Spiro compounds and their use in the pharmaceutical field

Abstract

The present invention relates to spiro compounds and their applications in the pharmaceutical field. Specifically, this application discloses a compound represented by formula (I), its isotope-labeled compounds, optical isomers, tautomers, or pharmaceutically acceptable salts, or the crystalline or solvate forms of the said compound or its pharmaceutically acceptable salts. [C1] TIFF2026530561000034.tif39156

Description

[Technical Field]

[0001] This application claims priority to Chinese invention patent application No. 202310998036.2 filed on 8 August 2023, and all disclosures of said prior application are incorporated herein by reference.

[0002] This invention relates to substituted 2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] compounds and their use in the pharmaceutical field. [Background technology]

[0003] Under normal physiological conditions, EPO (erythropoietin, erythroxine) is produced by stromal cells surrounding the renal tubules in response to local tissue hypoxia; however, in renal cell carcinoma, EPO is produced in tumor cells. Statistics show that two-thirds of renal cell carcinoma patients have elevated EPO levels compared to normal, and 8% of these patients develop polycythemia (Reviews in Urology. 2002, 4(4), 163-170). The elevated serum red blood cell concentration in these patients is thought to be mediated by EPO. On the other hand, increased erythrocyte counts increase the risk of venous thrombosis, bleeding, and vascular and neurological problems, and the treatment of stroke and heart disease poses a life-threatening risk to patients. Currently, existing treatments include prolonged intravenous bleeding, cell depressant therapies such as hydroxyuria and interferon-alpha, intravenous injection of radioactive phosphate, busulfan, and JAK inhibitors, such as rutanilocitinib.

[0004] Furthermore, since EPO levels are generally elevated in renal cell carcinoma, EPO can be considered a potential tumor marker. Because patients with high EPO levels in renal cell carcinoma may be more sensitive to high EPO levels, lowering EPO levels is a potential and effective way to treat polycythemia and renal cell carcinoma.

[0005] Therefore, it is hoped that developing EPO inhibitors that can significantly reduce EPO levels will enable their application in the treatment of various diseases such as polycythemia, renal cell carcinoma, and other cancers. [Overview of the project] [Means for solving the problem]

[0006] This invention provides a method for preparing spiro compounds having good chemical stability.

[0007] The inventors have succeeded in preparing novel spiro compounds with excellent chemical stability. The spiro compounds provided in this invention exhibit a significant reduction in EPO levels in various biochemical, biological, or cellular-related tests, and therefore have promising potential applications in the treatment of various diseases such as polycythemia, renal cell carcinoma, and other cancers.

[0008] In a first embodiment, the present invention provides a compound represented by formula (I), its isotope-labeled compound, optical isomer, tautomer, or pharmaceutically acceptable salt, or the crystalline or solvate form of the compound or its pharmaceutically acceptable salt. The compound represented by formula (I), its isotope-labeled compound, optical isomer, tautomer, or pharmaceutically acceptable salt, or the crystalline or solvate form of the compound or its pharmaceutically acceptable salt, can be used in the treatment of various EPO-related diseases, such as polycythemia, renal cell carcinoma, and other cancers. [ka] In equation (I), R 1 It is selected from H, D, F, Cl, Br, CF3, CN, R 2 It is selected from H, D, CF3, CH3, OCH3, OH, R 3 The following are selected from H, D, F, Cl, Br, CF3, CN, OCH3, OCH2F, OCHF2, and OCF3. R 4is selected from H, D, F, Cl, Br, CH3, CF3 and CN, R 5 is selected from H, D, F, Cl, Br, I, CH3, CF3, CN and OCH3, R 6 is selected from H, D, F, Cl, Br, I, CH3, CF3, CN and OCH3, X is selected from N and CR 7 , provided that R 7 is selected from H, D, F, Cl, Br, CF3, CN and CH3.

[0009] Preferably, said R 1 is selected from CF3 and CN.

[0010] Preferably, R 2 is selected from OCH3 and OH.

[0011] Preferably, R 3 is selected from OCH3, OCH2F, OCHF2 and OCF3.

[0012] Preferably, R 4 is selected from H, D, F, Cl and CH3.

[0013] Preferably, R 5 is selected from H, D, F, Cl, CH3, CF3 and OCH3.

[0014] Preferably, R 6 is selected from F, Cl and CH3.

[0015] Preferably, X is selected from N and CR 7 , provided that R 7 is selected from H, D, F, Br, CF3, CN and CH3.

[0016] In some most preferred embodiments, the compound of formula (I) of the present application is selected from each specific compound shown in each example of the present application.

[0017] Unless otherwise specified, the terms “compound represented by formula (I),” “compound of formula (I),” “compound of the present application,” “compound of the present invention,” or similar terms as used herein are also intended to include isotopically labeled compounds, optical isomers, tautomers, or pharmaceutically acceptable salts thereof, or crystalline or solvated forms of said compound or its pharmaceutically acceptable salt.

[0018] The term "optical isomer" refers to each isomer obtained when a compound has one or more chiral centers, with each chiral center having either an R configuration or an S configuration. Optical isomers include all diastereomers, enantiomers, meso compounds, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral column or chiral synthesis.

[0019] The term "tautomer" refers to an isomer that arises when an atom in a molecule rapidly moves between two positions. As those skilled in the art will understand, tautomers can coexist in a state of equilibrium.

[0020] Unless otherwise specified, compounds represented by formula (I) are also intended to include isotopically labeled compounds in which one or more atoms in the compound are replaced with their isotopic atoms.

[0021] Examples of isotopes suitable for inclusion in the compound of this invention include: 2 H(D), 3 Isotopes of hydrogen, such as H(T); 11 C, 13 C, and 14 Isotopes of carbon, such as C; 36 Isotopes of chlorine, such as Cl; 18 Fluorine isotopes such as F; 123 I, 125 Iodine isotopes such as I; 13 N, 15 Isotopes of nitrogen, such as N; 15 O, 17 O, and 18 Oxygen isotopes such as O; and, 35 There are sulfur isotopes like S.

[0022] The aforementioned isotope-labeled compounds (e.g., those containing radioactive isotopes) can be used in drug and / or substrate tissue distribution studies. Considering the ease of introduction and the convenience of detection means, for this purpose, deuterium (D) and carbon-14 ( 14 C) is useful.

[0023] Substitution with heavier isotopes, such as deuterium (e.g., D), can yield certain therapeutic benefits due to improved metabolic stability (e.g., extended half-life in the body or reduced dosage), and may therefore be a preferred choice in some cases. For this reason, in some embodiments, the compounds of the present application are isotope-labeled compounds in which hydrogen (H) is optionally substituted with deuterium (D) at each occurrence site.

[0024] Positron emission isotopes (for example, 11 C, 18 F, 15 O and 13 Substitution with N) can be used in positron emission topography (PET) studies and may also be used to detect the occupancy state of substrate receptors.

[0025] The isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, or by using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[0026] The compounds of the present invention can exist in the form of their pharmaceutically acceptable salts.

[0027] The term "pharmaceutically acceptable" means that the corresponding compound, carrier, or molecule is suitable for administration to humans. Preferably, the term refers to a mammal, and preferably a human, that has been certified by a regulatory body, such as the CFDA (China), EMEA (Europe), or FDA (United States).

[0028] The aforementioned pharmaceutically acceptable salts include their acid addition salts and base addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipine, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexylaminesulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrogen chloride / chloride, hydrogen bromide / bromide, hydrogen iodide / iodide This includes, but is not limited to, oxalates, 2-isethionates, lactates, malates, maleates, malons, methanesulfons, methylsulfates, naphthalenes, 2-naphthalenesulfons, nicotinates, nitrates, orotates, oxalates, hexadecanates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glucons, stearates, salicylates, tannates, tartrates, toluenesulfons, and trifluoroacetates. Suitable base addition salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tributylamine, and zinc salts. They may also form acid and alkali hemisalts such as hemisulfates and hemicalcium salts. For an overview of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth and Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0029] Furthermore, the compounds of this application may exist in a non-solvated form and in solvates with pharmaceutically acceptable solvents, such as water or ethanol. The compounds may exist in one or more crystalline states, i.e., in a polycrystalline form or as an amorphous solid. All of these forms are included within the scope of this disclosure.

[0030] Method for preparing compounds The compounds represented by formula (I) of the present invention can be synthesized by various methods well known to those skilled in the art. Exemplary synthesis methods are shown below, but these are known to those skilled in the art and can be modified as needed. If necessary, common techniques (including, but not limited to, related techniques such as filtration, distillation, recrystallization, and column chromatography) can be used to separate and purify the starting materials, intermediates, and final products in the reaction. Furthermore, the examples described herein specifically illustrate methods for synthesizing the compounds of the present invention.

[0031] The synthesis methods of the compounds of the present invention will be described in general terms below, using compound Ia and compound Ib as examples.

