液冷至0℃用甲醇(130mL)淬灭,再在60℃下搅拌1小时。反应液减压浓缩,剩余物用乙酸乙酯(200mL)溶解,再依次用水(200mL x 1)和饱和食盐水(200mL x 1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩后剩余物经过硅胶柱层析法(4:1石油醚/乙酸乙酯)分离纯化得到化合物1-6。 1H NMR(400MHz,CDCl 3)δ6.76-6.72(m,2H),6.66-6.64(m,1H),4.14-4.09(m,1H),3.82(br s,1H),3.72(s,3H),3.41-3.37(m,1H),3.17-3.12(m,1H),2.66-2.52(m,2H),2.01-1.96(m,2H)。MS-ESI计算值[M+H] +300和302,实测值300和302。
第五步
将化合物1-6(19.0g,63.3mmol)和化合物1-7(18.6g,76.0mmol)溶于吡啶(110mL)中,反应液在60℃下搅拌反应24小时。反应液减压浓缩后剩余物经过硅胶柱层析法(5:1石油醚/乙酸乙酯)分离纯化得到化合物1-8。MS-ESI计算值[M+H] +508和510,实测值508和510。 1H NMR(400MHz,CDCl 3)δ8.00-7.99(m,2H),7.88-7.85(m,2H),7.68-7.65(m,1H),7.20(dd,J＝8.8,2.4Hz,1H),6.71(d,J＝8.8Hz,1H),4.30(dd,J＝14.4,2.4Hz,1H),3.69(s,3H),3.52-3.48(m,1H),3.20-3.14(m,1H),2.51-2.39(m,2H),1.94-1.79(m,2H)。
第六步
将化合物1-8(2.00g,3.93mmol),氰化锌(739mg,6.30mmol)和四(三苯基膦)钯(546mg,0.472mmol)溶于N,N-二甲基甲酰胺(20mL)中,反应液在氮气保护下升温至100℃并搅拌12小时。反应液通过硅藻土过滤,滤渣用乙酸乙酯(100mL)洗涤,滤液依次用水(100mL x 3)和饱和食盐水(100mL x 1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩后剩余物经过硅胶柱层析法(3:1石油醚/乙酸乙酯)分离纯化得到化合物1-9。 1H NMR(400MHz,CDCl 3)δ8.16-8.14(m,1H),7.98(s,1H),7.91-7.87(m,2H),7.72-7.68(m,1H),7.40-7.37(m,1H),6.92-6.90(m,1H),4.37-4.32(m,1H),3.70(d,J＝2.8Hz,3H),3.64-3.60(m,1H), 3.23-3.16(m,1H),2.51-2.46(m,2H),2.00-1.85(m,2H)。MS-ESI计算值[M+Na] +477,实测值477。
第七步
将化合物1-9(700mg,1.54mmol)的乙醇(20mL)溶液加入盐酸羟胺(642mg,9.24mmol)和碳酸氢钠(388mg,4.62mmol)的水(20mL)溶液中,反应液在100℃搅拌3小时。反应液减压浓缩以除去乙醇,水相用乙酸乙酯(50mL x 2)萃取,有机相合并后用饱和食盐水(100mL x 1)洗涤,再用无水硫酸钠干燥,过滤,滤液减压浓缩后剩余物经过硅胶柱层析法(1:1石油醚/乙酸乙酯)分离纯化得到化合物1-10。MS-ESI计算值[M+H] +488,实测值488。
第八步
将氯化亚砜(244mg,2.05mmol)加入化合物1-11(97mg,0.431mmol)的二氯甲烷(5mL)溶液中,反应液在氮气保护下升温至60℃搅拌12小时。反应液减压浓缩后剩余物溶于氯仿(6mL)中,依次向其中加入吡啶(1.40g,17.6mmol)和化合物1-10(200mg,0.410mmol),新的反应液在氮气保护下升温至80℃搅拌3小时。反应液减压浓缩后剩余物经过薄层层析法(1:1石油醚/乙酸乙酯)分离纯化得到化合物1-12。MS-ESI计算值[M+H] +694,实测值694。
第九步
将氢氧化钠(1.0mg,0.0250mmol)加入乙腈(3mL)中,升温至50℃搅拌2小时,再将化合物1-12(60.0mg,0.0865mmol)加入其中,反应液在80℃下搅拌24小时。反应液减压浓缩后剩余物经过薄层层析法(2:1石油醚/乙酸乙酯)分离纯化得到化合物1-13。MS-ESI计算值[M+H] +676,实测值676。
第十步
将氢氧化钠(3.6mg,0.0888mmol)加入化合物1-13(20.0mg,0.0296mmol)的四氢呋喃(1mL)和水(2mL)溶液中,反应液在50℃下搅拌10小时。反应液减压浓缩,加水(10mL),用盐酸(1M)调节pH值到4,再用乙酸乙酯萃取(20mL x 3),有机相合并后用饱和食盐水洗涤(50mL x 2),再用无水硫酸钠干燥,过滤,减压浓缩,剩余物经过高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物1。 1H NMR(400MHz,CD 3OD)δ8.60(d,J＝1.6Hz,1H),8.08-8.06(m,1H),8.02-7.97(m,4H),7.93-7.89(m,1H),7.87-7.85(m,1H),7.82-7.79(m,1H),7.03(d,J＝8.4Hz,1H),4.52-4.48(m,1H),3.66-3.64(m,1H),3.41-3.37(m,1H),2.51-2.39(m,2H),2.01-1.83(m,2H)。MS-ESI计算值[M+H] +662,实测值662。
实施例2
合成路线：
Figure PCTCN2022111904-appb-000041
第一步
氮气保护下,将化合物2-1(1.39g,7.94mmol)溶于干燥二氯甲烷(20mL)中,再加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(3.45g,9.08mmol)和二异丙基乙胺(1.47g,11.4mmol),再加入肼基甲酸叔丁酯(1.00g,7.57mmol),反应液在25℃下搅拌12小时,向反应液中加入水(20mL),用二氯甲烷(20mL x 1)萃取。饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(1:1石油醚/乙酸乙酯)得到化合物2-2。 1H NMR(400MHz,DMSO-d 6)δ10.28(br s,1H),9.13(br s,1H),7.55-7.49(m,1H),7.40-7.38(m,1H),7.34-7.30(m,1H),1.43(s,9H)。MS-ESI计算值[M+Na] +311,实测值311。
第二步
氮气保护下,将化合物2-2(2.87g,9.94mmol)溶于无水甲醇(10mL)中,再加入盐酸甲醇(4M,13.7mL,54.7mmol),反应液在25℃下搅拌1小时,将反应液旋干,向反应液中加入40mL饱和碳酸氢钠水溶液,用二氯甲烷:甲醇＝10:1(50mL x 3)萃取,饱和食盐水(100mL x 1)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩得到化合物2-3。 1H NMR(400MHz,CD 3OD)δ7.48-7.44(m,1H),7.35-7.33(m,1H),7.21-7.17(m,1H)。
第三步
氮气保护下将化合物1-8(500mg,0.984mmol)溶于无水N,N-二甲基甲酰胺(10mL)中,加入三乙胺(299mg,2.95mmol),苄醇(532mg,4.92mmol),四(三苯基膦)钯(56.8mg,49.2mmol),反应液在一氧化碳(15 Psi)氛围下120℃下搅拌12小时,向反应液中加入水(20mL),用乙酸乙酯(20mL x 1)萃取。有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(2:1石油醚/乙酸乙酯),得到化合物2-4。 1H NMR(400MHz,CDCl 3)δ8.46-8.45(m,1H),7.98(s,1H),7.86-7.79(m,3H),7.57-7.53(m,1H),7.47-7.45(m,2H),7.43-7.34(m,3H),6.86-6.84(m,1H),5.36(q,J＝12.4Hz,2H),4.35-4.31(m,1H),3.68(s,3H),3.25-3.19(m,1H),2.53-2.43(m,2H),1.97-1.82(m,2H),1.28-1.26(m,1H)。
第四步
氮气保护下将化合物2-4(330mg,0.586mmol)溶于无水甲醇(10mL)中,加入10％钯碳(50.0mg),反应液在氢气(15psi)氛围下40℃下搅拌12小时,将反应液过滤除去钯碳,母液浓缩得到化合物2-5。MS-ESI计算值[M+H] +474,实测值474。
第五步
氮气保护下,将化合物2-5(1.80g,3.80mmol)溶于无水N,N-二甲基甲酰胺(20mL)中,加入化合物2-3(860mg,4.56mmol),二异丙基乙胺(2.46g,19.0mmol),50％丙基磷酸三环酸酐溶液(7.26g,11.4mmol),反应液在130℃下搅拌12小时,向反应液中加入水(40mL),用乙酸乙酯(40mL x 1)萃取。有机相用饱和食盐水洗涤(40mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(2:1石油醚/乙酸乙酯),得到化合物2-6。MS-ESI计算值[M+H] +626,实测值626。
第六步
氮气保护下,将化合物2-6(1.29g,2.06mmol)溶于四氢呋喃(20mL)和水(5mL)中,加入一水合氢氧化锂(432mg,10.3mmol),反应液在25℃下搅拌12小时,反应液旋蒸除去四氢呋喃,剩余液体用1M盐酸水溶液调节pH＝5,用混合溶剂(30mL,二氯甲烷/甲醇＝10:1)萃取,饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用高效液相色谱法(中性,碳酸氢铵体系)纯化得到化合物2。 1H NMR(400MHz,CD 3OD)δ8.56-8.55(m,1H),8.07(d,J＝8.4Hz,1H),8.02–8.00(m,2H),7.88-7.86(m,1H),7.83-7.79(m,1H),7.75-7.70(m,1H),7.58(d,J＝8.4Hz,1H),7.42(t,J＝8.8Hz,1H),7.10-7.07(m,1H),4.53-4.49(m,1H),3.61-3.60(m,1H),3.40-3.33(m,1H),2.50-2.38(m,2H),2.01-1.84(m,2H)。MS-ESI计算值[M+H] +612,实测值612。
