New pyrrole compounds

Abstract

The present invention relates to a series of novel pyrrole compounds and their preparation methods and uses. Specifically, the present invention relates to compounds represented by general formula (1) and their preparation methods, as well as the use of the compounds represented by general formula (1) and their optical isomers, crystalline forms and pharmaceutically acceptable salts in the preparation of drugs for the prevention or treatment of diseases associated with fungal infections. [Formula 1] TIFF2023505238000052.tif44150

Description

[Technical Field]

[0001] This application claims the benefit of Chinese Patent Application No. CN 201911256772.0, filed December 3, 2019, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a series of novel pyrrole compounds and methods for their preparation and use. [Background technology]

[0003] Background of the Invention Invasive fungal infections (IFIs) are one of the most serious threats to human health, claiming an average of more than 1.5 million lives annually worldwide. Although fungal infections can occur in healthy individuals, most occur in immunocompromised patients, making fungal-targeting antifungal drugs the primary means of treating IFIs. With the increasing use of immunosuppressants and the increasing number of patients undergoing oncology radiation therapy, chemotherapy, intravenous placement, and long-term intensive care unit (ICU) care, IFIs have attracted increasing attention due to their increasing morbidity and mortality rates. However, clinically common antifungal drugs are limited, primarily consisting of azoles, polyenes, echinocandins, and 5-fluorocytosine (Biochem Pharmacol, 2017, 133:86-96).

[0004] Azoles are the most commonly used antifungal drugs and can be classified into imidazoles and triazoles based on their chemical structure. Imidazole drugs (e.g., miconazole and ketoconazole) were first developed and have high antifungal activity, but their high toxicity limits their topical use. Later, triazole drugs were developed, which can be administered in vivo to treat IFI, primarily by inhibiting 14-α-lanosterol demethylase (CYP51) via a cytochrome P450 enzyme-dependent mechanism. The conversion of lanosterol to ergosterol in the fungal membrane is inhibited, resulting in the accumulation of toxic sterols in fungal cells, inhibiting fungal growth and replication. The main problems with azoles are drug resistance and their inhibition of CYP51 homologous enzymes in humans (e.g., CYP3A4 and CYP2C9). They tend to cause drug interactions with some drugs. Polyene drugs are only effective against fungi that contain sterols in their outer membrane, and their exact antifungal mechanism remains unclear. Among polyene drugs, amphotericin B is currently the most effective anti-IFN-γ drug, but it has serious toxic and adverse effects, including fever, chills, and nephrotoxicity [Med Mycol, 2017, 55(1):118-124]. Echinocandin compounds inhibit cell wall synthesis by inhibiting β-glucan. Only three echinocandin drugs are in clinical use: caspofungin, micafungin, and anidulafungin. However, these drugs have a narrow antibacterial spectrum, are ineffective against cryptococcal bacteria, are poorly absorbed in the gastrointestinal tract, and require only a single daily intravenous dose to maintain in vivo drug concentrations. Furthermore, the emergence of echinocandin-resistant fungi due to genetic mutations has limited their use [Lancet, 2003, 362(9390):1142-1151]. 5-Fluorocytosine is an analog of pyrimidine, a major component of RNA and DNA, and inhibits cell proliferation primarily by interfering with intracellular pyrimidine metabolism and the synthesis of DNA, RNA, and proteins. In addition to the four major antibacterial agents mentioned above, WO2009 / 130481 also discloses a series of novel pyrrole compounds with relatively high antifungal activity. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2009 / 130481 [Non-patent literature]

[0006] [Non-Patent Document 1] Biochem Pharmacol, 2017, 133:86-96 [Non-patent document 2] Med Mycol,2017,55(1):118-124 [Non-patent document 3] Lancet, 2003, 362(9390):1142-1151 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, medical treatment is an important strategy for IFI. However, the limited availability of drugs and increasing drug resistance, toxicity, and side effects have made the demand for the development of novel antifungal drugs even more urgent. Therefore, new antifungal drugs are urgently needed for clinical use to provide positive therapeutic effects to patients. [Means for solving the problem]

[0008] Summary of the Invention The present invention provides a series of compounds having the structure represented by formula (1), or an optical isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof. [ka] where "*" is a chiral center, R 1is H, C1-C6 alkyl, (C1-C3)alkoxyl-(C2-C3)alkyl-, (C3-C6)cycloalkyl-(C1-C3)alkyl-, C3-C6 cycloalkyl or halogenated C1-C6 alkyl, R 2 is H, C1-C3 alkyl or C3-C6 cycloalkyl, R 3 is H or a halogen, R 4 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, aryl or heteroaryl, wherein said aryl or said heteroaryl may be substituted with 1 to 3 of the following substituents: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxyl, and when substituted with several substituents, the substituents may be the same or different; R 5 is H, Me, OMe or a halogen, W is -O- or -NR 6 -, where R 6 is H, C1-C3 alkyl or C3-C6 cycloalkyl, Q is -O- or -NR 7 -, where R 7 is H, C1-C3 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, aryl or heteroaryl, wherein said aryl or said heteroaryl may be substituted by 1 to 3 of the following radicals: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxyl, and when substituted by several substituents, said substituents may be the same or different.

[0009] In another embodiment, in the formula (1), R 1 H, Me, Et, n- Pr,i- Pr, t- Bu, -CH2CH2OMe [ka] is.

[0010] In another embodiment, in the formula (1), R 2 is H, Me, Et or [ka] is.

[0011] In another embodiment, in the formula (1), R 3 is H or F.

[0012] In another embodiment, in the formula (1), R 4 teeth, [ka] where R 8 , R 9 are independently H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxyl.

[0013] In another embodiment, in the formula (1), R 5 is H, F, Cl or OMe.

[0014] In another embodiment, in the above formula (1), W is -O- or -NMe-.

[0015] In another embodiment, in the formula (1), Q is —O— or —NR 7 -, where R 7 H, Me, Et, n- Pr, I- Pr, t- Bu, i- Bu, [ka] and R 10 and 11 are independently H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxyl.

[0016] In some embodiments of the present invention, the above compounds, isomers or pharmaceutically acceptable salts are [ka] The file is TIFF0007746266000007.tif107151.

[0017] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of formula (1), or an optical isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as an active pharmaceutical ingredient.

[0018] Another object of the present invention is to provide the use of the compound or its optical isomer, pharmaceutically acceptable inorganic or organic salt for the treatment of fungal infections and related diseases. DETAILED DESCRIPTION OF THE INVENTION

[0019] It is to be understood that both the foregoing general description and the following detailed description of the invention are exemplary and illustrative, and are intended to provide further explanation of the scope of the invention as claimed.

[0020] Definitions and Explanations

[0021] Unless otherwise specified, the following terms and phrases as used herein are intended to have the meanings indicated below. Particular terms or phrases should not be considered indefinite or unclear in the absence of a specific definition, but should be understood in accordance with their ordinary definition. Product names provided herein are intended to refer to the corresponding product or its active pharmaceutical ingredients. The term "pharmaceutically acceptable," as employed herein, refers to compounds, combinations, and / or preparations that are, within the scope of sound medical judgment, applicable for exposure to human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0022] The term " pharmaceutically acceptable salt " refers to the form of existence of a compound that does not cause significant irritation to the applied organism and does not eliminate the biological activity and properties of the compound.In some specific embodiments, pharmaceutically acceptable salts are obtained by reacting the compound of formula (1) with acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids, and aspartic acid, glutamic acid and other acidic amino acids.