[0032] Scheme 1: Intermediate Ia-2 is obtained by heating Ia-1 (synthesized by known methods or commercially available) and DAST in an organic solvent, with the preferred solvent for this step being dichloromethane or dichloroethane, and the preferred reaction temperature being 70°C to 90°C. Intermediate Ia-2 is reacted with a base to obtain intermediate Ia-3, with the preferred base for this step being sodium hydroxide, potassium hydroxide, or cesium carbonate, and the preferred solvent for this step being methanol. Intermediate Ia-3 is cyclized under the action of sulfonyl chloride and a base to obtain compound Ia, with the preferred base for this step being triethylamine or diisopropylethylamine, and the preferred temperature being 70°C to 90°C. [ka]

[0033] Scheme 2: Intermediate Ib-2 is obtained by reacting Ib-1 (synthesized by known methods or commercially available) with a reducing agent in an organic solvent, with methanol or ethanol as the preferred solvent for this step and a preferred reaction temperature of 0°C to 30°C. Intermediate Ib-2 is reacted with a dehydrating agent to obtain compound Ib, with Burgess reagent [N(triethylammonium sulfonyl)carbamate methyl, CAS: 29684-56-8] or p-toluenesulfonic acid as the preferred temperature of this step and a preferred temperature of 70°C to 90°C. [ka]

[0034] By referring to the synthetic routes of the exemplary compounds Ia and Ib described above and the synthetic routes shown in each of the following specific examples, those skilled in the art can synthesize other structurally similar compounds of formula (I) as needed, with appropriate modifications.

[0035] Use of compounds Experiments have shown that the compound of this invention has excellent inhibitory activity against EPO. Therefore, the compound of this invention can be used as an EPO inhibitor to treat EPO-related diseases, particularly diseases associated with excessively high EPO levels.

[0036] In a second embodiment, the present invention provides a pharmaceutical composition containing the above-described compound of the present invention (i.e., the compound of formula (I)) or a pharmaceutically acceptable salt thereof.

[0037] The pharmaceutical compositions of the present invention can be prepared by methods well known in the pharmaceutical field and can be administered by various routes depending on whether it is a topical or systemic treatment and on the site to be treated. Administration may be topical (including delivery to the ophthalmology and mucous membranes (including the nasal mucosa, vaginal mucosa and rectal mucosa)), pulmonary (e.g., inhalation or blowing of powder or aerosol into the trachea, nasal cavity, epidermis and transcutaneously using a nebulizer), ocular, oral, or parenteral. Methods for delivery to the ocular region may include topical administration (eye drops), subconjunctival, periocular or intravitreal injection, or introduction by a balloon catheter or ophthalmic implant placed in the conjunctival sac by surgical method. Parenteral administration may be intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or it may include intracranial (e.g., intrasacral or intraventricular) administration. Parenteral administration may be in the form of a single dose and may be performed, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders.

[0038] When a solid carrier is used, the formulation may be formed as a tablet, filled into a hard gelatin capsule in the form of a powder or granules, or in the form of a lozenge or tablet. The solid carrier may contain common excipients, such as binders, fillers, tablet lubricants, disintegrants, and wetting agents. If necessary, these tablets may be film-coated by conventional techniques. When a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, ointment, soft gelatin capsule, sterile carrier for injection, aqueous or non-aqueous liquid suspension, or a dry product that can be reconstituted with water or another suitable carrier immediately before use. The liquid formulation may contain common additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, flavorings, and / or colorings. For parenteral administration, the carrier is usually at least largely sterile water, but physiological saline, glucose solution, etc., may also be used. An injection suspension may also be used, in which case a common suspending agent may be used. Furthermore, preservatives and buffers may be added to parenteral formulations. The pharmaceutical composition is prepared by conventional methods well known to those skilled in the art, according to the desired formulation containing a predetermined amount of the active ingredient (i.e., the compound of this application).

[0039] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, and solvents include water, ethanol, polyhydric alcohols (such as propylene glycol, polyethylene glycol, and glycerin), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).

[0040] These compositions may further contain various excipients, such as preservatives, humectants, emulsifiers, and dispersants. Various antimicrobial and antifungal agents (e.g., parahydroxybenzoic acid esters, chlorobutanol, phenol, sorbic acid, etc.) can be used to ensure inhibition of microbial activity. They may also contain isotonic agents such as sugars and sodium chloride. To delay the absorption of injectable pharmaceutical preparations, absorption-delaying excipients (e.g., aluminum monostearate or gels, etc.) can be used.

[0041] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or calcium hydrogen phosphate) and may further include the following components: (a) fillers or diluents (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., (e) agar, calcium carbonate, potato or cassava starch, alginic acid, certain synthetic silicates, sodium carbonate; (f) elution retarders (e.g., paraffin); (g) absorption enhancers (e.g., quaternary ammonium compounds); (h) wetting agents (e.g., cetanol and glycerol monostearate); (i) adsorbents (e.g., kaolin and bentonite); (g) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate); or mixtures thereof.

[0042] Similar types of solid compositions can be used as fillers for soft gelatin capsules and hard gelatin capsules, for example, by using lactose or high molecular weight polyethylene glycol as excipients.

[0043] Solid dosage forms (e.g., tablets, sugar-coated tablets, capsules, pills, and granules) can also be prepared using coatings or outer shells (e.g., enteric coatings, as known in the art). These formulations may also contain light-shielding agents and may be designed as compositions that release one or more active compounds in a delayed manner at specific sites within the intestinal tract. Examples of materials that can be used for embedding the composition include polymers and waxes. Furthermore, the active ingredients can also be used in microencapsulated form, in which case one or more of the above-mentioned excipients may be appropriately included.

[0044] Liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. These liquid formulations may contain, in addition to the active compound, inert diluents commonly used in the industry (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethylene carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide), oils (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and sorbitan fatty acid esters, or mixtures thereof.

[0045] In addition to these inert diluents, the composition includes wetting agents, emulsifiers and suspending agents, flavorings, seasonings and fragrances, and the like.

[0046] In addition to the active compound, the suspension may contain a suspending agent (e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, peristaltic aluminum oxide, bentonite, agar, gum arabic, or mixtures thereof).

[0047] Formulations for topical administration of the compound of this application include ointments, powders, sprays, and inhalants. In these formulations, the active composition is mixed under sterile conditions with a physiologically acceptable carrier and, if necessary, with a preservative, buffer, or propellant. Ophthalmic formulations (ophthalmic ointments, powders, and solutions) are also included in the scope of this application.

[0048] The amount of the compound of this application contained in the pharmaceutical composition and formulation can be appropriately determined by a person skilled in the art depending on the purpose, and for example, it can be present in the pharmaceutical composition or formulation in a therapeutically effective amount.

[0049] In a third embodiment, the application provides the use of the compound of the present invention (i.e., compound of formula (I)) or a pharmaceutically acceptable salt thereof, or the use of the compound of the present invention (i.e., compound of formula (I)) or a pharmaceutically acceptable salt thereof, in the preparation of an EPO inhibitor drug.

[0050] In a fourth embodiment, the application also provides a method for treating diseases or conditions related to EPO (in particular to excessively high levels of EPO), the method comprising administering a therapeutically effective amount of the compound of the present invention (i.e., the compound of formula (I)) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, to a patient in need thereof.

[0051] In a fifth aspect, the application also provides the use of the compounds of the present invention (i.e., compounds of formula (I)) or pharmaceutically acceptable salts thereof in the preparation of pharmaceuticals for the treatment of diseases or conditions related to EPO (in particular, related to excessively high levels of EPO).

[0052] The patient is preferably a mammal, and more preferably a human patient. The route of administration during the treatment process may be oral, topical (including, but not limited to, topical patches, sprays, etc.), parenteral (including subcutaneous, intramuscular, intradermal, and intravenous administration), intrabronchial, or intranasal administration.

[0053] In some embodiments, the diseases and conditions associated with EPO include polycythemia, renal cell carcinoma, and other cancers.

[0054] Other similar cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancers (e.g., cancers of the throat, larynx, nasopharynx, oropharynx, lips, and oral cavity), liver cancers (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancers (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchial cancer, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), thyroid cancer, parathyroid cancer, skin cancers (e.g., squamous cell carcinoma, Kabosi sarcoma, Markel cell carcinoma), and brain cancers (e.g., astrocytoma, neural tube germ cell tumor, ventricular ligamentoma, neuroectodermal tumor, pineal gland tumor).

[0055] In some preferred embodiments, the diseases and conditions associated with EPO are polycythemia.

[0056] In some preferred embodiments, the disease and condition associated with EPO is renal cell carcinoma.

[0057] The "therapeutic effective dose" of the compound of this application for treating the above-mentioned diseases can be reasonably determined by an experienced physician or researcher based on factors such as the patient's condition, physical condition, disease severity, and route of administration. [Modes for carrying out the invention]

[0058] The present application will be further described below with reference to specific embodiments.

[0059] The present invention will be further described below with reference to specific examples. It should be understood that these examples are merely for illustrative purposes and are not intended to limit the scope of the present invention.

[0060] In the following examples, experimental methods where specific conditions are not explicitly stated generally follow the usual conditions for such reactions or the conditions recommended by the manufacturer.