实施例3
合成路线：
Figure PCTCN2022111904-appb-000042
第一步
将化合物3-1(1.00g,4.86mmol)溶于无水乙醇(20mL)中,将此混合溶液加入到盐酸羟胺(2.03g,29.2mmol)和碳酸氢钠(1.23g,14.6mmol)的水(20mL)溶液中,混合物在100℃搅拌3小时。反应液过滤,滤液浓缩,剩余物经硅胶柱层析法(3:1石油醚/乙酸乙酯)分离纯化得到化合物3-2。MS-ESI计算值[M+H] +239,实测值239。 1H NMR(400MHz,DMSO-d 6)δ8.11(br s,1H),7.88(br s,1H),7.85-7.83(m,1H),7.77-7.75(m,1H),7.64-7.62(m,1H)。
第二步
将化合物2-5(200mg,0.422mmol),1,1’-羰基二咪唑(75.4mg,0.465mmol)溶于N-甲基吡咯烷酮(5mL)中,混合液在氮气保护下25℃搅拌1小时。将化合物3-2(151mg,0.634mmol)加入至反应液中,反应液在氮气保护下升温至130℃搅拌10小时。反应液用水(20mL)稀释,用乙酸乙酯(20mL x 3)萃取。合并有机相后依次用水(20mL x 3)、饱和食盐水(60mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经薄层层析法(2:1石油醚/乙酸乙酯)分离纯化得到化合物3-3。MS-ESI计算值[M+H] +676,实测值676。
第三步
将化合物3-3(60.0mg,0.0888mmol)溶于无水四氢呋喃(1mL)和水(2mL)中,将氢氧化钠(10.7mg,0.266mmol)加入至混合液中。混合液在40℃搅拌1小时。反应液通过减压浓缩除去四氢呋喃,剩余物用水(10mL)稀释,用盐酸水溶液(1M)调pH至5,用乙酸乙酯(10mL x 2)萃取。合并有机相后用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物3。 1H NMR(400MHz,CD 3OD)δ8.66-8.36(m,1H),8.03-8.01(m,1H),7.99-7.94(m,2H),7.93-7.85(m,3H),7.82-7.65(m,2H),7.11-7.00(m,1H),4.53-4.49(m,1H),3.65-3.63(m,1H),3.41-3.37(m,1H),2.47-2.39(m,2H),1.96-1.87(m,2H)。MS-ESI计算值[M+H] +662,实测值662。
实施例4
合成路线：
Figure PCTCN2022111904-appb-000043
第一步
将化合物4-1(40.0mg,0.213mmol)溶于无水N,N-二甲基甲酰胺(5mL)中,在氮气保护下加入N,N-羰基二咪唑(40.0mg,0.247mmol),并在30℃下搅拌2小时,氮气保护下加入化合物1-10(100mg,0.205mmol),混合物升温至110℃继续搅拌反应10小时。反应液用乙酸乙酯(20mL)稀释,再依次用水(20mL x 3)和饱和食盐水(20mL x 1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩后剩余物经过薄层层析法(2:1石油醚/乙酸乙酯)分离纯化得到化合物4-2。MS-ESI计算值[M+H] +640,实测值640。
第二步
参照实施例1第十步方法得到化合物4。 1H NMR(400MHz,CD 3OD)δ8.61(d,J＝2.0Hz,1H),8.28-8.26(m,1H),8.09-8.07(m,1H),8.00-7.97(m,2H),7.87-7.79(m,2H),7.76-7.72(m,1H),7.54-7.46(m,2H),7.21-6.84(m,2H),4.51-4.47(m,1H),3.63-3.57(m,1H),3.37-3.34(m,1H),2.48-2.34(m,2H),1.99-1.83(m,2H)。MS-ESI计算值[M+H] +626,实测值626。
实施例5
合成路线：
Figure PCTCN2022111904-appb-000044
第一步
将化合物5-1(61.0mg,0.369mmol),1-羟基苯并三氮唑(66.5mg,0.492mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(94.4mg,0.492mmol)溶于无水N,N-二甲基甲酰胺(3mL)中,加入N,N-二异丙基乙胺(95.5mg,0.739mmol),并在30℃下搅拌0.5小时,再加入化合物1-10(120mg,0.246mmol),混合物在30℃继续搅拌反应10小时。反应液用乙酸乙酯(20mL)稀释,再依次用水(20mL x 3)和饱和食盐水(20mL x 1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩后剩余物经过薄层层析法(1:1石油醚/乙酸乙酯)分离纯化得到化合物5-2。MS-ESI计算值[M+H] +635,实测值635。
第二步
参照实施例1第九步方法得到化合物5-3。MS-ESI计算值[M+H] +617,实测值617。
第三步
参照实施例1第十步方法得到化合物5。 1H NMR(400MHz,CD 3OD)δ8.62(d,J＝1.6Hz,1H),8.09-8.07(m,1H),8.00-7.92(m,3H),7.86-7.79(m,2H),7.55-7.51(m,1H),7.24-7.22(m,1H),7.09-7.05(m,1H),7.00-6.98(m,1H),4.51-4.47(m,1H),3.61-3.57(m,1H),3.36-3.30(m,1H),2.83(s,6H),2.48-2.34(m,2H),2.05-1.81(m,2H)。MS-ESI计算值[M+H] +603,实测值603。
实施例6
合成路线：
Figure PCTCN2022111904-appb-000045
第一步
将化合物6-1(47.1mg,0.308mmol)溶于无水N,N-二甲基甲酰胺(15mL)中,向反应液中加入N,N-羰基二咪唑(49.9mg,0.308mmol)。反应液在30℃下搅拌3小时,再向反应液中加入化合物1-10(100mg,0.205mmol),反应液在110℃下搅拌12小时。向反应液中加入水(50mL),用乙酸乙酯萃取(20mL x 3),合并有机相,有机相用饱和食盐水(50mL x 1)洗涤,无水硫酸钠干燥,过滤,母液浓缩,粗产物经过薄层层析法分离(2:1石油醚/乙酸乙酯)得到化合物6-2。 1H NMR(400MHz,CD 3OD)δ8.62-8.61(m,1H),8.43-8.42(m,1H),8.00-7.97(m,2H),7.94-7.91(m,1H),7.90-7.88(m,1H),7.82-7.80(m,1H),7.63-7.59(m,1H),7.49-7.48(m,1H),6.91-6.89(m,1H),4.34-4.30(m,1H),4.02(s,3H),3.65-3.58(m,4H),3.25-3.19(m,1H),2.48-2.43(m,2H),1.95-1.81(m,2H)。MS-ESI计算值[M+H] +605,实测值605。
第二步
将化合物6-2(120mg,0.198mmol)溶于四氢呋喃(1.5mL)和水(3mL)中,向反应液中加氢氧化钠(47.6mg,1.19mmol)。反应液在50℃下搅拌反应10小时,减压浓缩除去溶剂,残渣用水稀释,并用盐酸水溶液(1M)调节pH到4左右。用乙酸乙酯萃取(30mL x 3),合并有机相,有机相用饱和食盐水(50mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液浓缩,剩余物用高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物6。 1H NMR(400MHz,CD 3OD)δ8.64-8.63(m,1H),8.39-8.38(m,1H),8.08-8.06(m,1H),8.01-7.97(m,2H),7.90-7.88(m,1H),7.83-7.78(m,2H),7.72-7.68(m,1H),7.01-6.90(m,1H),4.49-4.45(m,1H),4.09(s,3H),3.59-3.56(m,1H),3.37-3.34(m,1H),2.51-2.38(m,2H),1.99-1.90(m,1H),1.89-1.82(m,1H)。MS-ESI计算值[M+H] +591,实测值591。
实施例7
合成路线：
Figure PCTCN2022111904-appb-000046
第一步
将化合物7-1(48.5mg,0.308mmol)溶于无水N,N-二甲基甲酰胺中(1mL),加入N,N-羰基二咪唑(49.9mg,0.308mmol)。反应液在30℃下搅拌3小时。再向反应液中加入化合物1-10(100mg,0.205mmol),反应液在110℃下搅拌13小时。加入水(50mL),再用乙酸乙酯(20mL x 3)萃取,合并有机相,有机相用饱和食盐水(50mL x 1)洗涤,无水硫酸钠干燥,过滤,滤液浓缩,剩余物经过薄层层析法分离(2:1石油醚/乙酸乙酯)得到化合物7-2。 1H NMR(400MHz,CD 3OD)δ8.78-8.74(m,1H),8.62-8.61(m,1H),8.04-8.03(m,1H),7.98-7.90(m,3H),7.85-7.83(m,1H),7.66-7.62(m,1H),7.52-7.49(m,1H),6.95-6.93(m,1H),4.37-4.33(m,1H),3.70-3.64(m,4H),3.30-3.24(m,1H),2.52-2.44(m,2H),1.95-1.85(m,2H)。MS-ESI计算值[M+H] +609,实测值609。
第二步
