Compound and use thereof

Abstract

Disclosed in the present invention are a compound and the use thereof, which belong to the field of medicinal chemistry. Further disclosed is the compound having a structure as shown in formula (I), or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound has a good PDE3 and / or PDE4 inhibitory effect, and can be used for treating PDE3 and / or PDE4-related conditions.

Description

A compound and its application

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on June 28, 2023, with application number 202310775924.8 and invention name “A compound and its application”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and in particular to a compound and application thereof. Background Art

[0003] Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), playing a crucial role in regulating cellular activity. Currently, there are 11 known members of the PDE family. PDE3 is primarily distributed in smooth muscle cells and participates in regulating cardiac contractility and vascular smooth muscle. Inhibition of PDE3 results in smooth muscle relaxation and bronchodilation. PDE4 is primarily distributed in various immune cells, airway epithelial cells, and fibroblasts. Inhibition of PDE4 can elevate cAMP levels in inflammatory and immunomodulatory cells, thereby suppressing inflammatory cell function and relaxing airway smooth muscle.

[0004] Chronic obstructive pulmonary disease (COPD) and asthma are common, complex inflammatory diseases of the respiratory tract characterized by airway obstruction. Currently, only roflumilast, a PDE inhibitor, has been approved for the clinical treatment of COPD. However, dose-dependent adverse reactions limit its widespread clinical use. Due to the limitations of using either PDE3 or PDE4 inhibitors alone, dual inhibition of PDE3 / PDE4 has emerged as a new strategy for the targeted treatment of COPD and asthma. A growing number of experiments have confirmed that dual-target PDE3 / PDE4 inhibitors exhibit synergistic inhibitory effects, resulting in both anti-inflammatory and bronchodilatory effects.

[0005] Ensifentrine (RPL554) is a novel inhaled PDE3 / PDE4 inhibitor for the treatment of COPD and asthma. It exhibits dual anti-inflammatory and bronchodilatory properties and is in Phase III clinical trials. However, data also show that its inhibitory activity against PDE4 is modest, and its anti-inflammatory effects are suboptimal. Therefore, there is a need to develop a PDE3 / PDE4 dual-target inhibitor with good tolerability, a broad therapeutic window, and a high safety profile, or a PDE3 or PDE4 inhibitor with minimal side effects.

[0006] Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a compound and its application. The compound has a good PDE3 and / or PDE4 inhibitory effect and can be used to treat diseases related to PDE3 and / or PDE4.

[0008] In order to achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0009] The present invention provides a compound having a structure represented by formula (I), or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0010] Among them, A 1 、A 2 is a nitrogen atom, A 3 For carbon atoms.

[0011] when is a single bond, When it is a double bond, R 2 Empty.

[0012] when is a double bond, When it is a single bond, R 1 Empty.

[0013] R 1 、R 2 、R 6 、R 7 Independently selected from hydrogen, substituted or unsubstituted straight chain or branched C 1～ C6 alkyl, substituted or unsubstituted C 2～ C6 alkenyl, substituted or unsubstituted C 2～ C6 alkynyl or C n H 2n R 8 .

[0014] n is selected from integers between 0 and 4.

[0015] R 8 is selected from substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR a 、-OC(O)R a 、-OC(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a Rb 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b C n H 2n R c 、-SR a 、-S(O)R a 、-S(O)NR a R b 、-S(O)2R a 、-S(O)2NR a R b 、-NR a S(O)2R b , -CN, -NH2, -CF3, or one or more thereof.

[0016] The 3- to 10-membered cycloalkyl groups include, but are not limited to, the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0017] The 4-10 membered heterocycloalkyl group includes but is not limited to the following substituted or unsubstituted groups: oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, dihydrofuranyl, imidazolinyl, tetrahydropyridinyl, dihydropyranyl, [1,2,4]triazolo[4,3-a]pyrazinyl, pyrroloimidazolyl, 2-keto-pyridinyl, 3-keto-pyridazinyl and the like.

[0018] The 6-10 membered aryl group includes, but is not limited to, substituted or unsubstituted phenyl or naphthyl.

[0019] The 5- to 10-membered heteroaryl groups include, but are not limited to, substituted or unsubstituted pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, and the like.

[0020] R3 、R 4 and R 5 Independently selected from hydrogen, halogen, substituted or unsubstituted straight chain or branched C 1～ One or more of C6 alkyl groups.

[0021] The straight chain or branched C 1～ The C6 alkyl group is preferably one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl and hexyl.

[0022] R a 、R b 、R c independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, methylimino, methoxyimino, methylsulfonyl, hydroxyl, cyano, nitro, substituted or unsubstituted straight chain or branched C 1～ C6 alkyl, substituted or unsubstituted C 1～ C4 alkoxy, substituted or unsubstituted C 2～ C6 alkenyl, substituted or unsubstituted C 2～ C6 alkynyl, one or more of substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl.

[0023] The C 1～ C4 alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0024] The C 1～ The scope of C6 alkyl is the same as above and will not be repeated here.

[0025] The C 2～ C6 alkenyl includes, but is not limited to, ethenyl, propenyl, 2-methylpropenyl, allyl, butenyl, 2-methylbutenyl, 2-ethylbutenyl, cyclopentenyl, cyclohexenyl, and the like.

[0026] The C 2～ C6 alkynyl includes, but is not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 4-methyl-1-butynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-propynyl, 1-hexyn, 2-hexyn, 3-hexyn, 4-methyl-1-pentyn, 3-methyl-1-pentyn, 4-methyl-2-pentyn, 2,2-dimethyl-1-butynyl, and the like.

[0027] The scope of the substituted or unsubstituted 3- to 10-membered cycloalkyl group, 4- to 10-membered heterocycloalkyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group is the same as above and will not be repeated here.

[0028] E 1 Selected from -(CH2) m -, where m is 1, 2, or 3.

[0029] E 2 Selected from -O-, -NH-, -S-, or -CR 9 R 10 -.

[0030] R 9 、R 10 independently selected from hydrogen, deuterium, substituted or unsubstituted straight chain or branched C 1～ One or more of C6 alkyl groups.

[0031] The C 1～ The preferred range of C6 alkyl is the same as above and will not be repeated here.

[0032] Or, R 6 and R 7 And the adjacent oxygen atoms and phenyl carbon atoms are connected to form a ring.

[0033] The ring is a substituted or unsubstituted 5-membered or 6-membered monocyclic heterocyclic group.

[0034] The 5-membered or 6-membered monocyclic heterocyclic group may be further fused or spiro-coupled with an aryl group, a heteroaryl group or a heterocycloalkyl group to form a fused ring group, a spiro ring group or a bridged ring group.

[0035] Preferably, the substituents of the substituted 3-10 membered cycloalkyl, substituted 4-10 membered heterocycloalkyl, substituted 6-10 membered aryl, substituted 5-10 membered heteroaryl are selected from deuterium, oxo, thio, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted straight chain or branched C 1～ C6 alkyl, substituted or unsubstituted C 3～ C 10 Cycloalkyl, substituted or unsubstituted C 2～ C6 alkenyl, substituted or unsubstituted C 2～ C6 alkynyl, C n H 2n OR a 、-C n H 2n OC(O)R a 、-C n H 2n OC(O)NR a R b 、-Cn H 2n C(O)R a 、-C n H 2n C(O)OR a 、-C n H 2n C(O)NR a R b 、-C n H 2n NR a R b 、-C n H 2n NR a C(O)R b 、-C n H 2n NR a C(O)OR b 、-C n H 2n NR a C(O)NR b C n H 2n R c 、-C n H 2n SR a 、 -C n H 2n S(O)R a 、-C n H 2n S(O)NR a R b 、-C n H 2n S(O)2R a 、-C n H 2n S(O)2NR a R b 、-C n H 2n NR a S(O)2R b 、-C n H 2n CN, -C n H 2n NH2, -C n H 2n One or more of CF3.

[0036] The present invention preferably, the above-mentioned substituted straight chain or branched C 1～ C6 alkyl, substituted C 1～ The substituents of the C4 alkoxy group are selected from deuterium, oxo, thio, halogen, hydroxy, cyano, nitro, Cn H 2n OR a 、-C n H 2n OC(O)R a 、-C n H 2n OC(O)NR a R b 、-C n H 2n C(O)R a 、-C n H 2n C(O)OR a 、-C n H 2n C(O)NR a R b 、-C n H 2n NR a R b 、-C n H 2n NR a C(O)R b 、-C n H 2n NR a C(O)OR b 、-C n H 2n NR a C(O)NR b C n H 2n R c 、-C n H 2n SR a 、-C n H 2n S(O)R a 、-C n H 2n S(O)NR a R b 、-C n H 2n S(O)2R a 、-C n H 2n S(O)2NR a R b 、-C n H 2n NR a S(O)2R b 、-C n H 2n CN、-C n H 2nNH2, -C n H 2n One or more of CF3.

[0037] The present invention preferably, the substituted C 2～ The substituents of the C6 alkenyl group are selected from deuterium, oxo, thio, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted C 1～ C6 alkyl, substituted or unsubstituted C 2～ C6 alkynyl, substituted or unsubstituted C 3～ C 10 Cycloalkyl, C n H 2n OR a 、-C n H 2n OC(O)R a 、-C n H 2n OC(O)NR a R b 、-C n H 2n C(O)R a 、-C n H 2n C(O)OR a 、-C n H 2n C(O)NR a R b 、-C n H 2n NR a R b 、-C n H 2n NR a C(O)R b 、-C n H 2n NR a C(O)OR b 、-C n H 2n NR a C(O)NR b C n H 2n R c 、-C n H 2n SR a 、-C n H 2n S(O)R a 、-C n H 2n S(O)NR a R b 、-C n H2n S(O)2R a 、-C n H 2n S(O)2NR a R b 、-C n H 2n NR a S(O)2R b 、-C n H 2n CN, -C n H 2n NH2, -C n H 2n One or more of CF3.

[0038] The present invention preferably, the substituted C 2～ The substituents of the C6 alkynyl group are selected from deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, substituted or unsubstituted C 1～ C6 alkyl, substituted or unsubstituted C 2～ C6 alkenyl, substituted or unsubstituted C 3～ C 10 Cycloalkyl, -C n H 2n OR a 、-C n H 2n OC(O)R a 、-C n H 2n OC(O)NR a R b 、-C n H 2n C(O)R a 、-C n H 2n C(O)OR a 、-C n H 2n C(O)NR a R b 、-C n H 2n NR a R b 、-C n H 2n NR a C(O)R b 、-C n H 2n NR a C(O)OR b 、-C n H 2n NR a C(O)NRb C n H 2n R c 、-C n H 2n SR a 、-C n H 2n S(O)R a 、-C n H 2n S(O)NR a R b 、-C n H 2n S(O)2R a 、-C n H 2n S(O)2NR a R b 、-C n H 2n NR a S(O)2R b 、-C n H 2n CN, -C n H 2n NH2, -C n H 2n One or more of CF3.

[0039] Preferably, in the formula (I), R 6 and R 7 The 5-membered or 6-membered monocyclic heterocyclic group formed by connecting adjacent oxygen atoms and phenyl carbon atoms is selected from 1,3-dioxolyl or 1,4-dioxaneyl.

[0040] Preferably, the aryl group fused or spiro-coupled to the 5-membered or 6-membered monocyclic heterocyclic group is selected from substituted or unsubstituted phenyl or naphthyl.

[0041] Preferably, the heteroaryl group fused or spiro with the 5-membered or 6-membered monocyclic heterocyclic group is selected from one or more of substituted or unsubstituted pyridyl, indolyl, quinoxalyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0042] Preferably, the heterocycloalkyl group fused or spiro to the 5-membered or 6-membered monocyclic heterocyclic group is selected from substituted or unsubstituted oxetanyl, azetidinyl, azepanyl, diazepanyl, oxazepanyl, 8-aza-bicyclo[3.2.1]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, One or more of pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, homopiperazinyl, quinuclidine, dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl, and dihydropyranyl.

[0043] Preferably, the substituents of the substituted 5-membered or 6-membered monocyclic heterocyclic group, substituted aryl group, substituted heteroaryl group, substituted heterocycloalkyl group are independently selected from substituted or unsubstituted straight chain or branched C 1～ C6 alkyl, substituted or unsubstituted C 1～ One or more of C4 alkoxy, halogen, hydroxy, nitro, cyano, amino, etc.

[0044] The above straight chain or branched C 1～ C6 alkyl, C 1～ The scope of C4 alkoxy and the preferred scope of its substituents are the same as above and will not be repeated here.

[0045] In the present invention, the above-mentioned -C(O), -S(O), and -S(O)2 all represent that an oxygen atom is connected to a carbon atom or a sulfur atom via a double bond, wherein a horizontal line indicates the connection position.

[0046] Pharmaceutically acceptable salts of the structure represented by the above formula (I) include, but are not limited to, one or more of hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, and trifluoroacetate.

[0047] Preferably, the compound of the present invention has any of the following structures, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0048] The present invention also provides a pharmaceutical composition comprising the above compound and pharmaceutically acceptable excipients.

[0049] The auxiliary material can be a carrier, a vehicle, a diluent or other auxiliary materials.

[0050] The present invention also provides the use of the above compound or the above pharmaceutical composition in the preparation of a drug for treating diseases related to PDE3 and / or PDE4.

[0051] Preferably, the PDE3 and / or PDE4-related disease is one or more of inflammation, bronchiectasis, chronic obstructive pulmonary disease, and asthma.

[0052] Compared to the prior art, the compounds provided by the present invention and their uses have the structure represented by Formula (I), or deuterated compounds thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof. These compounds exhibit potent PDE3 and / or PDE4 inhibitory effects and can be used to treat PDE3 and / or PDE4-related disorders. DETAILED DESCRIPTION

[0053] To further illustrate the present invention, the compounds and applications of the present invention are described in detail below with reference to the examples.