[0061] The experimental materials and reagents used in the following examples, unless otherwise specified, can be obtained from commercially available sources or referenced literature, and are all standard instruments and equipment commonly used in organic synthesis and analysis, as well as the main reagents and instruments used in biological experiments.

[0062] In this specification, the following abbreviations are used: BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; Cp * :Pentamethylmetallocene; DAST:Diethylaminotrifluoride sulfur; DCM:Dichloromethane; DMSO:Dimethylsulfoxide; DMA:N,N-dimethylacetamide; DMF:N,N-dimethylformamide; DMI:1,3-dimethyl-2-imidazolidinone; dppf:Diphenylphosphinoferrocene; ESI-MS:Electrospray mass spectrometry; KHMDS:Hexamethyldisilazane; MsCl:Methylsulfonyl chloride; NCS:N-Chlorosuccinate Imide; NFSI: N-fluorobisbenzenesulfonamide; NMP: N-methylpyrrolidone; NMP: N-methylpyrrolidone; Pd2dba3: Tris(dibenzylideneacetone)dipalladium; PPTS: Pyridine-p-toluenesulfonate; Selectfluor: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2,2,2]octanedi(tetrafluoroboric acid) salt; SFC: supercritical fluid chromatography; TBSOTf: tert-butyldimethylsilyltrifluoromethanesulfonate; THF: tetrahydrofuran.

[0063] Example 1: Preparation of 1'-chloro-8-difluoromethoxy-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline [ka]

[0064] Step 1: Synthesis of 1-chloro-3'-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)-8-fluoro-6H-spiro[isoquinoline-5,4'-oxazoline]-2'-one

[0065] 1-Chloro-3'-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)-6,7-dihydro-8-H-spiro[isoquinoline-5,4'-oxazoline]-2'8-dione (synthesized according to WO2021 / 220170; 1.01 g) was dissolved in DCM (10 mL), DAST (14 mL) was added at room temperature, and the mixture was stirred at 80°C for 4 hours. The reaction mixture was added dropwise to saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and obtained 79.7 mg of the target compound by column chromatography. ESI-MS m / z: 507.28 [M+H+CH3CN] +

[0066] Step 2: Synthesis of (1-chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)-amino)-8-fluoro-5,6-dihydroisoquinoline-5-yl)methanol

[0067] Compound 1-chloro-3'-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)-8-fluoro-6H-spiro[isoquinoline-5,4'-oxazoline]-2'-one (57 mg) was dissolved in MeOH (10 mL), and 4 M NaOH (0.3 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 1 hour. After three extractions with ethyl acetate, the preparation plate was separated by rotation drying to obtain the target compound (12 mg). ESI-MS m / z: 438.29 [MH] -

[0068] Step 3: Synthesis of 1'-chloro-8-difluoromethoxy-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline

[0069] Compound (1-chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)-amino)-8-fluoro-5,6-dihydroisoquinoline-5-yl)methanol (12 mg) was dissolved in toluene (1 mL), and MsCl (21 μL) and Et3N (76 μL) were added. The mixture was stirred at 80°C for 1 hour. Saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. After rotational drying, the mixture was separated by preparative liquid chromatography to obtain the target compound, compound 1 (5.0 mg). ESI-MS m / z: 422.34 [M+H] + , 1 H NMR(500MHz,DMSO-d6)δ8.33(d,1H),7.85(t,1H),7.35(t,1H),7.27(dd,1H),7.0 3(d,1H),5.84(ddd,1H),4.37(d,1H),3.94(d,1H),2.60(ddd,1H),2.51(ddd,1H).

[0070] Examples 1-A and 1-B: Preparation of (S)-1'-chloro-8-difluoromethoxy-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline and (R)-1'-chloro-8-difluoromethoxy-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline [ka]

[0071] The racemic compound 1'-chloro-8-difluoromethoxy-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline (i.e., the compound of Example 1) yielded a pair of enantiomers by prepared SFC. Of these, the enantiomer eluted first from the chiral column was the enantiomer of Example 1-A, and the enantiomer eluted later was the enantiomer of Example 1-B (the absolute configurations of the two compounds, Example 1-A and 1-B, have not yet been determined; for the sake of explanation, the chiral center of Example 1-A is randomly designated as S, and the chiral center of Example 1-B is designated as R).

[0072] Example 1-A: (S')-1'-chloro-8-difluoromethoxy-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline: SFC (RT=4.37 min, ee=99.7%). The analytical method used a DAIEL CHIRALPAKAD-H column (0.46 cm × 25 cm), with isopropyl alcohol and n-hexane as the mobile phase (volume ratio of 30%:70%), and a flow rate of 1 mL / min. ESI-MS m / z: 422.34 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ8.40(d,1H),7.94-7.91(m,1H),7.42(t,1H),7.34(dd,1H),7 .10(d,1H),5.91(ddd,1H),4.44(d,1H),4.00(d,1H),2.67(ddd,1H),2.57(ddd,1H).

[0073] Example 1-B: (R)-1'-chloro-8-difluoromethoxy-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline: SFC (RT=4.90 min, ee=99.3%). The analytical method is the same as above. ESI-MS m / z: 422.34[M+H] + ; 1H NMR(500MHz,DMSO-d6)δ8.40(d,1H),7.94-7.91(m,1H),7.42(t,1H),7.34(dd,1H),7 .10(d,1H),5.91(ddd,1H),4.44(d,1H),4.01(d,1H),2.67(ddd,1H),2.57(ddd,1H).

[0074] Example 2: Synthesis of 1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline [ka]

[0075] Step 1: Synthesis of 1'-chloro-3-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)-6'7'-dihydrodispiro[oxazoline-4'5'-isoquinoline-8',2''-[1,3]dioxolan]-2-one

[0076] 1'-Chloro-6',7'-dihydrodispiro[oxazoline-4,5'-isoquinoline-8',2''-[1,3]dioxolane]-2-one (500 mg) was dissolved in DMF (10 mL), and CuBr (240 mg), Cs2CO3 (1.1 g), and 2-chloro-3-difluoromethoxy-5-trifluoromethylpyridine (840 mg) were added. The mixture was purged with nitrogen gas and reacted at 130°C with stirring. After the reaction was complete, the mixture was filtered, extracted with ethyl acetate, and rotary dried over anhydrous sodium sulfate. Column chromatography was performed using a rotary evaporator to obtain the target compound (536 mg). ESI-MS m / z: 508.23 [M+H] + .

[0077] Step 2: Synthesis of (1-chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)amino)-6,7-dihydro-5H-spiro[isoquinoline-8-2'-[1,3]dioxolane]-5-yl)methanol

[0078] 1'-Chloro-3-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)-6',7'-dihydrodispiro[oxazoline-4,5'-isoquinoline-8',2''-[1,3]dioxolane]-2-one (150 mg) was dissolved in MeOH (3 mL), and 4 M NaOH (0.7 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours. Extraction with ethyl acetate was performed, and the mixture was rotated dry to obtain the target compound (108 mg) from the preparation plate. ESI-MS m / z: 482.18 [M+H] +

[0079] Step 3: Synthesis of (1-chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)amino)-5-(hydroxymethyl)-6,7-dihydroisoquinoline-8(5H)-ketone

[0080] (1-Chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)amino)-6,7-dihydro-5H-spiro[isoquinoline-8-2'-[1,3]dioxolane]-5-yl)methanol (107 mg) was dissolved in THF (1 mL), HCl (0.4 mL) was added, and the mixture was stirred at 50°C for 1 hour. Extraction with ethyl acetate and rotational drying were performed to obtain the target compound (105 mg). ESI-MS m / z: 438.21 [M+H] + .

[0081] Step 4: Synthesis of 1'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one

[0082] (1-Chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridine-2-yl)amino)-5-(hydroxymethyl)-6,7-dihydroisoquinoline-8(5H)-ketone (105 mg) was dissolved in toluene (5 mL), and MsCl (186 μL) and Et3N (675 μL) were added. The mixture was stirred at 80°C. Extraction with ethyl acetate was performed, and the plate was rotate-dried to obtain the target compound (89 mg). ESI-MS m / z: 420.27 [M+H] + .

[0083] Step 5: Synthesis of 1'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-ol

[0084] 1'-Chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (89 mg) was dissolved in MeOH (20 mL), and NaBH4 (8 mg, 1 eq.) was added at 0°C. The mixture was stirred at 0°C for 30 min. Extraction with ethyl acetate was performed, and the mixture was rotate-dried to obtain the target compound (78 mg) from the preparation plate. ESI-MS m / z: 422.32 [M+H] + .

[0085] Step 6: Synthesis of 1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline

[0086] 1'-Chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-ol (45 mg) was dissolved in toluene (3 mL), Burgess' reagent (80 mg) was added, and the mixture was stirred at 90°C for 30 minutes. Extraction with ethyl acetate and rotation drying were performed to obtain the target compound (12 mg) from the prepared plate. ESI-MS m / z: 448.32 [M + HCO2]- ] - . 1 H NMR(500MHz,DMSO-d6)δ8.28(d,1H),7.91(s,1H),7.43(t,1H),7.30(d,1H),7 .09(d,1H),6.81(d,1H),6.35(dt,1H),4.36(d,1H),3.93(d,1H),2.62(d,2H).