[0023] Reference to a pharmaceutically acceptable salt should be understood to include solvent addition forms or crystalline forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed upon crystallization with a pharmaceutically acceptable solvent, such as water or ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of the compound of formula (1) can be conveniently prepared or formed by the methods specified herein. For example, hydrates of the compound of formula (1) can be conveniently prepared by recrystallization in a water / organic solvent mixture using an organic solvent, including, but not limited to, acetonitrile, tetrahydrofuran, ethanol, or methanol. In addition, the compounds referred to herein can exist in both unsolvated and solvated forms. In other words, for the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0024] In another specific example, the compound of formula (1) is prepared in different forms, including, but not limited to, amorphous, milled, and nanoparticle forms. The compound of formula (1) may also have polymorphic forms, including crystalline forms. Polymorphism involves different lattice arrangements of a compound with the same elemental composition. Polymorphs typically differ in X-ray diffraction patterns, infrared spectroscopy, melting point, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in the predominance of a single crystalline form.

[0025] In another embodiment, the compounds of formula (1) may have one or more stereocenters, so that they may appear in the form of a racemate, a racemic mixture, a single enantiomer, a diastereomer, or a single diastereomer. Depending on the characteristics of each substituent on the molecule, asymmetric centers may exist. Each of these asymmetric centers independently generates two optical isomers, and all possible mixtures of optical isomers and diastereomers, as well as pure or partially pure compounds, are within the scope of the present invention. The present invention includes all such isomeric forms of these compounds.

[0026] Unless otherwise stated, the absolute configuration of the stereocenter is indicated by the wedge bond. [ka] and dashed bonds [ka] and wedge or dashed bonds [ka] is a wavy line [ka] It is expressed as:

[0027] The compounds specified in the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium ( 3 H), I-125( 125 I) or C-14( 14 The compounds can be labeled with radioactive isotopes, such as C. All isotopic compositions of the compounds specified herein, whether radioactive or not, are within the scope of the invention.

[0028] The compounds specified in the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, including pharmaceutically acceptable excipients or carriers for the compounds specified in the present invention and their pharmaceutically acceptable salts in a safe and effective amount range. Here, "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the patient's condition without causing serious side effects. The safe and effective amount of the compound is determined by the age, condition, and treatment history of the patient, as well as other specific conditions of the patient.

[0029] "Pharmacologically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that are applicable to human use and must have sufficient purity and sufficiently low toxicity. Pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0030] The compounds specified in the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0031] Unless otherwise specified, the term "alkyl" refers to saturated aliphatic groups, including C1-C6 straight and branched chains. C1-C4 lower alkyls, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl, are preferred. As used herein, "alkyl" includes unsubstituted and substituted alkyls, particularly alkyls substituted with one or several halogen atoms. Suitable alkyls include CH3, CH3CH2, CF3, CHF2, CH3CH2, i Pr, n Pr, i Bu, n Bu, or t It's Bu.

[0032] "Cycloalkyl" refers to a C3-C6 all-carbon monocyclic aliphatic group, a C6-C12 bicyclic aliphatic group, a C6-C12 bridged cyclic aliphatic group, or a C6-C12 spiral cyclic aliphatic group, where one or more rings may contain one or more double bonds, but none of them has a completely conjugated π-electron system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene, etc.

[0033] "Alkoxyl" refers to an alkyl-O- group bonded to the matrix by oxygen. (C1-C3)alkoxyl-(C2-C3)alkyl- is a group formed by the bond between (C1-C3)alkoxyl and -(C2-C3)alkyl, which is bonded to the matrix by the (C2-C3)alkyl. (C3-C6)cycloalkyl-(C1-C3)alkyl- is a group formed by the bond between (C3-C6)cycloalkyl and (C2-C3)alkyl, which is bonded to the matrix by the (C1-C3)alkyl.

[0034] "Aryl" refers to an aromatic monocyclic or polycyclic ring system. Preferred aryls include, but are not limited to, phenyl. "Heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one or several ring atoms. Preferred C5-C10 heteroaryls are pyridinyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridone, oxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, hydroxyindolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, and methylpyridinyl. These include, but are not limited to, thiazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazolopyridine, isoquinolinyl, benzoacazinyl, 1,2,4-triazinyl, benzothiazolyl, and oxides thereof.

[0035] Unless otherwise specified, the term "heterocycloalkyl" refers to a saturated or partially saturated non-aromatic cyclic group composed of carbon atoms and nitrogen, oxygen, or sulfur heteroatoms. Such cyclic groups may be monocyclic or polycyclic. In the present invention, the number of heteroatoms in a heterocycloalkyl is preferably 1, 2, 3, or 4, and the nitrogen, carbon, or sulfur atom in a heterocycloalkyl can be artificially oxidized. The nitrogen atom can be optionally substituted with other groups to form a tertiary amine or a quaternary ammonium salt. Examples of heterocycloalkyl include, but are not limited to, aziridinyl, azetidin-1-yl, N-alkylazetidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-S-oxid-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl, and the like.

[0036] Unless otherwise specified, the terms "halogenated" or "halogen" by themselves or as part of another substituent refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, "halogenated alkyl" is intended to include monohalogenated alkyl or polyhalogenated alkyl. For example, "halogenated C1-C3 alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloropropyl, and 3-bromopropyl, etc.

[0037] The term "membered ring" includes any ring structure. The term "membered" refers to the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridinyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.

[0038] The term "fragment" refers to a specific portion or functional group of a molecule. A chemical fragment is usually considered to be a chemical entity contained in or adsorbed to a molecule.

[0039] Preparation of compounds Methods for preparing compounds of formula (1) are described in detail below, but these specific methods do not constitute any limitations on the present invention.

[0040] Compounds of formula (1) can be synthesized by combining standard synthetic techniques or well-known techniques with the techniques herein, as described above. In addition, the solvents, temperatures, and other reaction conditions described herein can be varied. The starting materials used to synthesize the compounds listed in Table 1 can be synthesized or obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, WI) or Sigma Chemical Co. (St. Louis, MO). The compounds identified herein and other related compounds with different substituents can be synthesized using the methods described in March, Advanced Organic Chemistry 4. th Ed(Wiley 1992);Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, Protective Groups in Organic Synthesis 3 rd Ed., (Wiley 1999). The general methods for preparing the compounds can be modified by using appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0041] In one embodiment, the compounds specified herein are prepared by known methods for this process. However, the conditions of the process, such as reactants, solvents, alkalis, amounts of compounds used, reaction temperature, and reaction time, are not limited to those described below. The compounds specified in the present invention can also be easily prepared by any combination of various synthetic methods described herein or known in the art, and such combinations are easy for those skilled in the art to carry out. Meanwhile, the present invention also provides a method for preparing a compound represented by formula (1), which is described below as Method A.

[0042] Method A includes the following steps: first, compound A1 reacts with compound A2 under alkaline conditions to form compound A3, which is further converted to compound A4 under the influence of strong alkali; then, the protecting group is removed from compound A4 to form compound A5, which is then reacted with an appropriate starting material to form compound A7; finally, compound A7 reacts with compound A8 to form target compound A9. [ka]

[0043] In the above reaction, W, R 1 , R 2 , R 3 , R 4 , R 5 and R 7 is as defined above.

[0044] It should be noted that the above features mentioned in the present invention or the features mentioned in the examples can be randomly combined. All features disclosed herein can be used in any combination, and each feature disclosed herein can be replaced by any alternative feature serving the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely generic examples for equivalent or similar features.

[0045] All the specific aspects, features and advantages of the above-mentioned compounds, methods and drug combinations will be detailed in the following description in order to clarify the content of the present invention.It should be understood in this specification that the following detailed description and examples describe specific examples that are used for reference only.After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations are also within the scope defined by this application.

