CN107954995A - Indole derivatives with CRTH2 inhibitor activities - Google Patents

Indole derivatives with CRTH2 inhibitor activities Download PDF

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Publication number
CN107954995A
CN107954995A CN201711237230.XA CN201711237230A CN107954995A CN 107954995 A CN107954995 A CN 107954995A CN 201711237230 A CN201711237230 A CN 201711237230A CN 107954995 A CN107954995 A CN 107954995A
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compound
cycloalkyl
alkyl
halogen
radical
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CN107954995B (en
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姚元山
陈斌
陈远
李敖
徐然
黄振昇
田东东
李宏伟
杨成帅
黎健
陈曙辉
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This application discloses the indole derivatives or its pharmaceutically acceptable salt with CRTH2 inhibitor activities as shown in formula (I), and it is being treated and the application in the relevant disease of CRTH2 acceptors.

Description

Indole derivatives having CRTH2 inhibitor activity
Technical Field
The present application relates to indole derivatives having CRTH2 inhibitor activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases related to the CRTH2 receptor.
Background
CRTH2(DP2 or GPR44) is a G protein coupled receptor, and is involved in activation and chemotaxis of Th2 lymphocytes, eosinophils and basophils after being combined with Prostaglandin (Prostaglandin) (PGD2), inhibits apoptosis of Th2 lymphocytes, and stimulates production of IL4, IL5 and IL 13. These interleukins are involved in important biological responses including recruitment and survival of eosinophils, mucus secretion, airway hyperreactivity, and production of immunoglobulin E (IgE).
Ramatroban (Ramatroban) is an antagonist of TP (thromboxane-type prostanoid receptor) receptors and has extremely strong vasoconstriction, bronchial smooth muscle contraction and platelet activation effects. Ramatroban is a weak CRTH2 receptor antagonist. Ramatroban has been approved in japan for the treatment of allergic rhinitis.
WO2005044260 reports compound OC459 and WO2005123731 reports compound QAW-039.
Disclosure of Invention
The present application relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
a is selected from
Represents a single bond or a double bond whenWhen it is a double bond, R7、R8Is absent;
R1、R2、R3、R4independently selected from H, halogen, hydroxy, cyano, hydroxy,Nitro, amino, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamide group, C3-6Cycloalkyl radical, C3-6Cycloalkylamido and 3-6 membered heterocycloalkyl, said amino, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamide group, C3-6Cycloalkyl radical, C3-6Cycloalkylamido and 3-6 membered heterocycloalkyl optionally substituted by halogen, hydroxy, COOH, C1-3Alkyl radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl;
R5selected from hydrogen, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Cycloalkyl is optionally substituted with halogen;
R6、R7、R8、R9independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-3Alkyl and C3-6Cycloalkyl, said amino, C1-3Alkyl and C3-6Cycloalkyl optionally substituted by halogen, hydroxy, C1-3Alkyl and C3-6Cycloalkyl substitution;
R10selected from H, CH3And a phenyl group.
In some embodiments, a is selected from
In some embodiments, a is selected from
In some embodiments, R1、R2、R3、R4Independently selected from H, halogen, nitro, C1-3Alkyl radical, C1-3Alkylamide group, C3-6Cycloalkyl and C3-6Cycloalkyl amide group, said C1-3Alkyl radical, C1-3Alkylamide group, C3-6Cycloalkyl and C3-6Cycloalkyl amido optionally substituted by halogen, hydroxy, C1-3Alkyl and C3-6Cycloalkyl is substituted.
In some embodiments, R1、R2、R3、R4Independently selected from H, halogen, nitro, C1-3Alkyl radical, C1-3Alkylamide group and C3-6Cycloalkyl amide group, said C1-3Alkyl radical, C1-3Alkylamide group and C3-6The cycloalkyl amide group is optionally substituted with halogen.
In some embodiments, R1、R4Is H.
In some embodiments, R2、R3Independently selected from H, halogen, nitro, C1-3Alkyl radical, C1-3Alkylamide group and C3-6Cycloalkyl amide group, said C1-3Alkyl is optionally substituted with halogen.
In some embodiments, R2、R3Independently selected from H, F, Cl, Br, nitro, methyl, methylamido and cyclopropylamido, said methyl group being optionally substituted with F.
In some embodiments, R2Selected from the group consisting of H, F, Cl, Br, nitro, methyl, methylamide, and cyclopropylamide.
In some embodiments, R3Selected from H, Cl and CF3。
In some embodiments, R5Selected from hydrogen and C1-3Alkyl radical, said C1-3Alkyl is optionally substituted with halogen.
In some embodiments, R5Selected from hydrogen and trifluoromethyl.
In some embodiments, R6、R7、R8、R9Independently selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Cycloalkyl is optionally substituted with halogen.
In some embodiments, R6、R7、R8、R9Independently selected from H, halogen, C1-3Alkyl and C3-6A cycloalkyl group.
In some embodiments, R6、R7、R8、R9Independently selected from H, F and methyl.
In some embodiments, R6、R7、R8、R9Independently selected from H and F.
In some embodiments, R10Is selected from CH3。
In some embodiments, the compound of formula (I) herein is selected from compounds of formula (II),
wherein R is2、R3、R5、R6、R7、R8And R9As defined above.
In some embodiments, the compounds of formula (I) herein are selected from the following compounds:
in another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
In another aspect, the present application relates to a method of treating a disease mediated by CRTH2 in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the present application relates to the use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of CRTH2 mediated diseases.
In another aspect, the application relates to a compound of formula (i) or a pharmaceutically acceptable salt thereof for the prevention or treatment of CRTH2 mediated diseases.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)2CH3) Monosubstituted (e.g. CH)2CH2F) Polysubstituted (e.g. CHFCH)2F、CH2CHF2Etc.) or completely substituted (CF)2CF3). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Herein Cm-nIt is the moiety that has an integer number of carbon atoms in the given range. E.g. "C1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then there are separate options for each R.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to the group — CN.
The term "amino" refers to the group-NH2A group.
The term "nitro" means-NO2A group.
The term "alkyl" refers to a group of formula CnH2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above.
The term "alkoxy" refers to-O-alkyl.
The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, fused ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, fused ring, or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, examples of tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thioxanyl, 1, 4-dioxane, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepinyl, and thiepanyl. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;
(ii) inhibiting the disease or disease state, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.