[0054] The structures of the compounds were determined by H NMR spectroscopy ( 1 H NMR) and mass spectrometry (MS), where:

[0055] 1 The H NMR spectra were measured using a Bruker Avance NEO 400 nuclear magnetometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3, Chloroform-d), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0056] The LC-MS measurement instrument was a Shimadzu LC-MS 2020 (ESI) mass spectrometer.

[0057] The HPLC measurement instrument was Shimadzu LC-2030C 3D (Plus) high pressure liquid chromatograph.

[0058] The preparative liquid chromatograph was Shimadzu LC-20AP.

[0059] The thin layer chromatography silica gel plate is GF254 silica gel plate produced by Yantai Xinnuo Chemical Co., Ltd.

[0060] The carrier for column chromatography was 200-300 mesh silica gel from Beijing Kaideli Technology Co., Ltd.

[0061] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0062] Unless otherwise specified, all reactions described below were carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere. The solvents were dry solvents, and the reaction temperatures were expressed in degrees Celsius.

[0063] Example 1: Synthesis of intermediates and compound 1

[0064] (1) Synthesis of intermediate compounds

[0065] 1) Synthesis of intermediate IM-01

[0066] Step 1. Synthesis of compound IM01B

[0067] IM01A (6.0 g) was dissolved in water (42 mL), and concentrated hydrochloric acid (3.3 mL) and potassium cyanate (4.4 g) were added sequentially. The reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the precipitated solid was collected by filtration. The filter cake was dried to obtain IM01B (4.0 g).

[0068] MS m / z(ESI):225.1[M+1] + .

[0069] Step 2. Synthesis of compound IM01C

[0070] A sodium ethoxide-ethanol solution (20 wt%, 32.5 g) was added to anhydrous ethanol (40 mL), followed by the addition of IM01B (4.0 g) and diethyl malonate (7.7 g). The reaction mixture was heated to 80°C and allowed to react for 16 hours. Upon completion of the reaction, the ethanol was removed by concentration under reduced pressure. The residue was dissolved in water, and dilute hydrochloric acid (2 M) was then added dropwise to the resulting solution under an ice bath to adjust the pH to 2. The solid was collected by filtration and the filter cake was dried to yield IM01C (3.0 g). MS m / z (ESI): 315.0 [M+23] + .

[0071] Step 3. Synthesis of compound IM01D

[0072] Compound IM01C (10.0 g) was added to phosphorus oxychloride (100 mL). The reaction mixture was stirred at 85°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature. The phosphorus oxychloride was removed by concentration under reduced pressure. The resulting residue was dissolved in dichloromethane (100 mL). The organic phase was washed with ice water (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated to yield IM01D (11.0 g).

[0073] MS m / z(ESI):293.1[M+1] + .

[0074] Step 4. Synthesis of compound IM-01

[0075] IM01D (10.0 g) was dissolved in isopropanol (100 mL) and 2,4,6-trimethylaniline (23.1 g) was added. The reaction mixture was incubated at 90°C for 16 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product, which was then purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain IM-01 (10.0 g).

[0076] MS m / z(ESI):392.2[M+1] + .

[0077] 1 H NMR(400MHz,DMSO-d6)δ9.42(br,1H),7.29(s,1H),7.03(s,1H),6.93(s,1H),6.52(s,1H),5.76( s,1H),3.93(t,J=6.4Hz,2H),3.89-3.80(m,6H),2.92(t,J=6.5Hz,2H),2.27(s,3H),2.14(s,6H).

[0078] 2) Synthesis of intermediate IM-02

[0079] Step 1. Synthesis of compound IM02B

[0080] IM02A (21 g) and ammonium acetate (2.5 g) were added to nitromethane (250 mL). The reaction mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 3 / 2) to obtain IM02B (24.0 g).

[0081] Step 2, synthesis of compound IM02C

[0082] Under a nitrogen atmosphere, a tetrahydrofuran solution of lithium aluminum tetrahydride (270 mL) was added to a three-necked flask. IM02B (24.0 g) was dissolved in tetrahydrofuran (250 mL) and slowly added dropwise to the three-necked flask at room temperature. After the addition was completed, the reaction solution was heated to 65°C and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and water (10 mL), 15% sodium hydroxide aqueous solution (10 mL) and water (30 mL) were slowly added in sequence. An appropriate amount of anhydrous sodium sulfate was added and stirring was continued for 20 minutes. The filtrate was collected by filtration. The filter cake was stirred in a mixed solvent of dichloromethane / methanol (10 / 1) for 20 minutes and filtered. The filtrates were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column (dichloromethane / methanol = 93 / 7) to obtain IM02C (15.0 g). MS m / z (ESI): 196.0 [M+1] + .

[0083] Step 3, Synthesis of Compound IM02D

[0084] IM02C (2.2 g) was dissolved in 1,2-dichloroethane (20 mL) and trimethylsilyl isocyanate (3.9 g) was added. The reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain IM02D (2.0 g). MS m / z (ESI): 239.2 [M+1] + .

[0085] Step 4. Synthesis of compound IM02E

[0086] A 20% sodium ethoxide-ethanol solution (14.0 g) was added to anhydrous ethanol (20 mL), followed by the addition of IM02D (2.0 g) and diethyl malonate (3.4 g). The reaction mixture was allowed to react at 80°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the ethanol. The residue was dissolved in water, and hydrochloric acid (2 M) was added dropwise under an ice bath to adjust the pH until solids formed. The precipitated solid was collected by filtration and dried to yield IM02E (1.5 g). MS m / z (ESI): 307.1 [M+1] + .

[0087] Step 5, Synthesis of Compound IM02F

[0088] IM02E (1.5 g) was added to phosphorus oxychloride (20 mL). Under a nitrogen atmosphere, the reaction mixture was stirred at 85°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The phosphorus oxychloride was removed by concentration under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL). The organic phase was washed with ice water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain IM02F (1.0 g). MS m / z (ESI): 307.1 [M+1] + .

[0089] Step 6. Synthesis of compound IM-02

[0090] IM02F (1.0 g) was dissolved in isopropanol (20 mL) and 2,4,6-trimethylaniline (2.2 g) was added. The reaction mixture was allowed to react at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and the resulting crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain IM-02 (1.0 g). MS m / z (ESI): 406.2 [M+1] + .

[0091] (2) Synthesis of Compound 1

[0092] IM-01 (200 mg) was dissolved in 2-butanone (20 mL), and 3-bromopropionitrile (376 mg), potassium carbonate (635 mg), and potassium iodide (509 mg) were added sequentially. The reaction mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain compound 1 (120 mg). MS m / z (ESI): 445.2 [M+1] + .

[0093] 1 H NMR (400MHz, CDCl3) δ7.02 (s, 2H), 6.70 (s, 1H), 6.64 (s, 1H), 5.37 (d, J = 0.8Hz, 1H), 4.16 (dt, J = 10.4 ,6.7Hz,4H),3.94-3.87(m,3H),3.73(d,J=0.8Hz,3H),2.96-2.85(m,4H),2.34(s,3H),2.17(s,6H).

[0094] Example 2: Synthesis of Compound 2

[0095] Step 1. Synthesis of Compound 2A

[0096] IM-01 (4.0 g), 2-(2-bromoethyl)isoindoline-1,3-dione (14.3 g), potassium carbonate (12.7 g), and sodium iodide (9.2 g) were added to 2-butanone (40 mL). The reaction solution was stirred at 85°C for 16 hours. After the reaction was completed, the solvent was dried. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 2A (0.8 g). MS m / z (ESI): 565.4 [M+1] + .

[0097] Step 2, synthesis of compound 2

[0098] 2A (800 mg) was dissolved in ethanol (10 mL), and hydrazine hydrate (212 mg) was added. The mixture was stirred at 85°C under a nitrogen atmosphere for 16 hours. After the reaction was completed, the filtrate was filtered, concentrated, and purified by Flash reverse phase chromatography to obtain compound 2 (300 mg). MS m / z (ESI): 435.2 [M+1] + .

[0099] 1H NMR (400MHz, DMSO-d6) δ8.35(s,1H),6.97(s,1H),6.86(s,2H),6.67(s,1H),5.33(s,1H),4.28(t,J=6.4Hz,2H),3.91(t,J= 5.9Hz,2H),3.80(s,3H),3.62(s,3H),3.04(t,J=6.4Hz,2H),2.90(t,J=5.8Hz,2H),2.21(s,3H),1.96(s,6H),1.23(s,2H).

[0100] Example 3: Synthesis of Compound 3

[0101] Compound 2 (40 mg) and acetic anhydride (14 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (19 mg). The reaction mixture was stirred at 25°C for 2 hours. After the reaction, the reaction mixture was concentrated, and the resulting crude product was purified by Flash reverse phase chromatography to obtain compound 3 (10 mg, TFA salt). MS m / z (ESI): 477.2 [M+1] + .

[0102] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.28(s,1H),7.08(s,3H),6.78(s,1H),5.57(s,1H),4.32(s,2H),4.06 (s,2H),3.85(s,3H),3.65(s,3H),3.48(d,J=5.9Hz,2H),2.99(s,2H),2.32(s,3H),2.19(s,6H),1.82(s,3H).

[0103] Example 4: Synthesis of Compound 4

[0104] Compound 2 (40 mg) and methanesulfonic anhydride (24 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (19 mg). The reaction mixture was stirred at 25°C for 2 hours. After the reaction, the reaction mixture was concentrated, and the resulting crude product was purified by Flash reverse phase chromatography to obtain compound 4 (10 mg, TFA salt). MS m / z (ESI): 513.2 [M+1] + .

[0105] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.23(t,J=6.3Hz,1H),7.07(s,3H),6.75(s,1H),5.56(s,1H),4.38(s, 2H),4.06(s,2H),3.84(s,3H),3.64(s,4H),3.42(s,2H),2.96(s,2H),2.95(s,3H),2.30(s,4H),2.18(s,5H).

[0106] Example 5: Synthesis of Compounds 5 and 6

[0107] Step 1. Synthesis of compound 5B

[0108] At 0°C, 5A (2.0 g) and triethylamine (2.08 g) were dissolved in anhydrous dichloromethane (20 mL), and a solution of p-toluenesulfonyl chloride (3.1 g) in dichloromethane (30 mL) was added dropwise. After the addition was complete, the reaction solution was stirred at 0°C for 4 hours. After the reaction was completed, the solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain 5B (3.0 g). MS m / z (ESI): 301.1 [M+1] + .

[0109] Step 2: Synthesis of Compounds 5C and 5D

[0110] 5B (1.0 g) was dissolved in N,N-dimethylformamide (10 mL), and then IM-01 (1.5 g), potassium carbonate (2.5 g), and potassium iodide (2.1 g) were added in sequence. The reaction solution was heated to 80°C and stirred for 16 hours. After the reaction was completed, it was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by Flash reverse phase chromatography to obtain 5C (0.45 g) and 5D (0.1 g). 5C and 5D: MS m / z (ESI): 520.2 [M+1] + .

[0111] Step 3, synthesis of compound 5

[0112] Dissolve 5C (100 mg) in methanol (1.0 mL) and add dilute hydrochloric acid (2 mol / L, 1.0 mL). Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, concentrate the reaction mixture to obtain a crude product. The crude product is purified by flash reverse phase chromatography to obtain compound 5 (80 mg). MS m / z (ESI): 480.5 [M+1] + .

[0113] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.15-7.07(m,3H),6.75(s,1H),5.54(s,1H) ),4.59-4.48(m,3H),4.36-4.28(m,1H),4.08(t,J=6.4Hz,2H),3.85(s,3H),3.70 (dd,J=8.8,3.4Hz,1H),3.63(s,3H),3.43-3.37(m,1H),3.35-3.29(m,1H),3.01( t,J=6.4Hz,2H),2.33(s,3H),2.20(s,6H),2.05-1.95(m,1H),1.87-1.76(m,1H).

[0114] Step 4, synthesis of compound 6

[0115] 5D (50 mg) was dissolved in methanol (0.5 mL) and dilute hydrochloric acid (2 mol / L, 0.50 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by flash reverse phase chromatography to obtain compound 6 (40 mg). MS m / z (ESI): 480.2 [M+1] + .

[0116] 1 H NMR(400MHz,DMSO-d6)δ7.47(s,1H),7.07(d,J=1.8Hz,2H),7.00–6.92(m,3H),6.72(s,1H),6.57 (s,1H),5.23(s,1H),4.90-4.86(m,2H),4.64(t,J=5.6Hz,1H),4.53(t,J=5.7Hz,1H),4.01-3.89( m,4H),3.85(d,J=4.0Hz,3H),3.80(s,3H),3.76-3.67(m,2H),3.58(s,3H),2.91-2.86(m,3H),2. 30(s,3H),2.26(s,2H),2.10(d,J=5.3Hz,6H),2.05(s,3H),1.84-1.73(m,1H),1.46-1.36(m,1H).

[0117] Example 6: Synthesis of Compound 7

[0118] Compound 2 (40 mg) and methylcarbamoyl chloride (9 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (11 mg). The reaction mixture was stirred at 25°C for 2 hours. After the reaction, the reaction mixture was concentrated, and the resulting crude product was purified by Flash reverse phase chromatography to obtain compound 7 (10 mg). MS m / z (ESI): 492.3 [M+1] + .

[0119] 1 H NMR(400MHz,DMSO-d6)δ7.04(s,3H),6.77(s,1H),5.54(s,1H),4.25(s,2H),4.04(s ,2H),3.84(s,3H),3.65(s,6H),3.42(s,2H),2.98(s,2H),2.30(s,3H),2.16(s,6H).

[0120] Example 7: Synthesis of Compound 8

[0121] Step 1. Synthesis of Compound 8A

[0122] Compound 2 (70 mg) and 4-nitrophenyl chloroformate (36 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (33 mg). The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated, and the resulting crude product was purified by Flash reverse phase chromatography to yield 8A (60 mg). MS m / z (ESI): 600.2 [M+1] + .

