HK1251576B - Indole derivatives as crth2 inhibitors - Google Patents

Description

Indole derivatives as CRTH2 inhibitors

Technical Field

The present application relates to indole derivatives as CRTH2 inhibitors, a preparation method thereof, a pharmaceutical composition containing the compound, and the use thereof in treating diseases associated with the CRTH2 receptor.

Background Art

CRTH2 (DP2 or GPR44) is a G protein-coupled receptor that, upon binding to prostaglandin (PGD2), participates in the activation and chemotaxis of Th2 lymphocytes, eosinophils, and basophils, inhibits Th2 lymphocyte apoptosis, and stimulates the production of IL4, IL5, and IL13. These interleukins participate in important biological responses, including the recruitment and survival of eosinophils, mucus secretion, airway hyperresponsiveness, and the production of immunoglobulin E (IgE).

Ramatroban is a thromboxane-type prostanoid receptor (TP) antagonist with potent vasoconstriction and platelet activation. It is a weak CRTH2 receptor antagonist and has been approved in Japan for the treatment of allergic rhinitis.

WO2005044260 reports compound OC459, and WO2005123731 reports compound QAW-039.

Summary of the Invention

The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

in,

represents a single bond or a double bond;

n is selected from 1, 2, or 3;

L is selected from a single bond or a methylene group optionally substituted with R;

X ¹ is selected from CR ⁷ or N;

X ² is selected from CR ⁹ or N;

^R1 is selected from H, _C1-3 alkyl, or CN;

R ² is selected from -COOH or -C(O)-OC _1-3 alkyl;

R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from H, halogen, —OH, —NO ₂ , —NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, or C _3-6 cycloalkyl, wherein the —NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, or C _3-6 cycloalkyl is optionally substituted with R;

R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently selected from H, halogen, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, -S(═O) ₂ -C _1-3 alkyl, C _3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, -S(═O) ₂ -C _1-3 alkyl, C _3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with R;

R is independently selected from halogen, -OH, -CN, _-NH2 , -COOH, Me, Et, _-CF3 , _-CHF2 , _-CH2F , _-NHCH3 , or -N( _CH3 ) ₂ .

In some embodiments, R ¹ is selected from C _1-3 alkyl. In some embodiments, R ¹ is methyl.

In some embodiments, ^R2 is -COOH.

In some embodiments, R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from H, halogen, C _1-3 alkyl, C _1-3 alkoxy, or C _3-6 cycloalkyl, wherein the C _1-3 alkyl, C _1-3 alkoxy, or C _3-6 cycloalkyl is optionally substituted with R.

In some embodiments, R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from H, halogen, or C _1-3 alkyl, _which is optionally substituted with R.

In some embodiments, R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from H, F, Cl, or methyl optionally substituted with R.

In some embodiments, R ³ and R ⁶ are H.

In some embodiments, R ⁴ and R ⁵ are independently selected from H, F, Cl, CH ₃ , and CF ₃ .

In some embodiments, R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently selected from H, halogen, C _1-3 alkyl, —S(═O) ₂ —C _1-3 alkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C _1-3 alkyl, —S(═O) ₂ —C _1-3 alkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with R.

In some embodiments, R ⁷ and R ¹⁰ are H.

In some embodiments, R ⁸ and R ⁹ are independently selected from H, halogen, C _1-3 alkyl, —S(═O) ₂ —C _1-3 alkyl, phenyl, or 5-6 membered heteroaryl, wherein the C _1-3 alkyl, —S(═O) ₂ —C _1-3 alkyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with R.

In some embodiments, R ⁸ and R ⁹ are independently selected from H, F, Cl, methyl, —S(═O) ₂ —CH ₃ , phenyl, pyridinyl, or pyrazolyl, wherein the methyl, —S(═O) ₂ —CH ₃ , phenyl, pyridinyl, or pyrazolyl is optionally substituted with R.

In some embodiments, R ⁸ is selected from H, Cl, methyl, —S(═O) ₂ —CH ₃ , phenyl, pyridinyl, or pyrazolyl, wherein the methyl, —S(═O) ₂ —CH ₃ , phenyl, pyridinyl, or pyrazolyl is optionally substituted with R.

In some embodiments, R ⁹ is selected from H, F, Cl, or methyl, which is optionally substituted with R.

In some embodiments, R is independently selected from F, Cl, -OH, -CN, -COOH, Me, Et, _-CF3 , _-CHF2 , or _-CH2F .

In some embodiments, R is independently selected from F, Cl, or Me.

In some embodiments, the compound of formula (I) of the present application is selected from the compound of formula (II),

wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ , X ¹ , X ² , L and n are as defined above.

In some embodiments, the compound of formula (I) of the present application is 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. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

On the other hand, the present application relates to a method for treating a disease mediated by CRTH2 in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

On the other hand, 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 preparation of a drug for preventing or treating CRTH2-mediated diseases.

On the other hand, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating CRTH2-mediated diseases.

definition

Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence of the particular atom is normal and the compound after the substitution is stable.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl _group may be unsubstituted ( _CH2CH3 ), _{monosubstituted} (such as _CH2CH2F ), polysubstituted (such as _CHFCH2F , _{CH2CHF2 ,} etc.), or fully substituted ( _{CF2CF3 )} . It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.

Herein, C _mn means that the moiety has an integer number of carbon atoms in a given range. For example, "C _1-6 " means 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 once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

When n=2, it means that the above group is or

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "alkyl" refers to a hydrocarbon group of the general formula _{CnH2n +1} . The alkyl group can be straight-chain or branched. For example, the term " _C1-6 alkyl" refers to an alkyl group containing 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, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

The term "alkoxy" refers to an -O-alkyl group.

The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring. Non-limiting examples of cycloalkyl 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 "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings, or multiple fused rings containing 6 to 14, especially 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

The term "treatment" means administering the compound or formulation described herein to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state;

(ii) inhibiting the disease or disease state, i.e., curbing its development;

(iii) ameliorating 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 invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention 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 based on their own knowledge and this disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that 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 problems or complications, commensurate with a reasonable benefit/risk ratio.