[0046] For all examples, 1 H-NMR was recorded on a Vian Mercury 400 NMR spectrometer, and chemical shifts are expressed in δ (ppm). If not specified, the silica gel for separation was 200–300, and the eluent ratio was by volume.

[0047] In the present invention, the following abbreviations are used: ACN is acetonitrile, Ar is argon, CDCl3 is deuterated chloroform, CD3OD is deuterated methanol, (COCl)2 is oxalyl chloride, DCM is dichloromethane, DIPEA is diisopropylethylamine, Diox or Dioxane is 1,4-dioxane, DMF is dimethylformamide, DMSO is dimethylsulfoxide, EA or EtOAc is ethyl acetate, EtOH is ethanol, h is hour, H2 is hydrogen, HOAc is acetic acid, K2CO3 is potassium carbonate, KI is potassium iodide, K3PO4 is is potassium phosphate, LC-MS is liquid chromatography-mass spectrometry, LiOH is lithium hydroxide, mL is methanol, MeOH is methanol, MgCl2 is magnesium chloride, min is minute, MS is mass spectrometry, NaBH(OAc)3 is sodium triacetoxyborohydride, NaH is sodium hydride, NaNO2 is sodium nitrite, Na2SO4 is sodium sulfate, NMR is nuclear magnetic resonance, PD2(dba)3 is tris(dibenzylideneacetone)-dipalladium, PE is petroleum ether, SOCl2 is dichlorosulfoxide,t- BuONa is sodium tert-butoxide, TEA is triethylamine, THF is tetrahydrofuran, Toluene is toluene, TsCl is p-toluenesulfonyl chloride, and Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. [Example]

[0048] Specific examples

[0049] Example 1: Compound 1 [ka]

[0050] Synthetic Route [ka]

[0051] Step 1: Preparation of Compound 1-1 tert-Butyl 3-hydroxymethylpiperazine-1-formate (1.0 g, 4.63 mmol) and 1,2-difluoro-4-nitrobenzene (809 mg, 5.1 mmol) were dissolved in DMF (20 mL). DIPEA (1.8 g, 13.89 mmol) was added to this solution and heated to 120 °C overnight. After the reaction was completed as monitored by LC-MS, water (100 mL) was added to the reaction mixture and extracted with EA (50 mL x 2). The combined organic phases were rinsed with saturated brine (50 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated, and the residue was purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to give a yellow solid compound (600 mg, 60% yield). ESI-MS m / z: 356.1 [M+H] + .

[0052] Step 2: Preparation of Compound 1-2 Compound 1-1 (3.6 g, 10 mmol) was dissolved in DMF (30 mL), and NaH (60% content, 440 mg, 11 mmol) was added to the solution in an ice-salt bath. The reaction mixture was heated to 80 °C overnight. After completion of the reaction as monitored by LC-MS, the reaction mixture was cooled, poured into ice-water (100 mL), and extracted with EA (50 mL x 2). The combined organic phases were then rinsed successively with water (150 mL x 2) and saturated brine (50 mL). After drying over anhydrous Na2SO4, the filtrate was concentrated, and the residue was subjected to column chromatography (PE / EA = 20 / 1 to 10 / 1) to give a yellow solid compound (2.1 g, 62% yield). ESI-MS m / z: 336.1 [M+H] + .

[0053] Step 3: Preparation of Compounds 1-3 Compound 1-2 (2.0 g, 6.0 mmol) was dissolved in EA (40 mL). HCl / dioxane solution (4.0 M, 10 mL) was added to this solution and stirred at room temperature for 3 hours. After the reaction was completed by LC-MS monitoring, the reaction solution was directly concentrated to obtain a yellow solid crude product (2.0 g, 100% yield), which was used directly in the next reaction without purification. ESI-MS m / z: 236.1 [M+H] + .

[0054] Step 4: Synthesis of Compounds 1-4 The crude product 1-3 (2.0 g, 6.0 mmol) obtained in the previous step was suspended in diethylene glycol dimethyl ether (20 mL). 2-Chloro-5-fluoropyrimidine (875 mg, 6.6 mmol) and anhydrous K2CO3 (4.15 g, 30 mmol) were added to this solution, which was then heated to 100 °C and reacted for 6 h. After completion of the reaction monitored by LC-MS, the reaction solution was cooled and filtered. The resulting filter cake was pulped with cold water (10 mL), the solution was filtered, and the resulting filter cake was rinsed successively with water and PE. After drying, a yellow solid (1.6 g, 80% yield) was obtained. ESI-MS m / z: 332.1 [M+H] + .

[0055] Step 5: Preparation of Compounds 1-5 The crude product 1-4 (1.6 g, 4.8 mmol) obtained in the previous step was dissolved in MeOH (20 mL). Pd / C (10%, 200 mg) was added to this solution and the mixture was allowed to react overnight at room temperature. After the reaction was monitored by LC-MS, the reaction solution was filtered and the filtrate was concentrated to give a pale yellow solid (1.1 g, 79% yield). ESI-MS m / z: 302.1 [M+H] + .

[0056] Step 6: Preparation of Compound 1 The crude product 1-5 (300 mg, 1 mmol) obtained in the previous step was dissolved in DCM (20 mL). Under Ar protection, TEA (202 mg, 2.0 mmol) was added to this solution. After cooling to 0 °C in an ice-salt bath, a DCM solution of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (314 mg, 1.2 mmol; see WO2009130481 for synthesis) was added dropwise and allowed to react at room temperature for 30 min. After completion of the reaction monitored by LC-MS, the reaction solution was quenched with ice water. After separation, the aqueous phase was extracted with DCM (20 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a pale yellow solid (260 mg, 49% yield).

[0057] 1 H NMR(400MHz,DMSO-d6)δ:10.25(s,1H),8.79(s,2H),7.55-7.43(m,5H),7.17-7. 08(m,2H),6.79(d,J=8.9Hz,1H),6.32(s,1H),4.58(dd,J=12.1,1.5Hz,1H),4.21 (d,J=11.5Hz,1H),3.87(t,J=9.8Hz,1H),3.78(s,3H),3.64(d,J=11.6Hz,1H),2. 96(t,J=9.9Hz,1H),2.79(d,J=12.1,2H),2.61-2.51(m,2H),2.19(s,3H);ESI-MS m / z: 527.2 [M+H] + .

[0058] Using different chiral starting materials or chiral separation methods, two optical isomers of compound 1, having the structural formula shown below, can be obtained. [ka]

[0059] Example 2: Compound 2 [ka]

[0060] Preparation route: [ka]

[0061] Step 1: Preparation of Compound 2-1 Compound 1-3 (705 mg, 3.0 mmol), 2-bromo-4,6-dimethylpyridine (670 mg, 3.6 mmol), sodium tert-butoxide (721 mg, 7.5 mmol), and BINAP (187 mg, 0.3 mmol) were dissolved in Toluene (50 mL). Under Ar protection, the solution was heated to 100 °C and reacted overnight. After completion of the reaction monitored by LC-MS, the reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to give a yellow solid (360 mg, 35% yield). ESI-MS m / z: 341.1 [M+H] + .

[0062] Step 2: Preparation of Compound 2-2 The crude product 2-1 (360 mg, 1.06 mmol) obtained in the previous step was dissolved in MeOH (20 mL). Pd / C (10%, 50 mg) was added to this solution, and H2 was introduced and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction monitored by LC-MS, the reaction solution was filtered, and the filtrate was concentrated to give a pale yellow solid crude product (270 mg, 82% yield). ESI-MS m / z: 311.1 [M+H] + .