将化合物7-2(106mg,0.174mmol)溶于四氢呋喃(1mL)和水(2mL)中,向反应液中加氢氧化钠(20.9mg,0.522mmol)。反应液在50℃下搅拌反应10小时,减压浓缩除去溶剂,剩余物用水(20mL)稀释,并用盐酸水溶液(1M)调节pH到4左右,再用乙酸乙酯(30mL x 3)萃取,合并有机相,有机相用饱和食盐水(50mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液浓缩,剩余物用高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物7。 1H NMR(400MHz,CD 3OD)δ8.76-8.74(m,1H),8.61-8.60(m,1H),8.19-8.17(m,1H),8.08-7.97(m,3H),7.88-7.86(m,1H),7.82-7.78(m,1H),7.71-7.67(m,1H),7.01-6.99(m,1H),4.50-4.45(m,1H),3.65-3.59(m,1H),3.39-3.34(m,1H),2.52-2.39(m,2H),1.98-1.63(m,2H)。MS-ESI计算值[M+H] +595,实测值595。
实施例8
合成路线：
Figure PCTCN2022111904-appb-000047
第一步
将化合物8-1(59.3mg,0.308mmol)溶于无水二氯甲烷(4mL)中,向反应液中加入1-羟基苯并三氮唑(41.6mg,0.308mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(59.0mg,0.308mmol)和三乙胺(51.9mg,0.513mmol)。反应液在30℃下搅拌1小时,加入化合物1-10(100mg,0.205mmol),反应液在30℃下继续搅拌11小时。向反应液中加入水(10mL),用二氯甲烷萃取(10mL x 3),合并有机相,有机相用饱和食盐水(30mL x 1)洗涤,无水硫酸钠干燥,过滤,滤液浓缩,粗产物经过薄层层析法分离(2:1石油醚/乙酸乙酯)得到化合物8-2。MS-ESI计算值[M+H] +662,实测值662。
第二步
将氢氧化钠(0.604mg,0.0151mmol)溶于无水乙腈(2mL)中。反应液在60℃下搅拌2小时,再加入化合物8-2(100mg,0.151mmol),反应液在80℃下继续搅拌2小时。反应液减压浓缩,将剩余物溶于二氯甲烷(20mL),有机相用饱和食盐水(10mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液浓缩,粗产物经过薄层层析法分离(2:1石油醚/乙酸乙酯)得到化合物8-3。MS-ESI计算值[M+H] +644,实测值644。
第三步
将化合物8-3(36.0mg,0.0760mmol)溶于四氢呋喃(1mL)和水(1mL)中,向反应液中加氢氧化钠(6.7mg,0.168mmol)。反应液在60℃下搅拌反应2小时,减压浓缩除去溶剂,剩余物用水稀释,并用盐酸水溶液(1M)调节pH到7左右,所形成的混合物减压浓缩,剩余物用高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物8。 1H NMR(400MHz,CD 3OD)δ8.49-8.48(m,1H),7.97-7.95(m,1H),7.90-7.86(m,2H),7.77-7.74(m,1H),7.71-7.67(m,1H),7.60-7.53(m,1H),7.47-7.44(m,1H),6.92-6.90(m,1H),4.40-4.36(m,1H),3.52-3.51(m,1H),3.28-3.25(m,1H),2.34-2.26(m,2H),1.87-1.73(m,2H)。MS-ESI计算值[M+H] +630,实测值630。
实施例9
合成路线：
Figure PCTCN2022111904-appb-000048
第一步
将盐酸羟胺(350mg,5.03mmol)溶于水(8mL)中,在15℃下加入碳酸氢钠(403mg,4.79mmol),并搅拌至无气泡产生,再滴加化合物9-1(1.00g,4.79mmol)的乙醇(8mL)溶液,混合物在15℃搅拌反应2小时。反应液减压浓缩,然后加水(10mL)稀释,用乙酸乙酯(20mL x 3)萃取,合并有机相后用饱和氯化钠水溶液(20mL x 2)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物9-2。 1H NMR(400MHz,CDCl 3)δ8.29-8.28(m,2H),7.62-7.57(m,2H),7.40-7.36(m,1H)。
第二步
将化合物9-2(1.03g,4.61mmol)溶于无水N,N-二甲基甲酰胺(10mL)和盐酸乙酸乙酯(4M,4mL,16.0mmol)中,在15℃下加入N-氯代丁二酰亚胺(615mg,4.61mmol),反应液在15℃下搅拌12小时。15℃下加水(20mL),用乙酸乙酯(20mL x 3)萃取,合并有机相后用饱和食盐水(20mL x 3)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物9-3。 1H NMR(400MHz,CDCl 3)δ8.19(s,1H),7.72-7.69(m,2H),7.58-7.54(m,1H)。MS-ESI计算值[M+H] +258,实测值258。
第三步
将化合物1-8(3.00g,5.90mmol)溶于无水四氢呋喃(30mL)中,在15℃下加入四甲基乙二胺(12.5g,107 mmol)和三甲基硅乙炔(2.98g,30.3mmol)。反应液用氮气置换三次,加入碘化亚铜(112mg,0.590mmol)和四(三苯基膦)钯(341mg,0.295mmol)。反应液在氮气保护下升温至60℃搅拌12小时。15℃下加饱和氯化铵水溶液(20mL)淬灭反应,再用乙酸乙酯萃取(20mL x 3)。合并有机相后用饱和食盐水(20mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经硅胶柱层析法(5:1石油醚/乙酸乙酯)分离纯化得到化合物9-4。MS-ESI计算值[M+H] +526,实测值526。
第四步
将化合物9-4(2.96g,5.63mmol)溶于无水甲醇(30mL)中,向反应液中加入碳酸钾(2.33g,16.9mmol),反应液在25℃搅拌12小时。反应液过滤,滤液用水(30mL)稀释,再用乙酸乙酯萃取(30mL x 3),合并有机相后用饱和氯化钠水溶液(30mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后剩余物经硅胶柱层析法(5:1石油醚/乙酸乙酯)分离纯化得到化合物9-5。 1H NMR(400MHz,CDCl 3)δ8.00-7.98(m,2H),7.87-7.84(m,2H),7.67-7.63(m,1H),7.24-7.22(m,1H),6.79-6.76(m,1H),4.34-4.30(m,1H),3.69(s,3H),3.53-3.51(m,1H),3.22-3.16(m,1H),3.05(s,1H),2.49-2.44(m,2H),1.91-1.81(m,2H)。MS-ESI计算值[M+H] +454,实测值454。
第五步
将化合物9-5(1.35g,2.98mmol)和化合物9-3(1.15g,4.47mmol)溶于无水四氢呋喃(20mL)中,加入碘化亚铜(113mg,0.595mmol)和碳酸钾(823mg,5.95mmol),反应液于30℃氮气保护下搅拌12小时。反应液用水(20mL)和饱和氯化铵水溶液(20mL)淬灭,再用乙酸乙酯(30mL x 2)萃取,合并有机相。有机相用饱和食盐水洗涤(30mL x 2),无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经硅胶柱层析法(3:1石油醚/乙酸乙酯)分离纯化得到化合物9-6。 1H NMR(400MHz,CDCl 3)δ8.27(d,J＝2.0Hz,1H),8.04(s,1H),7.90-7.86(m,2H),7.76-7.73(m,2H),7.66-7.57(m,1H),7.26-7.24(m,2H),6.94(d,J＝8.4Hz,1H),6.57(s,1H),4.41-4.33(m,1H),3.70(s,3H),3.62-3.61(m,1H),3.27-3.21(m,1H),2.51-2.46(m,2H),1.95-1.85(m,2H)。MS-ESI计算值[M+H] +675,实测值675。
第六步
将化合物9-6(1.50g,2.22mmol)和氢氧化钠(267mg,6.67mmol)溶于水(10mL)和无水四氢呋喃(5mL)中,反应液在40℃下搅拌2小时。冷却到室温,将反应液减压浓缩,加水(20mL),用盐酸(1M)调pH到3-4,混合物用乙酸乙酯萃取(20mL x 3),合并有机相后用饱和食盐水洗涤(20mL x 2),无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物9。 1H NMR(400MHz,DMSO-d 6)δ8.19(d,J＝2.0Hz,1H),8.15-8.08(m,2H),8.06-8.02(m,2H),7.97-7.96(m,1H),7.91-7.88(m,1H),7.87-7.80(m,1H),7.70-7.68(m,1H),7.22(s,1H),7.08-7.05(m,1H),4.45-4.42(m,1H),3.55-3.53(m,1H),3.45-3.39(m,1H),2.31-2.24(m,2H),1.87-1.74(m,2H)。MS-ESI计算值[M+H] +661,实测值661。
实施例10
合成路线:
Figure PCTCN2022111904-appb-000049
第一步
将化合物10-1(3.75g,16.7mmol)溶于无水N,N-二甲基甲酰胺(60mL)中,在15℃下加入二异丙基乙胺(3.24g,25.1mmol)和苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(8.12g,18.4mmol),并升温至50℃搅拌30分钟,加入叔丁氧羰基肼(2.65g,20.0mmol),混合物在50℃下搅拌反应12小时。反应液加水(20mL),用乙酸乙酯(20mL x 3)萃取,合并有机相后用饱和氯化钠溶液(20mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经硅胶柱层析法(3:1石油醚/乙酸乙酯)分离纯化得到化合物10-2。 1H NMR(400MHz,CDCl 3)δ7.58-7.56(m,2H),7.46-7.42(m,1H),6.68(br s,1H),1.43(s,9H)。MS-ESI计算值[M-Boc+H] +239,实测值239。