As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in 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 prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms 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 the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I, and ³⁶ Cl, respectively.

Certain isotopically labeled compounds of the present invention (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.

Further, substitution with heavier isotopes such as deuterium (i.e., ^2H ) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein deuterium substitution may be partial or full, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures 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, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

In all administration methods described herein, the compound of formula I is administered at a daily dose of 0.01 to 200 mg/kg body weight, preferably 0.02 to 100 mg/kg body weight, more preferably 0.1 to 20 mg/kg body weight, in the form of single or divided doses.

The compounds of the present application can 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 combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

An important consideration in synthetic route planning in the art is the selection of a suitable protecting group for a reactive functional group (such as the amino group in this 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 in this application are incorporated herein in their entirety.

In some embodiments, the compound of the general formula (I) of the present application can be prepared by a person skilled in the art of organic synthesis using standard methods in the art via Route 1:

The following abbreviations are used herein: aq represents water; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents 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 represents ethyl acetate; EtOH represents 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; NaCNBH ₃ represents sodium cyanoborohydride; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc ₂ represents methyl thiocyanate; O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl ₂ represents thionyl chloride; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF represents tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamide.

For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification.

Example

Example 1

first step

Compound 1a (50.00 g, 324.28 mmol) was dissolved in methanol (1 L), and a solution of sodium hydroxide (38.91 g, 972.84 mmol) in water (150 mL) was added. After stirring at 5-10°C for 15 minutes, iodomethane (80.54 g, 567.49 mmol) was added. The reaction solution was heated to reflux and stirred for 16 hours. After the reaction solution was concentrated to dryness, water (300 mL) was added, and the pH was adjusted to 3-4 with 1N hydrochloric acid. The precipitated solid was collected by filtration to obtain compound 1b (51.00 g, light yellow solid, yield: 91%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.97 (br.s., 1H), 7.94-7.86 (m, 1H), 7.58-7.50 (m, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.24-7.16 (m, 1H), 2.39 (s, 3H).

Step 2

Compound 1b (51.00 g, 303.19 mmol) was dissolved in methanol (1 L), and thionyl chloride (108.21 g, 909.57 mmol) was added. The reaction mixture was heated to reflux and stirred for 16 hours. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution, and the pH was adjusted to 7. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield compound 1c (55.00 g, pale yellow solid, 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (d, J = 7.6 Hz, 1H), 7.62-7.54 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 3.82 (s, 3H), 2.42 (s, 3H).

Step 3

Compound 1c (55.00 g, 301.80 mmol) was dissolved in dichloromethane (1 L). Meta-chloroperbenzoic acid (153.18 g, 754.50 mmol, 80%) was added at 0°C. The reaction mixture was stirred at 5-15°C for 5 hours before being quenched with saturated sodium thiosulfate solution (150 mL). The pH was adjusted to 8-9 with sodium carbonate solution. The organic phase was then washed with saturated sodium bicarbonate solution (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was slurried with a mixture of petroleum ether and ethyl acetate (200 mL, v/v = 10/1) and filtered to obtain compound 1d (62.90 g, white solid, 97%). ¹ H NMR (400MHz, CDCl ₃ ) δ8.15-8.10(m,1H),7.72-7.64(m,3H),3.97(s,3H),3.34(s,3H).

Step 4

Compound 1d (55.00 g, 256.72 mmol) was dissolved in tetrahydrofuran (1 L), and lithium hexamethyldisilazide (308.06 mmol, 1 M, 308.06 mL) was slowly added dropwise at -78°C. The reaction mixture was warmed to 5-15°C and stirred for 3 hours. Water (500 mL) was then added to quench the mixture, and the pH was adjusted to 6-7 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (800 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was recrystallized from ethyl acetate (200 mL) to afford compound 1e (39.00 g, yellow solid, 74%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06-7.99 (m, 2H), 7.99-7.93 (m, 1H), 7.87-7.81 (m, 1H), 4.11 (s, 2H).

Step 5

Compound 1e (3.50 g, 23.46 mmol) and compound 1f (4.28 g, 23.46 mmol) were dissolved in 1,2-dichloroethane (250 mL), and trifluoroacetic acid (70 mg, 0.62 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was washed with saturated sodium bicarbonate solution (250 mL) and extracted with dichloromethane (150 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The mixture was then isolated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-60%) to obtain compound 1g (4.4 g, yellow solid, yield: 36%). MS-ESI calculated [M+H] ⁺ value: 314, found: 314.

Step 6

Compound 1g (4.40g, 14.04mmol) was dissolved in N,N-dimethylformamide (50mL), and cesium carbonate (6.86g, 21.06mmol) was added. Ethyl bromoacetate (2.81g, 16.85mmol) was slowly added dropwise with stirring. The reaction mixture was stirred at 15-20°C for 16 hours, poured into water (300mL), and extracted with ethyl acetate (150mL x 2). The organic phase was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 1h (5.5g, yellow solid, yield: 98%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.78 (m, 1H), 7.61-7.48 (m, 2H), 7.36 (d, J=7.2 Hz, 1H), 7.24-7.16 (m, 1H), 7.12-7.08 (m, 1H), 7.04-6.96 (m, 1H), 6.58 (s, 1H), 4.87 (d, J=3.2 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.45 (s, 3H), 1.30 (t, J=7.2 Hz, 3H). MS-ESI calcd. [M+H] ⁺ 400, found 400.

Step 7

Compound 1h (1.60 g, 4.01 mmol) was dissolved in tetrahydrofuran (50 mL), and a solution of lithium hydroxide (840.40 mg, 20.03 mmol) in water (10 mL) was added. The reaction mixture was stirred at 25°C for 2 hours, then neutralized to pH 4-5 with dropwise addition of 1N hydrochloric acid, and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with a mixed solvent of petroleum ether/ethyl acetate (20 mL, v/v = 2/1) to afford compound 1 (1.4 g, 94% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87-7.78 (m, 1H), 7.69-7.59 (m, 2H), 7.47-7.37 (m, 2H), 7.09-6.95 (m, 2H), 6.93 (s, 1H), 5.07 (d, J=2.4 Hz, 2H), 2.45 (s, 3H). MS-ESI calculated value [M+H] ⁺ 372, found 372.