The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I and36cl, and the like.
Certain isotopically-labelled compounds of the present application (e.g. with3H and14c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as15O、13N、11C and18f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)2H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.
The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of the general formula I described herein, the daily dose is from 0.01 to 200mg/kg body weight, preferably from 0.02 to 100mg/kg body weight, more preferably from 0.1 to 20mg/kg body weight, in single or divided doses.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
An important consideration in the art of synthetic route planning is the selection of suitable protecting Groups for reactive functional Groups (such as amino Groups in the present application), for example, reference may be made to Greene's Protective Groups in organic Synthesis (4th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc. all references cited herein are incorporated herein in their entirety.
The following abbreviations are used in this application: aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amino protecting group; BOC represents tert-butylcarbonyl, which is an amino protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA for diisopropylethylamine; SOCl2Represents thionyl chloride; CS2Represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu4NF represents tetrabutyl ammonium fluoride; iPrOH represents 2-propanol; mp represents melting point; LDA stands for lithium diisopropylamide.
For clarity, the invention is further illustrated by examples, which do not limit the scope of the application. All reagents used herein were commercially available and used without further purification.
Examples
Example 1
First step of
Compound 1a (1.32g,7.41mmol) was dissolved in methanol (35mL), thionyl chloride (1.32g,11.12mmol) was added in portions, and the reaction solution was heated to 60 ℃ and stirred for 4 hours, and then directly concentrated to dryness to give compound 1b (1.40g, white solid, yield: 97%).1H NMR(400MHz,CDCl3)δ8.54(d,J＝1.2Hz,1H),8.03-7.98(m,1H),7.95-7.90(m,1H),7.52(d,J＝5.6Hz,1H),7.43(d,J＝5.6Hz,1H),3.96(s,3H).
Second step of
Compound 1b (1.40g,7.28mmol) was dissolved in dichloromethane (50mL), m-chloroperoxybenzoic acid (4.43g,21.84mmol, 80%) was added at 0 deg.C, the reaction was stirred at 30 deg.C for 16 hours and quenched by addition of saturated sodium thiosulfate solution (20mL), and the pH was adjusted to 7-8 with sodium carbonate solution. The organic phase was washed with saturated aqueous sodium bicarbonate (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give compound 1c (1.73g, white solid, yield: 89%).1H NMR(400MHz,CDCl3)δ8.26-8.18(m,1H),8.03(s,1H),7.80(d,J＝7.6Hz,1H),7.28(d,J＝7.2Hz,1H),6.80(d,J＝6.8Hz,1H),3.97(s,3H).
The third step
Compound 1c (200mg,0.89mmol) was dissolved in methanol (20mL), wet palladium on carbon (20mg, 10%, water: 50%) was added, the reaction solution was stirred under hydrogen (15psi) atmosphere at room temperature for 16 hours, then filtered, and the filtrate was concentrated under reduced pressure to dryness to give compound 1d (200mg, white solid, yield: 99%).1H NMR(400MHz,CD3OD)δ8.16-8.11(m,2H),7.80(d,J＝8.4Hz,1H),3.95(s,3H),3.62-3.56(m,2H),3.48-3.43(m,2H).
The fourth step
Compound 1d (150mg,0.66mmol) was dissolved in tetrahydrofuran (5mL), a diisobutylaluminum hydride solution (2.65mmol,1M,2.65mL) was slowly added dropwise at 5-15 deg.C, the reaction mixture was stirred for 4 hours, then water (10mL) and 1N hydrochloric acid (5mL) were added, and extraction was performed with ethyl acetate (20 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by thin layer silica gel chromatography (petroleum ether/ethyl acetate ═ 1/1) to give compound 1e (80mg, white solid, yield: 60%).1H NMR(400MHz,CD3OD)δ7.66(d,J＝7.6Hz,1H),7.52-7.46(m,2H),4.70(s,2H),3.58-3.50(m,2H),3.43-3.36(m,2H).
The fifth step
Compound 1e (80.00mg,403.55mmol) was dissolved in dichloromethane (10mL), manganese dioxide (281mg,3.23mmol) was added, the reaction solution was stirred at room temperature for 3 hours, then filtered, and the filtrate was directly concentrated to dryness to give compound 1f (71mg, white solid, yield: 89%).1H NMR(400MHz,CDCl3)δ10.10(s,1H),8.02-7.96(m,1H),7.95-7.89(m,2H),3.62-3.45(m,4H).
The sixth step
Compound 1f (71mg,0.36mmol) and compound 1g (85mg,0.36mmol) were dissolved in 1, 2-dichloroethane (5mL), triethylsilane (210mg,1.81mmol) and trifluoroacetic acid (62mg,0.54 mmol). The reaction solution was heated to 50 ℃ and stirred for 16 hours. The reaction was washed with saturated sodium bicarbonate solution (10mL) and extracted with dichloromethane (10mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure and purified by thin layer chromatography on silica gel (petroleum ether/ethyl acetate 5/1) to give compound 1h (120 mg).
MS-ESI calculated value [ M + H%]+416, found 416.
Seventh step
Compound 1h (120mg,0.18mmol) was dissolved in tetrahydrofuran (5mL), and a solution of lithium hydroxide (39mg,0.92mmol) in water (1mL) was added to reactThe solution was stirred at 15 ℃ for 2 hours, neutralized to pH 4-5 by dropwise addition of 1N hydrochloric acid, and extracted with ethyl acetate (10 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high performance liquid chromatography to give compound 1(44 mg).1H NMR(400MHz,CD3OD) delta 7.57-7.55(M,1H),7.38-7.36(M,1H),7.26(s,1H),7.25-7.19(M,1H),7.00-6.92(M,1H),6.87-6.79(M,1H),4.93(s,2H),4.15(s,2H),3.51-3.43(M,2H),3.30-3.26(M,2H),2.35(s,3H), MS-ESI calculation [ M + H ] M + H]+388, measured value 388.
Example 2
First step of
Compound 2a (71mg, white solid, yield: 41%) was obtained from compound 1c through 2-step reaction according to the procedure of example 1. MS-ESI calculated value [ M + H%]+195, found value 195.