第二步
将化合物10-2(4.65g,13.7mmol)溶于乙酸乙酯(30mL)和盐酸乙酸乙酯(4M,20mL,80.0mmol)中,反应液在15℃下搅拌2h。反应液减压浓缩,剩余物用石油醚/乙酸乙酯(3/1,100mL)打浆,过滤,滤饼用石油醚(50mL)洗涤,减压干燥得到化合物10-3。 1H NMR(400MHz,DMSO-d 6)δ11.96-11.85(m,1H),7.95-7.93(m,1H),7.87-7.85(m,1H),7.78-7.74(m,1H)。
第三步
将化合物10-3(1.00g,3.64mmol)溶于水(30mL)中,在15℃下用碳酸氢钠固体调pH为8-9。所得混合物用二氯甲烷/甲醇萃取(9:1,20mL x 3),合并有机相,用无水硫酸钠干燥,过滤,减压浓缩得到化合物10-4。 1H NMR(400MHz,DMSO-d 6)δ9.70(br s,1H),7.86-7.84(m,1H),7.80-7.76(m,1H),7.67-7.63(m,1H)。
第四步
将化合物2-5(500mg,1.06mmol)和化合物10-4(302mg,1.27mmol)溶于无水N,N-二甲基甲酰胺(8mL)中,在15℃氮气保护下向反应液中加入3-正丙基环磷酸酐(50％乙酸乙酯溶液,1.01g,3.17mmol)和二异丙基乙胺(410mg,3.17mmol),反应液在130℃搅拌12小时。反应液加水(20mL),用乙酸乙酯萃取(20mL x 3),合并有机相后用饱和氯化钠水溶液(20mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余 物经硅胶柱层析法(3:1石油醚/乙酸乙酯)分离纯化得到化合物10-5。MS-ESI计算值[M+H] +676,实测值676。
第五步
将化合物10-5(137mg,0.203mmol)和氢氧化钠(24.3mg,0.608mmol)溶于无水四氢呋喃(1mL),水(2.5mL)和乙醇(1mL)中,反应液于40℃搅拌2小时。冷却到室温,将反应液减压浓缩,加水(20mL),用盐酸(1M)调pH到3-4,混合物用乙酸乙酯萃取(20mL x 3),有机相用饱和食盐水洗涤(20mL x 2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗产物经高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物10。 1H NMR(400MHz,CD 3OD)δ8.52(d,J＝2.0Hz,1H),8.07-8.05(m,1H),8.04-7.99(m,3H),7.98(s,1H),7.94-7.89(m,1H),7.87-7.78(m,2H),7.09-7.07(m,1H),4.53-4.48(m,1H),3.67-3.65(m,1H),3.41-3.37(m,1H),2.48-2.43(m,2H),1.98-1.85(m,2H)。MS-ESI计算值[M+H] +662,实测值662。
实施例11
合成路线：
Figure PCTCN2022111904-appb-000050
第一步
氮气保护下,将化合物9-1(2.20g,10.6mmol)溶于无水甲醇(20mL)中,加入碳酸钾(2.92g,21.1mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(2.43g,12.7mmol),反应液在25℃下搅拌12小时,向反应液中加入水(40mL),用乙酸乙酯(50mL x 1)萃取。有机相用饱和食盐水洗涤(50mLx 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(50：1石油醚/乙酸乙酯),得到化合物11-1。 1H NMR(400MHz,CDCl 3)δ7.56-7.51(m,2H),7.33-7.29(m,1H),3.64(s,1H)。
第二步
氮气保护下,将化合物2-5(300mg,0.634mmol)溶于干燥四氢呋喃(10mL)中,零度下滴加硼烷四氢呋喃溶液(1M,1.9mL,1.90mmol),反应液在0℃下搅拌1小时,向反应液中加入冰水(20mL),用乙酸乙酯(20mL x 1)萃取。饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(1:1石油醚/乙酸乙酯)得到化合物11-2。MS-ESI计算值[M+Na] +482,实测值482。
第三步
氮气保护下,将化合物11-2(320mg,0.697mmol)溶于无水二氯甲烷(5mL)中,加入戴斯马丁过碘烷(443mg,1.04mmol),反应液在25℃下搅拌12小时,向反应液中加入饱和碳酸钠水溶液(20mL,用乙酸乙酯(20mL x 1)萃取。有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(2:1石油醚/乙酸乙酯),得到化合物11-3。MS-ESI计算值[M+H] +458,实测值458。
第四步
氮气保护下将碳酸氢钠(1.54mg,0.184mmol)加入溶于水(5mL)的盐酸羟胺(12.8mg,0.184mmol)中,待气体放完后,向反应液中滴加溶于乙醇(5mL)的化合物11-3(80.0mg,0.175mmol),反应液在80℃下搅拌2小时,将反应液旋干,向剩余物中加入水(10mL),用乙酸乙酯(20mL x 1)萃取,无水硫酸钠干燥,过滤,减压浓缩得到化合物11-4。MS-ESI计算值[M+H] +473,实测值473。
第五步
氮气保护下将化合物11-4(77.0mg,0.163mmol)溶于无水N,N-二甲基甲酰胺(5mL)和盐酸乙酸乙酯溶液(4M,5mL,8mmol)中,加入N-氯代丁二酰亚胺(21.8mg,0.163mmol),反应液在25℃下搅拌12小时,向反应液中加入水(20mL),用乙酸乙酯(20mL x 1)萃取。有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩得到化合物11-5。MS-ESI计算值[M+H]+507,实测值507。
第六步
氮气保护下,将化合物11-5(82.0mg,0.162mmol)溶于无水四氢呋喃(10mL)中,加入化合物11-1(49.6mg,0.243mmol),碘化亚铜(6.2mg,0.324mmol),碳酸钾(44.7mg,0.324mmol),反应液在30℃下搅拌12小时,向反应液中加入水(20mL),用乙酸乙酯(20mL x 1)萃取。有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用薄层层析法分离纯化(2:1石油醚/乙酸乙酯),得到化合物11-6。MS-ESI计算值[M+H]+675,实测值675。
第七步
参照实施例2第六步方法得到化合物11。 1H NMR(400MHz,CD 3OD)δ8.39(d,J＝1.6Hz,1H),8.10(d,J＝7.6Hz,1H),8.00-7.97(m,2H),7.94-7.90(m,2H),7.85-7.77(m,2H),7.66-7.63(m,1H),7.03(s,1H),6.98(d,J＝8.4Hz,1H),4.54-5.50(m,1H),3.55-3.49(m,1H),3.33-3.28(m,1H),2.38-2.21(m,2H),1.94-1.83(m,2H)。MS-ESI计算值[M+H] +661,实测值661。
实施例12
合成路线：
Figure PCTCN2022111904-appb-000051
第一步
氮气保护下将化合物12-1(70.2mg,0.369mmol)溶于无水N,N-二甲基甲酰胺(16mL)中,加入N,N-羰基二咪唑(64.9mg,0.400mmol),反应液在30℃下搅拌2小时,再加入化合物1-10(150mg,0.308mmol),反应液在110℃下搅拌10小时,向反应液中加入水(30mL),用乙酸乙酯(20mL x 1)萃取,有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用薄层层析法分离纯化(1:1石油醚/乙酸乙酯)得到化合物12-2。MS-ESI计算值[M+Na] +664,实测值664。
第二步
参照实施例2第六步方法得到化合物12。 1H NMR(400MHz,CD 3OD)δ8.62(d,J＝2.0Hz,1H),8.18-8.16(m,1H),8.08(d,J＝8.0Hz,1H),8.04-7.98(m,3H),7.93-7.86(m,3H),7.83-7.79(m,1H),7.02(d,J＝8.4Hz,1H),4.52-4.48(m,1H),3.66-3.58(m,1H),3.39-3.33(m,1H),2.50-2.41(m,2H),1.98-1.82(m,2H)。MS-ESI计算值[M+H] +628,实测值628。
实施例13
合成路线：
Figure PCTCN2022111904-appb-000052
第一步
参照实施例12第一步方法得到化合物13-2。MS-ESI计算值[M+H] +604,实测值604。
第二步
参照实施例2第六步方法得到化合物13。 1H NMR(400MHz,CD 3OD)δ8.55(d,J＝2.0Hz,1H),8.11-8.08(m,1H),8.05(d,J＝8.0Hz,1H),8.01(s,1H),7.97(d,J＝8.0Hz,1H),7.81-7.77(m,2H),7.63-7.59(m,1H),7.23(d,J＝8.4Hz,1H),7.15-7.11(m,1H),6.94(d,J＝8.4Hz,1H),4.48-4.44(m,1H),4.00(s,3H),3.56-3.55(m,1H),3.33-3.28(m,1H),2.49-2.36(m,2H),1.97-1.78(m,2H)。MS-ESI计算值[M+H] +590,实测值590。
实施例14
合成路线：
Figure PCTCN2022111904-appb-000053
第一步
参照实施例12第一步方法得到化合物14-2。MS-ESI计算值[M+H] +626,实测值626。
第二步