Example 2

first step

Compound 1h (1.50 g, 3.76 mmol) was dissolved in a mixed solvent of ethanol/ethyl acetate (150 mL, v/v = 2/1), and wet palladium on carbon (150 mg, 10%, 50% water content) was added. The reaction mixture was stirred at 25°C under a hydrogen atmosphere (15 psi) for 16 hours, then filtered through celite, and the filtrate was concentrated to afford compound 2a (1.50 g, yellow solid, yield: 94%). ¹ H NMR (400 MHz, CDCl3) δ 7.91-7.81 (m, 1H), 7.58-7.44 (m, 2H), 7.17-7.05 (m, 2H), 6.92-6.84 (m, 1H), 6.44 (br. s., 1H), 5.06 (t, J = 8.4 Hz, 1H), 4.81 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.88-3.60 (m, 2H), 2.38 (br. s., 3H), 1.30 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 402, found 402.

Step 2

Compound 2a (1.50 g, 3.74 mmol) was dissolved in tetrahydrofuran (50 mL), and a solution of lithium hydroxide (783.91 mg, 18.68 mmol) in water (10 mL) was added. The reaction mixture was stirred at 25°C for 2 hours, then neutralized to pH 4-5 with dropwise addition of 1N hydrochloric acid. The mixture was then extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with a mixed solvent of petroleum ether/ethyl acetate (20 mL, v/v = 2/1) to afford compound 2 (1.30 g, 89% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89-7.79 (m, 1H), 7.64-7.53 (m, 2H), 7.31-7.23 (m, 1H), 7.21-7.11 (m, 1H), 6.89-6.75 (m, 1H), 6.37 (br. s., 1H), 5.19 (t, J=8.4 Hz, 1H), 4.95 (s, 2H), 4.04-3.94 (m, 1H), 3.64-3.54 (m, 1H), 2.40 (br. s., 3H). MS-ESI calcd. [M+H] ⁺ 374, found 374.

Example 3

Compound 3 (22 mg, 35% yield) was synthesized from compound 1e and compound 3a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82-7.80 (m, 1H), 7.67-7.55 (m, 2H), 7.42-7.40 (m, 1H), 7.36-7.30 (m, 1H), 7.22-7.16 (m, 1H), 6.90 (br. s., 2H), 5.02 (br. s., 2H), 2.43 (s, 3H). MS-ESI calcd. [M+H] ⁺ 372, found 372.

Example 4

Compound 4 (12 mg, 34% yield) was synthesized from compound 1e and compound 4a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.86-7.79 (m, 1H), 7.70-7.56 (m, 2H), 7.48 (d, J=1.6 Hz, 1H), 7.44-7.38 (m, 1H), 7.36-7.34 (m, 1H), 7.13-7.07 (m, 1H), 6.94 (s, 1H), 5.06-5.05 (d, 2H), 2.45 (s, 3H). MS-ESI calcd. [M+H] ⁺ 388, found 388.

Example 5

Compound 5 (24 mg, yield: 39%) was synthesized from Compound 1e and Compound 5a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.88-7.79 (m, 1H), 7.70-7.59 (m, 2H), 7.42-7.40 (m, 2H), 7.34-7.33 (m, 1H), 7.22-7.16 (m, 1H), 6.95 (s, 1H), 5.07-5.06 (m, 2H), 2.45 (s, 3H). MS-ESI calcd. [M+H] ⁺ 388, found 388.

Example 6

first step

To a solution of compound 1f (10.00 g, 67.04 mmol) and cesium carbonate (32.77 g, 100.56 mmol) in 100 mL of N,N-dimethylformamide was added dropwise ethyl bromoacetate (13.44 g, 80.45 mmol) at room temperature. The reaction mixture was incubated at 60°C for 3 hours. After completion, 200 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with ethyl acetate (100 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-50%) to obtain the target compound 6a (15.00 g, light yellow oil, yield: 95%). ¹ HNMR (400MHz, CDCl ₃ )δ7.19-7.17(m,1H),7.07-7.05(m,1H),6.89-6.87(m,1H),6.26(s,1H),4.75(s,2H),4.23(m,2H),2.38(s,3H),1.25(m,3H).

Step 2

Compound 6c (60 mg, white solid, 60%) was synthesized from compound 6a and compound 6b according to the method of Example 1. MS-ESI calculated value [M+H] ⁺ 414, found 414.

Step 3

Compound 6 (10 mg, 18% yield) was synthesized from compound 6c according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.06-7.99 (m, 1H), 7.60-7.50 (m, 2H), 7.36-7.28 (m, 1H), 7.21-7.13 (m, 1H), 6.93-6.87 (m, 1H), 6.84-6.78 (m, 1H), 6.29-6.27 (m, 1H), 4.99-4.98 (m, 2H), 4.27-4.26 (m, 2H), 2.27 (s, 3H). MS-ESI calcd. [M+H] ⁺ 386, found 386.

Example 7

Compound 7 (54 mg, yield: 71%) was synthesized from compound 6c according to the method of Example 2. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94-7.92 (m, 1H), 7.49-7.41 (m, 1H), 7.40-7.33 (m, 1H), 7.28-7.18 (m, 1H), 7.06-7.05 (m, 1H), 6.86-6.75 (m, 1H), 6.49 (br. s., 1H), 4.96 (s, 2H), 4.64 (br. s., 1H), 3.71-3.60 (m, 1H), 3.54-3.44 (m, 1H), 2.90 (br. s., 1H), 2.59-2.33 (m, 4H). MS-ESI calcd. [M+H] ⁺ 388, found 388.