[0087] Examples 2-A and 2-B: Preparation of (R)-1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline and (R)-1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline [ka]

[0088] A racemic compound, 1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline (i.e., the compound of Example 2), was prepared by SFC to obtain a pair of enantiomers. The enantiomer eluted first from the chiral column was Example 2-A, and the enantiomer eluted later was Example 2-B. (The absolute configurations of the two compounds, Example 2-A and 2-B, have not yet been determined; for the sake of explanation, the chiral center of Example 2-A is randomly designated as S, and the chiral center of Example 2-B is designated as R.)

[0089] Example 2-A: (R)-1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline: SFC (RT=5.10 min, ee=99.6%). The analytical method used a DAIEL CHIRALPAKIE-3 column (0.46 cm × 25 cm), with isopropyl alcohol and n-hexane as the mobile phase (volume ratio of 30%:70%), and a flow rate of 1 mL / min. ESI-MS m / z: 404.5 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ8.27(d,1H),7.90(s,1H),7.42(t,1H),7.29(dd,1H),7.08(s,1H),6.82-6.78(dq, 1H), 6.34 (dt, 1H), 4.35 (d, 1H), 3.92 (d, 1H), 2.63-2.60 (m, 2H).

[0090] Example 2-B: (S)-1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline: SFC (RT=5.73 min, ee=98.2%). The analytical method used a DAIEL CHIRALPAKIE-3 column (0.46 cm × 25 cm), with isopropyl alcohol and n-hexane as the mobile phase (volume ratio of 30%:70%), and a flow rate of 1 mL / min. ESI-MS m / z: 404.5 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ8.27(d,1H),7.91(s,1H),7.42(t,1H),7.29(dd,1H),7.08(s ,1H),6.82-6.78(dq,1H),6.34(dt,1H),4.35(d,1H),3.92(d,1H),2.63-2.59(m,2H).

[0091] Example 3: Synthesis of 1'-chloro-8'-fluoro-7-methoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline [ka]

[0092] Step 1: Synthesis of 1'-chloro-3-(4-methoxy)-5-(trifluoromethyl)pyridine-2-yl)-6',7'-dihydrodispiro[oxazoline-4,5'-isoquinoline-8',2''-[1,3]dioxolan]-2one

[0093] 1'-Chloro-6',7'-dihydrodispiro[oxazoline-4,5'-isoquinoline-8',2''-[1,3]dioxolane]-2-one (1.2g) was dissolved in toluene (15mL), and 2-chloro-4-methoxy-5-trifluoromethylpyridine (1.0g), Pd2(dba)3 (0.296g), BINAP (0.403g), and Cs2CO3 (1.97g) were added. The mixture was then purged with nitrogen gas and reacted at 100°C. ESI-MS m / z: 472.32 [M+H] +

[0094] Step 2: Synthesis of 1-chloro-3'-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)-6,7-dihydro-8H-spiro[isoquinoline-5,4'-oxazoline]-2',8-dione

[0095] 1'-Chloro-3-(4-methoxy)-5-(trifluoromethyl)pyridine-2-yl)-6',7'-dihydrodispiro[oxazoline-4,5'-isoquinoline-8',2''-[1,3]dioxolane]-2-one (1.14 g, 1.0 eq.) was dissolved in THF (10 mL), 4N HCl (4 mL) was added, and the reaction was carried out at 50 °C for 3 hours. The solution was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (1.14 g). ESI-MS m / z: 428.39 [M+H] + .

[0096] Step 3: Synthesis of 1-chloro-8-fluoro-3'-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)-6H-spiro[isoquinoline-5,4'-oxazoline]-2'-one

[0097] 1-Chloro-3'-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)-6,7-dihydro-8H-spiro[isoquinoline-5,4'-oxazoline]-2',8-dione (1.1 g) was dissolved in DCM (10 mL), DAST (4.1 g) was added, and the reaction was carried out at 80°C. The reaction mixture was added dropwise to saturated sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the target compound (100 mg) was obtained by column chromatography. ESI-MS m / z: 428.50 [MH] -

[0098] Step 4: Synthesis of (1-chloro-8-fluoro-5-((4-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)-5,6-dihydroisoquinoline-5-yl)methanol

[0099] 1-Chloro-8-fluoro-3'-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)-6H-spiro[isoquinoline-5,4'-oxazoline]-2'-one (80 mg) was dissolved in EtOH (5 mL), 4N NaOH (90 μL) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (90 mg). ESI-MS m / z: 403.32 [M+H] +

[0100] Step 5: Synthesis of 1'-chloro-8'-fluoro-7-methoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline (1-Chloro-8-fluoro-5-((4-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)-5,6-dihydroisoquinoline-5-yl)methanol (90 mg) was dissolved in toluene (3 mL), MsCl (0.172 mL) and Et3N (0.62 mL) were added, and the mixture was reacted at 80°C for 2 hours. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The target compound (28 mg) was obtained from the prepared plate. ESI-MS m / z: 386.31 [M+H]+ , 1 H NMR(500MHz, Acetonitrile-d3)δ8.38(d,J=4.8Hz, 1H), 8.22(s,1H),7.74(s,1H),7.34(dd,1H),6.28(s,1H),5.82(ddd,1H),4.43(d,1H),3.97(d,1H),3.93(s,3H),2.80(ddd,2H),2.60(ddd,1H).

[0101] Example 4: Synthesis of 1'-chloro-8'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-7-ol [ka]

[0102] 13 mg of 1'-chloro-8'-fluoro-7-methoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline (i.e., the compound from Example 3)) was dissolved in 3 mL of DMA, 21 mg of LiCl was added, and the mixture was reacted at 85°C. Dilute hydrochloric acid was then added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and purified using a silica gel thin-layer chromatography plate to obtain the target compound (10 mg). ESI-MS m / z: 371.18 [MH] - , 1 H NMR(500MHz,DMSO-d6)δ8.40(d,1H), 8.22(s,1H),7.85(s,1H),7.32(dd,1H),5.89(ddd,1H),5.32(s,1H),4.36(d,1H),4.15(d,1H),2.71-2.66(m,2H).

[0103] Example 5: Synthesis of 1'-chloro-8-difluoromethoxy-8'-methoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0104] 1'-Chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (50 mg) was dissolved in methanol (1 mL), and PPTS (6 mg) and (CH3O)3CH (126 mg) were added. The mixture was reacted at 120°C for 14 hours. After cooling to room temperature, the solvent was rotated dry, and the target compound (11.3 mg) was separated and purified using a preparative plate. ESI-MS m / z: 478.31[M-H+CH3CN]-, 1 H NMR(500MHz,DMSO-d6)8.33(d,1H),7.90(s,1H),7.45(t,1H),7.28(d,1H),7.09(s,1H) ,5.31(dd,1H),4.46(d,1H),3.88(d,1H),3.70(s,3H),2.57(dd,1H),2.48-2.43(m,1H).

[0105] Example 6: Synthesis of 1'-chloro-8-difluoromethoxy-8'-methyl-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0106] Step 1: Synthesis of 1'-chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-5,5'-isoquinoline]-8'-trifluoromethanesulfonic acid ester

[0107] 1'-Chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (300 mg) was dissolved in THF (6 mL) and the temperature was lowered to -78°C. KHMDS (0.858 mL) was added dropwise. After 0.5 hours, PhNTf2 (306 mg) was dissolved in 1 mL of THF and slowly added dropwise to the reaction mixture, and the reaction was allowed to proceed for 1 hour. 2 mL of saturated NH4Cl was added for extraction, and the target compound (195 mg) was separated by column chromatography.

[0108] Step 2: Synthesis of 1'-chloro-8-difluoromethoxy-8'-methyl-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]

[0109] 1'-Chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-trifluoromethanesulfonic acid (20 mg), MeB(OH)2 (6.5 mg), K3PO4 (23 mg), Pd(dppf)Cl2 (5 mg), 1,4-dioxane (1 mL), and H2O (1 mL) were added to a reaction tube, purged with nitrogen, and reacted at 70°C for 1 hour. The solvent was extracted, and the prepared plate was purified by rotary drying to obtain the target compound (10 mg). ESI-MS m / z[M+H] + 418.32, 1 H NMR(500MHz,DMSO-d6)8.29(d,1H),7.90(s,1H),7.44(t,1H),7.30(s,1H),7. 10(s,1H),6.15(td,1H),4.40(s,1H),3.85(s,1H),2.46(s,2H),2.31(dd,3H).