参照实施例2第六步方法得到化合物14。 1H NMR(400MHz,CD 3OD)δ8.61(d,J＝2.0Hz,1H),8.07(d,J＝8.0Hz,1H),8.01-7.96(m,3H),7.89-7.86(m,1H),7.83-7.79(m,1H),7.75-7.71(m,1H),7.49-7.44(m,1H),7.01(d,J＝8.8Hz,1H),4.52-4.48(m,1H),3.64-3.58(m,1H),3.39-3.35(m,1H),2.52-2.38(m,2H),2.00-1.91(m,1H),1.90-1.81(m,1H)。MS-ESI计算值[M+H] +612,实测值612。
实施例15
合成路线：
Figure PCTCN2022111904-appb-000054
第一步
氮气保护下,将化合物15-1(200mg,1.25mmol)溶于干燥二氯甲烷(10mL)中,加入戴斯马丁过碘烷(792mg,1.87mmol),反应液在25℃下搅拌2小时,向反应液中加入饱和碳酸钠溶液(20mL),用乙酸乙酯(20mL x 1)萃取。饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(5:1石油醚/乙酸乙酯)得到化合物15-2。 1H NMR(400MHz,CDCl 3)δ10.40(s,1H),7.45-7.39(m,1H),7.23-7.21(m,1H),7.19-7.04(m,1H)。
第二步
氮气保护下,将化合物15-2(195mg,1.23mmol)溶于无水甲醇(20mL)中,加入碳酸钾(443mg,1.04mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(284mg,1.48mmol),反应液在25℃下搅拌12小时,向反应液中加入水(40mL),用乙酸乙酯(50mL x 1)萃取。有机相用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(20:1石油醚/乙酸乙酯),得到化合物15-3。 1H NMR(400MHz,CDCl 3)δ7.27-7.25(m,1H),7.24-7.21(m,1H),7.05-7.01(m,1H),3.61(s,1H)。
第三步
参照实施例12第五步方法得到化合物15-4。MS-ESI计算值[M+H] +625,实测值625。
第四步
参照实施例2第六步方法得到化合物15。 1H NMR(400MHz,CD 3OD)δ8.39(d,J＝2.0Hz,1H),8.05(d,J＝8.0Hz,1H),8.01-7.99(m,2H),7.83-7.79(m,1H),7.69-7.66(m,1H),7.63-7.57(m,1H),7.51-7.49(m,1H),7.36-7.32(m,1H),7.13(s,1H),7.00(d,J＝8.8Hz,1H),4.50-4.47(m,1H),3.56-3.48(m,1H),3.33-3.29(m,1H),2.45-2.43m,2H),1.93-1.85(m,2H)。MS-ESI计算值[M+H] +611,实测值611。
实施例16
合成路线：
Figure PCTCN2022111904-appb-000055
第一步
参照实施例12第一步方法得到化合物16-2。MS-ESI计算值[M+H] +658,实测值658。
第二步
参照实施例2第六步方法得到化合物16。 1H NMR(400MHz,CD 3OD)δ8.61(d,J＝2.0Hz,1H),8.35-8.33(m,1H),8.05(d,J＝8.0Hz,1H),8.00-7.96(m,2H),7.87-7.84(m,1H),7.82-7.77(m,2H),7.66-7.59(m,2H),6.99(d,J＝8.4Hz,1H),4.49-4.45(m,1H),3.62-3.57(m,1H),3.37-3.31(m,1H),2.49-2.37(m,2H),1.96-1.81(m,2H)。MS-ESI计算值[M+H] +644,实测值644。
实施例17
合成路线：
Figure PCTCN2022111904-appb-000056
第一步
参照实施例13第一步方法得到化合物17-2。MS-ESI计算值[M+H] +609,实测值609。
第二步
参照实施例2第六步方法得到化合物17。 1H NMR(400MHz,CD 3OD)δ9.01(s,1H),8.84(d,J＝5.2Hz,1H),8.44(d,J＝2.0Hz,1H),8.18(d,J＝4.8Hz,1H),8.13(d,J＝7.6Hz,1H),8.08-8.06(m,2H),7.90-7.86(m,1H),7.85-7.82(m,1H),7.10(d,J＝8.4Hz,1H),4.47-4.43(m,1H),3.60-3.58(m,1H),3.51-3.45(m,1H),2.43-2.28(m,2H),1.94-1.86(m,1H),1.81-1.72(m,1H)。MS-ESI计算值[M+H] +595,实测值595。
实施例18
合成路线：
Figure PCTCN2022111904-appb-000057
第一步
氮气保护下将化合物18-1(29.9mg,0.160mmol)溶于无水二氯甲烷(5mL)中,加入三乙胺(24.9mg,0.246mmol),1-羟基苯并三唑(25.0mg,0.185mmol)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(35.4mg,0.185mmol),反应液在25℃下搅拌0.5小时,再加入化合物1-10(60.0mg,0.123mmol),反应液在20℃下搅 拌11.5小时,向反应液中加入水(20mL),用二氯甲烷(20mL x 1)萃取,有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用薄层层析法分离纯化(2:1石油醚/乙酸乙酯)得到化合物18-2。MS-ESI计算值[M+Na] +678,实测值678。
第二步
氮气保护下,将氢氧化钠(0.3mg,0.00800mmol)溶于乙腈(5mL)中,在25℃下搅拌1小时,再加入化合物18-2(50.0mg,0.0760mmol),4A分子筛(20.0mg)和无水硫酸镁(20.0mg,0.166mmol),反应液在80℃下搅拌11小时,向反应液中加入水(20mL),用混合溶剂(20mL x 1)(二氯甲烷/甲醇＝10:1)萃取,无水硫酸钠干燥,过滤,减压浓缩,剩余物用高效液相色谱法(中性,碳酸氢铵体系)纯化得到化合物18。 1H NMR(400MHz,CD 3OD)δ8.60(d,J＝1.6Hz,1H),8.06(d,J＝8.4Hz,1H),8.02-7.98(m,2H),7.87-7.84(m,1H),7.82-7.79(m,1H),7.63(t,J＝8.4Hz,1H),7.26-7.21(m,2H),7.02(d,J＝8.8Hz,1H),4.51-4.47(m,1H),3.91(s,3H),3.63-3.57(m,1H),3.38-3.33(m,1H),2.53-2.39(m,2H),1.99-1.83(m,2H)。MS-ESI计算值[M+H] +624,实测值624。
实施例19
合成路线：
Figure PCTCN2022111904-appb-000058
第一步
参照实施例18第一步方法得到化合物19-2。MS-ESI计算值[M+H] +660,实测值660。
第二步
氮气保护下,将氢氧化钠(0.4mg,0.00800mmol)溶于乙腈(5mL)中,在25℃下搅拌1小时,再加入化合物19-2(50.0mg,0.091mmol),4A分子筛(30.0mg)和无水硫酸镁(30.0mg,0.249mmol),反应液在80℃下 搅拌11小时,向反应液中加入水(20mL),用乙酸乙酯(20mL x 1)萃取,有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩得到化合物19-3。MS-ESI计算值[M+H] +642,实测值642。
第三步
参照实施例2第六步方法得到化合物19。 1H NMR(400MHz,CD 3OD)δ8.59(d,J＝2.0Hz,1H),8.04(d,J＝7.6Hz,1H),8.00-7.96(m,2H),7.87-7.84(m,1H),7.81-7.77(m,1H),7.66-7.65(m,3H),7.01(d,J＝8.4Hz,1H),4.50-4.46(m,1H),3.63-3.58(m,1H),3.38-3.31(m,1H),2.49-2.37(m,2H),1.98-1.82(m,2H)。MS-ESI计算值[M+H] +628,实测值628。
实施例20
合成路线：
Figure PCTCN2022111904-appb-000059
第一步
将化合物20-1(500mg,1.63mmol),20-2(480mg,1.63mmol),磷酸钾(693mg,3.26mmol)和1,1-双(二苯基膦)二茂铁氯化钯(119mg,0.163mmol)加入到1,4-二氧六环(5mL)和水(1mL)中。反应液在氮气保护下80℃搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL x 2)萃取。合并有机相,用饱和食盐水洗涤(30mL x 1),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用硅胶柱色谱法分离纯化(3:1石油醚/乙酸乙酯)得到化合物20-3。 1H NMR(400MHz,CDCl 3)δ7.32-7.29(m,3H),7.05-7.01(m,2H),6.89(s,1H)。MS-ESI计算值[M+H] +247,实测值247。
第二步
将化合物20-3(50.0mg,0.203mmol),碳酸钾(56.0mg,0.406mmol),碘化亚铜(7.7mg,0.0406mmol),L-脯氨酸(9.3mg,0.00811mmol)和1-8(103mg,0.203mmol)加入到二甲基亚砜(2mL)中。反应液在氮气 保护下110℃搅拌反应12小时。向反应液中加入水(10mL),用乙酸乙酯(20mL x 2)萃取。合并有机相,用饱和食盐水洗涤(20mL x 3),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用制备薄层层析法分离纯化(3:1石油醚/乙酸乙酯)得到化合物20-4。MS-ESI计算值[M+H] +674,实测值674。