Example 8

Compound 8 (19 mg, yield: 33%) was synthesized from Compound 6a and Compound 8a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02-8.00 (m, 1H), 7.59-7.56 (m, 1H), 7.33-7.32 (m, 1H), 7.12 (s, 1H), 6.93-6.82 (m, 1H), 6.83-6.80 (m, 1H), 6.36-6.33 (m, 1H), 5.01-5.00 (m, 2H), 4.31-4.29 (m, 2H), 2.28 (s, 3H). MS-ESI calcd. [M+H] ⁺ 422, found 422.

Example 9

Compound 9 (4 mg, 10% yield) was synthesized from Compound 1f and Compound 9a according to the method of Example 1, except that p-toluenesulfonic acid was used instead of trifluoroacetic acid. ^1H NMR (400 MHz, CD ₃ OD) δ 8.18-8.08 (m, 1H), 7.63-7.47 (m, 2H), 7.29-7.19 (m, 1H), 7.14-7.12 (m, 1H), 6.94-6.88 (m, 1H), 6.86-6.82 (m, 1H), 6.33-6.31 (m, 1H), 4.94 (s, 2H), 3.95-3.92 (m, 2H), 2.70-2.57 (m, 2H), 2.19 (s, 3H). MS-ESI calcd. [M+H] ⁺ 400, found 400.

Example 10

first step

Compound 10a (13.30 g, 84.42 mmol) was dissolved in dichloromethane (75 mL) and methanol (30 mL). Trimethylsilyldiazomethane (126.64 mmol, 63.32 mL, 2 M) was slowly added dropwise at 0°C. The reaction mixture was heated to 5-15°C and stirred for 2 hours. The reaction mixture was concentrated to dryness and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-60%) to afford compound 10b (9.80 g, brown oil, 68% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.03 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 3.96 (s, 3H). MS-ESI calcd [M+H] ⁺ 172, found 172.

Step 2

Compound 10b (9.80 g, 57.12 mmol) and sodium methanesulfinate (14.58 g, 142.80 mmol) were dissolved in dimethyl sulfoxide (100 mL). The reaction mixture was heated to 100°C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was poured into water (600 mL) and extracted with ethyl acetate (400 mL x 2). The combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide compound 10c (8.10 g, pink solid, yield: 66%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 9.01 (d, J=5.2 Hz, 1H), 8.00 (d, J=5.2 Hz, 1H), 4.02 (s, 3H), 3.41 (s, 3H). MS-ESI calculated value [M+H] ⁺ 216, found 216.

Step 3

Compound 10c (8.00 g, 37.17 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium hexamethylsilylamide (44.60 mmol, 1 M, 44.60 mL) was slowly added at -78°C. The reaction mixture was warmed to room temperature and stirred for 3 hours before being quenched with water (200 mL). 1N hydrochloric acid was then added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (250 mL x 2). The organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 10d (4.36 g, yellow solid, yield: 64%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (s, 1H), 9.19 (d, J=5.2 Hz, 1H), 7.92-7.90 (m, 1H), 4.12 (s, 2H). MS-ESI calculated value [M+H] ⁺ 184, found 184.

Step 4

Compound 10d (78 mg, 0.43 mmol) and compound 6a (100 mg, 0.43 mmol) were dissolved in 1,2-dichloroethane (10 mL), and triethylsilane (247 mg, 2.13 mmol) and p-toluenesulfonic acid monohydrate (121 mg, 0.64 mmol) were added. The reaction solution was heated to 60°C and stirred for 16 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (10 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 10e was then isolated and purified by thin-layer silica gel chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 10e (98 mg, yellow solid, yield: 20%). MS-ESI calculated [M+H] ⁺ value: 401, found: 401.

Step 5

Compound 10 (10 mg, 19% yield) was synthesized from compound 10e according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.91 (br. s., 1H), 8.67 (br. s., 1H), 7.89 (d, J=2.8 Hz, 1H), 7.51-7.40 (m, 1H), 7.11-6.99 (m, 3H), 5.06 (br. s., 1H), 3.83 (s, 1H), 2.55-2.47 (m, 3H). MS-ESI calcd. [M+H] ⁺ 373, found 373.

Example 11

Compound 11b was obtained from compound 11a via three-step reaction according to the method of Example 10, and then compound 11 (17 mg, yield: 29%) was synthesized from compound 11b and compound 6a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.69 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.66-7.58 (m, 1H), 7.46-7.38 (m, 1H), 7.08 (s, 1H), 7.07-6.97 (m, 2H), 5.08 (s, 2H), 2.47 (s, 3H). MS-ESI calcd [M+H] ⁺ 373, found 373.

Example 12

first step

Compound 12a (2.00 g, 9.61 mmol) was added to a solution of thionyl chloride (2.29 g, 19.20 mmol) in methanol (20 mL) at 0°C, heated to 30°C, and stirred for 16 hours. The reaction mixture was stripped of solvent under reduced pressure, then diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate (20 mL) and saturated brine (50 mL x 3), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was removed from the filtrate under reduced pressure to yield compound 12b (1.20 g, colorless liquid, yield: 56%) as a colorless liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25-8.24 (m, 1H), 7.80-7.78 (m, 1H), 7.30-7.25 (m, 1H), 3.97 (s, 3H).

Step 2

Sodium methanesulfinate (827 mg, 8.10 mmol) was added to a solution of compound 12b in N,N-dimethylformamide (5 mL), heated to 90°C, and stirred for 2 hours. The reaction mixture was poured into water (30 mL), stirred for 10 minutes, and filtered to obtain compound 12c (910 mg, white solid, yield: 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30-8.28 (m, 1H), 7.98 (s, 1H), 7.95-7.93 (m, 1H), 4.02 (s, 3H), 3.39 (s, 3H).

Step 3

Sodium hydride (135 mg, 3.39 mmol, 60%) was added to a solution of compound 12c (910 mg, 3.22 mmol) in tetrahydrofuran (20 mL) at 0°C. The mixture was warmed to 20°C and stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (5 mL), extracted with ethyl acetate (5 mL x 3), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was added to a mixture of ethyl acetate (0.5 mL) and petroleum ether (20 mL), stirred for 10 minutes, and filtered to obtain compound 12d (650 mg, yellow solid, yield: 81%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 8.22-8.15 (m, 2H), 4.19 (s, 2H).