[0123] Step 2, synthesis of compound 8

[0124] 8A (60 mg) and methoxyamine hydrochloride (10 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (20 mg). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated, and the resulting crude product was purified by flash reverse phase chromatography to obtain compound 8 (10 mg, TFA salt). MS m / z (ESI): 508.3 [M+1] + .

[0125] 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),9.35(s,1H),7.26(s,1H),7.08(s,3H),6.78(s,1H),5.57(s,1H),4.35(d,J=5.6Hz,2 H),4.06(s,2H),3.85(s,3H),3.64(s,3H),3.55-3.52(m,3H),3.51(d,J=6.2Hz,2H),2.99(s,2H),2.31(s,3H),2.19(s,6H).

[0126] Example 8: Synthesis of Compound 9

[0127] Step 1. Synthesis of Compound 9B

[0128] Dissolve 9A (10 g) in tetrahydrofuran (100 mL), cool to -78°C under nitrogen, and add a 2M solution of lithium diisopropylamide in tetrahydrofuran (28.2 mL) dropwise. After the addition is complete, stir the mixture at -78°C for 1 hour, then add iodomethane (9.61 g) dropwise. Stir the reaction mixture at room temperature for 16 hours. After the reaction is complete, quench the mixture with saturated ammonium chloride solution (100 mL), and extract the aqueous phase with ethyl acetate (150 mL x 2). The resulting organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The crude product is purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to yield 9B (7.0 g).

[0129] 1 H NMR (400MHz, CDCl3) δ6.91-6.85 (m, 3H), 3.87 (m, 7H), 1.64 (d, J = 7.3Hz, 3H).

[0130] Step 2, Synthesis of Compound 9C

[0131] 9B (5.0 g) was dissolved in tetrahydrofuran (50 mL), and a 2M borane dimethyl sulfide solution (26.1 mL) was added. The mixture was stirred at 70°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to 0°C and methanol (5 mL) was added dropwise to quench the reaction. The reaction mixture was then concentrated to yield 9C (5.0 g). MS m / z (ESI): 196.2 [M+1] + .

[0132] Step 3, Synthesis of Compound 9D

[0133] 9C (1.0 g) was dissolved in dichloroethane (20 mL) and trimethylsilyl isocyanate (1.77 g) was added. The reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated, and dried under vacuum to obtain 9D (1.1 g). MS m / z (ESI): 239.0 [M+1] + .

[0134] Step 4. Synthesis of Compound 9E

[0135] A 20% sodium ethoxide-ethanol solution (8.85 g) was added to anhydrous ethanol (10 mL), followed by the addition of 9D (1.25 g) and diethyl malonate (2.08 g). The reaction mixture was allowed to react at 80°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the ethanol. The residue was dissolved in water, and hydrochloric acid (2 M) was added dropwise under ice to adjust the pH to 5. After filtration through celite, the filtrate was extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (dichloromethane / methanol = 20 / 1) to yield 9E (1.2 g). MS m / z (ESI): 306.9 [M+1] + .

[0136] Step 5. Synthesis of Compound 9F

[0137] Under a nitrogen atmosphere, compound 9E (1.1 g) was added to phosphorus oxychloride (10 mL). The reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove phosphorus oxychloride. The resulting residue was dissolved in dichloromethane (50 mL), washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain 9F (1.0 g). MS m / z (ESI): 307.0 [M+1] + .

[0138] Step 6. Synthesis of Compound 9G

[0139] 9F (1.0 g) was dissolved in isopropanol (50 mL) and 2,4,6-trimethylaniline (2.23 g) was added. The reaction mixture was allowed to react at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 9G (0.8 g). MS m / z (ESI): 406.0 [M+1] + .

[0140] Step 7. Synthesis of Compound 9H

[0141] 9G (300 mg) was added to toluene (10 mL), followed by tert-butyl (2-hydroxyethyl)carbamate (173 mg) and cyanomethylenetri-n-butylphosphine (515 mg). The mixture was stirred at 120°C for 4 hours under nitrogen. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 9H (210 mg). MS m / z (ESI): 549.5 [M+1] + .

[0142] Step 8. Synthesis of Compound 9I

[0143] 9H (100 mg) was added to a 4M hydrochloric acid / dioxane solution (5 mL) and stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain 9I (90 mg). MS m / z (ESI): 449.1 [M+1] + .

[0144] Step 9, Synthesis of Compound 9

[0145] 9I (100 mg) was added to dichloromethane (5 mL), followed by phenyl carbamate (46 mg) and triethylamine (68 mg). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by flash reverse phase chromatography to obtain compound 9 (40 mg). MS m / z (ESI): 492.0 [M+1] + .

[0146] 1 H NMR (400MHz, DMSO-d6) δ7.18-6.99(m,3H),6.78(s,1H),6.54(s,1H),6.01(s,2H),5.62(s,1H),4.34-4.06(m,3H),3. 96-3.76(m,4H),3.64(s,3H),3.51-3.32(m,2H),3.29-3.15(m,1H),2.32(s,3H),2.22(s,6H),1.22(d,J=7.0Hz,3H).

[0147] Example 9: Synthesis of Compound 10

[0148] Compound 10 (25 mg) was obtained by referring to the synthesis method of Example 8. MS m / z (ESI): 506.1 [M+1] + .

[0149] 1H NMR (400MHz, DMSO-d6) δ7.12(s,1H),7.07(d,J=4.8Hz,2H),6.77(s,1H),6.52(s,1H),5.98(s,2H),5.61(s,1H),4.64-4.60(m,1H),4.27(s ,2H),3.86(s,3H),3.65-3.59(m,4H),3.41(s,2H),2.98(s,1H),2.32 (s,3H),2.23(s,3H),2.20(s,3H),1.48(m,2H),0.91(t,J=7.3Hz,3H).

[0150] Example 10: Synthesis of Compound 11

[0151] Compound 11 (60 mg) was obtained by referring to the synthesis method of intermediate IM-01 and Example 8. MS m / z (ESI): 462.1 [M+1] + .

[0152] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),7.19(s,1H),7.07(d,J=14.5Hz,3H),6.58(s,1H),6.25-5.95(m,4H),5.65(s,1H ),4.26(t,J=6.8Hz,2H),4.06(t,J=6.2Hz,2H),3.39(d,J=5.9Hz,2H),2.97(t,J=6.0Hz,2H),2.33(s,3H),2.19(s,6H).

[0153] Example 11: Synthesis of Compound 12

[0154] Step 1. Synthesis of Compound 12B

[0155] 12A (5.2 g) and ammonium acetate (0.6 g) were added to nitromethane (50 mL). The reaction mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 3 / 2) to afford 12B (6 g).

[0156] 1H NMR (400MHz, DMSO-d6) δ8.21(d,J=13.5Hz,1H),8.06(d,J=13.5Hz,1H),7.49(d,J=1.9Hz,1H),7.40(d d,J=8.3,1.8Hz,1H),7.04(d,J=8.4Hz,1H),4.09(q,J=7.0Hz,2H),3.82(s,3H),1.35(t,J=7.0Hz,3H).

[0157] Step 2, Synthesis of Compound 12C

[0158] Under a nitrogen atmosphere, a tetrahydrofuran solution of lithium aluminum tetrahydride (60 mL, 1 mol / L) was added to a three-necked flask. 12B (6.0 g) was dissolved in tetrahydrofuran (60 mL) and slowly added dropwise to the three-necked flask at room temperature. After the addition was complete, the reaction solution was heated to 65°C and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then water (6 mL), 15% sodium hydroxide aqueous solution (6 mL) and water (18 mL) were slowly added in sequence. An appropriate amount of anhydrous sodium sulfate was added and stirring was continued for 20 minutes. The filtrate was collected by filtration. The filter cake was stirred in a mixed solvent of dichloromethane / methanol (10 / 1) for 20 minutes and filtered. The filtrates were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column (dichloromethane / methanol = 93 / 7) to obtain 12C (3.8 g). MS m / z (ESI): 196.0 [M+1] + .

[0159] Step 3. Synthesis of Compound 12D

[0160] 12C (2.2 g) was dissolved in dichloroethane (20 mL), and trimethylsilyl isocyanate (3.9 g) was added. The reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 12D (2.0 g). MS m / z (ESI): 239.1 [M+1] + .

[0161] Step 4. Synthesis of Compound 12E

[0162] A 20% sodium ethoxide-ethanol solution (14.0 g) was added to anhydrous ethanol (20 mL), followed by the addition of 12D (2.0 g) and diethyl malonate (3.4 g). The reaction mixture was allowed to react at 80°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the ethanol. The residue was dissolved in water, and hydrochloric acid (2 M) was added dropwise under an ice bath to adjust the pH to 2 until solids formed. The precipitated solid was collected by filtration and dried to yield 12E (1.5 g). MS m / z (ESI): 307.1 [M+1]+ .

[0163] Step 5. Synthesis of Compound 12F

[0164] 12E (1.5 g) was added to phosphorus oxychloride (20 mL). The reaction mixture was stirred at 85°C under a nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The phosphorus oxychloride was removed by concentration under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL). The organic phase was washed with ice water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain 12F (1.0 g). MS m / z (ESI): 307.1 [M+1] + .

[0165] Step 6. Synthesis of Compound 12G

[0166] 12F (1.0 g) was dissolved in isopropanol (20 mL) and 2,4,6-trimethylaniline (2.2 g) was added. The reaction mixture was allowed to react at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and the resulting crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 12G (1.0 g). MS m / z (ESI): 406.1 [M+1] + .

[0167] Step 7. Synthesis of Compound 12H

[0168] 12G (1.0 g) was added to toluene (10 mL), followed by the addition of tert-butyl (2-hydroxyethyl)carbamate (0.6 g) and cyanomethylenetri-n-butylphosphine (1.8 g). The reaction mixture was stirred at 120° C. for 2 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 12H (0.5 g). MS m / z (ESI): 549.1 [M+1] + .

[0169] Step 8. Synthesis of Compound 12I

[0170] 12H (200 mg) was added to a 4M hydrochloric acid / dioxane solution (5 mL). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated to obtain 12I (160 mg). MS m / z (ESI): 449.1 [M+1] + .

[0171] Step 9. Synthesis of Compound 12

[0172] 12I (200 mg), phenyl carbamate (92 mg), and triethylamine (226 mg) were added to dichloromethane (5 mL). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated. The crude product was purified by flash reverse phase chromatography to obtain compound 12 (20 mg). MS m / z (ESI): 492.1 [M+1] + .

[0173] 1 H NMR (400MHz, DMSO-d6) δ6.96(s,1H),6.85(s,2H),6.66(s,1H),6.10(t,J=5.8Hz,1H),5.45(s,2H),5.29(s,1H),4.18(t,J=6.7Hz,2H),3.92(t ,J=6.0Hz,2H),3.87-3.82(m,2H),3.80(s,3H),3.35(d,J=6.6Hz,2H),2.90(t,J=5.9Hz,2H),2.22(s,3H),1.97(s,6H),1.22(t,J=6.9Hz,3H).

[0174] Example 12: Synthesis of Compound 13

[0175] Compound 13 (150 mg) was obtained by referring to the synthesis method of Example 11. MS m / z (ESI): 476.2 [M+1] + .

[0176] 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),7.10(s,2H),7.05(s,1H),6.96(s,1H),6.60(s,1H),6.06(s,2H),5.61(s,1H),4.33-4 .30(m,2H),4.29-4.22(m,4H),4.06(t,J=6.3Hz,2H),3.39(d,J=5.8Hz,2H),2.94(t,J=6.2Hz,2H),2.33(s,3H),2.19(s,6H).

[0177] Example 13: Synthesis of Compound 14

[0178] Compound 14 (20 mg) was obtained by referring to the synthesis method of Example 11. MS m / z (ESI): 492.1 [M+1] + .

[0179] 1H NMR (400MHz, DMSO-d6) δ6.94(s,1H),6.85(s,2H),6.66(s,1H),6.10(t,J=5.9Hz,1H),5.44(s,2H),5.31(s,1H),4.18(t,J=6.8Hz,2H),4.06(q ,J=6.9Hz,2H),3.91(t,J=6.0Hz,2H),3.62(s,3H),3.39-3.34(m,2H),2.89(t,J=6.0Hz,2H),2.22(s,3H),1.97(s,6H),1.33(t,J=7.0Hz,3H).

[0180] Example 14: Synthesis of Compound 15

[0181] Step 1. Synthesis of Compound 15B

[0182] 15A (10.0 g) and ethyl 1,3-dioxindole-2-carboxylate (11.6 g) were dissolved in methanol (10 mL), followed by the slow addition of triethylamine (2.2 g). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by Flash reverse phase chromatography to obtain 15B (9.0 g). MS m / z (ESI): 284.2 [M+1] + .

[0183] Step 2, Synthesis of Compound 15C

[0184] 15B (10.0 g) and 2,2-dimethoxypropane (14.7 g) were dissolved in toluene (100 mL) and reacted at 120°C for 5 minutes under nitrogen. p-Toluenesulfonic acid (0.3 g) was slowly added and stirred at 120°C for 2 hours. The reaction solution was cooled to room temperature and concentrated. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain 15C (8.0 g). MS m / z (ESI): 324.1 [M+1] + .

[0185] Step 3. Synthesis of Compound 15D

[0186] 15C (8.0 g) was dissolved in a dichloromethane / methanol mixture (V / V = 1 / 1, 100 mL), followed by the dropwise addition of hydrazine hydrate (12.4 g). After the addition was complete, the reaction mixture was stirred at 25°C for 72 hours. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to yield 15D (5.0 g). MS m / z (ESI): 194.1 [M+1] + .

[0187] Step 4. Synthesis of Compound 15E

[0188] 15D (5.0 g) was dissolved in dichloroethane (50 mL), followed by the addition of trimethylsilyl isocyanate (8.9 g). The reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 15E (4.0 g). MS m / z (ESI): 237.1 [M+1] + .