[0063] Step 3: Preparation of Compound 2 The crude product 2-2 (250 mg, 0.8 mmol) obtained in the previous step was dissolved in DCM (20 mL). Under Ar protection, TEA (162 mg, 1.6 mmol) was added to this solution, and the mixture was cooled to 0 °C in an ice-salt bath. A DCM solution of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (261 mg, 1 mmol; see WO2009130481 for synthesis method) was added dropwise and reacted at room temperature for 30 min. After the reaction was monitored by LC-MS, ice water was added to the reaction solution to quench the reaction. After separation, the aqueous phase was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (CHCl2 / MeOH = 100 / 1 to 20 / 1) to give a pale yellow solid (160 mg, yield 37%).

[0064] 1 H NMR(400MHz,DMSO-d6)δ:10.20(s,1H),7.54-7.42(m,5H),7.16-7.06(m,2H),6.78(d,J =8.9Hz,1H),6.66(s,1H),6.40(s,1H),6.25(s,1H),4.54(dd,J=11.5,1.5Hz,1H),4.25( d,J=11.5Hz,1H),3.89(t,J=9.8Hz,1H),3.76(s,3H),3.60(d,J=11.6Hz,1H),2.9(t,J= 9.9Hz,1H),2.76(d,J=11.9Hz,2H),2.65-2.50(m,5H),2.45(s,3H),2.19(s,3H);ESI-MS m / z:536.2[m+H] + .

[0065] Using different chiral starting materials or chiral separation methods, two optical isomers of compound 2, which has the structural formula shown below, can be obtained. [ka]

[0066] Example 3: Compound 3 [ka]

[0067] Compound 3 can be prepared in the same manner as in Example 2, except that the starting material, 2-bromo-4,6-dimethylpyridine, is replaced with 2-bromo-6-methylpyridine.

[0068] 1 H NMR(400MHz,DMSO-d6)δ:10.22(s,1H),7.56-7.41(m,6H),7.15(s,1H),7.04(d,J=8.9Hz,1H),6. 77(d,J=8.9Hz,1H),6.67(d,J=8.9Hz,1H),6.41(d,J=8.9Hz,1H),6.24(s,1H),4.55(dd,J=11.5, 1.5Hz,1H),4.26(d,J=11.5Hz,1H),3.88(t,J=9.8Hz,1H),3.80(s,3H),3.63(d,J=11.6Hz,1H),2 .95(t,J=9.9Hz,1H),2.77(d,J=11.7Hz,2H),2.62-2.51(m,2H),2.45(s,3H),2.19(s,3H);ESI-MS m / z:522.2[m+H] + .

[0069] Example 4: Compound 4 [ka]

[0070] Compound 4 can be prepared in the same manner as in Example 1, except that the starting material 2-chloro-5-fluoropyrimidine is replaced with 2-chloropyrimidine.

[0071] 1H NMR(400MHz,DMSO-d6)δ:10.23(s,1H),8.50(d,J=9.3Hz,2H),7.56-7.43(m, 5H),7.13(s,1H),7.02(d,J=8.8Hz,1H),6.87-6.80(m,2H),6.25(s,1H),4.52 (dd,J=11.0,1.5 Hz,1H),4.23 (d,J=11.2 Hz,1H),3.86 (t,J=9.8 Hz,1H),3.81 (s,3H),3.62 (d,J=11.5 Hz,1H),2.96 (t,J=9.9 Hz,1H),2.80 (d,J=11.7 Hz,2H),2.65-2.53 (m,2H),2.19 (s,3H); ESI-MS m / z: 509.2 [m+H] + .

[0072] Example 5: Compound 5 [ka]

[0073] Compound 5 can be prepared in the same manner as in Example 2, except that the starting material, 2-bromo-4,6-dimethylpyridine, is replaced with 2-bromopyridine.

[0074] 1 H NMR (400 MHz,DMSO-d6) δ: 10.22 (s,1H),8.12 (d,J=9.5 Hz,1H),7.56-7.41 (m,6H),7.15 (s,1H),7.04 (d,J=8.9 Hz,1H),6.83-6.73 (m,2H),6.63 (d,J=8.9 Hz,1H),6.24 (s,1H),4.53 (dd,J=11.2,1.5 Hz,1H),4.25 (d,J=11.3 Hz,1H),3.87 (t,J=9.8 Hz,1H),3.79 (s,3H),3.62 (d,J=11.0 Hz,1H),2.96 (t,J=9.9 Hz,1H),2.78 (d,J=11.7 Hz,2H),2.62-2.53 (m,2H),2.18 (s,3H); ESI-MS m / z: 508.2 [m+H] + ..

[0075] Example 6: Compound 6 [ka]

[0076] Preparation route: [ka]

[0077] Step 1: Preparation of Compound 6-1 Compound 1-3 (705 mg, 3.0 mmol) and isobutyraldehyde (325 mg, 4.5 mmol) were dissolved in 1,2-dichloroethane (30 mL). HOAc was added to the solution and stirred at room temperature for 1 hour. NaBH(OAc)3 was added and the reaction was allowed to proceed overnight at room temperature. After the reaction was monitored by LC-MS, the reaction solution was diluted with DCM, rinsed with saturated aqueous NaHCO3, and separated. The organic phase was then concentrated, and the residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a yellow solid (350 mg, 40% yield). ESI-MS m / z: 292.1 [M+H] + .

[0078] Step 2: Preparation of Compound 6-2 The crude product 6-1 (300 mg, 1.03 mmol) obtained in the previous step was dissolved in MeOH (20 mL). Pd / C (10%, 60 mg) was added to this solution, and H2 was introduced and the mixture was allowed to react overnight at room temperature. After the reaction was monitored by LC-MS, the reaction solution was filtered and the filtrate was concentrated to give a pale yellow solid (200 mg, 74% yield). ESI-MS m / z: 262.1 [M+H] + .

[0079] Step 3: Preparation of Compound 6 The crude product 6-2 (200 mg, 0.76 mmol) obtained in the previous step was dissolved in DCM (20 mL). Under Ar protection, TEA (162 mg, 1.6 mmol) was added to this solution, and the mixture was cooled to 0 °C in an ice-salt bath. A DCM solution of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (260 mg, 1 mmol; see WO2009130481 for synthesis method) was added dropwise and reacted at room temperature for 30 min. After the reaction was monitored by LC-MS, ice water was added to the reaction solution to quench the reaction. After separation, the aqueous phase was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a pale yellow solid (120 mg, yield 32%).

[0080] 1 H NMR (400 MHz,DMSO-d6) δ: 10.25 (s,1H),7.54-7.42 (m,5H),7.11 (s,1H),7.03 (d,J=9.5 Hz,1H),6.78 (d,J=9.4 Hz,1H),6.25 (s,1H),4.54 (dd,J=11.5,1.5 Hz,1H),4.25 (d,J=11.5 Hz,1H),3.89 (s,3H),3.21-3.15(m,1H),2.96 (t,J=9.9 Hz,1H),2.76 (d,J=11.9 Hz,2H),2.61-2.50 (m,2H),2.19 (s,3H),2.09- 2.00 (m,2H),1.65-1.55 (m,2H),0.91 (ss,6H); ESI-MS m / z: 487.2 [M+H] + .

[0081] Example 7: Compound 7 [ka]

[0082] Compound 7 can be obtained by the same production method as in Example 6, except that the starting material isobutyraldehyde is replaced with cyclopropylformaldehyde.