Second step of
Compound 2(4mg, yield: 7%) was synthesized from compound 2a and compound 1g according to the procedure of example 1.1HNMR(400MHz,CD3OD) δ 7.58(d, J ═ 7.6Hz,1H),7.43(d, J ═ 7.6Hz,1H),7.33(d, J ═ 6.8Hz,1H),7.29(s,1H),7.26-7.20(M,1H),7.02-6.96(M,1H),6.90(d, J ═ 6.8Hz,1H),6.88-6.82(M,1H),4.94(s,2H),4.17(s,2H),2.35(s,3H), MS-ESI calcd [ M + H, 2H ]]+386, found 386.
Example 3
First step of
Compound 3a (25.00g,114.15mmol) was dissolvedIn methanol (250mL), concentrated sulfuric acid (5.60g,57.08mmol) was slowly added dropwise. The resulting reaction solution was stirred and refluxed at 70 ℃ for 5 hours. After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction system to adjust the pH to 7, and the mixture was concentrated under reduced pressure to remove a large amount of methanol and extracted with ethyl acetate (250 mL. times.2). The organic phases were combined, dried, concentrated to dryness under reduced pressure and purified by silica gel column chromatography (100-0% petroleum ether/ethyl acetate) to give compound 3b (25.00 g).1H NMR(400MHz,CDCl3) δ 3.93(s,3H)7.04(t, J ═ 8.8Hz,1H)7.59-7.62(m,1H),8.04-8.07(m, 1H). MS-ESI calculated value [ M + H%]+234, found 234.
Second step of
Compound 3b (24.00g,102.99mmol) was dissolved in methanol (300mL) and then N, N-dimethylformamide (100mL), triethylamine (100mL) and [1, 1-bis (diphenylphosphino) ferrocene were added]Palladium dichloride (12.62g,15.45 mmol). After the reaction mixture was stirred at 80 ℃ under a carbon monoxide atmosphere (50psi) for 16 hours, the reaction mixture was filtered, concentrated under reduced pressure, and extracted with ethyl acetate (500 mL. times.2). The organic phases were combined, dried and concentrated to dryness under reduced pressure, and then purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-0%) to give compound 3c (11.00 g).1H NMR(400MHz,CDCl3) Δ 3.95(s,3H),3.97(s,3H),7.20-7.24(M,1H),8.21-8.23(M,1H),8.63-8.65(M,1H). MS-ESI calculated value [ M + H]+213, found 213.
The third step
Compound 3c (11.00g,51.85mmol) was dissolved in dimethyl sulfoxide (50mL) and sodium methylsulfinate (5.82g,57.04mmol) was added. The resulting reaction mixture was stirred at 90 ℃ for 16 hours, poured into ice water (300mL), and extracted with ethyl acetate (400 mL. times.2). The organic phases were combined, dried, concentrated to dryness under reduced pressure, and then separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-0%) to give compound 3d (11.00 g).1H NMR(400MHz,CDCl3) Δ 3.93(s,3H),3.93(s,3H),3.97(s,3H),8.21-8.29(M,1H),8.30-8.36(M,1H),8.37(s,1H). MS-ESI calculation [ M + H]+273, found 273.
The fourth step
Compound 3d (10.00g,36.73mmol) was dissolved in tetrahydrofuran (300mL) and lithium hexamethyldisilazide (7.99g,47.75mmol) was slowly added dropwise at-78 ℃. After the resulting reaction solution was stirred at-78 ℃ for 3 hours, it was quenched with a saturated ammonium chloride solution and adjusted to pH 7, concentrated under reduced pressure to remove most of tetrahydrofuran, and then extracted with ethyl acetate (500 mL. times.2). The organic phases were combined, dried and concentrated to dryness under reduced pressure to give compound 3e (8.00 g).1H NMR(400MHz,CDCl3) δ 4.02(s,3H),4.17(s,2H),3.97(s,3H),8.09(d, J ═ 8.0Hz,1H),8.59-8.61(M,1H),8.66(s,1H), MS-ESI calculated value [ M + H ═ 1H ]]+241, measured value 241.
The fifth step
Compound 3e (4.00g,16.65mmol) was dissolved in acetonitrile (50mL), followed by addition of anhydrous sodium carbonate (5.29g,49.95mmol), stirring at 20 ℃ for 0.5 hour after the addition, and addition of 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2,2,2 octane bis (tetrafluoroborate) salt (12.98g,36.63 mmol). After the resulting reaction solution was stirred at 20 ℃ for 0.5 hour, it was quenched with a saturated ammonium chloride solution and adjusted to pH 7, and extracted with ethyl acetate (50 mL. times.2). The organic phases were combined, dried, concentrated to dryness under reduced pressure, and then separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-0%) to obtain compound 3f (3.40 g).1H NMR(400MHz,CDCl3) δ 4.05(s,3H),8.18(d, J ═ 8.0Hz,1H),8.73(d, J ═ 8.4Hz,1H),8.77(s,1H), MS-ESI calculated value [ M + H]+277, found 277.
The sixth step
Compound 3f (1.50g,5.43mmol) was dissolved in tetrahydrofuran (30mL) and sodium borohydride (230mg,6.08mmol) was added slowly at 0 ℃. The resulting reaction solution was stirred at 0 ℃ for 2 hours, quenched with 1N hydrochloric acid and adjusted to pH 7, concentrated under reduced pressure to remove most of tetrahydrofuran, and extracted with ethyl acetate (50 mL. times.2). The organic phases were combined, dried, concentrated to dryness under reduced pressure, and then separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-0%) to obtain 3g (1.20g) of the compound.1H NMR(400MHz,CDCl3) Δ 3.93(s,3H),5.72(M,1H),8.24-8.25(M,3H). MS-ESI Calculations [ M + H]+279, found 279.
Seventh step
After 3g (1.20g,4.31mmol) of the compound was dissolved in methylene chloride (20mL), diethylsulfide trifluoride (1.39g,8.62mmol) was slowly added dropwise at 0 ℃. After the resulting reaction solution was stirred at 20 ℃ for 16 hours, it was quenched with a saturated sodium bicarbonate solution and adjusted to pH 7, and extracted with dichloromethane (10 mL. times.2). The organic phases were combined, dried and concentrated to dryness under reduced pressure, and then separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-0%) to give compound 3h (180 mg).1H NMR(400MHz,CDCl3) δ 4.02(s,3H),5.95-6.13(M,1H),8.00(dd, J ═ 8.4Hz, J ═ 1.2Hz,1H),8.40-8.46(M,2H), MS-ESI calculated value [ M + H ]]+277, found 277.