[0189] Step 5. Synthesis of Compound 15F

[0190] A 20% sodium ethoxide-ethanol solution (28.7 g) was added to anhydrous ethanol (50 mL), followed by the addition of 15E (4.0 g) and diethyl malonate (6.8 g). The reaction mixture was allowed to react at 80°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the ethanol. The residue was dissolved in water, and hydrochloric acid (2 M) was added dropwise under an ice bath to adjust the pH until solids formed. The precipitated solid was collected by filtration and dried to yield 15F (2.5 g). MS m / z (ESI): 305.1 [M+1] + .

[0191] Step 6. Synthesis of Compound 15G

[0192] 15F (2.4 g) was added to phosphorus oxychloride (20 mL). Under a nitrogen atmosphere, the reaction mixture was stirred at 85°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The phosphorus oxychloride was removed by concentration under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL). The organic phase was washed with ice water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain 15G (2.4 g). MS m / z (ESI): 305.0 [M+1] + .

[0193] Step 7. Synthesis of Compound 15H

[0194] 15G (1.0 g) was dissolved in isopropanol (20 mL), and 2,4,6-trimethylaniline (2.2 g) was added. The reaction mixture was reacted at 90°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 15H (0.8 g). MS m / z (ESI): 404.2 [M+1] + .

[0195] Step 8. Synthesis of Compound 15I

[0196] 15H (500 mg) was added to toluene (10 mL), followed by the addition of tert-butyl (2-hydroxyethyl)carbamate (300 mg) and cyanomethylenetri-n-butylphosphine (897 mg). The reaction mixture was stirred at 120° C. for 2 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 15I (400 mg). MS m / z (ESI): 547.2 [M+1] + .

[0197] Step 9. Synthesis of Compound 15J

[0198] 15I (200 mg) was added to a 4M hydrochloric acid / dioxane solution (5 mL). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated to obtain 15J (200 mg). MS m / z (ESI): 447.2 [M+1] + .

[0199] Step 10, Synthesis of Compound 15

[0200] 15J (150 mg), phenyl carbamate (69 mg), and triethylamine (170 mg) were added to dichloromethane (5 mL). The reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated. The crude product was purified by flash reverse phase chromatography to obtain compound 15 (30 mg). MS m / z (ESI): 490.2 [M+1] + .

[0201] 1 H NMR (400MHz, DMSO-d6) δ6.84(d,J=6.2Hz,3H),6.66(s,1H),6.10(t,J=5.8Hz,1H),5.44(s,2H),5.26(s,1H),4.17(t,J= 6.8Hz,2H),3.89(t,J=6.0Hz,2H),3.35(d,J=7.0Hz,2H),2.85(t,J=6.0Hz,2H),2.23(s,3H),1.95(s,6H),1.61(s,6H).

[0202] Example 15: Synthesis of Compound 16

[0203] Step 1. Synthesis of Compound 16B

[0204] IM-01 (500 mg) was added to toluene (10 mL), followed by tert-butyl (2-hydroxyethyl)(methyl)carbamate (338 mg) and cyanomethylenetri-n-butylphosphine (1.50 g). The mixture was stirred at 120°C for 4 hours under nitrogen. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 16B (250 mg). MS m / z (ESI): 549.1 [M+1] + .

[0205] Step 2, Synthesis of Compound 16

[0206] 16B (200 mg) was added to a 4M hydrochloric acid / dioxane solution (2 mL). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated to obtain compound 16 (170 mg). MS m / z (ESI): 449.0 [M+1] + .

[0207] 1 H NMR (400MHz, DMSO-d6) δ7.05(d,J=3.3Hz,3H),6.76(s,1H),5.54(s,1H),4.57-4.51(m,2H),4.03(t,J=6.3Hz,2H),3.83(s,3H),3.63(s,3H),3.35 -3.29(m,2H),2.98(t,J=6.3Hz,2H),2.66(s,3H),2.29(s,3H),2.13(s,6H).

[0208] Example 16: Synthesis of Compounds 17 and 18

[0209] IM-01 (200 mg), 4-bromo-2-methylbutan-2-ol (470 mg), potassium carbonate (635 mg), and potassium iodide (509 mg) were added to 2-butanone (10 mL). The reaction mixture was stirred at 85°C for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure. The crude product was purified using a silica gel column (dichloromethane / methanol = 20 / 1) to obtain compound 17 (15 mg) and compound 18 (60 mg).

[0210] Compound 17, MS m / z (ESI): 478.3 [M+1] + .

[0211] 1H NMR (400MHz, DMSO-d6) δ6.95(s,1H),6.85(s,2H),6.66(s,1H),5.32(s,1H),4.36(s,1H),4.27-4.17(m,2H),3.91(t,J= 5.8Hz,2H),3.80(s,3H),3.61(s,3H),2.90(t,J=5.8Hz,2H),2.22(s,3H),1.96(s,6H),1.85-1.75(m,2H),1.17(s,6H).

[0212] Compound 18, MS m / z (ESI): 478.2 [M+1] + .

[0213] 1 H NMR (400MHz, CDCl3) δ6.99(s,2H),6.69(s,1H),6.63(s,1H),5.32(s,1H),4.14(t,J=6.4Hz,2H),4.01-3.95(m, 2H),3.90(s,3H),3.72(s,3H),2.89(t,J=6.3Hz,2H),2.33(s,3H),2.16(s,6H),1.97-1.89(m,2H),1.25(s,6H).

[0214] Example 17: Synthesis of Compound 19

[0215] Step 1. Synthesis of Compound 19B

[0216] 19A (10.0 g) was dissolved in tetrahydrofuran (175 mL), followed by the addition of triethylamine (7.3 mL). The resulting mixture was cooled to -10°C, and ethyl chloroformate (5.0 mL) was then added dropwise. The reaction mixture was stirred at -10°C for 20 minutes, and a solution of concentrated aqueous ammonia (105 mL) in tetrahydrofuran (105 mL) was added. The reaction mixture was stirred at -10°C for 30 minutes, and then stirred at room temperature for 90 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 19B (9.0 g). MS m / z (ESI): 210.1 [M+1] + .

[0217] Step 2, Synthesis of Compound 19C

[0218] Under a nitrogen atmosphere, lithium aluminum tetrahydride (1.81 g) was added to a three-necked flask, and anhydrous tetrahydrofuran (80 mL) was slowly added. 19B (5.0 g) was dissolved in anhydrous tetrahydrofuran (180 mL) and slowly added dropwise to the three-necked flask at 0°C. After the addition was completed, the reaction solution was heated to 65°C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then water (1.8 mL), 15% sodium hydroxide aqueous solution (1.8 mL) and water (5.4 mL) were slowly added in sequence. An appropriate amount of anhydrous sodium sulfate was added and stirring was continued for 20 minutes. The filtrate was collected by filtration. The filter cake was stirred in a mixed solvent of dichloromethane / methanol (10 / 1) for 20 minutes and filtered. The filtrates were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column (dichloromethane / methanol = 24 / 1) to obtain 19C (3.5 g). MS m / z (ESI): 196.1 [M+1] + .

[0219] Step 3, Synthesis of Compound 19D

[0220] 19C (2.0 g) was dissolved in 1,2-dichloroethane (30 mL), and trimethylsilyl isocyanate (2.94 g) was added. The reaction mixture was stirred at 85°C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 19D (2.1 g). MS m / z (ESI): 239.1 [M+1] + .

[0221] Step 4. Synthesis of Compound 19E

[0222] A 20% sodium ethoxide ethanol solution (14.0 g) was added to anhydrous ethanol (20 mL), and 19D (2.0 g) and diethyl malonate (3.4 g) were added sequentially. The reaction mixture was reacted at 80°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove ethanol. The residue was dissolved in water, and hydrochloric acid (2 M) was added dropwise under an ice bath to adjust the pH until solids appeared. The precipitated solid was collected by filtration and dried to obtain 19E (1.5 g). MS m / z (ESI): 307.2 [M+1] + .

[0223] Step 5. Synthesis of Compound 19F

[0224] 19E (1.4 g) was added to phosphorus oxychloride (20 mL). The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The phosphorus oxychloride was removed by concentration under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL). The organic phase was washed with ice water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 19F (1.4 g). MS m / z (ESI): 307.1 [M+1] + .

[0225] Step 6. Synthesis of Compound 19G

[0226] 19F (1.4 g) was dissolved in isopropanol (20 mL), and 2,4,6-trimethylaniline (1.85 g) was added. The reaction mixture was allowed to react at 90°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the resulting crude product was purified on a silica gel column (dichloromethane / methanol = 14 / 1) to obtain 19G (160 mg). MS m / z (ESI): 406.1 [M+1] + .

[0227] Step 7. Synthesis of Compound 19H

[0228] 19G (140 mg) was added to toluene (5 mL), followed by the addition of tert-butyl (2-hydroxyethyl)carbamate (84 mg) and cyanomethylenetri-n-butylphosphine (250 mg). The reaction mixture was stirred at 120°C for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was concentrated. The crude product was purified on a silica gel column (dichloromethane / methanol = 24 / 1) to obtain 19H (140 mg). MS m / z (ESI): 549.3 [M+1] + .

[0229] Step 8. Synthesis of Compound 19I

[0230] 19H (140 mg) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to yield 19I (125 mg). MS m / z (ESI): 449.1 [M+1] + .

[0231] Step 9, Synthesis of Compound 19

[0232] 19I (100 mg), phenyl carbamate (46 mg), and triethylamine (113 mg) were added to dichloromethane (2.5 mL). The reaction mixture was stirred at 25°C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash reverse phase chromatography to obtain compound 19 (20 mg). MS m / z (ESI): 492.3 [M+1] + .

[0233] 1 H NMR (400MHz, DMSO-d6) δ6.93(s,1H),6.81(s,2H),6.68(d,J=1.5Hz,1H),6.09(t,J=5.3Hz,1H),5.45(s,2H),4.93(d,J=1.6Hz,1H),4.19( t,J=6.2Hz,2H),3.78(d,J=1.5Hz,3H),3.66(d,J=1.6Hz,3H),3.37(s,2H),3.32(d,J=2.1Hz,4H),2.67(s,2H),2.18(s,3H),1.98(s,6H).

[0234] Example 18: Synthesis of Compound 20

[0235] Step 1. Synthesis of Compound 20B

[0236] At 0°C, sodium hydride (0.85 g) was added portionwise to a solution of 20A (4 g) in tetrahydrofuran (130 mL). After the addition was complete, the mixture was stirred at room temperature for 30 minutes, and then tert-butyl (2-bromoethyl)carbamate (8.4 g) was added. The reaction solution was heated to 40°C and reacted for 3 hours. After the reaction was completed, the reaction solution was added to ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 4 / 1) to obtain 20B (7.9 g). MS m / z (ESI): 314.0 [M+1] + .

[0237] Step 2, Synthesis of Compound 20C

[0238] Dissolve 20B (7.9 g) in dichloromethane (80 mL) and slowly add trifluoroacetic acid (26 mL) dropwise. Stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction mixture to obtain 20C (9.5 g). MS m / z (ESI): 213.7 [M+1] + .

[0239] Step 3, Synthesis of Compound 20D

[0240] 20C (9.0 g) was dissolved in 1,2-dichloroethane (250 mL), and trimethylsilyl isocyanate (16.6 g) was added. After replacing the nitrogen atmosphere, the mixture was heated at 90°C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to obtain a crude product. The crude product was slurried with methyl tert-butyl ether to obtain 20D (3.7 g). MS m / z (ESI): 256.9 [M+1] + .

[0241] Step 4. Synthesis of Compound 20E

[0242] 20D (3.0 g) was dissolved in ethanol (80 mL), and diethyl malonate (4.7 g) and sodium ethoxide (4.0 g) were added. The mixture was heated under reflux under nitrogen for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, dissolved in water, and the pH was adjusted to 5 with dilute hydrochloric acid. The solution was filtered and the filtrate was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to give 20E (1.0 g). MS m / z (ESI): 324.9 [M+1] + .

[0243] Step 5. Synthesis of Compound 20F

[0244] 20E (700 mg) was dissolved in phosphorus oxychloride (37 mL) and reacted at 70°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched by adding ice water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was spin-dried to obtain a crude product. The crude product was purified on a silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to obtain 20F (230 mg). MS m / z (ESI): 324.8 [M+1] + .

[0245] Step 6. Synthesis of Compound 20G

[0246] 20F (220 mg) and 2,4,6-trimethylaniline (458 mg) were dissolved in propylene glycol (7 mL) and reacted at 90°C for 10 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 20G (211 mg). MS m / z (ESI): 424.2 [M+1] + .

[0247] Step 7, Synthesis of Compound 20H

[0248] 20G (210 mg), tert-butyl (2-hydroxyethyl)carbamate (104 mg), and cyanomethylenetri-n-butylphosphine (359 mg) were dissolved in toluene (5 mL). After replacing the nitrogen atmosphere, the mixture was heated at 120°C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 20H (235 mg). MS m / z (ESI): 567.2 [M+1] + .

[0249] Step 8. Synthesis of Compound 20I

[0250] 20H (235 mg) was dissolved in a 1.4-dioxane hydrochloride solution (4 M, 2.5 mL) and reacted at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain 20I (239 mg). MS m / z (ESI): 467.2 [M+1] + .

[0251] Step 9. Synthesis of Compound 20

[0252] 20I (200 mg) was dissolved in dichloromethane (3 mL), and phenyl carbamate (59 mg) and triethylamine (130 mg) were added. After nitrogen displacement, the mixture was reacted at 25°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain compound 20 (150 mg). MS m / z (ESI): 509.9 [M+1] + .

[0253] 1 H NMR (400MHz, DMSO-d6) δ7.11(s,1H),6.85(s,1H),6.80(s,1H),6.76(s,1H),6.11(t,J=5.7Hz,1H),5.46(s,2H),4.94(s,1H),4.64-4.57( m,1H),4.20(q,J=6.5Hz,2H),3.79(s,3H),3.71(s,3H),3.36(q,J=6.4Hz,2H),3.24-2.96(m,4H),2.17(s,3H),2.05(s,3H),1.90(s,3H).