[0083] 1 H NMR (400 MHz,DMSO-d6) δ: 10.23 (s,1H),7.55-7.43 (m,5H),7.12 (s,1H),7.02 (d,J=9.5 Hz,1H),6.79 (d,J=9.4 Hz,1H),6.24 (s,1H),4.53 (dd,J=11.5,1.5 Hz,1H),4.23 (d,J=11.5 Hz,1H),3.87 (s,3H),3.21-3.13(m,1H),2.95 (t,J=9.9 Hz,1H),2.74 (d,J=11.9 Hz,2H),2.61-2.52 (m,2H),2.18 (s,3H),2.09- 2.01 (m,2H),1.63~1.53(m,1H),1.15~1.23(m,1H),0.55~0.45(m,2H),0.32~0.23(m,2H); ESI‐MS m / z:485.2[M+H] + .

[0084] Example 8: Compound 8 [ka]

[0085] Compound 8 can be prepared in the same manner as in Example 6, except that the starting material isobutyraldehyde is replaced with pivalaldehyde.

[0086] 1H NMR(400 MHz,DMSO-d6) δ: 10.24 (s,1H),7.54-7.43 (m,5H),7.10 (s,1H),7.01 (d,J=9.5 Hz,1H),6.77 (d,J=9.4 Hz,1H),6.25 (s,1H),4.52 (dd,J=11.5,1.5 Hz,1H),4.24 (d,J=11.5 Hz,1H),3.86 (s,3H),3.20-3.12 (m,1H),2.92 (t,J=9.9 Hz,1H),2.72 (d,J=11.9 Hz,2H),2.60-2.49 (m,2H),2.17 (s,3H),2.10- 2.01 (m,2H),1.65-1.52 (m,1H),1.15-1.02(m,9H);ESI-MS m / z:501.2[M+H] + .

[0087] Example 9: Compound 9 [ka]

[0088] Compound 9 can be obtained by the same preparation method as in Example 1, except that the starting material 3,4-difluoronitrobenzene is replaced with 2,4,5-trifluoronitrobenzene.

[0089] 1 H NMR (400 MHz,DMSO-d6) δ: 10.28 (s,1H),8.78 (s,2H),7.53-7.42 (m,5H),7.06 (s,1H),6.93 (d,J=10.2 Hz,1H),6.30 (s,1H),4.57 (dd,J=11.1,1.5 Hz,1H),4.21 (d,J=11.5 Hz,1H),3.86 (t,J=9.7 Hz,1H),3.79 (s,3H),3.65 (d,J=11.6 Hz,1H),2.95 (t,J=9.9 Hz,1H),2.78 (d,J=12.1,2H),2.61-2.52 (m,2H),2.19 (s,3H); ESI-MS m / z: 545.2 [M+H] + .

[0090] Example 10: Compound 10 [ka]

[0091] Compound 10 can be obtained by the same production method as in Example 1, except that the raw material 3,4-difluoronitrobenzene is replaced with 2-nitro-4,5-difluorotoluene.

[0092] 1 H NMR (400 MHz,DMSO-d6) δ: 10.26 (s,1H),8.78 (s,2H),7.53-7.43 (m,5H),7.03 (s,1H),6.87 (s,1H),6.26 (s,1H),4.57 (dd,J=11.1,1.5 Hz,1H),4.21 (d,J=11.5 Hz,1H),3.86 (t,J=9.7 Hz,1H),3.79 (s,3H),3.65 (d,J=11.6 Hz,1H),2.95 (t,J=9.9 Hz,1H),2.78 (d,J=12.1,2H),2.61-2.50 (m,2H),2.19 (s,3H),2 .11 (s,3H); ESI-MS m / z: 541.2 [M+H] + .

[0093] Example 11: Compound 11 [ka]

[0094] Compound 11 can be obtained by the same preparation method as in Example 1, except that the starting material 3,4-difluoronitrobenzene is replaced with 2-nitro-4,5-difluoroanisole.

[0095] 1H NMR (400 MHz,DMSO-d6) δ: 10.25 (s,1H),8.77 (s,2H),7.53-7.42 (m,5H),7.09 (s,1H),6.55 (s,1H),6.26 (s,1H),4.58 (dd,J=11.2,1.5 Hz,1H),4.22 (d,J=11.5 Hz,1H),3.87-3.82 (m,4H),3.79 (s,3H),3.65 (d,J=11.5 Hz,1H),2.95 (t,J=9.5 Hz,1H),2.78 (d,J=11.6,2H),2.62-2.50 (m,2H),2.17 (s,3H); ESI-MS m / z: 557.2 [M+H] + .

[0096] Example 12: Compound 12 [ka]

[0097] Preparation route: [ka]

[0098] Step 1: Preparation of Compound 12-1 tert-Butyl 4-(2-fluoro-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-formate (3.55 g, 10 mmol) was dissolved in DCM (50 mL). DIPEA (2.6 g, 20 mmol) and TsCl (2.3 g, 12 mmol) were added successively to this solution, and the mixture was stirred overnight at room temperature. After the reaction was monitored by LC-MS, the reaction mixture was added to water (50 mL) and separated. The aqueous layer was then extracted with DCM (30 mL). The combined organic phases were rinsed successively with water (50 mL) and saturated brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to give a pale yellow jelly (4.0 g, 78% yield). ESI-MS m / z: 510.1 [M+H] + .

[0099] Step 2: Preparation of Compound 12-2 Compound 12-1 (1.4 g, 2.75 mmol) was dissolved in EtOH (20 mL). Then, methylamine alcohol solution (25%-30%, 1.8 g, ca. 55 mmol) was added to this solution, and the reaction was carried out overnight at 80 °C in a sealed tube. After the reaction was monitored by LC-MS, the reaction solution was concentrated, and the residue was purified by column chromatography (PE / EA = 5 / 1-1 / 1) to obtain a yellow jelly (480 mg, 50% yield). ESI-MS m / z: 349.1 [M+H] + .

[0100] Step 3: Preparation of Compound 12-3 Compound 12-2 (3.48 g, 10.0 mmol) was dissolved in EA (50 mL), and then HCl / dioxane (4.0 M, 15 mL) was added to the solution and stirred at room temperature for 3 h. After the reaction was completed as monitored by LC-MS, the reaction solution was directly concentrated to give a yellow solid crude product (3.5 g, 100% yield), which was used directly in the next reaction without purification. ESI-MS m / z: 249.1 [M+H] + .

[0101] Step 4: Preparation of Compound 12-4 The crude product 12-3 (2.1 g, 6.0 mmol) obtained in the previous step was suspended in diethylene glycol dimethyl ether (20 mL). 2-Chloro-5-fluoropyrimidine (875 mg, 6.6 mmol) and anhydrous K2CO3 (4.15 g, 30 mmol) were added to the suspension, and the mixture was heated to 100 °C for 6 h. After the reaction was monitored by LC-MS, the reaction solution was cooled and filtered. The resulting filter cake was pulped with cold water (10 mL). This solution was filtered, and the resulting filter cake was rinsed successively with water and PE and dried to give a yellow solid (1.5 g, 72% yield). ESI-MS m / z: 345.1 [M+H] + .

[0102] Step 5: Preparation of Compound 12-5 The crude product 12-4 (1.5 g, 4.36 mmol) obtained in the previous step was dissolved in methanol (20 mL). Pd / C (10%, 200 mg) was added to this solution, and H2 was introduced and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction monitored by LC-MS, the reaction solution was filtered, and the filtrate was concentrated to give a pale yellow solid (1.0 g, 73% yield). ESI-MS m / z: 315.1 [M+H] + .