Eighth step
The compound was dissolved in tetrahydrofuran (10mL) for 3h (480mg,1.71mmol), and then diisobutylaluminum hydride (603.67mg,4.28mmol) was slowly added dropwise at 0 ℃. The resulting reaction solution was stirred at 20 ℃ for 5 hours, quenched with 1N hydrochloric acid and adjusted to pH 7, and extracted with ethyl acetate (60 mL. times.2). The organic phases were combined, dried, concentrated to dryness under reduced pressure and isolated and purified by silica gel layer chromatography (petroleum ether/ethyl acetate 2/1) to give compound 3i (180 mg).1H NMR(400MHz,CDCl3) δ 7.88(d, J ═ 8.0Hz,1H),7.80(s,1H),7.75(d, J ═ 8.0Hz,1H),5.89-6.08(M,1H),4.90(s,2H), MS-ESI calculated value [ M + H ═ 1H ]]+253, found 253.
The ninth step
Compound 3i (180mg,0.71mmol) was dissolved in dichloromethane (10mL) and manganese dioxide (496mg,5.71mmol) was added. The resulting reaction mixture was stirred at 20 ℃ for 2 hours, filtered, and concentrated under reduced pressure to dryness to give compound 3j (160 mg).1H NMR(400MHz,CDCl3) δ 10.17(s,1H),8.24-8.33(M,2H),8.11(d, J ═ 8.0Hz,1H),5.99-6.18(M,1H). MS-ESI calcd for [ M + H ], (M + H)]+251, found value 251.
The tenth step
Compound 3j (52mg,0.21mmol) and compound 3k (60mg,0.23mmol) were dissolved in 1, 2-dichloroethylTo an alkane (5mL), triethylsilane (193mg,1.66mmol) and trifluoroacetic acid (118mg,1.04mmol) were added at 0 ℃. The reaction mixture was stirred at 60 ℃ for 2 hours, then quenched by the addition of water (5mL), adjusted to pH 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane (50 mL. times.2). The organic phases were combined, dried, concentrated to dryness under reduced pressure and isolated and purified by silica gel layer chromatography (petroleum ether/ethyl acetate 4/1) to give 3l (50mg) of compound. MS-ESI calculated value [ M + H%]+498, found 498.
The eleventh step
After 3l (40mg,0.08mmol) of the compound was dissolved in dichloromethane (5mL), trifluoroacetic acid (9mg,0.0091mmol) was added, and the reaction mixture was stirred at 20 ℃ for 2 hours, concentrated under reduced pressure to dryness, and then separated and purified by high performance liquid chromatography to give compound 3(24 mg).1H NMR(400MHz,DMSO-d6) δ 8.12(d, J ═ 8.0Hz,1H),7.71-7.80(M,2H)7.38(dd, J ═ 8.4, J ═ 4.4Hz,1H)7.22(d, J ═ 7.6Hz,1H),6.89(t, J ═ 8.4Hz,1H),6.67-6.85(M,1H),4.97(s,2H),4.24(s,2H),2.33(s,3H), MS-ESI calculation [ M + H, 2H ], 2.33(s,3H), MS-ESI calculation]+442, found 442.
Example 4
First step of
Compound 4a was reacted according to the synthetic method of Compound 3c in example 3 to give Compound 4b (5.80 g).1H NMR(400MHz,CDCl3)δ8.25-5.24(d,J＝6.4Hz,1H),8.15-8.08(m,2H),7.64-7.63(d,J＝6.4Hz,1H),7.43-7.39(t,J＝8.0,1H),4.00(s,3H).
Second step of
Compound 4b Compound 4c (105mg) was obtained through a multi-step reaction according to the synthesis method in example 1.1HNMR(400MHz,CDCl3)δ7.94(s,1H),7.63-7.62(m,1H),7.40-7.36(m,1H),7.30(s,1H),7.26-7.22(m,1H),6.88-6.87(m,1H),4.03(s,2H),3.54-3.51(m,2H),3.36-3.32(m,2H),2.34(s,3H).
The third step
To a solution of compound 4c (105mg,0.32mmol) in N, N-dimethylformamide (5mL) at 25 deg.C were added cesium carbonate (156mg,0.48mmol) and tert-butyl bromoacetate (93mg,0.48 mmol). After the resulting reaction was further stirred for 1 hour, the reaction was quenched by adding a saturated ammonium chloride solution (30mL) to the reaction system, followed by extraction with ethyl acetate (50 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 4d (141 mg). MS-ESI calculated value [ M + H%]+443, found 443.
The fourth step
Compound 4d was reacted according to the synthetic method of compound 3 in example 3 to give compound 4(25 mg).1H NMR(400MHz,DMSO-d6) Δ 7.56-7.54(M,1H),7.40-7.35(M,2H),7.26-7.24(M,1H),7.05-7.03(M,1H),7.02-6.86(M,1H),4.88(s,2H),4.09(s,2H),3.60-3.57(M,2H),3.35-3.30(M,2H),2.27(M,3H), MS-ESI calculation [ M + H]+388, measured value 388.
Example 5
First step of
Compound 5a (50mg,0.38mmol) and compound 1f (78mg,0.38mmol) were dissolved in 1, 2-dichloroethane (5mL) and trifluoroacetic acid (130mg,1.14mmol) was added. The reaction solution was stirred at 50 ℃ for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate solution (10mL) and extracted with ethyl acetate (15 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the crude product was isolated and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate 2/1) to give compound 5b (115 mg).
1H NMR(400MHz,CDCl3)δ7.90(s,1H),7.63-7.61(m,4H),7.36-7.31(m,3H),7.16-7.05(m,3H),4.13(s,2H),3.47-3.43(m,2H),3.29-3.26(m,2H),2.39(s,3H).