Step 4

Compound 12e (50 mg, yellow solid, yield: 52%) was synthesized from compound 12d and compound 1f according to the method of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94-7.92 (m, 1H), 7.86-7.84 (m, 1H), 7.63 (s, 1H), 7.33-7.30 (m, 1H), 7.05-7.03 (m, 1H), 6.99-6.98 (m, 1H), 6.66 (s, 1H), 2.51 (s, 3H).

Step 5

Cesium carbonate (64 mg, 0.20 mmol) was added to a solution of compound 12e (50 mg, 0.13 mmol) and tert-butyl bromoacetate (31 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 30°C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by thick-gel chromatography (petroleum ether/ethyl acetate = 4/1) to afford compound 12f (40 mg, yellow solid, 40% yield). ¹ H NMR (400MHz, CDCl ₃ )δ7.95-7.93(m,1H),7.86-7.84(m,1H),7.59(s,1H),7.22-7.21(m,1H) ,7.09-7.03(m,2H),6.69(s,1H),4.78(s,2H),2.44(s,3H),1.47(s,9H).

Step 6

Trifluoroacetic acid (0.2 mL) was added to a solution of compound 12f (50 mg, 0.10 mmol) in 2 mL of dichloromethane at 0°C, the temperature was raised to 30°C, and the mixture was stirred for 4 hours. The solvent was removed from the reaction mixture under reduced pressure. The residue was purified by preparative HPLC to give compound 12 (23 mg, yield: 52%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98-7.96 (m, 1H), 7.89-7.87 (m, 1H), 7.59 (s, 1H), 7.27-7.24 (m, 1H), 7.12-7.06 (m, 2H), 6.73 (s, 1H), 4.98 (s, 2H), 2.48 (s, 3H). MS-ESI calcd [M+H] ⁺ 440, found 440.

Example 13

Compound 13a was reacted in multiple steps according to the method of Example 12 to give 13 (20 mg, yield: 42%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.83-7.81 (m, 1H), 7.52-7.50 (m, 1H), 7.25-7.23 (m, 1H), 7.09-7.06 (m, 2H), 6.73 (s, 1H), 4.97 (s, 2H), 2.48 (s, 3H). MS-ESI calcd [M+H] ⁺ 440, found 440.

Example 14

Compound 14 (10 mg, 12% yield) was obtained from compound 12d and compound 4a according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.93 (m, 1H), 7.86-7.84 (m, 1H), 7.57 (s, 1H), 7.32-7.30 (m, 2H), 7.17-7.15 (m, 1H), 6.70 (s, 1H), 4.89 (s, 2H), 2.46 (s, 3H). MS-ESI calculated value [M+H] ⁺ 456, found 456.

Example 15

Compound 15 (20 mg, yield: 25%) was obtained from Compound 12d and Compound 15a according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.93 (m, 1H), 7.85-7.83 (m, 1H), 7.64 (s, 1H), 7.22-7.18 (m, 2H), 7.13-7.11 (m, 1H), 6.69 (s, 1H), 4.94 (s, 2H), 2.45 (s, 3H), 2.40 (s, 3H). MS-ESI calcd. [M+H] ⁺ 436, found 436.

Example 16

Compound 16 (25 mg, 31% yield) was obtained from compound 12d and compound 3a according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97-7.95 (m, 1H), 7.88-7.86 (m, 1H), 7.59 (s, 1H), 7.36-7.34 (m, 1H), 7.03-6.98 (m, 2H), 6.72 (s, 1H), 4.93 (s, 2H), 2.47 (s, 3H). MS-ESI calculated value [M+H] ⁺ 440, found 440.

Example 17

Compound 17 (30 mg, yield: 81%) was obtained from Compound 13b and Compound 5a according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.82-7.80 (m, 1H), 7.48-7.46 (m, 1H), 7.38 (s, 1H), 7.24-7.22 (m, 2H), 6.73 (s, 1H), 4.95 (s, 2H), 2.46 (s, 3H). MS-ESI calculated value [M+H] ⁺ 456, found 456.

Example 18

Compound 18 (20 mg, 45% yield) was obtained from Compound 13b and Compound 4a according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.79-7.77 (m, 1H), 7.46-7.45 (m, 1H), 7.32-7.30 (m, 2H), 7.16-7.14 (m, 1H), 6.72 (s, 1H), 4.92 (s, 2H), 2.45 (s, 3H). MS-ESI calcd. [M+H] ⁺ 456, found 456.

Example 19

Compound 19 (9 mg, 33% yield) was obtained from Compound 13b and Compound 15a according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.78-7.76 (m, 1H), 7.53-7.51 (m, 1H), 7.20-7.18 (m, 2H), 7.13-7.11 (m, 1H), 6.70 (s, 1H), 4.93 (s, 2H), 2.44 (s, 3H), 2.41 (s, 3H). MS-ESI calcd. [M+H] ⁺ 436, found 436.

Example 20

Compound 20 (7 mg, yield: 26%) was obtained from Compound 13b and Compound 3a according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.79-7.77 (m, 1H), 7.49-7.47 (m, 1H), 7.34-7.33 (m, 1H), 7.02-6.92 (m, 2H), 6.72 (s, 1H), 4.91 (s, 2H), 2.46 (s, 3H). MS-ESI calculated value [M+H] ⁺ 440, found 440.

Example 21

first step

Compound 21b (1.00 g, light yellow solid, yield: 83%) was obtained from compound 21a through multiple steps according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.66-7.64 (m, 1H), 7.24-7.18 (m, 2H), 7.07-7.01 (m, 2H), 6.55 (s, 1H), 4.77 (s, 2H), 2.44 (s, 3H), 1.47 (s, 9H).