[0103] Step 6: Preparation of Compound 12 The crude product 12-5 (167 mg, 0.5 mmol) obtained in the previous step was dissolved in DCM (15 mL). Under Ar protection, TEA (101 mg, 1.0 mmol) was added to this solution, and the mixture was cooled to 0 °C in an ice-salt bath. A DCM solution of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (167 mg, 0.6 mmol, see WO2009130481 for synthesis method) was added dropwise and reacted at room temperature for 30 min. After the reaction was monitored by LC-MS, ice water was added to the reaction solution to quench the reaction. After separation, the aqueous phase was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a pale yellow solid (100 mg, 37% yield).

[0104] 1 H NMR (400 MHz,DMSO-d6) δ: 10.25 (s,1H),8.76 (s,2H),7.55-7.43 (m,5H),6.71-6.65 (m,3H),6.25 (s,1H),3.86 (s,3H),3.64 (d,J=12.3 Hz,1H),3.22-3.11 (m,2H),3.02 (d,J=10.1 Hz,2H),2.97-2.81 (m,3H),2.75-2.65 (m,4H),2.19 (s,3H); ESI-MS m / z: 540.2 [m+H] + .

[0105] The two optical isomers of compound 12, having the structural formula shown below, can be obtained using different chiral starting materials or chiral separation methods. [ka]

[0106] Example 13: Compound 13 [ka]

[0107] Preparation route: [ka]

[0108] Step 1: Preparation of Compound 13-1 Compound 12-3 (745 mg, 3.0 mmol), 2-bromo-4,6-dimethylpyridine (670 mg, 3.6 mmol), sodium tert-butoxide (721 mg, 7.5 mmol), and BINAP (187 mg, 0.3 mmol) were dissolved in toluene (50 mL). Under Ar protection, the solution was heated to 100 °C and reacted overnight. After completion of the reaction monitored by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to give a yellow solid (300 mg, 28% yield). ESI-MS m / z: 354.1 [M+H] + .

[0109] Step 2: Preparation of Compound 13-2 Compound 13-1 (300 mg, 0.85 mmol) obtained in the previous step was dissolved in MeOH (20 mL). Pd / C (10%, 60 mg) was added to this solution, and H2 was introduced and the reaction was allowed to proceed overnight at room temperature. After the reaction was monitored by LC-MS, the reaction solution was filtered, and the filtrate was concentrated to give a pale yellow solid crude product (200 mg, 72% yield). ESI-MS m / z: 324.1 [M+H] + .

[0110] Step 3: Preparation of Compound 13 The crude product 13-2 (200 mg, 0.62 mmol) obtained in the previous step was dissolved in DCM (20 mL). Under Ar protection, TEA (132 mg, 1.3 mmol) was added to this solution, and the mixture was cooled to 0 °C in an ice-salt bath. A DCM solution of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (261 mg, 1 mmol; see WO2009130481 for synthesis method) was added dropwise and reacted at room temperature for 30 min. After the reaction was monitored by LC-MS, ice water was added to the reaction solution to quench the reaction. After separation, the aqueous phase was extracted with DCM (20 mL × 2). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a pale yellow solid (100 mg, 29% yield).

[0111] 1 H NMR (400 MHz,DMSO-d6) δ: 10.22 (s,1H),7.54-7.42 (m,5H),6.75-7.68 (m,4H),6.43 (s,1H),6.25 (s,1H),3.85 (s,3H),3.65 (d,J=11.8 ESI-MS m / z: 549.2 [M+H] + .

[0112] Using different chiral starting materials or chiral separation methods, two optical isomers of compound 13, which has the structural formula shown below, can be obtained. [ka]

[0113] Example 14: Compound 14 [ka]

[0114] Preparation route: [ka]

[0115] Step 1: Preparation of Compound 14-1 Diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (6 g, 20 mmol) was dissolved in THF (50 mL). The solution was cooled to 0 °C in an ice-salt bath, and NaH (1.2 g, 30 mmol, 60%) was added in batches. The mixture was heated to room temperature and stirred for 1 h. The solution was then cooled to 0 °C again, and Mel (8.5 g, 60 mmol) was added. The mixture was allowed to react overnight at room temperature. After the reaction was monitored by LC-MS, the reaction mixture was quenched with cold dilute hydrochloric acid (pH 7-8) and concentrated. The residue was then added to DCM (80 mL), and after separating the solution, the aqueous phase was extracted with DCM (50 mL*2), and the organic phases were combined and rinsed successively with water (100 mL) and saturated brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to give a pale yellow solid (5.9 g, 90% yield), which was used directly in the next reaction. ESI-MS m / z: 330.1 [M+H] + .

[0116] Step 2: Preparation of Compound 14-2 Compound 14-1 (5.9 g, 18 mmol) was dissolved in EtOH (100 mL). To this solution was added a solution of NaOH (4.32 g, 108 mmol) in water (100 mL), heated to reflux, and allowed to react overnight. After the reaction was completed as monitored by LC-MS, EtOH was removed by rotary evaporation, and the solution was adjusted to pH 2 with concentrated hydrochloric acid in an ice-salt bath to produce a solid precipitate, which was stirred for 1 hour and filtered. The filter cake was then rinsed successively with water and PE and dried to give a pale yellow solid (3.4 g, 70% yield). The crude product was used directly in the next reaction. ESI-MS m / z: 274.1 [M+H] + .

[0117] Step 3: Preparation of Compound 14-3 Compound 14-2 (5.8 g, 21.2 mmol) was suspended in ethanolamine (15 mL). The solution was heated to 175 °C under Ar protection and reacted for 1 h. After the reaction was completed as monitored by LC-MS, the reaction solution was cooled, diluted with water (30 mL), and extracted with EA (20 mL × 2). The organic phases were then combined, rinsed successively with water (20 mL) and saturated brine (20 mL), dried, concentrated, and the residue was subjected to neutral alumina column chromatography to give an off-white solid (2.8 g, 71% yield). ESI-MS m / z: 186.1 [M+H] + .

[0118] Step 4: Preparation of Compound 14-4 Compound 14-3 (556 mg, 3 mmol) was dissolved in DCM (10 mL). Under Ar protection, the solution was cooled to 0 °C in an ice-salt bath, and then (COCl) (419 mg, 3.3 mmol) was added dropwise and reacted at room temperature for 1 h. After completion of the reaction monitored by LC-MS, the reaction solution was concentrated to give a brownish-yellow oil (248 mg, 90% yield), which was used directly in the next reaction.

[0119] Step 5: Preparation of Compound 14 Compound 1-5 (300 mg, 1 mmol) was dissolved in DCM (20 mL). Under Ar protection, TEA (202 mg, 2.0 mmol) was added to this solution, which was then cooled to 0 °C in an ice-salt bath. Compound 14-4 (331 mg, 1.2 mmol) was added dropwise and reacted at room temperature for 30 min. After completion of the reaction monitored by LC-MS, the reaction solution was quenched with ice water and separated. The aqueous phase was then extracted with DCM (20 mL x 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a pale yellow solid (270 mg, 50% yield).

[0120] 1H NMR (400 MHz, DMSO-d6) δ: 10.26 (s,1H),8.79 (s,2H),7.55-7.43 (m,5H),7.17-7.08 (m,2H),6.79 (d,J=9.2 Hz,1H),6.32 (s,1H),4.57 (dd,J=12.1,1.5 Hz,1H),4.25-4.15 (m,3H),3.87 (t,J=9.8 Hz,1H),3.64 (d,J=11.6 Hz,1H),2.96 (t,J=9.9 Hz,1H),2.76 (d,J=12.1,2H),2.62-2.52 (m,2H),2.18 (s,3H),1.22 (t,3H); ESI-MS m / z: 541.2 [M+H] + .

[0121] Example 15: Compound 15 [ka]

[0122] Compound 15 can be obtained by the same production method as in Example 14, except that the starting material iodoethane is replaced with isobutyl bromide.