[0254] Example 19: Synthesis of Compound 21

[0255] Compound 20 (50 mg) was dissolved in dichloromethane (1 mL), and m-chloroperbenzoic acid (101 mg) was added at 0°C. The mixture was then warmed to room temperature and stirred for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was then purified by Flash reverse phase chromatography to obtain compound 21 (10 mg). MS m / z (ESI): 541.9 [M+1] + .

[0256] 1 H NMR (400MHz, DMSO-d6) δ7.41(s,1H),6.97(s,2H),6.88(s,1H),6.35(s,1H),5.75(s,2H),5.43(s,1H),4.71(d,J=9.6H z,1H),4.31(s,1H),4.21(s,2H),3.90(s,3H),3.84(s,3H),3.37(s,2H),3.17(s,2H),2.25-2.13(m,6H),1.96(s,3H).

[0257] Example 20: Synthesis of Compound 22

[0258] Compound 22 (57 mg) was obtained by referring to the synthesis method of Example 19. MS m / z (ESI): 494.3 [M+1] + .

[0259] 1 H NMR (400MHz, DMSO-d6) δ7.06(s,2H),6.85(s,1H),6.68(s,1H),6.57(s,1H),6.03(s,2H),5.42(s,1H),4.42(d,J=5.0Hz, 2H),4.28-4.24(m,2H),4.22(d,J=4.9Hz,2H),3.82(s,3H),3.67(s,3H),3.40(d,J=6.1Hz,2H),2.29(s,3H),2.20(s,6H).

[0260] Example 21: Synthesis of Compound 23

[0261] Step 1. Synthesis of compound 23B

[0262] 23A (10.0 g) was dissolved in N,N-dimethylformamide (100 mL), and sodium azide (4.6 g) was slowly added. The reaction mixture was stirred at 25°C for 16 hours. After the reaction was completed, water (200 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to yield 23B (11 g).

[0263] Step 2. Synthesis of Compound 23C

[0264] A 20% sodium ethoxide-ethanol solution (104 g) was added to anhydrous ethanol (100 mL), followed by the addition of 23B (10.0 g) and diethyl malonate (25.0 g). The reaction mixture was allowed to react at 80°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The ethanol was removed by concentration under reduced pressure, and the residue was dissolved in water. Hydrochloric acid (2 M) was added dropwise in an ice bath to adjust the pH to 2. The precipitated solid was collected by filtration and dried to yield 23C (12 g). MS m / z (ESI): 278.1 [M+1] + .

[0265] Step 3. Synthesis of Compound 23D

[0266] 23C (12.0 g) was added to N,N-dimethylformamide (120 mL), followed by benzyl bromide (11.1 g) and potassium carbonate (12.0 g). The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, water (200 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to yield 23D (10 g). MS m / z (ESI): 368.1 [M+1]+.

[0267] Step 4. Synthesis of Compound 23E

[0268] 23D (10.0 g) was slowly added to trifluoroacetic acid / trifluoromethanesulfonic acid (V / V = 4 / 1, 25 mL) and stirred at 90°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The crude product was purified by Flash reverse phase chromatography to obtain 23E (3.0 g). MS m / z (ESI): 248.1 [M+1] + .

[0269] Step 5. Synthesis of Compound 23F

[0270] 23E (3.0 g) was added to acetonitrile (30 mL), followed by iodomethane (2.6 g) and potassium carbonate (3.3 g). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain 23F (2.6 g). MS m / z (ESI): 262.1 [M+1] + .

[0271] Step 6. Synthesis of Compound 23G

[0272] 23F (2.6 g) was added to a 5 M sodium hydroxide solution in ethanol (20 mL). The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and diluted with water. The pH was adjusted to 2 with 1 M dilute hydrochloric acid. The resulting solution was purified by flash reverse phase chromatography to yield 23G (800 mg). MS m / z (ESI): 234.1 [M+1]+.

[0273] Step 7. Synthesis of Compound 23H

[0274] 23G (50 mg) and a small amount of N,N-dimethylformamide were added to dichloromethane (5 mL), followed by the dropwise addition of oxalyl chloride (32 mg) at 0°C. The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to afford 23H (60 mg).

[0275] Step 8. Synthesis of Compound 23I

[0276] 23H (60 mg), IM-02 (107 mg), and triethylamine (48 mg) were added to dichloromethane (5 mL). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 23I (70 mg). MS m / z (ESI): 664.3 [M+1] + .

[0277] Step 9. Synthesis of compound 23

[0278] 23I (70 mg), palladium / carbon (50 mg), and palladium hydroxide / carbon (50 mg) were added to methanol (10 mL). The reaction mixture was stirred at 30°C under a hydrogen atmosphere for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated. The crude product was purified by flash reverse phase chromatography to obtain compound 23 (5 mg). MS m / z (ESI): 574.3 [M+1] + .

[0279] 1H NMR(400MHz,DMSO-d6)δ14.65(s,1H),8.32(s,1H),7.22(s,1H),7.10(s,2H),6.97(s,1H),6.77(s,1H),5.57(s,1H),4.41(s,2H),4.1 2(d,J=6.5Hz,2H),4.01(s,1H),3.90(s,2H),3.68(s,1H),3.64(s,2H),2.95(s,1H),2.31(s,3H),2.16(s,5H),1.35(t,J=6.9Hz,3H).

[0280] Example 22: Synthesis of Compound 24

[0281] Compound 24 (15 mg) was obtained by referring to the synthesis method of Example 11. MS m / z (ESI): 554.2 [M+1] + .

[0282] 1 H NMR (400MHz, DMSO-d6) δ7.46-7.33(m,5H),7.08(s,1H),6.86(s,2H),6.70(s,1H),6.10(t,J=5.6Hz,1H),5.44(s,2H),5.33(s,1H),5 .14(s,2H),4.18(t,J=6.6Hz,2H),3.92(t,J=5.7Hz,2H),3.63(s,3H),3.35(d,J=6.4Hz,2H),2.88(s,2H),2.22(s,3H),1.97(s,6H).

[0283] Example 23: Synthesis of Compound 25

[0284] Step 1. Synthesis of Compound 25A

[0285] 24H (600 mg) was dissolved in methanol (10 mL), followed by the addition of palladium on carbon (100 mg). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 25A (500 mg). MS m / z (ESI): 521.3 [M+1] + .

[0286] Step 2, Synthesis of Compound 25B

[0287] 25A (200 mg), 3-hydroxytetrahydrofuran (51 mg) and cyanomethylenetri-n-butylphosphine (278 mg) were dissolved in toluene (5 mL). Under a nitrogen atmosphere, the reaction solution was refluxed at 120°C and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 24 / 1) to obtain 25B (100 mg). MS m / z (ESI): 591.3 [M+1] + .

[0288] Step 3. Synthesis of Compound 25C

[0289] 25B (100 mg) was added to a hydrochloric acid / dioxane solution (4 M, 2 mL). The reaction mixture was stirred at 25°C for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain 25C (90 mg). MS m / z (ESI): 491.2 [M+1] + .

[0290] Step 4, Synthesis of Compound 25

[0291] Compound 25C (90 mg), phenyl carbamate (38 mg), and triethylamine (93 mg) were added to dichloromethane (2 mL). The reaction mixture was stirred at 25°C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash reverse phase chromatography to obtain compound 25 (20 mg). MS m / z (ESI): 534.3 [M+1] + .

[0292] 1 H NMR (400MHz, DMSO-d6) δ6.94(s,1H),6.85(s,2H),6.68(s,1H),6.10(t,J=5.5Hz,1H),5.45(s,2H),5.32(s,1H),5.06(s,1H),4.18(t,J=6.6Hz,2 H),3.94-3.89(m,2H),3.88-3.70(m,4H),3.62(s,3H),3.35(d,J=6.3Hz, 2H), 2.90 (t, J = 5.6Hz, 2H), 2.28-2.18 (m, 4H), 1.97 (s, 6H), 1.93 (s, 1H).

[0293] Example 24: Synthesis of Compound 26

[0294] Step 1. Synthesis of Compound 26A

[0295] 25A (800 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (537 mg) were dissolved in acetonitrile (10 mL), followed by the addition of cesium carbonate (601 mg). The reaction mixture was stirred at 80 ° C for 10 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature. After dilution with water (50 mL), it was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 26A (180 mg). MS m / z (ESI): 603.3 [M+1] + .

[0296] Step 2, Synthesis of Compound 26B

[0297] 26A (180 mg) was added to a hydrochloric acid / dioxane solution (4 M, 4 mL). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain 26B (150 mg). MS m / z (ESI): 503.2 [M+1] + .

[0298] Step 3. Synthesis of Compound 26C

[0299] 26B (100 mg) was dissolved in dichloromethane (2 mL), followed by the addition of triethylamine (88 mg) and 23H (44 mg). The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified using a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 26C (70 mg). MS m / z (ESI): 718.3 [M+1] + .

[0300] Step 4, Synthesis of Compound 26

[0301] 26C (67 mg) was dissolved in methanol (1 mL), followed by the addition of palladium on carbon (30 mg) and palladium hydroxide on carbon (30 mg). Under a hydrogen atmosphere, the reaction solution was heated to 30°C and stirred for 4 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash reverse phase chromatography to obtain compound 26 (27.5 mg). MS m / z (ESI): 628.3 [M+1] + .

[0302] 1H NMR(400MHz,DMSO-d6)δ14.66(s,1H),10.66(s,1H),8.31(s,1H),7.23(s,1H),7.10(s,2H),6.87(s,1H),5.63(s,1H ), 4.86 (q, J = 8.5Hz, 2H), 4.42 (s, 2H), 4.02 (s, 2H), 3.90 (s, 3H), 3.69 (s, 5H), 2.95 (s, 2H), 2.31 (s, 3H), 2.14 (s, 6H).

[0303] Example 25: Synthesis of Compound 27

[0304] Compound 27 (6.5 mg) was obtained by referring to the synthesis method of Example 24. MS m / z (ESI): 600.3 [M+1] + .

[0305] 1 H NMR(400MHz,DMSO-d6)δ14.67(s,1H),10.58(s,1H),8.31(s,1H),7.12(s,2H ),7.05(s,1H),6.77(s,1H),5.56(s,1H),4.42(s,2H),4.01(s,2H),3.91(d,J =6.8Hz,5H),3.70(d,J=5.8Hz,2H),3.66(s,3H),2.94(t,J=6.1Hz,2H),2.32( s,3H),2.15(s,6H),1.29-1.22(m,1H),0.62-0.53(m,2H),0.35-0.28(m,2H).

[0306] Example 26: Synthesis of Compound 28

[0307] Compound 28 (12 mg) was obtained by referring to the synthesis method of Example 24. MS m / z (ESI): 604.3 [M+1] + .

[0308] 1H NMR (400MHz, DMSO-d6) δ14.67(s,1H),10.58(s,1H),8.31(s,1H),7.11(d,J=6.6Hz,3H),6.79(s,1H),5.58(s,1H),4.42(s ,2H),4.24-4.16(m,2H),4.02(s,2H),3.91(s,3H),3.74-3.63(m,7H),3.30(s,3H),2.95(s,2H),2.32(s,3H),2.15(s,6H).

[0309] Example 27: Synthesis of Compound 29

[0310] Step 1. Synthesis of Compound 29B

[0311] 29A (200 mg) was dissolved in thionyl chloride (5 mL) and heated at 80°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was directly spin-dried to obtain 29B (215 mg).

[0312] Step 2, Synthesis of Compound 29

[0313] 29B (215 mg) was dissolved in dichloromethane (10 mL), and 14B (548 mg) and triethylamine (370 mg) were added. After nitrogen displacement, the mixture was reacted at 25°C for 18 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 4) to obtain compound 29 (476 mg). MS m / z (ESI): 588.2 [M+1] + .

[0314] 1 H NMR(400MHz,DMSO-d6)δ9.01(t,J=5.8Hz,1H),8.54(d,J=5.1Hz,1H),7.81(s,1H), 7.72(d,J=5.1Hz,1H),6.94(s,1H),6.84(s,2H),6.67(s,1H),5.33(s,1H),4.36(t ,J=5.8Hz,2H),4.05(p,J=6.3Hz,2H),3.89(t,J=5.9Hz,2H),3.78-3.67(m,2H),3. 62(s,3H),2.86(d,J=6.0Hz,2H),2.21(s,3H),1.95(s,6H),1.33(t,J=6.9Hz,3H).

[0315] Example 28: Synthesis of Compound 30

[0316] Compound 29 (200 mg), (E)-benzaldehyde oxime (54 mg), RockPhos-Pd-G3 (86 mg), and cesium carbonate (244 mg) were dissolved in toluene (5 mL) and heated at 80°C under a nitrogen atmosphere for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash reverse phase chromatography to obtain compound 30 (14 mg). MS m / z (ESI): 570.0 [M+1] + .

[0317] 1 H NMR (400MHz, DMSO-d6) δ10.61 (s, 1H), 8.81 (s, 1H), 7.45 (d, J = 6.7Hz, 1H), 7. 12(s,2H),7.07(s,1H),6.78(s,1H),6.63(s,1H),6.38(d,J=6.6Hz,1H),5.5 9(s,1H),4.47(s,2H),4.15-4.09(m,2H),4.02(s,2H),3.69(d,J=5.1Hz,2H) ,3.65(s,3H),2.95(s,2H),2.32(s,3H),2.19(s,6H),1.35(t,J=6.9Hz,3H).

[0318] Example 29: Synthesis of Compound 31

[0319] Step 1. Synthesis of compound 31A

[0320] IM-02 (500 mg) was added to toluene (5 mL), followed by tert-butyl (3-hydroxycyclobutyl)carbamate (346 mg) and cyanomethylenetri-n-butylphosphine (890 mg). The reaction mixture was stirred at 120°C for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was concentrated. The crude product was purified on a silica gel column (dichloromethane / methanol = 24 / 1) to obtain 31A (200 mg). MS m / z (ESI): 575.4 [M+1] + .