Step 2

Under nitrogen, 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (9 mg, 0.01 mmol) was added to a mixture of compound 21a (70 mg, 0.14 mmol), 4-pyridineboronic acid (19 mg, 0.15 mmol), and potassium phosphate (73 mg, 0.35 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL). The mixture was heated to 60°C and stirred for 1.5 hours. The mixture was diluted with ethyl acetate (20 mL), washed with saturated brine (10 mL x 3), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was purified on a thick silica gel chromatography plate (petroleum ether/ethyl acetate = 4/1) to afford compound 21b (65 mg, yellow solid, yield: 92%). ¹ H NMR (400MHz, CDCl ₃ )δ8.08(s,1H),7.80-7.70(m,3H),7.50-7.48(m,1H),7.21-7.20(m,1H),7.13-7. 10(m,1H),7.02-7.00(m,1H),6.63(s,1H),4.79(s,2H),2.48(s,3H),1.48(s,9H).

Step 3

Compound 21 (25 mg, 47% yield) was obtained from compound 21b according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.86-8.85 (m, 2H), 8.46 (s, 1H), 8.30-8.28 (m, 2H), 8.21-8.19 (m, 1H), 7.68-7.66 (m, 1H), 7.46-7.44 (m, 1H), 7.14-7.04 (m, 3H), 5.13 (s, 2H), 2.51 (s, 3H). MS-ESI calcd. [M+H] ⁺ 449, found 449.

Example 22

Compound 21b and compound 22a were reacted according to the method of Example 21 to give compound 22 (20 mg, yield: 44%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.69-7.67 (m, 1H), 7.44-7.41 (m, 2H), 7.23-7.21 (m, 2H), 7.17-7.13 (m, 2H), 7.05-7.03 (m, 1H), 6.62 (s, 1H), 4.95 (s, 2H), 2.47 (s, 3H). MS-ESI calculated value [M+H] ⁺ 500, found 500.

Example 23

Compound 21b and compound 23a were reacted according to the method of Example 21 to give compound 23 (15 mg, yield: 48%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.84-7.82 (m, 1H), 7.44-7.42 (m, 2H), 7.11-7.08 (m, 1H), 7.04-7.01 (m, 1H), 6.90 (s, 1H), 5.10 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H). MS-ESI calcd. [M+H] ⁺ 452, found 452.

Example 24

Compound 21b and compound 24a were reacted according to the method of Example 21 to give compound 24 (7 mg, yield: 52%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.62-8.61 (m, 1H), 8.52 (s, 1H), 8.29-8.26 (m, 1H), 8.09-8.08 (m, 1H), 7.74-7.72 (m, 1H), 7.55-7.53 (m, 1H), 7.43-7.42 (m, 1H), 7.11-7.09 (m, 1H), 7.02-7.01 (m, 2H), 5.10 (s, 2H), 2.50 (s, 3H). MS-ESI calcd. [M+H] ⁺ 467, found 467.

Example 25

Compound 21b and compound 25a were reacted according to the method of Example 21 to give compound 25 (30 mg, yield: 56%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.76 (s, 1H), 8.62-8.60 (m, 1H), 8.05 (s, 1H), 7.82-7.80 (m, 1H), 7.60-7.59 (m, 2H), 7.46-7.44 (m, 1H), 7.13-7.11 (m, 1H), 7.10 (s, 1H), 7.08-7.03 (m, 1H), 5.12 (s, 2H), 2.51 (s, 3H). MS-ESI calcd. [M+H] ⁺ 483, found 483.

Example 26

first step

To a solution of compound 26a (15.20 g, 81.63 mmol) in 150 mL of dichloromethane at 0°C, oxalyl chloride (20.72 g, 163.26 mmol, 14.29 mL) and 1 mL of N,N-dimethylformamide were added dropwise. The mixture was allowed to react at 0°C for 1 hour and then concentrated. To the concentrate, 200 mL of dichloromethane and aluminum chloride (32.65 g, 244.89 mmol) were added and stirred at room temperature for 16 hours. The reaction was complete. The reaction solution was poured into 200 mL of ice water and extracted with dichloromethane (100 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried, filtered, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-50%) to obtain the target compound 26b (9.1 g, yellow solid, yield: 71%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.44 (dd, J=2.6, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 7.34-7.28 (m, 1H), 3.87 (s, 2H).

Step 2

To a solution of compound 26b (8.50 g, 50.54 mmol) in 150 mL of dichloromethane at 0°C was added m-chloroperbenzoic acid (32.71 g, 151.62 mmol, 80%). The reaction mixture was stirred at room temperature for 2 hours. After completion, 600 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100-50%) to obtain the target compound 26c (7.90 g, light yellow solid, yield: 78%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12-8.10 (m, 1H), 8.04-8.02 (m, 1H), 7.62 (m, 1H), 4.16 (s, 2H).

Step 3

Compound 26d (85 mg, pale yellow oily liquid, yield: 42%) was obtained by reacting compound 26c with compound 1f according to the method of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75-7.68 (m, 1H), 7.27-7.24 (m, 1H), 7.16 (m, 1H), 7.03-6.95 (m, 2H), 6.89-6.81 (m, 2H), 6.55 (s, 1H), 2.43 (s, 3H).

Step 4

Compound 26 (18 mg, 19% yield) was obtained from compound 26d through multiple reactions according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.91-7.85 (m, 1H), 7.37 (d, J = 9.6 Hz, 2H), 7.26-7.16 (m, 2H), 7.02 (s, 1H), 6.92 (d, J = 9.6 Hz, 1H), 2.46 (s, 3H). MS-ESI calculated value [M+Na] ⁺ 412, found 412.

Example 27

Compound 27 (40 mg, 25% yield) was synthesized from compound 26c and compound 4a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.93-7.86 (m, 1H), 7.50 (s, 1H), 7.43-7.33 (m, 2H), 7.19-7.11 (m, 2H), 7.05 (s, 1H), 5.02-4.97 (m, 2H), 2.47 (s, 3H). MS-ESI calculated value [M+Na] ⁺ 428, found 428.