[0110] Example 7: Synthesis of 1',8'-dichloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0111] 1'-Chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-trifluoromethanesulfonate (50 mg), LiCl (1.2 mg) [Cp * Ru(MeCN)3OTf] (0.6 mg) and NMP (1 mL) were added to a reaction tube, nitrogen was purged, and the mixture was reacted at 100°C for 3 hours. The solvent was extracted, rotated dry, and purified on a preparative plate to obtain the target compound (5.2 mg). ESI-MS m / z[M+H] + 438.19, 1 H NMR (500MHz, DMSO-d6) 8.40(d,1H),7.94(s,1H),7.42(t,1H),7.36(d,1H),7.12(s,1H),6.59(t,1H),4.45(d,1H),4.02(d,1H),2.62(d,2H).

[0112] Example 8: Synthesis of 1'-chloro-8-difluoromethoxy-6,8'-bis(trifluoromethyl)-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0113] Step 1: Synthesis of 1'-chloro-8-difluoromethoxy-8'-iodo-6-trifluoromethyl-3H,6'H-spiro[imidazo[2-a]pyridine-2,5'-isoquinoline]

[0114] 1'-Chloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-trifluoromethanesulfonate (75 mg), NaI (105 mg), [Cp *Ru(MeCN)3OTf] (14.2 mg) and DMI (5 mL) were added to a reaction tube, and the mixture was reacted at 100°C for 12 hours under nitrogen purging. The solvent was extracted, rotated dry, and purified on a preparative plate to obtain the target compound (52.6 mg).

[0115] Step 2: Synthesis of 1'-chloro-8-difluoromethoxy-6,8'-bis(trifluoromethyl)-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]

[0116] 1'-Chloro-8-difluoromethoxy-8'-iodo-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] (30.0 mg, 1.0 eq.), copper powder (25.4 mg), and diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (57.8 mg) were added to DMF (2.0 mL), purged with nitrogen, and reacted at 100°C for 2 hours. The mixture was extracted, rotated dry, and purified by preparative plate to obtain the target compound (0.9 mg). ESI-MS: [M+H] + 472.30, 1 1H NMR (500MHz, CD3CN) 1 H NMR(500MHz,Acetonitrile-d3)8.38(d,1H),7.55(t,1H),7.39(d,1H),7.24-7.20(m,1H), 7.20(t,1H),6.99(d,1H),4.34(d,1H),3.90(d,1H),2.78-2.71(m,1H),2.70-2.63(m,1H).

[0117] Example 9: Synthesis of 1',7'-dichloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0118] Step 1: Synthesis of 1',7'-dichloro-8-difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one

[0119] 1'-Chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (127 mg)TsOH (52 mg) and CH3CN (4 mL) were added to a reaction flask and reacted at 50°C for 12 hours. The reaction mixture was purified by rotational drying of the preparation plate to obtain the target compound (36 mg).

[0120] Step 2: Synthesis of 1',7'-dichloro-8-difluoromethoxy-6-trifluoromethyl-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5]-isoquinoline-8'-ol

[0121] 1',7'-Dichloro-8-difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (36 mg) was dissolved in MeOH (2 mL). NaBH4 (3 mg) was added and the mixture was reacted in an ice bath for 0.5 hours. Water was added for extraction, and the compound was purified using a preparative plate to obtain the target compound (20 mg).

[0122] Step 3: Synthesis of 1',7'-dichloro-8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]

[0123] 1',7'-Dichloro-8-difluoromethoxy-6-trifluoromethyl-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-ol (20 mg) was dissolved in 1,4-dioxane (3 mL), and Burgess reagent (31 mg) was added and the mixture was reacted at 100°C for 1 hour. Water was added for extraction, and the compound was purified in a preparative plate to obtain the target compound (0.73 mg). ESI-MS m / z:[M+H] + 438.18, 1 H NMR(500MHz,CD3CN)8.16(d,1H),7.46(t,1H),7.18(d,1H),7.06(t,1H),6.9 3(d,1H),6.87(d,1H),4.25(d,1H),3.82(d,1H),2.98(dd,1H),2.69(d,1H).

[0124] Example 10: Synthesis of 1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0125] Step 1: Synthesis of 8'-((tert-butyldimethylsilicone)oxy)-1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-5'-isoquinoline]

[0126] 1'-Chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (200 mg) and 6-dimethylpyridine (257 mg) were dissolved in DCM (10 mL), purged with nitrogen, and then TBSOTf (380 mg) was added under ice bath. The mixture was reacted at room temperature for 10 minutes and then at 40°C for 2 hours. Water was added for extraction, and the mixture was centrifuged and dried to obtain the target compound (221.6 mg) by column chromatography.

[0127] Step 2: Synthesis of 1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-5'-isoquinoline]-8'-one

[0128] 8'-((tert-butyldimethylsilyl)oxy)-1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] (221.6 mg) was dissolved in MeCN (10 mL), cooled to 0°C, Selectfluor (159.4 mg) was added, and the mixture was reacted at room temperature for 3 hours. Water was added for extraction, the mixture was dried, and the target compound (75.6 mg) was obtained by column chromatography.

[0129] Step 3: Synthesis of 1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-6',7'-dihydro-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-trifluoromethanesulfonic acid

[0130] 1'-Chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (40.0 mg) was dissolved in THF (8 mL), cooled to -78°C, KHMDS (0.11 mL) was added dropwise, and the mixture was stirred at -78°C for 0.5 hours. Then, PhNTf2 (48.6 mg) was added and the mixture was stirred at -78°C for 2 hours. The mixture was quenched and rotated dry, and the prepared plate was purified to obtain the target compound (15.4 mg).

[0131] Step 4: Synthesis of 1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'-H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]

[0132] 1'-Chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-yltrifluoromethanesulfonate (15.4 mg)br / >Pd(PPh3)4 (3.1 mg) and LiCl (9.3 mg) were dissolved in THF (2 mL), the mixture was purged with nitrogen gas, and Bu3SnH (11.9 mg) was added. The mixture was reacted at room temperature for 3 hours, extracted, and spin-dried. The prepared plate was purified to obtain the target compound (2.0 mg). ESI-MS m / z[M+H] + 422.26, 1 1H NMR (500MHz, CD3CN) 8.23(d,1H),7.59(p,1H),7.27(dd,J=5.0,0.7Hz,1H),7.18(t,1H),7.00(d ,1H),6.52(ddd,1H),4.41(d,1H),3.96(d,1H),3.04(dt,1H),2.73(dd,1H).

[0133] Examples 10-A and 10-B: Preparation of (R)-1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] and (S)-1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0134] The racemic compound 1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] (i.e., the compound of Example 10) yields a pair of enantiomers by a prepared SFC, of ​​which the enantiomer eluted first from the chiral column is Example 10-A, and the enantiomer eluted later is Example 10-B (the absolute configurations of the two compounds, Example 10-A and 10-B, have not yet been determined, and for the sake of explanation, the chiral center of Example 10-A is randomly designated as S, and the chiral center of Example 10-B is designated as R).

[0135] Example 10-A: (R)-1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]:SFC (RT=2.81 min, ee=99.8%). The analytical method used was a column dicol PAK IE (0.46 cm × 25 cm). The mobile phase was isopropyl alcohol and n-hexane (volume ratio of the two:20%:80%). ESI-MS m / z:422.4[M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ8.26(d,1H),7.96(s,1H),7.39(t,1H),7.31(dd,1H),7. 11(s,1H),6.46(dd,1H),4.44(d,1H),4.12(d,1H),3.00(dd,1H),2.89(dd,1H).

[0136] Example 10-B: (S)-1'-chloro-8-difluoromethoxy-7'-fluoro-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]:SFC (RT=3.68min, ee=99.9%). The analytical method used a DAIEL CHIRALPAK IE column (0.46cm × 25cm). The mobile phase was isopropyl alcohol and n-hexane (volume ratio of 20%:80%). ESI-MS m / z: 422.4[M+H] + ;1 H NMR(500MHz,DMSO-d6)δ8.26(d,1H),7.96(s,1H),7.39(t,1H),7.31(dd,1H),7. 11(s,1H),6.46(dd,1H),4.44(d,1H),4.11(d,1H),3.00(dd,1H),2.89(dd,1H).

[0137] Example 11: Synthesis of 6'-bromo-8-difluoromethoxy-4',5'-difluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] [ka]

[0138] Step 1: Synthesis of N'-(6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2',1'-naphthalene]-4'-ylidene)-4-toluenesulfonylhydrazone

[0139] 6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3'H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one (synthesis steps refer to steps 1-4 of Example 2) (200 mg), TsNHNH2 (110 mg), and TsOH (10 mg) were added to MeOH (5 mL) and reacted at 80°C for 12 hours, followed by extraction and concentration. The preparative plates were purified to obtain the target compound (140 mg).