Second step of
Cesium carbonate (165mg,0.51mmol) was added to a solution of compound 5b (105mg,0.34mmol) and tert-butyl bromoacetate (99mg,0.51mmol) in N, N-dimethylformamide (20mL) at 0 ℃. The reaction solution was stirred at 25 ℃ for 18 hours. The reaction mixture was extracted with 30mL of a saturated aqueous ammonium chloride solution and ethyl acetate (50 mL. times.3). The combined organic phases were washed with saturated aqueous sodium chloride (30mL x 3) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was removed from the filtrate under reduced pressure to give crude compound 5c (143 mg).
The third step
To a solution of compound 5c (143mg,0.34mmol) in 5mL of ethyl acetate was added 2mL of a solution of hydrogen chloride in ethyl acetate (4M), and the reaction was stirred for an additional 2 hours. The reaction was quenched with 20mL water, extracted with ethyl acetate (50mL x 3), and the combined organic phases were washed with saturated aqueous sodium chloride (30mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative high performance liquid chromatography to give compound 5(16 mg).1H NMR(400MHz,DMSO-d6) Δ 7.61-7.59(M,1H),7.38-7.32(M,4H),7.04-7.02(M,1H),6.97-6.95(M,1H),4.91(s,2H),4.13(s,2H),3.53-3.51(M,2H),3.27-3.23(M,2H),2.34(s,3H). MS-ESI calculated value [ M + H]+370, found 370.
Example 6
First step of
Compound 6a and compound 1f were reacted according to the synthetic method of compound 5 in example 5 to give compound 6(84 mg).1H NMR(400MHz,DMSO-d6)δ7.63-7.61(m,1H),7.43-7.30(m,3H),7.05(s,1H),7.05-7.03(m,1H),4.97(s,2H),4.13(s,2H),3.54-3.51(M,2H),3.26-3.24(M,2H),2.32(s,3H). MS-ESI calculated values [ M + H]+404, measured value 404.
Example 7
Compound 7a and compound 1f were reacted according to the synthesis method of compound 5 in example 5 to give compound 7(28 mg).1H NMR(400MHz,DMSO-d6) Δ 7.61-7.59(M,1H),7.35-7.33(M,1H),7.29(s,1H),7.23-7.21(M,1H),7.16(s,1H),6.87-6.85(M,1H),4.90(s,2H),4.10(s,2H),3.54-3.52(M,2H),3.25(s,2H),2.32(s,3H),2.30(s,3H), MS-ESI calculation [ M + H ] M]+384, found 384.
Example 8
First step of
Compound 8a and compound 1f were reacted according to the synthesis method of compound 5 in example 5 to give compound 8(21 mg).1H NMR(400MHz,DMSO-d6) Δ 7.56-7.39(M,8H),7.39-7.20(M,3H),7.04(s,1H),4.78(s,2H),4.07(s,2H),3.52-3.49(M,2H),3.24-3.20(M,2H), MS-ESI calculation [ M + H ]]+432, found 432.
Example 9
First step of
Compound 9a and compound 1f were reacted according to the synthetic method of compound 5 in example 5 to give compound 9(43 mg).1H NMR(400MHz,CD3OD) delta 7.57-7.55(M,1H),7.39(s,1H),7.31-7.30(M,2H),7.26-7.24(M,1H),6.96-6.93(M,1H),4.92(s,2H),4.18(s,2H),3.50-3.46(M,2H),3.28(s,2H),2.35(s,3H). MS-ESI calculation [ M + H]+404, measured value 404.
Example 10
First step of
Compound 10a and compound 1f were reacted according to the synthesis method of compound 5 in example 5 to give compound 10(47 mg).1H NMR(400MHz,DMSO-d6) Δ 7.63-7.57(M,1H),7.57(s,1H),7.37-7.34(M,2H),7.29(s,1H),7.17-7.15(M,1H),4.98(s,2H),4.13(s,2H),3.54-3.51(M,2H),3.28-3.24(M,2H),2.32(s,3H). MS-ESI calculation [ M + H]+449, found 449.
Example 11
First step of
Compound 11a and compound 1f were reacted according to the synthetic method of compound 5 in example 5 to give compound 11(47 mg).1H NMR(400MHz,DMSO-d6) Δ 7.80(s,1H),7.61-7.56(M,2H),7.36-7.32(M,2H),7.25-7.23(M,1H),5.02(s,2H),4.17(s,2H),3.51(s,2H),3.27-3.23(M,2H),2.37(s,3H). MS-ESI calculation [ M + H]+438, found value 438.
Example 12
First step of
Compound 12a and compound 1f were reacted according to the synthetic method of compound 5c in example 5 to give compound 12b (480 mg). MS-ESI calculated value [ M + H%]+471, found value 471.
Second step of
Compound 12b was reacted according to the synthetic method of compound 5 in example 5 to give compound 12(28 mg).1H NMR(400MHz,DMSO-d6) Δ 8.34(s,1H),7.91-7.89(M,1H),7.63-7.61(M,1H),7.44-7.42(M,1H),7.38-7.36(M,1H),7.33(s,1H),4.59(s,2H),4.23(s,2H),3.54-3.50(M,2H),3.28(M,2H),2.35(s,3H). MS-ESI calculation [ M + H]+415, found value 415.
Example 13
First step of
To a solution of compound 12b (390mg,0.83mmol) in 5mL of acetone were added zinc powder (1.08g,16.58mmol) and ammonium chloride solution (5mL,6M), and after stirring at 25 ℃ for 1 hour, filtration was performed, the filtrate was extracted with ethyl acetate (100mL × 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was isolated and purified by column chromatography (petroleum ether/ethyl acetate ═ 100-0%) to give compound 13a (320 mg). MS-ESI calculated value [ M + H%]+441, measured value 441.
Second step of
To a solution of compound 13a (70mg,0.16mmol) in 5mL of dichloromethane were added cyclopropylcarbonyl chloride (24mg,0.24mmol) and diisopropylethylamine (41mg,0.32 mmol). After the resulting reaction solution was stirred at 25 ℃ for 2 hours, a saturated ammonium chloride solution (20mL) was added to the reaction system to quench the reaction, followed by extraction with ethyl acetate (30 mL. times.3). The organic phases were combined, washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was separated and purified by thin layer silica gel chromatography (petroleum ether/ethyl acetate ═ 1/1) to give compound 13b (60 mg).