Example 28

Compound 28 (35 mg, 20% yield) was synthesized from compound 26c and compound 15a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89-7.83 (m, 1H), 7.36 (s, 1H), 7.31-7.26 (m, 1H), 7.19-7.12 (m, 2H), 7.10-7.05 (m, 1H), 6.97 (s, 1H), 5.02 (s, 2H), 2.43 (s, 3H), 2.39 (s, 3H). MS-ESI calcd. [M+Na] ⁺ 408, found 408.

Example 29

Compound 29 (15 mg, 12% yield) was synthesized from compound 26c and compound 5a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94-7.87 (m, 1H), 7.46-7.40 (m, 2H), 7.37-7.36 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.12 (m, 1H), 7.09 (s, 1H), 5.10-5.04 (m, 2H), 2.47 (s, 3H). MS-ESI calcd. [M+Na] ⁺ 428, found 428.

Example 30

Compound 30 (23 mg, 18% yield) was synthesized from compound 26c and compound 3a according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.92-7.86 (m, 1H), 7.48-7.35 (m, 2H), 7.24-7.20 (m, 1H), 7.08-7.03 (m, 2H), 7.03-6.96 (m, 1H), 4.99-4.94 (m, 2H), 2.47 (s, 3H). MS-ESI calcd. [M+H] ⁺ 390, found 390.

Example 31

Compound 31 (20 mg, yield: 28%) was obtained according to the synthesis method of Example 21. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 8.13-8.11 (m, 1H), 7.57-7.55 (m, 1H), 7.20-7.28 (m, 1H), 7.07-7.03 (m, 2H), 6.77 (s, 1H), 4.96 (s, 2H), 3.15 (s, 3H), 2.47 (s, 3H). MS-ESI calculated value [M+H] ⁺ 450, found 450.

Example 32

Compound 32 (35 mg, 30% yield) was synthesized from compound 1e and compound 32a according to the method of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.81 (m, 2H), 7.66-7.60 (m, 2H), 7.475-7.458 (m, 1H), 7.414-7.381 (m, 2H), 7.24-7.21 (m, 1H), 7.13-7.09 (m, 1H), 6.89 (s, 1H), 5.05 (s, 2H), 2.47 (s, 3H). MS-ESI calcd [M+H] ⁺ 354, found 354.

Example 33

first step

Compound 33b (crude product, 2.00 g, red solid) was obtained from compound 33a according to the synthesis method of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99-7.90 (m, 3H), 4.15 (s, 2H).

Step 2

Compound 33 (14 mg, 22% yield) was obtained from compound 33b and compound 1f according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76-7.74 (m, 1H), 7.55-7.53 (m, 1H), 7.28 (s, 1H), 7.23-7.20 (m, 1H), 7.12-7.00 (m, 2H), 6.63 (s, 1H), 4.93 (s, 2H), 2.44 (s, 3H). MS-ESI calculated value [M+H] ⁺ 406, found 406.

Example 34

Compound 34 (7 mg, 8% yield) was obtained from compound 33b and compound 5a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87-7.85 (m, 1H), 7.70-7.68 (m, 1H), 7.46-7.44 (m, 1H), 7.38-7.35 (m, 2H), 7.25-7.22 (m, 1H), 7.08 (s, 1H), 5.10 (s, 2H), 2.47 (s, 3H). MS-ESI calculated value [M+H] ⁺ 422, found 422.

Example 35

Compound 35 (47 mg, 45% yield) was obtained from compound 33b and compound 3a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84-7.82 (m, 1H), 7.67-7.65 (m, 1H), 7.39-7.32 (m, 2H), 7.25-7.21 (m, 1H), 7.02 (s, 1H), 6.96-6.91 (m, 1H), 5.07 (s, 2H), 2.45 (s, 3H). MS-ESI calculated value [M+H] ⁺ 406, found 406.

Example 36

Compound 36 (52 mg, 51% yield) was obtained from Compound 33b and Compound 15a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82-7.80 (m, 1H), 7.66-7.63 (m, 1H), 7.41-7.39 (m, 1H), 7.31-7.28 (m, 1H), 7.15 (s, 1H), 7.08-7.06 (m, 1H), 6.95 (s, 1H), 5.03 (s, 2H), 2.43 (s, 3H), 2.38 (s, 3H). MS-ESI calcd. [M+H] ⁺ 402, found 402.

Example 37

Compound 37 (32 mg, 32% yield) was obtained from compound 33b and compound 4a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.85-7.83 (m, 1H), 7.69-7.66 (m, 1H), 7.53-7.51 (m, 1H), 7.38-7.32 (m, 2H), 7.15-7.13 (m, 1H), 7.05 (s, 1H), 5.09 (s, 2H), 2.46 (s, 3H). MS-ESI calculated value [M+H] ⁺ 422, found 422.

Example 38

Compound 38 (10 mg, 18% yield) was obtained from Compound 33b and Compound 38a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87-7.82 (m, 2H), 7.70-7.68 (m, 1H), 7.56-7.53 (m, 1H), 7.44-7.42 (m, 1H), 7.36-7.35 (m, 1H), 7.12 (s, 1H), 5.21 (s, 2H), 2.51 (s, 3H). MS-ESI calcd. [M+H] ⁺ 456, found 456.

Example 39

first step

Compound 39a (10.00 g, 69.15 mmol) was dissolved in acetonitrile (180 mL). Potassium carbonate (28.67 g, 207.44 mmol) and ethyl bromoacetate (12.70 g, 76.06 mmol) were added to the reaction mixture, and the mixture was stirred at 50°C for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39b (crude product, 16.00 g, yellow oil). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (s, 1H), 7.31-7.21 (m, 3H), 4.21 (q, J = 7.2 Hz, 2H), 3.67 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H).

Step 2

Compound 39b (16.00 g, 69.35 mmol) was dissolved in methanol (200 mL) and water (40 mL). Lithium hydroxide monohydrate (11.64 g, 277.40 mmol) was added and the reaction was stirred at 25°C for 10 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 4 with 2N aqueous hydrochloric acid, filtered, and the filter cake dried to provide compound 39c (11.00 g, white solid, yield: 78%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 (s, 1H), 7.29-7.20 (m, 3H), 3.69 (s, 2H).