[0321] Step 2, Synthesis of Compound 31B

[0322] 31A (200 mg) was added to a hydrochloric acid / dioxane solution (4 M, 4 mL). The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash reverse phase chromatography to obtain 31B (120 mg). MS m / z (ESI): 475.3 [M+1] + .

[0323] Step 3. Synthesis of Compound 31C

[0324] 31B (120 mg) was dissolved in dichloromethane (2 mL), followed by the addition of triethylamine (128 mg) and 23H (64 mg). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 31C (120 mg). MS m / z (ESI): 690.3 [M+1] + .

[0325] Step 4, synthesis of compound 31

[0326] 31C (90 mg) was dissolved in methanol (2 mL), followed by the addition of palladium on carbon (18 mg) and palladium hydroxide on carbon (18 mg). Under a hydrogen atmosphere, the reaction solution was heated to 30°C and stirred for 14 hours. After the reaction was completed, the solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash reverse phase chromatography to obtain compound 31 (7 mg). MS m / z (ESI): 600.3 [M+1] + .

[0327] 1 H NMR(400MHz,DMSO-d6)δ7.80(d,J=8.3Hz,1H),6.94(s,1H),6.86(s,2H),6.64(s,1 H),5.32(s,1H),5.25-5.15(m,1H),4.25(dd,J=15.9,8.0Hz,1H),4.09-4.03(m,2H) ,3.95-3.88(m,3H),3.83(s,2H),3.61(s,3H),3.01-2.94(m,2H),2.89(t,J=6.0Hz ,2H),2.82-2.75(m,2H),2.22(s,3H),1.98(d,J=3.9Hz,6H),1.33(t,J=7.0Hz,3H).

[0328] Example 30: Synthesis of Compound 32

[0329] Step 1. Synthesis of Compound 32A

[0330] IM-01 (200 mg) was added to toluene (5 mL), followed by the addition of tert-butyl 3-hydroxyazetidine-1-carboxylate (133 mg) and cyanomethylenetri-n-butylphosphine (370 mg). The mixture was stirred at 120°C for 4 hours under nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 32A (100 mg). MS m / z (ESI): 547.2 [M+1] + .

[0331] Step 2, Synthesis of Compound 32B

[0332] 32A (100 mg) was added to dichloromethane (2 mL), followed by trifluoroacetic acid (1 ml). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was dried under vacuum to obtain 32B (70 mg). MS m / z (ESI): 447.0 [M+1] + .

[0333] Step 3. Synthesis of compound 32

[0334] 32B (70 mg) was added to dichloromethane (2 mL), followed by the addition of phenyl carbamate (32 mg) and triethylamine (79 mg). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash reverse phase chromatography to obtain compound 32 (30 mg). MS m / z (ESI): 490.2 [M+1] + .

[0335] 1 H NMR (400MHz, DMSO-d6) δ7.45-6.22(m,4H),5.98-5.81(m,2H),5.24(s,1H),4.99-4.80(m,1H),4.27-3. 70(m,8H),3.59(s,2H),3.57-3.45(m,2H),2.88(t,J=6.2Hz,2H),2.34-2.26(m,3H),2.13-1.99(m,6H).

[0336] Example 31: Synthesis of Compound 33

[0337] Step 1. Synthesis of compound 33A

[0338] p-Nitrophenyl chloroformate (1.26 g) and N,N-diisopropylethylamine (3.36 g) were dissolved in anhydrous dichloromethane (20 mL), followed by the addition of 33A (1.0 g). The mixture was stirred at room temperature for 14 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane / methanol = 24 / 1) to obtain 33B (0.62 g). MS m / z (ESI): 358.0 [M+1] + .

[0339] Step 2, synthesis of compound 33

[0340] Compound 2 (100 mg) and 33B (90 mg) were dissolved in acetonitrile (2 mL), followed by the addition of triethylamine (116 mg). The reaction was stirred at 80°C under a nitrogen atmosphere for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Flash reverse phase chromatography to obtain compound 33 (25 mg). MS m / z (ESI): 653.0 [M+1] + .

[0341] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),7.32(s,1H),7.11(d,J=7.1Hz,3H),6.79(s,1H),5.60(s,1H),4.78(s,2H),4.36(s,2H), 4.17(t,J=5.0Hz,2H),3.88-3.79(m,7H),3.65(s,3H),3.50(d,J=5.2Hz,2H),2.93(t,J=6.2Hz,2H),2.33(s,3H),2.20(s,6H).

[0342] Example 32: Synthesis of Compound 34

[0343] Step 1. Synthesis of compound 34A

[0344] IM-01 (2.0 g) was dissolved in N,N-dimethylformamide (20 mL), and 2-bromo-1,1-dimethoxyethane (6.0 g), potassium carbonate (6.3 g), and sodium iodide (4.59 g) were added sequentially. Stir at 83°C for 72 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with ethyl acetate (70 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 3 / 2) to obtain 34A (150 mg). MS m / z (ESI): 480.2 [M+1]+ .

[0345] Step 2, Synthesis of Compound 34B

[0346] 34A (130 mg) and concentrated hydrochloric acid (0.3 mL, 12 mol / L) were dissolved in 1,4-dioxane (1 mL). The reaction mixture was stirred at 25°C for 10 hours under a nitrogen atmosphere. After the reaction was completed, saturated aqueous sodium carbonate solution was added to the mixture to adjust the pH to 7-8, followed by dilution with water (3 mL) and extraction with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 34B (100 mg). MS m / z (ESI): 434.1 [M+1] + .

[0347] Step 3. Synthesis of compound 34

[0348] 34B (100 mg) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (89 mg) were dissolved in ethanol (2 mL). The reaction mixture was stirred at 78°C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, and sodium borohydride (44 mg, 1.15 mmol) and methanol (0.5 mL) were added. The temperature was then raised to 78°C and stirring was continued for 12 hours. The reaction solution was quenched with water and concentrated under reduced pressure. The resulting residue was redissolved in ethanol (1 mL) and palladium carbon (10 mg) was added. The mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Flash reverse phase chromatography to obtain compound 34 (15 mg). MS m / z (ESI): 610.2 [M+1] + .

[0349] 1 H NMR (400MHz, DMSO-d6) δ6.96(s,1H),6.85(s,2H),6.66(s,1H),5.32(s,1H),4.35(t,J=6.5Hz,2H),4.15(t,J=5.3Hz,2H),4.00(s,2H),3.9 1(t,J=6.0Hz,2H),3.80(s,3H),3.61(s,3H),3.08(t,J=5.4Hz,2H),2.97(t,J=6.6Hz,2H),2.89(t,J=5.9Hz,2H),2.22(s,3H),1.94(s,6H).

[0350] Example 33: Synthesis of Compound 35

[0351] Step 1. Synthesis of Compound 35A

[0352] IM-01 (1.0 g) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (590 mg) were dissolved in toluene (10 mL), and cyanomethylenetri-n-butylphosphine (1.9 g) was added. The reaction mixture was heated to 120°C under a nitrogen atmosphere for 10 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain 35A (0.5 g). MS m / z (ESI): 561.3 [M+1] + .

[0353] Step 2, Synthesis of Compound 35B

[0354] 35A (500 mg) was added to a 4 M solution of dioxane in hydrochloric acid (5 mL). The reaction mixture was allowed to react at 25°C for 1 hour. After the reaction was complete, the reaction mixture was directly dried to obtain 35B (0.42 g). MS m / z (ESI): 461.3 [M+1] + .

[0355] Step 3. Synthesis of compound 35C

[0356] 35B (110 mg) and 23H (50 mg) were dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (51 mg) was added. The reaction mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 60 / 1) to obtain 35C (80 mg). MS m / z (ESI): 676.2 [M+1] + .

[0357] Step 4. Synthesis of compound 35

[0358] 35C (80 mg) was dissolved in methanol (20 mL), and palladium hydroxide / carbon (8 mg) and palladium / carbon (8 mg) were added. The reaction mixture was reacted at 30°C under a hydrogen atmosphere for 72 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 35 (17 mg). MS m / z (ESI): 586.3 [M+1] + .

[0359] 1H NMR (400MHz, DMSO-d6) δ6.96(d,J=3.5Hz,1H),6.85(s,2H),6.64(d,J=7.9Hz,1H),6.13-6.02(m,1H),5.33(d,J=10.3Hz ,1H),4.38-4.04(m,1H),4.01-3.52(m,15H),2.90(q,J=5.9Hz,2H),2.81-2.72(m,1H),2.21(s,4H),2.03-1.85(m,6H).

[0360] Example 34: Synthesis of Compound 36

[0361] Step 1. Synthesis of compound 36B

[0362] 36A (100 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (73 mg), bis(acetonitrile)palladium dichloride (23 mg), and N,N-diisopropylethylamine (104 mg) were added to a methanol / acetonitrile mixed solvent (1 / 1, 5 mL). Under a carbon monoxide atmosphere (1 MPa), the reaction mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 36B (100 mg). MS m / z (ESI): 167.1 [M+1] + .

[0363] Step 2, Synthesis of Compound 36C

[0364] 36B (100 mg) and lithium hydroxide (75 mg) were dissolved in tetrahydrofuran (2 mL) and water (2 mL). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the pH was adjusted to 2 with 1 M dilute hydrochloric acid. The resulting solution was purified by flash reverse phase chromatography to obtain 36C (40 mg). MS m / z (ESI): 153.2 [M+1] + .

[0365] Step 3. Synthesis of compound 36

[0366] 36C (10 mg) was dissolved in N,N-dimethylformamide (2 mL), and HATU (26 mg) and diisopropylethylamine (22 mg) were then added thereto. The reaction solution was stirred at room temperature for 0.5 hours, and then compound 2 (25 mg) was added. The reaction solution was continued to stir at room temperature for 3 hours. After the reaction was completed, it was diluted with ethyl acetate to 100 mL and then washed with water (30 mL×3). The organic phase was dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The crude product was purified by thin layer preparative chromatography (dichloromethane / methanol=25 / 1) to give compound 36 (15 mg). MS m / z(ESI):569.2[M+1] + .

[0367] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.54(s,1H),6.97(s,1H),6.87(s,2H),6.68(s,1H),5.35(s,1H),4.32(t,J=6.7Hz,2H),4.08(t,J=7.1Hz,2 H),3.92(t,J=6.2Hz,2H),3.81(s,3H),3.68-3.54(m,5H),2.93-2.87(m, 2H),2.75(t,J=7.6Hz,2H),2.49-2.41(m,2H),2.22(s,3H),1.97(s,6H).

[0368] Example 35: Synthesis of Compound 37

[0369] Compound 37 (20 mg) was obtained by referring to the synthesis method of Example 23. MS m / z (ESI): 547.3 [M+1] + .

[0370] 1 H NMR(400MHz,DMSO-d6)δ6.86(d,J=5.1Hz,3H),6.66(s,1H),6.10(t,J=5.7Hz,1H) ,5.44(s,2H),5.31(s,1H),4.88(s,1H),4.18(t,J=6.6Hz,2H),3.91(d,J=6.1Hz,2 H),3.61(s,3H),3.39-3.33(m,2H),2.89(t,J=5.9Hz,2H),2.77(m,1H),2.68-2.54 (m,2H),2.37-2.27(m,2H),2.23(d,J=9.9Hz,6H),1.97(s,6H),1.79-1.69(m,1H).

[0371] Example 36: Synthesis of Compound 38

[0372] 38A (15 mg), N,N'-carbonyldiimidazole (22 mg), and triethylamine (46 mg) were dissolved in dichloromethane (5 mL). The reaction solution was stirred at 25°C for 2 hours, and then compound 2 (50 mg) was added. The reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by flash reverse phase chromatography to obtain compound 38 (5 mg). MS m / z (ESI): 591.2 [M+1] + .

[0373] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.74(s,1H),7.08(s,3H),6.78(s,3H),5.58(s,1H),4.31(s,2H),4.06(s,2H),3 .93-3.84(m,5H),3.65(s,3H),3.57(s,2H),3.45(d,J=6.3Hz,4H),3.37-3.29(m,2H),3.11(s,2H),3.09-2.96(m,4H).

[0374] Example 37: Synthesis of Compound 39

[0375] 39A (79 mg), compound 2 (150 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (145 mg), and N-methylimidazole (85 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was purified by flash reverse phase chromatography to obtain compound 39 (30 mg). MS m / z (ESI): 570.7 [M+1] + .

[0376] 1H NMR (400MHz, DMSO-d6) δ8.28(dd,J=7.3,2.1Hz,1H),8.04(dd,J=6.5,2.1Hz,1H),7.08(s,2H),7.04(s,1H),6.76(s,1H),6.50(t,J=6.9Hz,1H),5.5 3(s,1H),4.40(t,J=6.2Hz,2H),4.02(s,2H),3.85(s,3H),3.79(t,J=6.3 Hz,2H),3.64(s,3H),3.56(s,3H),2.97(s,2H),2.30(s,3H),2.13(s,6H).

[0377] Example 38: Synthesis of Compound 40

[0378] Step 1. Synthesis of Compound 40B

[0379] Potassium hydroxide (1.6 g) was dissolved in water (3 mL) to prepare a solution. 40A (2.0 g) was dissolved in methanol (20 mL) and the prepared potassium hydroxide solution was added. The reaction mixture was stirred for 10 minutes, and then iodoethane (2.47 g) was added dropwise. The reaction mixture was heated to 70°C under sealed conditions and stirred for 20 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 2–3 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 40B (0.35 g) in a 12% yield. MS m / z (ESI): 168.0 [M+1]+.

[0380] Step 2, Synthesis of Compound 40

[0381] 40B (46 mg), compound 2 (80 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (78 mg), and N-methylimidazole (45 mg) were dissolved in N,N-dimethylformamide (1.5 mL). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction mixture was purified by flash reverse phase chromatography to obtain compound 40 (15 mg). MS m / z (ESI): 584.3 [M+1] + .