The third step
Compound 13b was reacted according to the method of example 5 to give compound 13(4 mg).1H NMR(400MHz,DMSO-d6) Δ 9.54(s,1H),8.28(s,1H),7.61-7.60(M,2H),7.34-7.32(M,1H),7.28(s,1H),7.18(s,2H),4.60(s,2H),4.07(s,2H),3.68-3.60(M,2H),3.28-3.24(M,2H),2.30(s,3H),1.76-1.74(M,1H),0.75-0.71(M,4H). MS-ESI calculated value [ M + H ], [ M + H ]]+453, found 453.
Example 14
First step of
Compound 13a was reacted according to the method of example 13 to give compound 14(18 mg).1H NMR(400MHz,DMSO-d6) Δ 9.68(s,1H),8.27(s,1H),7.62-7.56(M,2H),7.34-7.30(M,2H),7.12(s,2H),4.61(s,2H),4.07(s,2H),3.52-3.50(M,2H),3.28-3.26(M,2H),2.31(s,3H),1.98(M,3H). MS-ESI calculated value [ M + H]+427, found 427.
Example 15
First step of
Compound 15a was reacted according to the synthetic method of compound 1g in example 1 to give compound 15b (1.50 g).1HNMR(400MHz,CDCl3)δ7.31-7.29(m,1H),7.18-7.15(m,2H),6.99-6.98(m,1H),6.54-6.54(m,1H),4.84(s,2H),4.29-4.16(m,2H),1.30-1.23(m,3H).
Second step of
Compound 15b and compound 1f were reacted according to the synthesis method of example 1 to give compound 15(15 mg).1H NMR(400MHz,CD3OD) Δ 7.62-7.60(M,1H),7.47-7.46(M,1H),7.39(s,1H),7.27-7.26(M,1H),7.12(s,1H),7.07-7.05(M,1H),6.96-6.93(M,1H),4.94(s,2H),4.16(s,2H),3.52-3.49(M,2H),3.34-3.33(M,2H), MS-ESI calculation [ M + H ] M + H]+374, found value 374.
Example 16
First step of
To a solution of compound 16a (25.00g,134.31mmol) in methanol (200mL) was slowly added liquid bromine (21.68g,135.66mmol) dropwise at 0 ℃. After the resulting reaction solution was further stirred for 0.5 hour, a saturated sodium thiosulfate solution (200mL) was added to the reaction system at 0 ℃ to quench the reaction, followed by addition of water (1000mL) for dilution, filtration, washing of the solid with water (200 mL. times.3), and drying under reduced pressure to give compound 16b (34.30 g).1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.20(s,1H),6.90(brs,2H).
Second step of
To a solution of compound 16b (4.00g,15.09mmol) in 50mL of dichloromethane was added diisopropylethylamine (2.54g,19.62mmol) and trifluoroacetic anhydride (3.49g,16.60mmol) at 0 ℃. Stirring the obtained reaction solution at 25 ℃ for 10 hours, adding saturated sodium chloride solution (100mL) into the reaction system at 0 ℃ to quench the reaction, adding 100mL of saturated sodium chloride solution to dilute the reaction,and extracted with ethyl acetate (100 mL. times.3). The combined organic phases were washed with saturated sodium chloride solution (100 mL. times.3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate 100-0%) to give compound 16c (5.20 g).1H NMR(400MHz,DMSO-d6)δ11.78(brs,1H),8.72(s,1H),8.56(s,1H).
The third step
Compound 16c was reacted according to the synthetic method of Compound 3c in example 3 to give Compound 16d (2.87 g).
The fourth step
To a solution of compound 16d (2.85g,11.67mmol) in concentrated hydrochloric acid (42.89mL,12N) and 50mL of acetic acid at 0 deg.C was slowly added sodium nitrite (1.21g,17.51mmol) in 20mL of water. After the reaction mixture was stirred for 1 hour, a suspension of cuprous chloride (3.47g,35.01mmol) in concentrated hydrochloric acid (42.89mL,12N) was added to the reaction system, and after stirring for 1 hour, the reaction system was dispersed in 200mL of a saturated sodium chloride solution and 250mL of ethyl acetate, the organic phase was separated, washed with a saturated sodium chloride solution (100mL × 5) and a saturated sodium bicarbonate solution (100mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-0%) to give compound 16e (2.60 g).1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.32(s,1H),3.93(s,3H).
The fifth step
To a solution of compound 16e (2.60g,9.86mmol) in N, N-dimethylformamide (30mL) was added methylsulfinic acid sodium salt (3.02g,29.58 mmol). After the resulting reaction solution was further stirred at 50 ℃ for 1 hour, water (100mL) was added to the reaction system to quench the reaction, and the reaction solution was filtered, and the solid was washed with water, then dissolved in ethyl acetate (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-0%) to give compound 16f (2.50 g).1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.42(s,1H),3.93(s,3H),3.50(s,3H).
The sixth step
Compound 16f was reacted according to the synthetic method of compound 3e in example 3 to give compound 16g (1.45 g).1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.87(s,1H),4.76(s,2H).
Seventh step
To a solution of compound 16g (1.45g,5.27mmol) in methanol (30mL) at 0 deg.C was added sodium borohydride (219mg,5.80mmol) in portions. After the obtained reaction mixture was further stirred for 0.5 hour, a saturated ammonium chloride solution (100mL) was added to the reaction system at 0 ℃ and extracted with ethyl acetate (100 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (100mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was subjected to column chromatography (petroleum ether/ethyl acetate 100-0%) to isolate and purify the compound 16h (1.20 g).1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.50(s,1H),6.68-6.66(d,J＝6.0Hz,1H),5.54-5.50(m,1H),4.20-4.15(m,1H),4.20-4.15(m,1H).
Eighth step
To a solution of compound 16h (1.20g,4.33mmol) in dichloromethane (20mL) at 0 deg.C was added methanesulfonyl chloride (595mg,5.20mmol) and triethylamine (876mg,8.66 mmol). The resulting reaction solution was stirred at 25 ℃ for 1 hour, and saturated sodium chloride solution (100mL) was added to the reaction system to quench it, and it was diluted with ethyl acetate (200 mL). The separated organic phase was washed with a saturated sodium chloride solution (50mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was isolated and purified by column chromatography (petroleum ether/ethyl acetate 100-0%) to give compound 16i (1.10 g).