第三步
将化合物20-4(20.0mg,0.0253mmol),和一水合氢氧化锂(2.1mg,0.0505mmol)加入到四氢呋喃(1mL)和水(1mL)中。反应液在氮气保护下20℃搅拌反应12小时。反应液减压浓缩。剩余物经高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物20。 1H NMR(400MHz,CD 3OD)δ8.27(s,1H),8.18(s,1H),8.07-7.97(m,3H),7.83-7.78(m,3H),7.69(s,1H),7.58-7.54(m,1H),7.49-7.46(m,1H),6.97-6.95(m,1H),4.47-4.44(m,1H),3.48-3.47(m,1H),3.27-3.25(m,1H),2.58-2.46(m,2H),1.95-1.90(m,2H)。MS-ESI计算值[M+H] +660,实测值660。
实施例21
合成路线：
Figure PCTCN2022111904-appb-000060
第一步
将21-1(57.8mg,0.369mmol)溶于N,N-二异丙基乙胺(3mL)中,加入1,1-羰基二咪唑(64.9mg,0.400mmol)。反应液在30℃搅拌反应1小时,然后加入化合物1-10(150mg,0.308mmol),反应液在110℃搅拌反应12小时。向反应液加入水(20mL),用乙酸乙酯(20mL x 2)萃取。合并有机相,用饱和食盐水洗涤(20mL x 3),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物为化合物21-2。MS-ESI计算值[M+H] +608,实测值608。
第二步
将化合物21-2(180mg,0.184mmol)和一水合氢氧化锂(15.5mg,0.369mmol)加入到四氢呋喃(2mL)和水(0.5mL)中。反应液在氮气保护下20℃搅拌反应12小时。反应液减压浓缩。剩余物经高效液相色谱法 (中性,碳酸氢铵体系)分离纯化得到化合物21。 1H NMR(400MHz,CD 3OD)δ8.59(d,J＝2.0Hz,1H),8.15-8.14(m,1H),8.07(d,J＝8.0Hz,1H),8.00-7.98(m,2H),7.84-7.78(m,2H),7.65-7.63(m,2H),7.54-7.52(m,1H),6.97-6.95(m,1H),4.49-4.44(m,1H),3.58-3.57(m,1H),3.35-3.33(m,1H),2.45-2.39(m,2H),1.94-1.82(m,2H)。MS-ESI计算值[M+H] +594,实测值594。
实施例22
合成路线：
Figure PCTCN2022111904-appb-000061
第一步
参照实施例21第一步方法得到化合物22-2。MS-ESI计算值[M+H] +592,实测值592。
第二步
参照实施例21第二步方法得到化合物22。 1H NMR(400MHz,CD 3OD)δ8.54(d,J＝2.0Hz,1H),8.22-8.21(m,1H),8.06(d,J＝8.0Hz,1H),8.00-7.95(m,2H),7.81-7.78(m,2H),7.74-7.68(m,1H),7.39-7.37(m,2H),6.95-6.93(m,1H),4.48-4.44(m,1H),3.58-3.56(m,1H),3.35-3.32(m,1H),2.44-2.38(m,2H),1.93-1.82(m,2H)。MS-ESI计算值[M+H] +578,实测值578。
实施例23
合成路线：
Figure PCTCN2022111904-appb-000062
Figure PCTCN2022111904-appb-000063
第一步
参照实施例21第一步方法得到化合物23-2。MS-ESI计算值[M+H] +599,实测值599。
第二步
参照实施例21第二步方法得到化合物23。MS-ESI计算值[M+H] +585,实测值585。 1H NMR(400MHz,CD 3OD)δ8.55(d,J＝2.0Hz,1H),8.37-8.35(m,1H),8.10(d,J＝8.0Hz,1H),8.03-8.01(m,2H),7.99-7.94(m,2H),7.93-7.90(m,3H),6.96-6.94(m,1H),4.47-4.43(m,1H),3.65-3.64(m,1H),3.37-3.34(m,1H),2.45-2.42(m,2H),1.95-1.81(m,2H)。
实施例24
合成路线：
Figure PCTCN2022111904-appb-000064
第一步
将24-1(64.5mg,0.369mmol)溶于二氯甲烷(3mL)中,加入1-羟基苯并三氮唑(83.2mg,0.615mmol)和1-(3-二甲氨基丙基)-3-乙醛盐酸盐(118mg,0.615mmol)。反应液在30℃搅拌反应1小时,然后加入化合物1-10(150mg,0.308mmol),反应液在30℃搅拌反应12小时。向反应液加入水(20mL),用乙酸乙酯(20mL x 2)萃取。合并有机相,用饱和食盐水洗涤(20mL x 3),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用制备薄层层析法分离纯化(1:1石油醚/乙酸乙酯)得到化合物24-2。MS-ESI计算值[M+H] +644,实测值 644。
第二步
将化合物24-2(100mg,0.113mmol)和粉末状氢氧化钠(5.0mg,0.124mmol)加入到乙腈(2mL)中。反应液在氮气保护下20℃搅拌反应1小时。然后加入水(2mL),反应液在20℃搅拌反应2小时。反应液减压浓缩。剩余物经高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物24。 1H NMR(400MHz,CD 3OD)δ8.58(d,J＝2.0Hz,1H),8.03-7.96(m,3H),7.86-7.70(m,3H),7.55-7.53(m,1H),7.40-7.38(m,1H),7.01-7.00(m,1H),4.50-4.46(m,1H),3.61-3.59(m,1H),3.37-3.35(m,1H),2.46-2.40(m,2H),1.95-1.83(m,2H)。MS-ESI计算值[M+H] +612,实测值612。
实施例25
合成路线：
Figure PCTCN2022111904-appb-000065
第一步
参照实施例24第一步方法得到化合物25-2。MS-ESI计算值[M+H] +644,实测值644。
第二步
参照实施例24第二步方法得到化合物25。 1H NMR(400MHz,CD 3OD)δ8.57(d,J＝2.0Hz,1H),8.26-8.24(m,1H),8.07(d,J＝8.0Hz,1H),8.04-7.96(m,2H),7.82-7.79(m,2H),7.54-7.51(m,1H),7.36-7.34(m,1H),6.99-6.96(m,1H),4.49-4.45(m,1H),3.59-3.57(m,1H),3.35-3.32(m,1H),2.46-2.44(m,2H),1.92-1.83(m,2H)。MS-ESI计算值[M+H] +612,实测值612。
实施例26
合成路线：
Figure PCTCN2022111904-appb-000066
第一步
参照实施例24第一步方法得到化合物26-2。MS-ESI计算值[M+H] +644,实测值644。
第二步
参照实施例24第二步方法得到化合物26。 1H NMR(400MHz,CD 3OD)δ8.57(d,J＝2.0Hz,1H),8.07-8.06(m,1H),8.02-8.01(m,1H),7.97-7.95(m,2H),7.83-7.81(m,2H),7.58-7.55(m,2H),6.97-6.95(m,1H),4.51-4.46(m,1H),3.59-3.56(m,1H),3.35-3.33(m,1H),2.38-2.33(m,2H),1.91-1.85(m,2H)。MS-ESI计算值[M+H] +612,实测值612。
实施例27
合成路线：
Figure PCTCN2022111904-appb-000067
Figure PCTCN2022111904-appb-000068
第一步
将化合物27-1(10.0g,67.6mmol)溶于无水二氯甲烷(100mL)中,加入二碳酸二叔丁酯(22.1g,101mmol),4-二甲基氨基吡啶(826mg,6.76mmol)和三乙胺(13.7g,13.5mmol)。反应液在25℃下搅拌反应3小时。向反应液加入水(50mL),用二氯甲烷(50mL x 2)萃取。合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用硅胶柱色谱法分离纯化(5:1石油醚/乙酸乙酯,)得到化合物27-2。 1H NMR(400MHz,CDCl 3)δ8.63(s,1H),1.67(s,9H)。
第二步
将化合物27-2(1.00g,4.03mmol),27-3(796mg,5.24mmol),磷酸钾(1.71g,8.06mmol)和1,1-双(二苯基膦)二茂铁氯化钯(295mg,0.403mmol)加入到1,4-二氧六环(10mL)和水(1mL)中。反应液在氮气保护下100℃搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(20mL x 2)萃取。合并有机相,用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用硅胶柱色谱法分离纯化(1:1石油醚/乙酸乙酯)得到化合物27-4。MS-ESI计算值[M+H] +176,实测值176。
第三步
将化合物27-4(70.0mg,0.364mmol)溶于无水二氯甲烷(2mL)中,在0℃下加入氢氧化钠水溶液(2M,0.545mL,1.09mmol),然后加入苄基三甲基三溴化铵(170mg,0.436mmol)。反应液在25℃下搅拌反应1小时。向反应液加入盐酸(1M,3mL)和水(10mL),用二氯甲烷(20mL x 2)萃取。合并有机相,用饱和食盐水洗涤(10mL x 2),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用制备薄层层析法分离纯化(3:1石油醚/乙酸乙酯)得到化合物27-5。 1H NMR(400MHz,CDCl 3)δ8.30-8.28(m,1H),7.48-7.46(m,1H),7.16-7.07(m,2H),4.08(s,3H)。MS-ESI计算值[M+H] +254和256,实测值254和256。