[0123] 1 H NMR (400 MHz,DMSO-d6) δ: 10.25 (s,1H),8.78 (s,2H),7.55-7.43 (m,5H),7.15-7.06 (m,2H),6.78 (d,J=9.2 Hz,1H),6.28 (s,1H),4.57 (dd,J=12.1,1.5 Hz,1H),4.25-4.15 (m,3H),3.86 (t,J=9.8 Hz,1H),3.64 (d,J=11.6 Hz,1H),2.96 (t,J=9.9 Hz,1H),2.76 (d,J=12.1,2H),2.57-2.48 (m,2H),2.18 (s,3H),2.02-1.98 (m,1H),1.12 (ss,6H); ESI-MS m / z: 569.2 [M+H] + .

[0124] Example 16: Compound 16 [ka]

[0125] Compound 16 can be obtained by the same production method as in Example 14, except that the starting material iodoethane is replaced with 2-bromoethyl methyl ether.

[0126] 1 H NMR (400 MHz,DMSO-d6) δ: 10.27 (s,1H),8.78 (s,2H),7.55-7.43 (m,5H),7.17-7.05 (m,2H),6.78 (d,J=9.8 Hz,1H),6.32 (s,1H),4.56-4.45 (m,2H),4.25-4.15 (m,2H),3.87 (t,J=9.8 Hz,1H),3.65-3.54 (m,3H),3.32 (s,3H),2.96 (t,J=9.9 Hz,1H),2.75 (d,J=11.8,2H),2.61-2.51 (m,2H),2.18 (s,3H); ESI-MS m / z: 571.2 [M+H] + .

[0127] Example 17: Compound 17 [ka]

[0128] Preparation route: [ka]

[0129] Step 1: Preparation of Compound 17-1 2-Furoic acid (11.2 g, 0.1 mol) was dissolved in DCM (150 mL). SOCl2 (36 mL, 0.5 mol) was added to the solution, and the reaction was carried out overnight at room temperature. After the reaction was completed by LC-MS monitoring, the reaction solution was concentrated to give a light brown jelly (13 g, 100% yield), which was used directly in the next reaction.

[0130] Step 2: Preparation of Compound 17-2 Potassium salt of monoethyl malonate (13.4 g, 78.5 mmol) was dissolved in ACN (80 mL). TEA (11.7 mL, 84.3 mmol) and anhydrous MgCl2 (9.12 g, 95.8 mmol) were added sequentially at 10 °C. The reaction mixture was allowed to react at room temperature for 2.5 h. The reaction mixture was then cooled to 0 °C, and a solution of compound 17-1 (5 g, 38.3 mmol) in ACN (30 mL) was added dropwise and the mixture was allowed to react overnight at room temperature. After the reaction was monitored by LC-MS, the reaction mixture was concentrated, and the toluene residue was heated to reflux to dissolve the residue. The mixture was then cooled and acidified with 13% dilute hydrochloric acid (50 mL) at 0-5 °C. The mixture was stirred for approximately 15 min and separated. The organic phase was then rinsed successively with dilute hydrochloric acid (50 mL × 2) and water (25 mL × 2), concentrated, and the residue was then purified by column chromatography (PE / EA = 10 / 1 to 4 / 1) to give a grayish-yellow solid (5 g, 72% yield). ESI-MS m / z: 183.1 [M+H] + .

[0131] Step 3: Preparation of Compound 17-3 Compound 17-2 (9.1 g, 50 mmol) was dissolved in HOAc (25 mL). Aqueous NaNO2 (4.5 g, 65 mmol) solution (30 mL) was slowly added dropwise over 1 h while maintaining the temperature at 0-5 °C. After a solid precipitated during the addition, the mixture was heated to room temperature and stirred for approximately 30 min. Water (200 mL) was added and the mixture was stirred for another 30 min. After the reaction was monitored by LC-MS, the reaction solution was filtered and the filtrate was extracted with DCM (50 mL x 2). The organic phases were then combined, rinsed successively with water (50 mL x 2) and saturated brine (50 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to give a pale yellow solid (7 g, 66% yield). ESI-MS m / z: 212.1 [M+H] + .

[0132] Step 4: Preparation of Compound 17-4 Acetyl EA (7.25 g, 56 mmol), zinc powder (9.8 g, 151 mmol), and NaOAc (10.2 g, 121 mmol) were dissolved in HOAc. This solution was heated to 60 °C, and compound 7-3 in HOAc (10.6 g, 50 mmol) was added in three batches with vigorous stirring while rapidly increasing the temperature to approximately 90 °C. The reaction was allowed to proceed for 3 h while maintaining the temperature at 60-75 °C. Zinc powder (4.9 g, 75 mmol) was then added and the reaction was continued for approximately 1 h. After completion of the reaction as monitored by LC-MS, the reaction solution was cooled, filtered, and the filtrate was concentrated by azeotropy with toluene to remove residual HOAc. Water (200 mL) and EA (50 mL) were added, stirred, and separated. The aqueous phase was then extracted with EA (30 mL × 2), and the combined organic phases were rinsed successively with aqueous sodium bicarbonate (100 mL × 2), water (100 mL × 2), and saturated brine (100 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated, and the residue was pulped with DCM / PE (1 / 6, 15 mL), filtered, and a pale yellow solid (5.8 g, 40% yield) was obtained. ESI-MS m / z: 292.1 [M+H] + .

[0133] Step 5: Preparation of Compound 17-5 Compound 17-4 (5.8 g, 20 mmol) was dissolved in THF (50 mL). The solution was cooled to 0 °C in an ice-salt bath, and NaH (1.2 g, 30 mmol, 60%) was added in batches. The mixture was heated to room temperature and stirred for 1 h. The solution was then cooled to 0 °C again, and Mel (8.5 g, 60 mmol) was added. The mixture was then allowed to react at room temperature overnight. After the reaction was monitored by LC-MS, the reaction mixture was quenched with cold dilute hydrochloric acid (pH 7-8) and concentrated. The residue was then added to DCM (80 mL). After separating the mixture, the aqueous phase was extracted with DCM (50 mL x 2). The combined organic phases were rinsed successively with water (100 mL) and saturated brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to give a pale yellow solid (5.5 g, 90% yield), which was used directly in the next reaction. ESI-MS m / z: 306.1 [M+H] + .

[0134] Step 6: Preparation of Compound 17-6 Compound 17-5 (5.5 g, 18 mmol) was dissolved in EtOH (100 mL). To this solution was added a solution of NaOH (4.32 g, 108 mmol) in water (100 mL), heated to reflux, and allowed to react overnight. After completion of the reaction monitored by LC-MS, EtOH was removed by rotary evaporation, and the solution was adjusted to pH 2 with concentrated hydrochloric acid in an ice-salt bath to produce a solid precipitate, which was stirred for 1 hour and filtered. The filter cake was then rinsed successively with water and PE and dried to give a pale yellow solid (2.5 g, 55% yield). The crude product was used directly in the next reaction. ESI-MS m / z: 250.1 [M+H] + .

[0135] Step 7: Preparation of Compound 17-7 Compound 17-6 (2.5 g, 10 mmol) was suspended in ethanolamine (10 mL). The solution was heated to 175 °C under Ar protection and reacted for 1 h. After completion of the reaction monitored by LC-MS, the reaction solution was cooled, diluted with water (30 mL), and extracted with EA (20 mL × 2). The organic phases were then combined, rinsed successively with water (20 mL) and saturated brine (20 mL), dried, and concentrated. The residue was then purified by neutral alumina column chromatography (PE / EA = 10 / 1 to 4 / 1) to give an off-white solid (805 mg, 50% yield). ESI-MS m / z: 162.1 [M+H] + .