The ninth step
Compound 16i was reacted according to the synthetic method for compound 1d in example 1 to give compound 16j (900 mg).1HNMR(400MHz,DMSO-d6)δ8.50(s,1H),8.47(s,1H),3.79-3.76(m,2H),3.52-3.49(m,2H).
The tenth step
DIBAL-H (1.15mL,1.15mmol,1M) was slowly added dropwise to a solution of compound 16j (200mg,0.77mmol) in 5mL of dichloromethane under nitrogen and at-78 ℃. The resulting reaction solution was stirred at-78 ℃ for 1 hour, and a saturated ammonium chloride solution (50mL) was added to the reaction system to quench the reaction, followed by extraction with ethyl acetate (50 mL. times.3). The organic phases were combined and washed with saturated sodium chloride solution (50mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was isolated and purified by column chromatography (100-0% petroleum ether/ethyl acetate) to give compound 16k (150 mg).1H NMR(400MHz,DMSO-d6)δ10.31-10.30(d,J＝2.0Hz,1H),8.33(s,1H),8.25(s,1H),3.77-3.74(m,2H),3.55-3.52(m,2H).
The eleventh step
Compound 16k and compound 16l were reacted according to the synthetic method in example 1 to give compound 16(26 mg).1HNMR(400MHz,CD3OD) delta 8.03(s,1H),7.30-7.27(M,1H),7.13(s,1H),6.87-6.80(M,2H),4.98(s,2H),4.31(s,2H),3.52-3.48(M,2H),3.24-3.21(M,2H),2.31(s,3H). MS-ESI calculation [ M + H]+456, found 456.
Example 17
First step of
To a solution of compound 17a (10.00g,52.89mmol) in 100mL of N, N-dimethylformamide were added isobutylene oxide (4.20g,58.18mmol) and potassium carbonate (10.96g,79.34 mmol). The resulting reaction solution was stirred at 20 ℃ for 0.5 hour, and a saturated sodium chloride solution (500mL) was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate (300 mL. times.3). The organic phases were combined and washed with saturated sodium chloride solution (100mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is separated by column chromatography (100-0% petroleum ether/ethyl acetate)Purification gave compound 17b (8.50 g).1HNMR(400MHz,CDCl3)δ7.33-7.31(d,J＝8.8Hz,2H),7.21-7.19(d,J＝8.4Hz,2H),3.02(s,2H),1.24(s,6H).
Second step of
To a suspension of aluminum trichloride (14.32g,107.28mmol) in carbon disulfide (160mL) at-10 deg.C was added a solution of compound 17b (8.00g,30.64mmol) in 160mL of carbon disulfide. The resulting reaction solution was stirred at 75 ℃ for 0.5 hour, then cooled to 0 ℃, and 1N diluted hydrochloric acid (200mL) was added to the reaction system, followed by extraction with ethyl acetate (150 mL. times.3). The organic phases were combined, washed with a saturated sodium chloride solution (100mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was separated and purified by column chromatography (petroleum ether/ethyl acetate ═ 100-0%) to give compound 17c (2.20 g).1H NMR(400MHz,CDCl3)δ7.24-7.22(m,1H),7.15(s,1H),7.06-7.03(d,J＝8.4Hz,1H),3.19(s,2H),1.37(s,6H).
The third step
Compound 17c was reacted according to the synthetic method for compound 1c in example 1 to give compound 17d (900 mg).1HNMR(400MHz,CDCl3)δ7.64-7.56(m,3H),3.36(s,2H),1.55(s,6H).
The fourth step
Compound 17d was reacted according to the synthesis method in example 3 to give compound 17e (340 mg).1H NMR(400MHz,CDCl3)δ10.12(s,1H),8.00-7.99(m,2H),7.90-7.88(d,J＝8.4Hz,1H),3.43(s,2H),1.61(s,6H).
The fifth step
Compound 17e and compound 1g were reacted according to the synthetic method in example 1 to give compound 17(40 mg).1HNMR(400MHz,CD3OD) δ 7.51-7.47(M,2H),7.35-7.33(d, J ═ 8.0Hz,1H),7.21-7.20(M,1H),6.98-6.97(M,1H),6.95-6.82(M,1H),4.81(s,2H),4.18(s,2H),3.38(s,2H),2.35(s,3H),1.47(s,6H) MS-ESI calcd [ M + H, 2H ], MS-ESI calcd for [ M,2H ], M,1H]+416, found 416.
Example 18
First step of
Compound 18a was reacted according to the synthetic method of 3c in example 3 to give compound 18b (2.60 g).1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.05-8.02(m,1H),7.88-7.85(m,1H),7.66-7.64(m,1H),7.41-7.39(m,1H),3.97(s,3H).
Second step of
Compound 18b was reacted according to the synthetic method in example 1 to give compound 18c (180 mg).1H NMR(400MHz,CDCl3)δ10.06(s,1H),8.23(s,1H),8.13-8.10(m,1H),7.58-7.56(m,1H),3.60-3.56(m,2H),3.51-3.48(m,2H).
The third step
Compound 18(41mg) was synthesized by reacting compound 18c with compound 1g according to the procedure of example 1.1HNMR(400MHz,DMSO-d6) Δ 7.54-7.45(M,2H),7.41-7.39(M,1H),7.38-7.34(M,1H),7.20-7.16(M,1H),6.90-6.84(M,1H),4.97(s,2H),4.11(s,2H),3.57-3.50(M,2H),3.26(s,2H),2.33(s,3H). MS-ESI calculation [ M + H]+388, measured value 388.
Example 19
First step of
Compound 19a was reacted according to the synthesis method in example 18 to give compound 19b (80 mg).1H NMR(400MHz,CDCl3)δ10.59(s,1H),8.03(d,J＝7.6Hz,1H),7.74(t,J＝7.6Hz,1H),7.64-7.62(m,1H),3.64-3.61(m,2H),3.52-3.48(m,2H).
Second step of
Compound 19(44mg) was synthesized from the reaction of compound 19b and compound 1g according to the method of example 1.1HNMR(400MHz,CD3OD) delta 7.37-7.35(M,1H),7.25-7.21(M,2H),6.99-6.91(M,2H),6.83(M,1H),4.94(s,2H),4.38(s,2H),3.63-3.59(M,2H),3.42-3.39(M,2H),2.34(s,3H). Calculations for MS-ESI [ M + H ] ([ M + H ]]+388, measured value 388.