[0382] 1H NMR (400MHz, DMSO-d6) δ9.91(t,J=5.6Hz,1H),8.29(d,J=7.2Hz,1H),8.05(d,J=6.5Hz, 1H),6.96(s,1H),6.84(s,2H),6.67(s,1H),6.51(t,J=6.8Hz,1H),5.32(s,1H),4.34(t, J=6.1Hz,2H),4.02(q,J=6.9Hz,2H),3.89(t,J=5.5Hz,2H),3.80(s,3H),3.76-3.68(m,2 H), 3.62 (s, 3H), 2.89 (t, J = 5.3Hz, 2H), 2.21 (s, 3H), 1.93 (s, 6H), 1.24 (t, J = 7.0Hz, 3H).

[0383] Example 39: Synthesis of Compound 41

[0384] Step 1. Synthesis of Compound 41A

[0385] Compound 40A (1.4 g) was dissolved in anhydrous ethanol (50 mL), followed by the addition of thionyl chloride (1 mL). The reaction mixture was incubated at 90°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by flash reverse phase chromatography to afford compound 41A (0.3 g). MS m / z (ESI): 168.1 [M+1] + .

[0386] Step 2, Synthesis of Compound 41B

[0387] 41A (300 mg) was dissolved in toluene (15 mL), followed by the addition of cyclopropylboronic acid (308 mg), copper acetate (326 mg), sodium bis(trimethylsilyl)amide (1645 mg), and pyridine (710 mg). The reaction mixture was reacted at 100°C under a nitrogen atmosphere for 48 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered and dried to give compound 41B (0.3 g). MS m / z (ESI): 207.9 [M+1]+.

[0388] Step 3. Synthesis of Compound 41C

[0389] 41B (300 mg) was dissolved in ethanol (10 mL), and water (2 mL) and sodium hydroxide (116 mg) were added sequentially. The reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, water (10 mL) was added to dilute it and extracted with methyl tert-butyl ether. The aqueous phase was adjusted to pH 2-3 with 1M hydrochloric acid aqueous solution, and ethyl acetate (30 mL × 3) was added for further extraction. The organic phases were combined and concentrated, and the residue was purified by flash reverse phase chromatography and freeze-dried to obtain compound 41C (30 mg). MS m / z (ESI): 179.9 [M+1] + .

[0390] Step 4. Synthesis of Compound 41

[0391] 41C (30 mg) was dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (70 mg), N-methylimidazole (41 mg), and compound 2 (109 mg) were added sequentially. The reaction mixture was incubated at 25°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was purified by flash reverse phase chromatography and freeze-dried to obtain compound 41 (9 mg). MS m / z (ESI): 596.3 [M+1] + .

[0392] 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),10.09(s,1H),8.27(dd,J=7.2,2.1Hz,1H),7.95(dd,J=6.7 ,2.0Hz,1H),7.10(d,J=12.1Hz,3H),6.78(s,1H),6.44(t,J=7.0Hz,1H),5.57(s,1H),4.40(t,J= 6.6Hz,2H),4.06(s,2H),3.85(s,3H),3.78(d,J=6.4Hz,2H),3.64(s,3H),3.43(td,J=7.5,3.7Hz ,1H),2.99(t,J=6.5Hz,2H),2.32(s,3H),2.17(s,6H),1.05(q,J=7.3Hz,2H),0.94-0.87(m,2H).

[0393] Example 40: Synthesis of Compound 42

[0394] Step 1. Synthesis of Compound 42A

[0395] IM-02 (1.0 g), 2-(2-bromoethyl)isoindoline-1,3-dione (3.5 g), potassium carbonate (3.1 g), and potassium iodide (2.5 g) were added to 2-butanone (20 mL). The mixture was stirred at 85°C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified using a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 42A (200 mg). MS m / z (ESI): 579.3 [M+1] + .

[0396] Step 2, Synthesis of Compound 42

[0397] 42A (120 mg) was dissolved in ethanol (10 mL) and hydrazine hydrate (31 mg) was added. The mixture was stirred at 85°C under a nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash reverse phase chromatography to obtain compound 42 (90 mg). MS m / z (ESI): 449.3 [M+1] + .

[0398] 1 H NMR (400MHz, DMSO-d6) δ7.99(s,2H),7.10(s,2H),6.98(s,1H),6.60(s,1H),5.27(s,1H),4.07(d,J=7.0Hz,2H),3.98-3 .90(m,4H),3.59(s,3H),3.10(d,J=6.6Hz,2H),2.88(t,J=6.3Hz,2H),2.31(s,3H),2.11(s,6H),1.33(t,J=6.9Hz,3H).

[0399] Example 41: Synthesis of Compound 43

[0400] Step 1. Synthesis of Compound 43A

[0401] Compound 42 (50 mg) and compound 23H (45 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (36 mg). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by flash reverse phase chromatography to obtain 43A (40 mg). MS m / z (ESI): 664.3 [M+1] + .

[0402] Step 2, Synthesis of Compound 43

[0403] 43A (40 mg), palladium / carbon (40 mg), and palladium hydroxide / carbon (40 mg) were added to methanol (10 mL). The reaction mixture was stirred at 30°C under a hydrogen atmosphere for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash reverse phase chromatography to obtain compound 43 (15 mg). MS m / z (ESI): 574.2 [M+1] + .

[0404] 1 H NMR (400MHz, CDCl3) δ6.99(s,2H),6.70(s,1H),6.65(s,1H),5.42(s,1H),4.23-4.20(m,2H),4.14-4.12(m,2H),4.10 (s,3H),4.09-4.06(m,2H),3.74-3.72(m,5H),2.92(t,J=6.3Hz,2H),2.33(s,3H),2.15(s,6H),1.48(t,J=7.0Hz,3H).

[0405] Example 42: Synthesis of Compound 44

[0406] Referring to the synthetic methods of Examples 40 and 41, compound 44 (10 mg) was obtained. MS m / z (ESI): 560.2 [M+1] + .

[0407] 1 H NMR(400MHz, CDCl3)δ7.00(s,2H),6.72(s,1H),6.63(s,1H),5.41(s,1H),4.20-4.24(m,2H),4.11(s,3H), 4.10-4.07(m,2H),3.92(s,3H),3.75(d,J=4.8Hz,2H),3.72(s,3H),2.95(s,2H),2.33(s,3H),2.16(s,6H).

[0408] Example 43: Synthesis of Compound 45

[0409] Compound 44B (50 mg) and phenyl carbamate (16 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (23 mg). The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated, and the resulting crude product was purified by Flash reverse phase chromatography to yield compound 45 (10 mg). MS m / z (ESI): 478.2 [M+1] + .

[0410] 1 H NMR (400MHz, CDCl3) δ7.01(s,2H),6.72(s,1H),6.62(s,1H),5.36(s,1H),4.22-4.13(m,2H),3. 92(s,5H),3.72(s,3H),3.52(t,J=6.6Hz,2H),2.94(t,J=6.3Hz,2H),2.34(s,3H),2.15(s,6H).

[0411] Example 44: Synthesis of Compound 46

[0412] Compound 44B (50 mg), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (26 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (48 mg), and N-methylimidazole (28 mg) were added to N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was purified by flash reverse phase chromatography to obtain compound 46 (5 mg). MS m / z (ESI): 570.2 [M+1] + .

[0413] 1 H NMR (400MHz, CDCl3) δ9.91 (s, 1H), 8.43 (d, J = 5.4Hz, 1H), 7.50 (d, J = 6.6Hz, 1H) ,6.96(s,2H),6.69(s,1H),6.64(s,1H),6.34(t,J=6.9Hz,1H),5.38(s,1H),4. 18(t,J=6.3Hz,2H),4.12-4.06(m,2H),3.90(s,3H),3.80(dd,J=15.0,5.9Hz,2 H),3.72(s,3H),3.62(s,3H),2.90(t,J=6.4Hz,2H),2.31(s,3H),2.18(s,6H).

[0414] Example 45: Synthesis of Compound 47

[0415] Step 1. Synthesis of Compound 47A

[0416] 4-Benzyloxy-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (50 mg) was dissolved in N,N-dimethylformamide (4 mL). HATU (170 mg) and diisopropylethylamine (93 mg) were added and stirred for 0.5 hours. 32B (80 mg) was added to the reaction solution and stirred for 3 hours. After the reaction was completed, the mixture was diluted to 50 mL with ethyl acetate, washed with water (30 mL x 3), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. 47A (100 mg) was obtained by preparative plate separation and purification. MS m / z (ESI): 662.3 [M+1] + .

[0417] Step 2, Synthesis of Compound 47

[0418] 47A (100 mg), palladium hydroxide on carbon (50 mg), and palladium on carbon (50 mg) were added to methanol (10 mL) and reacted at room temperature under a hydrogen atmosphere for 1 hour. After the reaction, the mixture was filtered, and the filtrate was concentrated and purified by flash reverse phase chromatography to obtain compound 47 (4.7 mg). MS m / z (ESI): 572.2 [M+1] + .

[0419] 1 H NMR (400MHz, DMSO-d6) δ7.57 (s, 1H), 7.26 (s, 1H), 7.10 (d, J = 5.1Hz, 2H), 7. 06(s,1H),5.94(s,1H),4.83(d,J=9.4Hz,1H),4.57(t,J=11.0Hz,1H),4.43( dd,J=11.8,7.5Hz,1H),4.11(t,J=6.6Hz,2H),3.87(d,J=11.3Hz,6H),3.75 (s,3H),3.59(dd,J=13.9,7.3Hz,1H),3.41–3.35(m,1H),2.35-2.24(m,9H).

[0420] Example 46: Synthesis of Compound 48

[0421] Morpholine-3-methanol (16 mg), N,N'-carbonyldiimidazole (19 mg), and triethylamine (58 mg) were dissolved in dichloromethane (5 mL) and stirred at 25°C for 2 hours. 44B (50 mg) was then added. The reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was concentrated and the crude product was purified by Flash reverse phase chromatography to obtain compound 48 (5 mg). MS m / z (ESI): 578.3 [M+1] + .

[0422] 1 H NMR (400MHz, CDCl3) δ7.01(s,2H),6.71(s,1H),6.63(s,1H),5.41(s,1H),4.25-4.06(m,5H),3.92(s,3H),3.90(s,1H),3.87(d,J=5.6H z,2H),3.75(d,J=6.1Hz,1H),3.72(s,3H),3.52-3.47(m,5H),3.12-3.02(m,1H),2.92(t,J=6.3Hz,2H),2.34(s,3H),2.14-2.17(m,6H).

[0423] Example 47: Synthesis of Compound 49

[0424] Step 1. Synthesis of Compound 49B

[0425] Dissolve triphenylmethane (1368 mg) and 1H-imidazole-5-carboxylic acid 49A (500 mg) in N,N-dimethylformamide (10 mL), and then add pyridine (0.5 mL). Under nitrogen protection, the mixture was heated to 50°C and stirred for 6 hours. After the reaction was completed, water (30 mL) was added to the reaction solution. The solid was collected by filtration and then washed with ethyl acetate (10 mL × 3) to obtain 49B (400 mg). MS m / z (ESI): 709.2 [2M+1] + .

[0426] Step 2, Synthesis of Compound 49C

[0427] 49B (90 mg) was dissolved in N,N-dimethylformamide (10 mL), and HATU (220 mg) and diisopropylethylamine (119 mg) were added sequentially. After stirring for 15 minutes, 32B (100 mg) was added. Stir for 3 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1–100 / 3) to obtain 49C (115 mg). MS m / z (ESI): 783.4 [M+1] + .

[0428] Step 3, Synthesis of Compound 49

[0429] Compound 49C (100 mg) was dissolved in a 5% trifluoroacetic acid solution in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by thin-layer chromatography and dried to afford compound 49 (18 mg). MS m / z (ESI): 541.0 [M+1] + .

[0430] 1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.41-8.02 (m, 1H), 7.74 (t, J = 6.2Hz, 1H ),7.30(s,1H),7.10(s,3H),6.08(s,1H),4.83-4.73(m,1H),4.57(t,J=11.0 Hz,1H),4.46-4.37(m,1H),4.18-4.04(m,2H),3.87(s,3H),3.76(s,3H),3.7 0-3.59(m,1H),3.40-3.28(m,1H),3.01(t,J=6.6Hz,2H),2.40-2.09(m,9H).

[0431] Example 48: Synthesis of Compound 50

[0432] 50A (19 mg) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of HATU (138 mg) and diisopropylethylamine (75 mg). The mixture was stirred for 0.5 hours, and 32B (65 mg) was added. After stirring for 4 hours, the reaction mixture was purified by flash reverse phase chromatography to obtain compound 50 (10 mg). MS m / z (ESI): 556.3 [M+1] + .

[0433] 1 H NMR(400MHz,DMSO-d6)δ7.11(s,2H),6.98(s,1H),6.62-6.24(m,1H),5.27(s, 1H),5.03-4.93(m,1H),4.82-4.70(m,1H),4.29-4.18(m,2H),3.95(t,J=6.4H z,2H),3.90-3.85(m,1H),3.81(s,3H),3.73-3.68(m,1H),3.59(s,3H),2.89( t,J=6.3Hz,2H),2.41(d,J=5.8Hz,3H),2.34-2.28(m,3H),2.12-2.02(m,6H).

[0434] Example 49: Synthesis of Compound 51

[0435] Compound 51 (20 mg) was obtained by referring to the synthesis method of Example 48. MS m / z (ESI): 543.3 [M+1] + .

[0436] 1 H NMR(400MHz, DMSO-d6)δ9.82(s,1H),9.20(t,J=5.9Hz,1H),7.31(s,1H),7.10(d,J= 3.2Hz,3H),6.09(s,1H),4.83(d,J=9.5Hz,1H),4.60(t,J=11.1Hz,1H),4.40(dd,J=1 1.8,6.9Hz,1H),4.12(dd,J=11.7,5.8Hz,2H),3.87(s,3H),3.76(s,3H),3.72-3.66( m,1H),3.41(dd,J=7.9,5.1Hz,1H),3.01(t,J=6.2Hz,2H),2.30(s,6H),2.24(s,3H).