[0136] Step 8: Preparation of Compound 17-8 Compound 17-7 (805 mg, 5 mmol) was dissolved in DCM (10 mL). The solution was cooled to 0 °C in an ice-salt bath under Ar protection, and then oxalyl chloride (700 mg, 5.5 mmol) was added dropwise and reacted at room temperature for 1 h. After the reaction was completed by LC-MS monitoring, the reaction solution was concentrated to give a brownish-yellow oil (1.13 g, 90% yield), which was used directly in the next reaction.

[0137] Step 9: Preparation of Compound 17 Compounds 1-5 (300 mg, 1 mmol) were dissolved in DCM (20 mL). Under Ar protection, TEA (202 mg, 2.0 mmol) was added to this solution, which was then cooled to 0 °C in an ice-salt bath. A DCM solution of 2-(3-(furan-2-yl)-1,5-dimethyl-1H-pyrrolin-2-yl)-2-oxoacetyl chloride (compound 17-8, 300 mg, 1.2 mmol) was added and the mixture was allowed to react at room temperature for 30 min. After the reaction was monitored by LC-MS, the reaction mixture was quenched with ice water and separated. The oil phase was then extracted with DCM (20 mL x 2). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a pale yellow solid (200 mg, 39% yield).

[0138] 1 H NMR(400MHz,DMSO-d6)δ:10.25(s,1H),8.79(s,2H),7.72(s,1H),7.17-7.08( m,3H),6.76-6.68(m,2H),6.18(s,1H),4.56(dd,J=11.3,1.5Hz,1H),4.20(d,J =11.5Hz,1H),3.87(t,J=9.8Hz,1H),3.78(s,3H),3.64(d,J=11.6Hz,1H),2.96 (t,J=9.9Hz,1H),2.78(d,J=12.1,2H),2.61-2.53(m,2H),2.16(s,3H);ESI-MS m / z: 517.2 [m+H] + .

[0139] Example 18: Compound 18 [ka]

[0140] Compound 18 can be prepared in the same manner as in Example 17, except that the starting material 2-furoin is replaced with 3-thiophenemalonic acid.

[0141] 1H NMR(400MHz,DMSO-d6)δ:10.27(s,1H),8.79(s,2H),7.95(d,J=2.3Hz,1H),7.85(dd,J=11.5,2.3 Hz,1H),7.38(dd,J=11.3,2.4Hz,1H),7.17-7.08(m,2H),6.76(d,J=11.2Hz,1H),6.22(s,1H),4. 56(dd,J=11.3,1.5Hz,1H),4.20(d,J=11.5Hz,1H),3.87(t,J=9.8Hz,1H),3.78(s,3H),3.66(d,J =11.6Hz,1H),2.95(t,J=9.9Hz,1H),2.77(d,J=12.1,2H),2.61-2.52(m,2H),2.17(s,3H);ESI-MS m / z:533.2[m+H] + .

[0142] Example 19: Compound 19 [ka]

[0143] Compound 19 can be prepared in the same manner as in Example 17, except that the starting material 2-furoic acid is replaced with nicotinic acid.

[0144] 1 H NMR(400MHz,DMSO-d6)δ:10.28(s,1H),9.13(s,1H),8.79(s,2H),8.73(d,J=11.5Hz,1H),8.42( d,J=10.8Hz,1H),7.55-7.52(m,1H),7.18-7.07(m,2H),6.79(d,J=11.2Hz,1H),6.21(s,1H),4.5 5(dd,J=11.3,1.5Hz,1H),4.21(d,J=11.5Hz,1H),3.86(t,J=9.8Hz,1H),3.79(s,3H),3.67(d,J= ESI-MS m / z:528.2[M+H] + .

[0145] Example 20: In vitro minimum inhibitory concentration (MIC) test The strains used in this test were inoculated onto Sabouraud-dextrose agar medium and cultured at 35°C for 5 days. Next, 1 mL of 0.2% Tween® diluted with 0.85% sterile saline was added to the Sabouraud-dextrose agar medium, the plate was shaken, and the solution collected from the plate surface was transferred to a sterile test tube. The supernatant containing the bacteria was transferred to a sterile test tube as a complete suspension, and 0.4 x 10 6 CFU / mL ~ 5 × 10 6 Dilutions of CFU / mL are prepared. The strain dilutions prepared herein are diluted 1:100 in RPMI 1640 culture medium. These biological suspensions are added to the wells of the plates containing the drug dilutions. All plates are incubated at 35°C for 24-48 hours, and the growth of the strains is assessed by monitoring light at a wavelength of 485 nm for each well. The MIC of a compound is defined as the lowest drug concentration that inhibits growth of more than 80% of the strains compared to a drug-free negative control. A indicates an MIC value > 0.1 μg / mL, B indicates an MIC value > 0.01 μg / mL, and C indicates an MIC value < 0.01 μg / mL.

[0146] [Table 1]

[0147] The data in the above table reveal that compared to the clinically applied antifungal drug itraconazole, the compounds identified in the present invention have stronger in vitro minimum inhibitory concentrations, which is highly significant for developing new antifungal drugs.

Claims

1. A compound of formula (1), or an optical isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof. 【Chemical 1】 where "*" is a chiral center, R １ is H, C1-C6 alkyl, (C1-C3)alkoxyl-(C2-C3)alkyl-, (C3-C6)cycloalkyl-(C1-C3)alkyl-, C3-C6 cycloalkyl or halogenated C1-C6 alkyl; R ２ is H, C1-C3 alkyl or C3-C6 cycloalkyl, R ３ is H or a halogen, R ４ is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with 1 to 3 of the following substituents: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxyl, and when substituted with several substituents, the substituents may be the same or different; R ５ is H, Me, OMe, or halogen; W is —O— or —NR ６ -, where R ６ is H, C1-C3 alkyl or C3-C6 cycloalkyl, Q is —O— or —NR ７ -, where R ７ is H, C1-C3 alkyl, C3-C6 cycloalkyl, isobutyl, 【Chemistry 2】 A compound of formula (1), or an optical isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is (C3-C6)cycloalkyl-(C1-C3)alkyl-, heterocyclic alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1 to 3 of the following substituents: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxyl. When substituted with several substituents, the substituents may be the same or different.

2. In the formula (1), R １ is H, Me, Et, ｎ－ Pr, ｉ－ Pr, ｔ－ Bu, -CH ２ CH ２ OMe, 【Chemistry 2】 The compound of claim 1, wherein

3. In the formula (1), R ２ is H, Me, Et or 【Chemistry 3】 3. The compound according to claim 1 or 2, wherein

4. In the formula (1), R ３ The compound according to any one of claims 1 to 3, wherein is H or F.

5. In the formula (1), R ４ teeth, 【Chemistry 4】 and R ８ and ９ are independently H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxyl.

6. In the formula (1), R ５ The compound according to any one of claims 1 to 5, wherein is H, F, Cl or OMe.

7. The compound according to any one of claims 1 to 6, wherein in the formula (1), W is -O- or -NMe-.

8. In the formula (1), Q is —O— or —NR ７ - and R ７ is H, Me, Et, ｎ－ Pr, Ｉ－ Pr, 【Chemistry 5】 and R １０ and １１ are independently H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxyl, halogenated C1-C3 alkyl, or halogenated C1-C3 alkoxyl.

9. The compound is 【Chemistry 6】 【change】 6. The compound according to any one of claims 1 to 5, wherein:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, or an optical isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.

11. The pharmaceutical composition described in claim 10, wherein the pharmaceutical composition is used to prevent or treat a fungal infection.

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