[0140] Step 2: Synthesis of 6'-bromo-8-difluoromethoxy-4',5'-difluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]

[0141] N'-(6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ylidene)-4-toluenesulfonylhydrazone (45 mg), NFSI (32.7 mg), and KF (27.6 mg) were added to Dioxane (2 mL) and reacted at 80°C for 12 hours. Water was added for extraction, the mixture was rotated dry, and purified on a preparative plate to obtain the target compound (3.1 mg). ESI-MS m / z[M+H] + 483.20, 485.20; 1 H NMR(500MHz,DMSO-d6)7.90(d,1H),7.72(dd,1H),7.42(t,1H),7.08(m,2H) ,5.79(ddd,1H),4.40(d,1H),3.93(d,1H),2.67(dd,1H),2.58-2.52(m,1H).

[0142] Example 12: Synthesis of 6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] [ka]

[0143] Step 1: Synthesis of 6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ol

[0144] 6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3'H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one (60 mg) was dissolved in MeOH (2 mL), NaBH4 (2 mg) was added, and the mixture was reacted at room temperature for 0.5 hours. After adding water, the mixture was extracted, rotated dry, and a plate was prepared for purification to obtain 31 mg of the target compound.

[0145] Step 2: Synthesis of 6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[2-a]pyridine-1'-naphthalene]

[0146] 6'-Bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ol (31 mg) and Burgess reagent (46 mg) were dissolved in toluene (2 mL) and reacted at 90°C for 5 hours. Water was added for extraction, the mixture was dried, and 5.6 mg of the target compound was obtained by preparative HPLC. ESI-MS m / z[M+H] + 465.07,467.14; 1 H NMR(500MHz,DMSO-d6)7.89(t,1H),7.56(dd,1H),7.43(t,1H),7.05(s,1H ),6.75(d,1H),6.24(dt,1H),4.31(d,1H),3.84(d,1H),2.59-2.55(m,2H).

[0147] Example 13: Synthesis of 6'-bromo-8-difluoromethoxy-5'-fluoro-4'-iodo-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] [ka]

[0148] Step 1: Synthesis of 6'-bromo-8-difluoromethoxy-5'-fluoro-4'-hydrazolidene-6-trifluoromethyl-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-a]pyridine-1'-naphthalene]

[0149] 6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3'H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one (40 mg), hydrazine hydrate (2 mL), and EtOH (2 mL) were added to a reaction tube and reacted at 80°C for 1 hour. Water was added for extraction, and the mixture was concentrated to obtain the target compound (40 mg).

[0150] Step 2: Synthesis of 6'-bromo-8-difluoromethoxy-5'-fluoro-4'-iodo-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]

[0151] 6'-Bromo-8-difluoromethoxy-5'-fluoro-4'-hydrazolidene-6-trifluoromethyl-3',4'-dihydro-2'H,3H-spiro[imidazo[1-a]pyridine-2,1'-naphthalene] (45 mg), I2 (25 mg), and Et3N (25 mg) were added to THF (2 mL) and reacted at room temperature for 0.5 hours. The preparative plate was purified by adding water for extraction and rotary drying to obtain 2.5 mg of the target compound. ESI-MS m / z[M+H] + 591.02, 592.84; 1 H NMR (500MHz, DMSO-d6) 7.91(q,1H),7.69(dd,1H),7.42(t,1H),7.08-7.04(m,3H),4.41(d,1H),3.88(d,1H),2.57-2.52(m,1H),2.41(dd,1H).

[0152] Example 14: Synthesis of 6'-bromo-4'-chloro-8-difluoromethoxy-5'-fluoro-4'-iodo-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-1'-naphthalene] [ka]

[0153] Step 1: Synthesis of 6’-bromo-8-difluoromethoxy-5’-fluoro-6-trifluoromethyl-2’H,3H-spiro[imidazo[2-a]pyridine-2,1’-naphthalen]-4’-yl trifluoromethanesulfonate

[0154] 6’-Bromo-8-difluoromethoxy-5’-fluoro-6-trifluoromethyl-2’,3’-dihydro-3’H,4’H-spiro[imidazo[1,2-a]pyridine-2,1’-naphthalen]-4’-one (200 mg) was dissolved in THF (5 mL) and cooled to -78°C. KHMDS (0.5 mL) was added dropwise. After 0.5 hours, PhNTf₂ (178 mg) was added and the reaction was allowed to proceed for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (NH₄Cl) solution, extracted, rotary evaporated to dryness, and purified by silica gel column chromatography to obtain the target product (145 mg).

[0155] Step 2: Synthesis of 6’-bromo-4’-chloro-8-difluoromethoxy-5’-fluoro-4’-iodo-6-trifluoromethyl-2’H,3H-spiro[imidazo[1,2-a]pyridine-2,1’-naphthalene]

[0156] 6’-Bromo-8-difluoromethoxy-5’-fluoro-6-trifluoromethyl-2’H,3H-spiro[imidazo[1,2-a]pyridine-2,1’-naphthalen]-4’-yl trifluoromethanesulfonate (30 mg), LiCl (3.1 mg), [Cp * Ru(MeCN)₃OTf] (1.2 mg) was added to NMP (2 mL), the system was purged with nitrogen, and the reaction was carried out at 100°C for 3 hours. Water was added for extraction, the mixture was rotary evaporated to dryness, and purified by preparative plate to obtain the target compound (14.5 mg). ESI-MS m / z [M+H] + 499.14, 500.69; 1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (t, 1H), 7.73 (dd, 1H), 7.42 (t, 1H), 7.10 (d, 1H), 7.07 (d, 1H), 6.43 (dd, 1H), 4.40 (d, 1H), 3.92 (d, 1H), 2.66-2.55 (m, 2H).

[0157] Example 15: Synthesis of 8-difluoromethoxy-4',5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[2-a]pyridine-2,1'-naphthalene] [ka]

[0158] Step 1: Synthesis of N'-(8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ylidene)-4-toluenesulfonylhydrazone

[0159] 8-Difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3'-H,4'-H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one (150 mg), TsNHNH2 (104 mg), and TsOH (2 mg) were added to MeOH (5 mL) and reacted at 80°C for 12 hours. The mixture was extracted and concentrated. The preparative plates were purified to obtain the target compound (55 mg).

[0160] Step 2: Synthesis of 8-difluoromethoxy-4',5'-difluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]

[0161] N'-(8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ylidene)-4-toluenesulfonylhydrazone (45 mg), NFSI (37 mg), K2CO3 (32.6 mg), and KF (13.7 mg) were added to dioxane (2 mL) and reacted at 80°C for 12 hours. Water was added for extraction, the mixture was rotated dry, and purified on a preparative plate to obtain the target compound (3.1 mg). ESI-MS m / z[M+H] + 405.00; 1H NMR(500MHz,DMSO-d6)7.90(d,1H),7.72(dd,1H),7.42(t,1H),7.08(m,2H) ,5.79(ddd,1H),4.40(d,1H),3.93(d,1H),2.67(dd,1H),2.58-2.52(m,1H).

[0162] Examples 15-A and 15-B: Preparation of (S)-8-difluoromethoxy-4',5'-difluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[2-a]pyridine-2-1'-naphthalene] and (R)-8-difluoromethoxy-4',5'-difluoro-6-trifluoromethyl-2',H,3H-spiro[imidazo[2-a]pyridine-2-1'-naphthalene] [ka]

[0163] The racemic compound 8-difluoromethoxy-4',5'-difluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] (i.e., the compound of Example 15) yielded a pair of enantiomers by prepared SFC. Of these, the enantiomer eluted first from the chiral column was the enantiomer of Example 15-A, and the enantiomer eluted later was the enantiomer of Example 15-B (the absolute configurations of the two compounds, Example 15-A and 15-B, have not yet been determined; for the sake of explanation, the chiral center of Example 15-A is randomly designated as S, and the chiral center of Example 15-B is designated as R).

[0164] Example 15-A:8-difluoromethoxy-4’,5’-difluoro-6-trifluoromethyl-2’H,3H-spiro[imidazo[1,2-a]pyridine-1’-naphthalene]: SFC (RT=8.49 min, ee=99.9%). The analysis method uses a DAICEL CHIRALPAK IG column (0.46 cm×25 cm), the mobile phase consists of ethanol, n-hexane (the volume ratio of the two is 9%:95%) and 0.1% diethylamine, and the flow rate is 1 mL / min. ESI-MS m / z: 405.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.43 (t, 1H), 7.41 (dt, 1H), 7.23-7.17 (m, 1H), 7.13 (dd, 1H), 7.06 (s, 1H), 5.69 (ddd, 1H), 4.41 (d, 1H), 3.90 (d, 1H), 2.65 (ddd, 1H), 2.56-2.52 (m, 1H).

[0165] Example 15-B: (R)-8-difluoromethoxy-4’,5’-difluoro-6-trifluoromethyl-2’H,3H-spiro[imidazo[1,2-a]pyridine-2,1’-naphthalene]: SFC (RT=9.88 min, ee=99.3%). The analysis method uses a DAICEL CHIRALPAK IG column (0.46 cm×25 cm), the mobile phase consists of ethanol, n-hexane (the volume ratio of the two is 9%:95%) and 0.1% diethylamine. Flow rate: 1 mL / min. ESI-MS m / z: 405.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.43 (t, 1H), 7.42 (dt, 1H), 7.19 (dd, 1H), 7.13 (dd, 1H), 7.05 (s, 1H), 5.69 (ddd, 1H), 4.41 (d, 1H), 3.90 (d, 1H), 2.65 (ddd, 1H), 2.56-2.52 (m, 1H).