第四步
将化合物27-5(80.0mg,0.315mmol)溶于无水四氢呋喃(1mL)中,在0℃下分批加入钠氢(18.9mg, 0.472mmol,60％纯度),在该温度下搅拌反应30分钟。然后向反应液中加入2-(三甲基硅)乙氧基甲基氯(63.0mg,0.378mmol),反应液在50℃下搅拌反应12小时。向反应液加入水(10mL),用乙酸乙酯(10mL x 3)萃取。合并有机相,用饱和食盐水洗涤(10mL x 1),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用制备薄层层析法分离纯化(5:1石油醚/乙酸乙酯)得到化合物27-6。MS-ESI计算值[M+H] +384和386,实测值384和386。
第五步
氮气保护下,将化合物1-8(800mg,0.634mmol)溶于干燥1,4-二氧六环(10mL)中,加入联硼酸频那醇酯(440mg,1.73mmol),乙酸钾(463mg,4.72mmol)和[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(129mg,0.157mmol),反应液在90℃下搅拌12小时,向反应液中加入水(40mL),用乙酸乙酯(40mL x 1)萃取。饱和食盐水洗涤(40mL x 1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(3:1石油醚/乙酸乙酯)得到化合物27-7。MS-ESI计算值[M+Na] +578,实测值578。
第六步
氮气保护下,将化合物27-7(250mg,0.450mmol)溶于丙酮(4mL)和水(2mL)中,加入高碘酸钠(356mg,1.67mmol)和乙酸铵(69.4mg,0.900mmol),反应液在50℃下搅拌12小时,反应液用1M盐酸水溶液调节pH<3,用乙酸乙酯(20mL x 1)萃取。有机相用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩得到化合物27-8。MS-ESI计算值[M+Na] +496,实测值496。
第七步
将化合物27-6(75.0mg,0.148mmol),27-8(84.1mg,0.178mmol),磷酸钾(62.9mg,0.296mmol)和1,1-双(二苯基膦)二茂铁氯化钯(10.8mg,0.0148mmol)加入到1,4-二氧六环(1mL)和水(0.2mL)中。反应液在氮气保护下80℃搅拌反应12小时。向反应液中加入水(10mL),用乙酸乙酯(10mL x 3)萃取。合并有机相,用饱和食盐水洗涤(10mL x 1),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物用硅胶柱色谱法分离纯化(5:1石油醚/乙酸乙酯)得到化合物27-9。MS-ESI计算值[M+H] +733,实测值733。
第八步
将化合物27-9(50.0mg,0.0574mmol)溶于甲醇(0.5mL)中,加入盐酸甲醇(4M,0.314mL,1.26mmol)。反应液在40℃搅拌反应2小时。向反应液加入饱和碳酸氢钠水溶液(10mL),用乙酸乙酯(10mL x 3)萃取。合并有机相,用饱和食盐水洗涤(10mL x 1),无水硫酸钠干燥,过滤,滤液减压浓缩。剩余物为化合物27-10。MS-ESI计算值[M+H] +603,实测值603。
第九步
将化合物27-10(30.0mg,0.0376mmol)和一水合氢氧化锂(3.2mg,0.0752mmol)加入到四氢呋喃(1mL)和水(1mL)中。反应液在氮气保护下20℃搅拌反应12小时。反应液减压浓缩。剩余物经高效液相色谱法(中性,碳酸氢铵体系)分离纯化得到化合物27。 1H NMR(400MHz,CD 3OD)δ8.59(s,1H),8.22-8.20(m, 1H),8.03-7.99(m,3H),7.86-7.83(m,1H),7.77-7.75(m,1H),7.50-7.48(m,1H),7.22-7.20(m,1H),7.16-7.14(m,1H),6.93-6.91(m,1H),4.47-4.42(m,1H),4.05(s,3H),3.51-3.49(m,1H),3.28-3.25(m,1H),2.45-2.39(m,2H),1.92-1.80(m,2H)。MS-ESI计算值[M+H] +589,实测值589。
生物学评价：
实验例1：本发明化合物对RORγ体外活性的测定
1.1实验材料及仪器如表1所示。
表1实验材料及仪器
实验材料及仪器 供应商
hRORg-LBD HDB
biotin-SRC1多肽 杭州中肽
SA-eu Perkin Elmer
SA-APC Perkin Elmer
Tris Sigma
KCl Sigma
Na-EDTA Invitrogen
DTT Sigma
BSA Roche
Envision微孔板检测仪 Perkin Elmer
1.2实验步骤
采用RORγ配体结合结构域(LBD)时间分辨荧光能量共振转移(TR-FRET)筛选本发明化合物对RORγ活性的调节。
将待测化合物稀释在DMSO中，并进一步稀释在分析缓冲液(50mM Tris pH 7.0,50mM KCl,1mM Na-EDTA,0.1mM DTT,0.01％BSA)中(4倍稀释，10个浓度，最高浓度5000nM)，最终DMSO浓度1％。将hRORγ-LBD蛋白稀释在分析缓冲液中，得到在384孔板中15nM的hRORγ-LBD最终浓度。在分析缓冲液中制备biotin-SRC1多肽(Biotin-SPSSHSSLTERHKILHRLLQEGSP)储液，并加入到各孔中(终浓度200nM)。将SA-eu(终浓度1nM)和SA-APC(终浓度50nM)的溶液也加入各孔中。
将最终分析混合物在4℃下孵育过夜，室温平衡1小时，1000rpm离心1分钟。在Envision微孔板检测仪上检测荧光读数，通过GraphPad Prism软件绘制发射波长665nM/615nM的荧光信号的比值与化合物浓度的对数曲线，计算化合物的50％有效浓度(EC 50)和50％抑制浓度(IC 50)。最大应答(Emax)为通过GraphPad Prism拟合确定的信号的上限峰值。
1.3实验结果如表2所示。
表2本发明化合物对RORγ体外活性的测定结果
化合物编号 EC 50(nM) E max
化合物1 9.1 114.1％
化合物2 7.2 112.2％
化合物3 10.9 94.5％
化合物4 38.2 155.6％
化合物5 27.1 92.4％
化合物6 36.9 56.6％
化合物7 12.3 68.6％
化合物9 17.0 37.2％
化合物10 7.9 75.7％
化合物11 15.4 90.2％
化合物12 20.2 126.0％
化合物13 17.4 116.4％
化合物14 23.0 110.3％
化合物15 16.9 117.5％
化合物16 20.2 126.0％
化合物17 58.9 86.0％
化合物20 14.1 114.7％
化合物21 14.8 101.6％
化合物22 13.9 93.3％
化合物23 13.6 120.8％
化合物24 8.5 116.7％
化合物25 154.6 100.8％
化合物26 20.9 81.3％
化合物27 726.1(IC 50)* /
*代表具有反向激动活性。
结论：本发明化合物对RORγ体外活性具有明显的激动作用或反向激动活性。
实验例2：本发明化合物促进CD4 +细胞分化为Th17细胞的能力测定
2.1实验材料及仪器
1.C57BL/6小鼠脾脏
2. 70μm滤网(BD)
3.红细胞裂解液(Absin)
4.Mouse CD4+T cell isolation kit(Stemcell)
5.CD3抗体(BD)
6.CD28抗体(BD)
7. 96孔U底板(Corning)
8.DPBS(Corning)
9.TGFβ(R&D)
10.IL-6(R&D)
11.IL-1β(BioLegend)
12.IL-23(BioLegend)
13.RPMI 1640培养液(Gibco)
14.青/链霉素(HyClone)
15.胎牛血清(HyClone)
16.非必需氨基酸(Gibco)
17.β-巯基乙醇(Sigma)
18.IFNγ抗体(BD)
19.IL-4抗体(BD)
20.PMA(sigma)
21.Ionomycin(Invitrogen)
22.高尔基体抑制剂(BD)
23.Staining buffer(Biolegend)
24.Fixation buffer(Biolegend)
25.Permeabilization buffer(Biolegend)
26.LIVE/DEAD stain kit(Invitrogen)
27.CD4抗体(Biolegend)
28.IL-17A抗体(Biolegend)
29.细胞计数仪(Beckman)
30.离心机(Eppendorf)
31.流式细胞仪(BD)
32.CO 2培养箱(Thermo)
2.2实验步骤
将CD3抗体于DPBS中稀释至5μg/mL，加入96孔U底板中，每孔50μL液体，于4℃包被过夜。
在培养液(RPMI 1640+10％胎牛血清+1％青链霉素+1％非必需氨基酸+0.05mMβ-巯基乙醇)中研磨C57BL/6小鼠脾脏，过70μm滤网制备单细胞悬液，300g离心3min。加入红细胞裂解液室温裂解3min。使用Mouse CD4 +T细胞分离试剂盒分离CD4 +细胞。将前一天包被的96孔U底板取出，吸去包被的液体，并用DPBS洗两次，再将上面得到的CD4 +细胞以5*10 5/mL的密度接种至包被过的孔中，每孔200μL细胞悬液；再加入CD28抗体(3μg/mL)、TGFβ(3ng/mL)、IL-6(30ng/mL)、IL-23(10ng/mL)、IL-1β(10ng/mL)、IFNγ抗体(10μg/mL)和IL-4抗体(10μg/mL)；再在孔中加入本发明化合物，于37℃，5％CO 2下培养3天。
在每个孔中加入500ng/mL的PMA和ionomycin，以及高尔基体抑制剂(1:1000)，37℃，5％CO 2下刺激4小时。