Step 3

Compound 39d (crude product, 420 mg, red solid) was obtained from compound 39c according to the synthesis method of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98-7.96 (m, 2H), 7.80-7.78 (m, 1H), 4.13 (s, 2H).

Step 4

Compound 39 (21 mg, 22% yield) was synthesized from compound 39d and compound 1f according to the method of Example 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91-7.90 (m, 1H), 7.67-7.64 (m, 1H), 7.44-7.40 (m, 2H), 7.06-6.99 (m, 3H), 5.09 (s, 2H), 2.46 (s, 3H). MS-ESI calculated value [M+H] ⁺ 406, found 406.

Example 40

Compound 40 (12 mg, 21% yield) was synthesized from compound 39d and compound 4a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.91-7.90 (m, 1H), 7.66-7.63 (m, 1H), 7.51-7.50 (m, 1H), 7.41-7.34 (m, 2H), 7.15-7.12 (m, 1H), 7.00 (s, 1H), 5.09 (s, 2H), 2.46 (s, 3H). MS-ESI calcd. [M+H] ⁺ 422, found 422.

Example 41

Compound 41 (17 mg, 26% yield) was synthesized from compound 39d and compound 3a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89-7.88 (m, 1H), 7.64-7.61 (m, 1H), 7.40-7.38 (m, 1H), 7.35-7.32 (m, 1H), 7.22-7.19 (m, 1H), 6.97 (s, 1H), 6.93-6.88 (m, 1H), 5.04 (s, 2H), 2.43 (s, 3H). MS-ESI calcd. [M+H] ⁺ 406, found 406.

Example 42

Compound 42 (52 mg, 56% yield) was synthesized from compound 39d and compound 15a according to the method of Example 12. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89-7.88 (m, 1H), 7.64-7.62 (m, 1H), 7.45-7.43 (m, 1H), 7.31-7.28 (m, 1H), 7.17 (s, 1H), 7.08-7.06 (m, 1H), 6.92 (s, 1H), 5.04 (s, 2H), 2.44 (s, 3H), 2.39 (s, 3H). MS-ESI calcd. [M+H] ⁺ 402, found 402.

Example 43

first step

Compound 43b (100 mg, yield: 39%) was synthesized from compound 43a and compound 1f according to the method of Example 1.

Step 2

Sodium perborate tetrahydrate (292 mg, 1.90 mmol) was added to a solution of compound 43b (300 mg, 0.76 mmol) in 1 mL of acetic acid at room temperature. The reaction mixture was allowed to react at 45°C for 1 hour. After completion of the reaction, 30 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (petroleum ether/ethyl acetate 100-10%) to obtain the target compound 43c (45 mg, light yellow oil, yield: 15%).

Step 3

Compound 43 (7 mg, 18% yield) was synthesized from compound 43c according to the method of Example 1. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.66 (s, 1H), 7.50-7.44 (m, 1H), 7.42-7.37 (m, 1H), 7.28-7.20 (m, 3H), 7.12-7.11 (m, 1H), 6.89-6.84 (m, 1H), 4.93-4.92 (m, 2H), 4.55-4.44 (m, 1H), 2.43 (s, 3H), 1.71-1.69 (m, 3H). MS-ESI calcd. [M+H] ⁺ 400, found 400.

Experimental Example 1

CHO-K1CRTH2β-arrestin cells (DiscoverX, catalog number 93-0291C2) were grown under standard conditions and seeded at 5000 cells/well in white-walled 384-well microplates with 20 μl of CellPlatingReagent 1 per well. Cells were incubated overnight at 37°C/5% _CO2 before testing. The test compound was serially diluted in DMSO with a dilution factor of 3 to obtain 8 serially diluted test compounds. Shortly before testing, the serially diluted test compound was further diluted with test buffer to 5 times the test concentration. 5 μl of the further diluted test compound was added to the cells and incubated at 37°C for 30 minutes. The vehicle concentration was 1%. 5 μl of 6XEC ₈₀ agonist (PGD2) in buffer was then added to the cells and incubated at 37°C for 90 minutes. The assay signal was generated by a one-time addition of 15 microliters (50% v/v) of PathHunter detection cocktail reagent followed by a one-hour incubation. The microplate was read using a PerkinElmer Envision ^™ instrument with chemiluminescent signals. The biological activity of the test compounds was analyzed using the CBIS data analysis suite (ChemInnovation, CA) and displayed as _IC50 values. The results are shown in Table 1.

Table 1

Note: +＞1.0μM; ++0.1～1.0μM; +++＜0.1μM; Conclusion: The compound of the present application has a strong antagonistic effect on CRTH2 receptor.

Claims (8)

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof, in, Indicates a double bond; n is selected from 1 or 2; L is selected from a single bond; ^X1 is selected from CR ⁷ ; ^X2 is selected from CR ⁹ ; ^R3 and ^R6 are H; ^R4 is selected from -F; ^R5 is selected from H; ^R7 , ^R9 , and ^R10 are independently selected from H; ^R8 is selected from H, -Cl, methyl, -S(=O) ₂ - _CH3 , or phenyl, wherein the methyl or phenyl group is optionally substituted with R; R is independently selected from -F or -Cl. 2. The compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R8 is selected from H, -Cl, methyl, -S(=O) ₂ - _CH3 , or phenyl, wherein the methyl or phenyl is substituted by R. 3. The compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R8 is selected from H, -Cl, or -S(=O) ₂ - _CH3 . 4. The compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R8 is selected from a methyl group substituted with R, and the R is selected from -F. 5. The compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R8 is selected from a phenyl group substituted with R, and the R is selected from -F or -Cl. 6. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds: 7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the compound of claim 6 or a pharmaceutically acceptable salt thereof. 8. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the compound of claim 6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the prevention or treatment of CRTH2-mediated diseases.