[0166] Example 16: Synthesis of 8-difluoromethoxy-4',5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] [ka]

[0167] Step 1: Synthesis of 8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-3',4'-dihydro-2'H,3H-spiro[imidazo[2-a]pyridine-2'-naphthalene]-4'-ol

[0168] 8-Difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3'H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one (60 mg) was dissolved in MeOH (2 mL), NaBH4 (6 mg) was added, and the mixture was reacted at 0°C for 0.5 hours. After that, water was added for extraction, the mixture was dried, a plate was formed, and the mixture was purified to obtain 21 mg of the target compound.

[0169] Step 2: Synthesis of 8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'-H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]

[0170] 8-Difluoromethoxy-5'-fluoro-6-trifluoromethyl-3',4'-dihydro-2'-H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ol (21 mg) and Burgess reagent (37 mg) were dissolved in toluene (2 mL) and reacted at 90°C for 0.5 hours. Water was added for extraction, and the mixture was rotated dry to prepare an HPLC. The compound was separated to obtain 4 mg of the target compound. ESI-MS m / z[M+H] + 387.31; 1H NMR(500MHz,DMSO-d6)7.53-7.51(m,1H),7.42(t,1H),7.29-7.25(m,1H),7.15-7.11(m,1H),7. 04(ddd,1H),6.92(d,1H),6.82(dd,1H),4.31(d,1H),3.79(d,1H),2.65(dt,1H),2.53(dd,1H).

[0171] Examples 16-A and 16-B: Preparation of (S)-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] and (R)-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] [ka]

[0172] The racemic compound 8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'-H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] (i.e., the compound of Example 16) was prepared by a prepared SFC to obtain a pair of enantiomers. Of these, the enantiomer eluted first from the chiral column was the enantiomer of Example 16-A, and the enantiomer eluted later was the enantiomer of Example 16-B (the absolute configurations of the two compounds, Example 16-A and 16-B, have not yet been determined; for the sake of explanation, the chiral center of Example 16-A is randomly designated as S, and the chiral center of Example 16-B is designated as R).

[0173] Example 16-A: (S)-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]: SFC (RT=7.26 min, ee=99.1%) The analytical method used was a DAIEL CHIRALPAK IG column (0.46 cm × 25 cm), with the mobile phase being ethanol and n-hexane (volume ratio of the two:5%:95%) and 0.1% diethylamine, and the flow rate was 1 mL / min. ESI-MS m / z:387.5[M+H]+;1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.45(t,1H),7.29-7.25(m,1H),7.14-7.09(m,1H),7.08( d,1H),7.04(s,1H),6.75(dd,1H),6.16(ddd,1H),4.32(d,1H),3.82(d,1H),2.58-2.53(m,2H).

[0174] Example 16-B: (R)-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'-H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]: The analytical method used a DAIEL CHIRALPAK IG column (0.46 cm × 25 cm), with the mobile phase being ethanol and n-hexane (volume ratio of 5%:95%) and 0.1% diethylamine, and the flow rate was 1 mL / min. ESI-MS m / z: 387.5 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.45(t,1H),7.29-7.25(m,1H),7.14-7.09(m,1H),7.08( d,1H),7.04(s,1H),6.75(dd,1H),6.16(ddd,1H),4.32(d,1H),3.82(d,1H),2.58-2.53(m,2H).

[0175] Example 17: Synthesis of 8-difluoromethoxy-1'-methyl-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0176] Step 1: Synthesis of 8-difluoromethoxy-1'-methyl-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one

[0177] 1'-Chloro-8-difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (100 mg) was dissolved in dioxane (5 mL), and H2O (1 mL), Pd(dppf)Cl2 (35.1 mg), and Cs2CO3 (156.4 mg) were added. The mixture was then purged with nitrogen, and trimethylboroxine (0.7 mL) was added. The mixture was reacted at 100°C for 13 hours. Water was added for extraction, and the plate was dried and purified to obtain 60 mg of the target compound.

[0178] Step 2: 8-Difluoromethoxy-1'-methyl-6-trifluoromethyl-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-ol

[0179] 8-Difluoromethoxy-1'-methyl-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one (38 mg) was dissolved in MeOH (3 mL), cooled to 0°C, and NaBH4 (3.6 mg) was slowly added and stirred for 30 minutes. Water was added for extraction, and the plate was dried and purified to obtain 12 mg of the target compound.

[0180] Step 3: Synthesis of 8-difluoromethoxy-1'-methyl-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]

[0181] 8-Difluoromethoxy-1'-methyl-6-trifluoromethyl-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-ol (12 mg) was dissolved in PhMe (2 mL), Burgess reagent (21.5 mg) was added, and the mixture was purged with nitrogen and reacted at 100°C for 1 hour. Water was added for extraction, and the preparation plate was purified by rotary drying to obtain Example 1705 mg of the target compound. ESI-MS m / z: 384.39 [M+H] + ; 1 H NMR(500MHz, Acetonitrile-d3)δ8.20(d,1H),7.41-7.39(m,1H),7.13(t,1H),6.98(s,1H),6.81(d,1H),6.69 (dd,1H),6.09-6.04(m,1H),4.20(d,1H),3.66(d,1H),2.52(dt,1H),2.44(s,3H),2.42(dd,1H). Example 18: Synthesis of 8-difluoromethoxy-5'-fluoro-6'-methyl-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene] [ka]

[0182] Step 1: Synthesis of 8-difluoromethoxy-5'-fluoro-6'-methyl-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one

[0183] 6'-bromo-8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one (80 mg), Pd(dppf)Cl2 (24.3 mg), and Cs2CO3 (108.2 mg) were added to dioxane (3 mL) and H2O (0.6 mL), purged with nitrogen gas, and then added to trimethylboroxine (0.47 mL). The mixture was reacted at 100°C for 1 hour. Water was added for extraction, and the preparative plate was purified by drying to obtain 59 mg of the target compound.

[0184] Step 2: Synthesis of N'-(8-difluoromethoxy-5'-fluoro-6'-methyl-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ylidene)-4-methylphenylsulfonylhydrazone

[0185] 8-Difluoromethoxy-5'-fluoro-6'-methyl-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one (59.4 mg), TsNHNH2 (40 mg), and TsOH (29.6 mg) were added to THF (5 mL), nitrogen was purged, and the mixture was reacted at 40°C for 2 hours. Water was added for extraction, and the preparative plates were purified by drying to obtain 97 mg of the target compound.

[0186] Step 3: Synthesis of 8-difluoromethoxy-5'-fluoro-6'-methyl-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]

[0187] N'-(8-difluoromethoxy-5'-fluoro-6'-methyl-6-trifluoromethyl-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-ylidene)-4-methylphenylsulfonylhydrazone (40 mg) and Cs2CO3 (66.8 mg) were added to dioxane (3 mL) and stirred at 90°C for 5 hours. Water was added for extraction, and the preparation plate was purified by rotary drying to obtain Example 18 (13 mg) of the target compound. ESI-MS m / z: 401.13 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.44(t,1H),7.14(t,1H),7.02(s,1H),6.95(d,1H),6.74(d,1 H),6.16-6.10(m,1H),4.28(d,1H),3.79(d,1H),2.57-2.52(m,1H),2.49-2.46(m,1H),2.21(s,3H).

[0188] Example 19: Synthesis of 8-difluoromethoxy-5'-fluoro-4'-iodo-6-trifluoromethyl-2'H,3H-spiro[imidazolium[1,2-a]pyridine-2,1'-naphthalene] [ka]

[0189] Step 1: Synthesis of 8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-trifluoromethanesulfonic acid ester

[0190] 500 mg of 8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2',3-dihydro-3H,4'H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-one was dissolved in 4 mL of THF, and the mixture was cooled to -78°C under nitrogen purging. Then, 1.5 mL of KHMDS was added dropwise to the reaction mixture and the mixture was allowed to react for 1 hour. PhNTf2 was dissolved in 2 mL of THF and slowly added dropwise to the reaction mixture and allowed to react for 30 minutes. The reaction was quenched with saturated NH4Cl solution, and 306 mg of the target compound was obtained by extraction, rotary evaporation, and silica gel column purification.

[0191] Step 2: Synthesis of 8-difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]

[0192] 8-Difluoromethoxy-5'-fluoro-6-trifluoromethyl-2'H,3H-spiro[imidazo[1,2-a]pyridine-2,1'-naphthalene]-4'-trifluoromethanesulfonate (135 mg), NaI (120 mg), [Cp * Ru(MeCN)3]OTf (15 mg) was dissolved in DMI (2 mL), purged with nitrogen, and reacted at 100°C for 16 hours. Water was added for extraction, and the mixture was purified by dry silica gel column chromatography to obtain 117 mg of the target compound. ESI-MS m / z: 513.20 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.44(t,1H),7.39(td,1H),7.17(ddd,1H),7.10(dd ,1H),7.06(s,1H),6.99(dd,1H),4.42(d,1H),3.87(d,1H),2.54(dd,1H),2.40(dd,1H).