Experimental example 1
Will be provided withCHO-K1 CRTH2 β -arrestin cells (discovery X, Cat. No. 93-0291C2) were grown under standard conditions and seeded in 384 white-walled microwell plates at 5000 cells/well, 20. mu.l of CellPlating Reagent 1 per well, cells before testing at 37 ℃/5% CO2Incubate overnight. Test compounds were serially diluted in DMSO at a 3-fold dilution factor to give 8 concentrations of test compound in serial dilutions. Shortly before testing, the previously serially diluted test compounds were further diluted with test buffer to 5-fold the test concentration. 5 microliter of further diluted test compound was added to the cells and incubated at 37 ℃ for 30 minutes. The concentration of the solvent is 1%. Another 5 microliters of 6XEC80Buffer of agonist (PGD2) was added to the cells and incubated at 37 ℃ for 90 min. Assay signals were generated by the addition of 15 microliters (50% v/v) of PathHunter test mix reagent in one portion followed by one hour incubation. By PerkinElmer EnvisionTMThe instrument chemiluminescence signal was used to read the microplate. Biological activity of test compounds was analyzed by CBIS data analysis kit (ChemInnovation, CA) with IC50And (6) displaying the value. The results of the experiment are shown in table 1.
TABLE 1
Note: + > 1.0 μ M; , +0.1 to 1.0. mu.M; less than 0.1 μ M;
and (4) conclusion: the compounds of the present application have a potent antagonistic effect on the CRTH2 receptor.
Experimental example 2
Plasma pharmacokinetic experiments 12 female C57BL/6 mice were used, randomly divided into two groups of 6 animals each. The first group of animals was given 1mg/kg of the test drug for intravenous injection and the second group was given 5mg/kg of the test drug for intragastric administration. The preparation solvent contains HPbCD and cosolventThe obtained intravenous or intragastric preparation is a clear solution. Both intravenous and gavage animals were bled at 0.0833, 0.25, 0.5, 1,2, 4, 8 and 24 hours post-dose using the saphenous vein with 3 samples per time point. The collected plasma samples were frozen at-80 ℃ and thawed prior to LC-MS/MS sample analysis. Adding acetonitrile containing an internal standard into the thawed plasma sample according to a certain proportion for protein precipitation, and centrifuging to obtain a supernatant for LC-MS/MS sample injection. The analytical instrument used API4000 or 5500 and an ACQUITY UPLC BEH C18 (2.1X 50mm,1.7 μm) column, using either an ESI positive or negative ion source to detect compound ionization. Each analysis batch contains 8 concentrations of standard sample, the ratio of the peak area of the tested compound to the peak area of the Internal Standard (IS) IS Y, the concentration of the tested compound in the plasma sample IS X, and the ratio IS 1/X2Linear regression is performed for the weighting coefficients to find the regression equation for the measured response versus concentration. Each analysis batch also contains corresponding quality control samples. Phoenix 6.3 was usedData processing is performed and corresponding PK parameters are obtained. Test knotAs shown in table 2.
TABLE 2

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
a is selected from
Represents a single bond or a double bond whenWhen it is a double bond, R7、R8Is absent;
R1、R2、R3、R4independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamide group, C3-6Cycloalkyl radical, C3-6Cycloalkylamido and 3-6 membered heterocycloalkyl, said amino, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamide group, C3-6Cycloalkyl radical, C3-6Cycloalkylamido and 3-6 membered heterocycloalkyl optionally substituted by halogen, hydroxy, COOH, C1-3Alkyl radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl;
R5selected from hydrogen, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Cycloalkyl is optionally substituted with halogen;
R6、R7、R8、R9independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-3Alkyl and C3-6Cycloalkyl, said amino, C1-3Alkyl and C3-6Cycloalkyl optionally substituted by halogen, hydroxy, C1-3Alkyl and C3-6Cycloalkyl substitution;
R10selected from H, CH3And a phenyl group.
2. The compound of claim 1, wherein A is selected from
3. The compound of claim 1, wherein R1、R2、R3、R4Independently selected from H, halogen, nitro, C1-3Alkyl radical, C1-3Alkylamide group, C3-6Cycloalkyl and C3-6Cycloalkyl amide group, said C1-3Alkyl radical, C1-3Alkylamide group, C3-6Cycloalkyl and C3-6Cycloalkyl amido optionally substituted by halogen, hydroxy, C1-3Alkyl and C3-6Cycloalkyl is substituted.
4. The compound of claim 1, wherein R5Selected from hydrogen and C1-3Alkyl radical, said C1-3Alkyl is optionally substituted with halogen.
5. The compound of claim 1, wherein R6、R7、R8、R9Independently selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Cycloalkyl is optionally substituted with halogen.
6. The compound of claim 1, wherein R10Is selected from CH3。
7. The compound of claim 1 selected from the group consisting of compounds of formula (II),
wherein R is2、R3、R5、R6、R7、R8And R9As defined in any one of claims 1 to 6.
8. The compound of claim 1 selected from the following compounds:
9. a pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
10. Use of a compound of formula (i) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, or a pharmaceutical composition as claimed in claim 9, in the manufacture of a medicament for the prophylaxis or treatment of CRTH2 mediated diseases.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053677A (en) * 2018-10-22 2018-12-21 济南韶远医药技术有限公司 A kind of preparation method of aromatic ring bithiophene -1,1- dioxide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110124683A1 (en) * 2007-11-13 2011-05-26 Oxagen Limited Use of CRTH2 Antagonist Compounds
CN104114169A (en) * 2011-12-16 2014-10-22 阿托佩斯治疗有限公司 Combination of CRTH2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110124683A1 (en) * 2007-11-13 2011-05-26 Oxagen Limited Use of CRTH2 Antagonist Compounds
CN104114169A (en) * 2011-12-16 2014-10-22 阿托佩斯治疗有限公司 Combination of CRTH2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053677A (en) * 2018-10-22 2018-12-21 济南韶远医药技术有限公司 A kind of preparation method of aromatic ring bithiophene -1,1- dioxide
CN109053677B (en) * 2018-10-22 2021-11-16 济南韶远医药技术有限公司 Preparation method of aromatic benzothiophene-1, 1-dioxide

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