刺激结束后将U底板300g离心3min，倒掉上清，用染色缓冲液r洗两次。将CD4抗体和LIVE/DEAD染液分别按照1:200和1:1000于染色缓冲液中稀释，每孔加入50μL染液，4℃染色30min，之后用染色缓冲液洗涤细胞两次。每孔加入100μL固定缓冲液，室温固定20min，用透化缓冲液洗两次。将IL-17A抗体按照1：200于透化缓冲液中稀释，每孔加入50μL染液，室温染色30min，之后用染色缓冲液洗两次。最后用150μL染色缓冲液重悬细胞，使用流式细胞仪检测IL-17A比例。
2.3实验结果如表3所示。
表3本发明化合物促进CD4 +细胞分化为Th17细胞的能力测定结果
化合物编号 IL-17A比例
DMSO 6％
化合物1 9.8％
化合物13 12％
化合物16 9.5％
化合物21 9.6％
化合物24 10.3％
化合物测试浓度：5μM。
结论：本发明化合物可以明显地促进CD4 +细胞分化为Th17细胞，进而提升IL-17A比例。
实验例3：本发明化合物药代动力学评价
3.1实验目的：测试化合物在Balb/c小鼠体内的药代动力学
3.2实验材料：
Balb/c小鼠(雌性,7～9周龄,上海斯莱克)
3.3实验操作：
以标准方案测试化合物静脉注射(IV)及口服给药(PO)后的啮齿类动物药代特征,实验中给予小鼠单次静脉注射及口服给药。静注溶媒为5％二甲基亚砜、30％的PEG400、65％的羟丙基β环糊精(10％)配成的混合溶媒。口服溶媒为0.5％羟丙甲纤维素和0.2％吐温配成的混合溶媒。该项目使用四只雌性Balb/c小鼠,两只小鼠进行静脉注射给药,给药剂量为0.5mg/kg,收集0h(给药前)和给药后0.0833,0.25,0.5,1,2,4,8,24h的血浆样品,另外两只小鼠口服灌胃给药,给药剂量为1mg/kg,收集0h(给药前)和给药后0.25,0.5,1,2,4,8,24h的血浆样品,收集24小时内的全血样品,3000g离心15分钟,分离上清得血浆样品,加入4倍体积含内标的乙腈溶液沉淀蛋白,离心取上清液加入等倍体积的水再离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如达峰浓度(C max),清除率(CL),半衰期(T 1/2),组织分布(Vdss),药时曲线下面积(AUC 0-last),生物利用度(F)等。
3.4实验结果如表4所示。
表4本发明化合物的药代动力学测试结果
Figure PCTCN2022111904-appb-000069
结论：本发明化合物具有良好的药代动力学性质,包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。
实验例4：本发明化合物对MC38小鼠结肠癌移植瘤模型的体内药效学研究
4.1实验目的：
本实验的目的是研究本发明化合物对MC38小鼠结肠癌移植瘤模型体内药效进行评估。
4.2实验动物：
种属：小鼠
品系：C57BL/6小鼠
周龄及体重：7周龄,体重18-23克
性别：雌性
供应商：上海斯莱克实验动物有限公司
4.3实验方法与步骤
4.3.1细胞培养
名称：MC38(小鼠结肠癌细胞)
来源：和元生物技术(上海)有限公司。由辉源生物科技(上海)有限公司保种维持传代。
细胞培养：培养液为含有10％胎牛血清的1640培养基,培养条件为37℃,5％二氧化碳。传代比例为1:2～1:3,每周传代2～3次。
4.3.2肿瘤细胞接种
将0.1mL(2×10 5个)细胞皮下接种于每只小鼠的右后背。同日将动物根据体重随机分组。
4.3.3受试物的配制
实验用溶媒为5％DMSO/95％(20％羟丙基β环糊精)。受试物用溶媒溶解,配制成一定浓度均一溶液,于4℃保存。
4.3.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2,a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)：计算公式如下：T/C％＝T RTV/C RTV×100％(T RTV：治疗组RTV；C RTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为RTV＝V t/V 0,其中V 0是分组给药时(即d 0)测量所得平均肿瘤体积,V t为某一次测量时的平均肿瘤体积,T RTV与C RTV取同一天数据。
4.4实验结果见表5。
表5本发明化合物对MC38小鼠结肠癌移植瘤模型的抑瘤药效评价(基于给药后第28天肿瘤体积计算得出)
Figure PCTCN2022111904-appb-000070
PD-1单抗来源：BioXcell。PD-1单抗于分组后第7天开始给药，化合物24于分组当天开始给药。
结论：本发明化合物与PD-1单抗联用对MC38小鼠结肠癌移植瘤模型具有优异的抑瘤效果。

Claims (14)

  1. 式(Ⅰ)化合物或其药学上可接受的盐，
    Figure PCTCN2022111904-appb-100001
    其中，
    T 1选自N和C(R 12)；
    T 2选自N和C(R 15)；
    环A选自5元杂芳基；
    R 11、R 12、R 13、R 14和R 15分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，其中所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R a取代；
    R 2选自C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
    R a分别独立地选自F、Cl、Br、I、-OH、-NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代；
    R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN和-COOH；
    R分别独立地选自F、Cl、Br、I、-OH和-NH 2；
    所述5元杂芳基中的“杂”表示1、2、3或4个分别独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。
  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，R a分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CH 3。
  3. 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 b分别独立地选自-COOH。
  4. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 11、R 12、R 13、R 14和R 15分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-O-CH 3和-NH-CH 3，其中所述-CH 3、-O-CH 3和-NH-CH 3分别独立地任选被1、2或3个R a取代。
  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 11、R 12、R 13、R 14和R 15分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-CF 3、-O-CH 3、-O-CH 2F、-O-CHF 2、-O-CF 3和-N-(CH 3) 2。
  6. 根据权利要求1或3所述化合物或其药学上可接受的盐，其中，R 2选自-CH 2-CH 3，其中所述-CH 2-CH 3任选被1、2或3个R b取代。
  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
    Figure PCTCN2022111904-appb-100002
  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，环A选自5元含氮杂芳基。
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2022111904-appb-100003
    Figure PCTCN2022111904-appb-100004
    其中，
    D 1选自O或NH；
    T 3、T 4、T 5和T 6分别独立地选自N和CH。
  10. 根据权利要求9所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2022111904-appb-100005
    Figure PCTCN2022111904-appb-100006
  11. 根据权利要求1-9任意一项所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2022111904-appb-100007
    其中，
    T 1选自N和C(R 12)；
    T 2选自N和C(R 15)；
    D 1、T 3、T 4、T 5和T 6如权利要求9所定义；
    R 11、R 12、R 13、R 14和R 15如权利要求1、4或5任意一项所定义；
    R 2如权利要求1、6或7任意一项所定义。
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2022111904-appb-100008
    其中，
    D 1、T 3、T 4、T 5、T 6、R 11、R 12、R 13、R 14、R 15和R 2如权利要求11所定义。
  13. 下列所示化合物或其药学上可接受的盐，
    Figure PCTCN2022111904-appb-100009
    Figure PCTCN2022111904-appb-100010
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2022111904-appb-100011
    Figure PCTCN2022111904-appb-100012
    Figure PCTCN2022111904-appb-100013
    Figure PCTCN2022111904-appb-100014
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