[0193] Example 20: Synthesis of 8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline] [ka]

[0194] Step 1: Synthesis of 8-difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-one

[0195] 1'-Chloro-8-difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-5'-isoquinoline]-8'-one (100 mg) was dissolved in N,N-dimethylacetamide (3 mL), and Pd(PPh3)4 (27.7 mg), HCOOH (16.6 mg), and TEA (38.5 mg) were added. After purging with nitrogen, the temperature was raised to 100°C and the mixture was reacted for 5 hours. Water was added for extraction, and the mixture was purified by dry silica gel column chromatography to obtain 90 mg of the target compound.

[0196] Step 2: Synthesis of N'-(8-difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-ylidene)-4-methylphenylsulfonylhydrazone

[0197] 8-Difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2,2a]pyridine-2,5'-isoquinoline]-8'-one (40 mg), TsNHNH2 (29 mg), and TsOH (2 mg) were added to THF (2 mL) and purged with nitrogen gas at 30°C for 4 hours. Water was added for extraction, the solution was dried, and the preparative plate was purified to obtain 48 mg of the target compound.

[0198] Step 3: Synthesis of 8-difluoromethoxy-6-trifluoromethyl-3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]

[0199] N'-(8-difluoromethoxy-6-trifluoromethyl-6',7'-dihydro-3H,8'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline]-8'-ylidene)-4-methylphenylsulfonylhydrazone (38 mg) was dissolved in dioxane (3 mL), K2CO3 (32 mg) was added, and the mixture was reacted at 90°C for 16 hours under nitrogen purging. Water was added for extraction, and the prepared plate was purified by rotary drying to obtain 9.7 mg of the target compound Example 20. ESI-MS m / z: 369.92 [M+H] + ; 1 H NMR(500MHz,Acetonitrile-d3)δ8.44(d,J=5.0Hz,1H),8.37(s,1H),7.54-7.51(m,1H),7.24(t,1H),7.24 (d,1H),6.94(d,1H),6.66(dd,1H),6.17(ddd,1H),4.31(d,1H),3.83(d,1H),2.67(dt,1H),2.57(dd,1H).

[0200] Biological detection The EPO inhibition rate of each compound was detected using Hep3B cells.

[0201] 5 x 10 4Hep3B cells (TCHu106 from the Chinese Academy of Sciences Cell Bank) were seeded onto plates at a concentration of / mL and cultured overnight in a 5% carbon dioxide incubator (Thermo Scientific BB150) at 37°C. The following day, the culture medium was replaced with a medium containing 0.5% FBS (Viva Cell C04001-500), and the cells were starved for 6 hours. Then, a DMSO solution of (6'-hydroxy-3'-(4-methoxyphenyl)-8'-oxo-8'H-spiro[cyclopentane-1,5'-indolidine]-7'-carbonyl)glycine or its analogue was added to a final concentration of 30 μM. The plate was then placed in a 5% carbon dioxide incubator at 37°C for 24 hours. Subsequently, a DMSO solution of the test compound was added, and the final concentrations of the compound were increased to 30000 nM, 7500 nM, 1875 nM, 469 nM, 117 nM, 29 nM, 7.3 nM, 1.8 nM, 0.5 nM, and 0.5 nM, for a total of 10 concentrations. These were allowed to react continuously for 48 hours, and the cell supernatant was collected. Detection was performed using an ELISA assay according to the specifications of the ELISA kit (Biotechnology (Shanghai) Co., Ltd., D711311-0096), and readings were taken at a wavelength of 450 nm (microplate reader, Thermo Scientific (Multisikan Go), 511191200).

[0202] The formula for calculating the inhibition rate of a compound is: Inhibition rate of compound = 1-100% * The formula is (EPO value of the administration well - EPO value of the blank well) / (EPO value of the control well - EPO value of the blank well). The inhibition rate is linearly fitted to obtain IC. 50 The values ​​are calculated. Among them, the control well is where the concentration of the compound being tested is 0 nM; the cell-containing well is where the final concentration is 30 μM and the cell-containing well is 32 hours after reaction with a DMSO solution of (6'-hydroxy-3'-(4-methoxyphenyl)-8'-oxo-8'H-spiro[cyclopentane-1,5'-indolidine]-7'-carbonyl)glycine or analogue; the EPO content is assumed to be 100%; the blank well is a cell-containing well with no compound added.

[0203] IC of the positive control compound and the compounds of several examples 50 data are shown in Table 1. (Due to instrument errors and differences in operator operating habits, the IC of compounds measured under different experimental conditions 50 values may show a certain degree of variation. Therefore, it should be understood that the numerical values shown in the table indicate relative magnitudes within a certain error range.)

[0204] As can be seen from Table 1, compared with the positive control compound, all the tested compounds of the examples have IC that of the positive control compound 50 equal to or lower than the IC 50 , that is, it shows that each tested compound of the examples has the potential for treating EPO-related diseases and has excellent activity of reducing EPO.

[0205]

Table 1

[0206] Although specific embodiments of the present invention have been described, it is not meant that these embodiments describe all possible forms of the present invention. More precisely, the words used in the present specification are not limited to descriptive words. It is obvious that those skilled in the art can make modifications and substitutions to the examples without departing from the gist of the present disclosure. Therefore, the appended claims are intended to cover all such changes and modifications that fall within the scope of the present invention.

Claims

1. A compound represented by formula (I), an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the said compound or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 however, R １ H, D, F, Cl, Br, CF ３ Selected from CN, R ２ H, D, CF ３ ,CH ３ , OCH ３ Selected from OH, R ３ is selected from H, D, F, Cl, Br, CF ３ , CN, OCH ３ , OCH ２ F, OCHF ２ , OCF ３ , R ４ H, D, F, Cl, Br, CH ３ CF ３ Selected from CN, R ５ H, D, F, Cl, Br, I, CH ３ CF ３ , CN, OCH ３ Selected from, R ６ H, D, F, Cl, Br, I, CH ３ CF ３ , CN, OCH ３ Selected from, X is N, CR ７ Selected from, in the formula, R ７ H, D, F, Cl, Br, CF ３ , CN, CH ３ A compound represented by formula (I), an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from the above, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

2. The aforementioned R １ CF ３ A compound according to claim 1, selected from CN, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

3. The aforementioned R ２ OCH ３ A compound according to claim 1 or 2, selected from OH and H, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

4. The aforementioned R ３ OCH ３ , OCH ２ F, OCHF ２ OCF ３ A compound according to any one of claims 1 to 3, selected from H, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

5. The aforementioned R ４ H, F, Cl, CH ３ A compound according to any one of claims 1 to 4, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from the above, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

6. The aforementioned R ５ H, F, Cl, I, CH ３ CF ３ , OCH ３ A compound according to any one of claims 1 to 5, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from the above, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

7. The aforementioned R ６ F, Cl, CH ３ A compound selected from H, according to any one of claims 1 to 6, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

8. The aforementioned X is N, CR ７ Selected from, in the formula, R ７ H, F, Br, CF ３ , CN, CH ３ A compound according to any one of claims 1 to 8, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from the above, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

9. The aforementioned R １ CF ３ And the R ２ OCH ３ Selected from OH, H, and the R ３ OCH ２ F is, and R ４ H, F, Cl, CH ３ Selected from, the R ５ H, F, Cl, I, CH ３ CF ３ , OCH ３ Selected from, the R ６ F, Cl, CH ３ Selected from, where X is N, CR ７ Selected from, in the formula, R ７ The compound according to any one of claims 1 to 8, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from H, F, and Br, or the crystalline or solvate form of the compound or the pharmaceutically acceptable salt thereof.

10. The aforementioned R １ CF ３ And the R ２ OCH ３ Selected from OH, H, and the R ３ OCHF ２ or H, and the R ４ H, F, Cl, CH ３ Selected from, the R ５ H, F, Cl, Br, I, CH ３ CF ３ , OCH ３ Selected from, the R ６ H, F, Cl, CH ３ Selected from, where X is N, CR ７ Selected from, in the formula, R ７ H, F, Br, CH ３ A compound according to any one of claims 1 to 8, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from the above, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof.

11. The compound is selected from the following compounds: the compound according to claim 1, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof. 【Chemistry 2】

12. The compound is selected from the following compounds: the compound according to claim 1, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof. 【Transformation 3】

13. A pharmaceutical composition, A compound according to any one of claims 1 to 12, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, adjuvants, or excipients.

14. Use of a compound according to any one of claims 1 to 12, an isotope-labeled compound thereof, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a crystalline or solvate form of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the preparation of a pharmaceutical for the treatment of diseases or conditions related to EPO.

15. The diseases and conditions associated with EPO are selected from polycythemia, renal cell carcinoma and other cancers, and include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, skin cancer and brain cancer, as described in claim 14.

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