[0437] Example 50: Synthesis of Compound 52

[0438] 14B (100 mg), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (39 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (71 mg), and N-methylimidazole (42 mg) were added to N,N-dimethylformamide (2 mL). The reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was purified by flash reverse phase chromatography to obtain compound 52 (10 mg). MS m / z (ESI): 584.3 [M+1] + .

[0439] 1H NMR (400MHz, CDCl3) δ10.32 (s, 1H), 8.43–8.32 (m, 1H), 7.58 (dd, J = 6.5, 1.9Hz, 1H ),7.01(s,2H),6.73(s,1H),6.69(s,1H),6.36(t,J=6.9Hz,1H),5.61(s,1H),4.7 1(d,J=6.0Hz,2H),4.16(q,J=6.8Hz,4H),3.93(d,J=6.1Hz,2H),3.74(s,3H),3.6 5(s,3H),2.98(t,J=6.2Hz,2H),2.34(s,3H),2.25(s,6H),1.49(t,J=7.0Hz,3H).

[0440] Example 51: Synthesis of Compounds 53 and 54

[0441] IM-02 (200 mg), 4-bromo-2-methylbutan-2-ol (412 mg), potassium carbonate (635 mg), and potassium iodide (491 mg) were added to 2-butanone (10 mL). The reaction solution was stirred at 85°C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane / methanol = 20 / 1) to obtain compound 53 (5 mg) and compound 54 (15 mg).

[0442] Compound 53: MS m / z (ESI): 492.3 [M+1] + .

[0443] 1 H NMR (400MHz, CDCl3) δ6.99(s,2H),6.68(s,1H),6.64(s,1H),5.32(s,1H),4.15-4.09(m,4H),4.01-3.97(m,2H),3. 71(s,3H),2.87(t,J=6.2Hz,2H),2.34(s,3H),2.16(s,6H),1.96-1.89(m,2H),1.47(t,J=7.0Hz,3H),1.26(s,6H).

[0444] Compound 54: MS m / z (ESI): 492.2 [M+1] + .

[0445] 1H NMR (400MHz, DMSO-d6) δ6.94(s,1H),6.85(s,2H),6.66(s,1H),5.31(s,1H),4.36(s,1H),4.27-4.16(m,2H),4.06(q,J=6.9Hz,2H),3.9 1(t,J=6.0Hz,2H),3.62(s,3H),2.88(t,J=5.9Hz,2H),2.22(s,3H),1.96(s,6H),1.85-1.76(m,2H),1.33(t,J=6.9Hz,3H),1.17(s,6H).

[0446] Example 52: Synthesis of Compound 55

[0447] Step 1. Synthesis of Compound 55B

[0448] 55A (2.0 g), 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.36 g), and cesium carbonate (8.54 g) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 10 hours. After completion of the reaction, water (1 mL) was added to quench the reaction. The resulting solution was purified by flash reverse phase chromatography to obtain 55B (2.0 g). MS m / z (ESI): 236.1 [M+1] + .

[0449] Step 2. Synthesis of Compound 55C

[0450] 55B (500 mg) was dissolved in tetrahydrofuran / water (V / V = 1 / 1, 10 mL), followed by the addition of lithium hydroxide (152 mg). The reaction mixture was allowed to react at 25°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, extracted with ether (3 mL), and the pH was adjusted to 2-3 with 1M dilute hydrochloric acid. The precipitated solid was collected by filtration and dried under vacuum to obtain 55C (220 mg). MS m / z (ESI): 222.2 [M+1] + .

[0451] Step 3. Synthesis of Compound 55

[0452] 55C (51 mg) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of HATU (102 mg) and diisopropylethylamine (53 mg). The reaction mixture was stirred at room temperature for 15 minutes, and compound 2 (90 mg) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (0.1 mL) was added to quench the mixture, and the resulting solution was purified by reverse phase chromatography to obtain compound 55 (22.45 mg). MS m / z (ESI): 638.2 [M+1] +.

[0453] 1 H NMR (400MHz, CDCl3) δ9.61(s,1H),8.55(s,1H),7.46(d,J=6.8Hz,1H),6.85(s,2H),6.71(s,1H),6.66(s,1H),6.43(t,J=6.8Hz,1H),5.4 6(s,1H),4.68(q,J=8.5Hz,2H),4.57(s,2H),4.03(s,2H),3.98-3.84(m,5H),3.76(s,3H),2.89(s,2H),2.27(s,3H),2.21-1.83(m,6H).

[0454] Example 53: Synthesis of Compound 56

[0455] Referring to the synthesis method of Example 48, compound 56 (18 mg) was obtained. MS m / z (ESI): 542.2 [M+1] + .

[0456] 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.76(s,1H),7.29(s,1H),7.13(s,2H),7.09(s,1H),6.05(s,1H),4.86-4.75(m,1H),4.58-4.42(m,2H) ,4.18-4.02(m,2H),3.87(s,3H),3.76(s,3H),3.67-3.59(m,1H),3.28 (s,1H),3.01(t,J=6.9Hz,2H),2.34(s,3H),2.30(s,3H),2.26(s,3H).

[0457] Example 54: Synthesis of Compound 57

[0458] Compound 57 (30 mg) was obtained by referring to the synthesis method of Example 30. MS m / z (ESI): 504.3 [M+1] + .

[0459] 1H NMR (400MHz, DMSO-d6) δ8.15(s,3H),7.33(s,1H),7.15(s,2H),7.10(s,1H),6.12(s,1H),4.81-4.79(m,1H),4.64-4.47(m,2H),4.18-4.09( m,4H),3.76(s,3H),3.38-3.35(m,1H),3.01(t,J=6.4Hz,2H),2.75(d,J=11.0Hz,1H),2.33-2.29(m,6H),2.18(s,3H),1.36(t,J=6.9Hz,3H).

[0460] Example 55: Synthesis of Compound 58

[0461] Step 1. Synthesis of Compound 58A

[0462] Under a nitrogen atmosphere, IM-02 (500 mg) was dissolved in acetonitrile (30 mL), and compound 5B (667 mg), potassium carbonate (1.2 g), and potassium iodide (1.02 g) were added sequentially. The reaction was allowed to proceed at 80°C for 72 hours. After the reaction was completed, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Flash reverse phase chromatography to obtain 58A (180 mg). MS m / z (ESI): 534.3 [M+1] + .

[0463] Step 2, Synthesis of Compound 58

[0464] 58A (100 mg) was dissolved in water (5 mL), and then 2 M methanolic hydrochloric acid (5 mL) was added and stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to 7-9. The precipitated solid was filtered to obtain a crude product, which was purified by reverse phase chromatography to obtain compound 58 (38 mg). MS m / z (ESI): 494.2 [M+1] + .

[0465] 1H NMR(400MHz,Chloroform-d&D2O)δ7.02(s,1H),6.99(s,1H),6.69(s,1H),6.63(s, 1H),5.34(s,1H),4.63-4.48(m,1H),4.25-4.04(m,4H),3.98-3.80(m,1H),3.72(s, 3H),3.67-3.59(m,1H),3.59-3.49(m,1H),3.45-3.35(m,1H),2.89(t,J=6.4Hz,2H ),2.34(s,3H),2.16(s,3H),2.14(s,3H),1.80-1.58(m,2H),1.48(t,J=7.0Hz,3H).

[0466] Example 56: Synthesis of Compound 59

[0467] Step 1. Synthesis of Compound 59B

[0468] 59A (200 mg) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (247 mg) and iodomethane (253 mg) were added sequentially. The reaction mixture was stirred at 25°C for 16 hours. After the reaction was completed, it was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting crude product was purified by Flash reverse phase chromatography to obtain 59B (80 mg). MS m / z (ESI): 182.7 [M+1] + .

[0469] Step 2, Synthesis of Compound 59C

[0470] 59B (200 mg) was dissolved in tetrahydrofuran / water (1 / 1, 10 mL), followed by the addition of lithium hydroxide (53 mg). The reaction mixture was stirred at 45°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was diluted with water, and the pH was adjusted to 2 with 1 M dilute hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and lyophilized to obtain 59C (80 mg). MS m / z (ESI): 155.1 [M+1] + .

[0471] Step 3. Synthesis of Compound 59

[0472] 59C (18 mg), compound 2 (50 mg), HATU (106 mg), and diisopropylethylamine (43 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was purified by flash reverse phase chromatography to obtain compound 59 (10.2 mg). MS m / z (ESI): 585.2 [M+1] + .

[0473] 1 H NMR (400MHz, DMSO-d6) δ9.62(t,J=6.0Hz,1H),8.13(d,J=4.2Hz,1H),8.04(d,J =4.2Hz,1H),6.94(s,1H),6.84(s,2H),6.67(s,1H),5.32(s,1H),4.36(t,J=6. 2Hz,2H),4.06(q,J=7.0Hz,2H),3.88(t,J=6.0Hz,2H),3.82–3.68(m,5H),3.62 (s,3H),2.87(t,J=6.2Hz,2H),2.21(s,3H),1.94(s,6H),1.33(t,J=7.0Hz,3H).

[0474] Example 57: Synthesis of Compound 60

[0475] Step 1. Synthesis of Compound 60A

[0476] IM-02 (1.0 g) was dissolved in toluene (20 mL), followed by the addition of 3-(tert-butyldimethylsilyloxy)propanol (0.71 g) and cyanomethylenetri-n-butylphosphine (1.81 g). The mixture was heated to 120°C under a nitrogen atmosphere and stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by Flash reverse-phase chromatography to yield 60A (280 mg). MS m / z (ESI): 578.3 [M+1] + .

[0477] Step 2, Synthesis of Compound 60

[0478] 60A (600 mg) was dissolved in dichloromethane (10 mL), and hydrogen fluoride-pyridine solution (617 mg) was slowly added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, it was quenched with saturated sodium bicarbonate (2 mL) and extracted with dichloromethane (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash reverse phase chromatography to obtain compound 60 (300 mg). MS m / z (ESI): 464.2 [M+1] +.

[0479] 1 H NMR(400MHz,Chloroform-d)δ7.01(s,2H),6.69(s,1H),6.63(s,1H),5.33(s,1H),4.21-4.08(m,4H),3.99(t,J=6.1Hz,2H),3 .80-3.73(m,2H),3.71(s,3H),2.89(t,J=6.5Hz,2H),2.34(s,3H),2.16(s,6H),1.80(p,J=5.7Hz,2H),1.48(t,J=7.0Hz,3H).

[0480] Example 58: Synthesis of Compound 61

[0481] Step 1. Synthesis of Compound 61A

[0482] Compound 60 (300 mg) was dissolved in DMSO (6 mL), followed by the addition of IBX (543.69 mg). The mixture was stirred at 25°C for 5 hours. After completion of the reaction, the mixture was quenched with water (0.5 mL). The reaction solution was purified by flash reverse-phase chromatography to yield 61A (200 mg). MS m / z (ESI): 462.1 [M+1]+.

[0483] Step 2, Synthesis of Compound 61

[0484] 61A (200 mg) was dissolved in acetonitrile / tert-butyl alcohol / water (2 / 2 / 1, 10 mL), followed by the addition of sodium dihydrogen phosphate (182.0 mg) and sodium chlorite (117.5 mg). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, saturated sodium thiosulfate solution (0.5 mL) was added to quench the mixture. The reaction mixture was purified by flash reverse phase chromatography to obtain compound 61 (17 mg). MS m / z (ESI): 478.1 [M+1] + .

[0485] 1 H NMR(400MHz,Chloroform-d&D2O)δ7.01(s,2H),6.69(s,1H),6.64(s,1H),5.38(s,1H),4.21-4.03(m,6H), 3.72(s,3H),2.97(t,J=7.4Hz,2H),2.90(t,J=6.5Hz,2H),2.34(s,3H),2.16(s,6H),1.48(t,J=7.0Hz,3H).

[0486] Example 59: Synthesis of Compound 62

[0487] Compound 62 (10 mg) was obtained by referring to the synthesis method of Example 48. MS m / z (ESI): 544.2 [M+1] + .

[0488] 1 H NMR (400MHz, CDCl3) δ9.48(s,1H),8.33(d,J=1.2Hz,1H),7.30(d,J=1.3Hz,1H),7.02(s,2H),6.69(s,1H),6.64(s,1H),5 .37(s,1H),4.23-4.07(m,6H),3.76-3.67(m,5H),2.92(t,J=6.3Hz,2H),2.34(s,3H),2.16(s,6H),1.48(t,J=7.0Hz,3H).

[0489] Example 60: Synthesis of Compound 63

[0490] Referring to the synthesis method of Example 48, compound 63 (10 mg) was obtained. MS m / z (ESI): 554.2 [M+1] + .

[0491] 1 H NMR(400MHz,Chloroform-d)δ9.02(s,1H),8.60(d,J=4.5Hz,1H),8.10(d,J= 7.8Hz,1H),7.83-7.73(m,1H),7.43-7.33(m,1H),6.98(s,2H),6.68(s,1H), 6.65(s,1H),5.38(s,1H),4.21-4.08(m,6H),3.79(q,J=6.5Hz,2H),3.71(s, 3H), 2.89 (t, J = 6.4Hz, 2H), 2.32 (s, 3H), 2.17 (s, 6H), 1.47 (t, J = 7.0Hz, 3H).

[0492] Example 61: Synthesis of Compound 64

[0493] Referring to the synthesis method of Example 48, compound 64 (24 mg) was obtained. MS m / z (ESI): 544.3 [M+1] + .

[0494] 1H NMR (400MHz, DMSO-d6) δ15.83-15.18(m,1H),8.89-6.79(m,6H),6.79-5.14(m,1H),4.22-3.48(m,11H),2.94-2.84(m,2H),2.35-2.21(m,3H),2.18 -1.91(m,6H),1.44-1.27(m,3H).

[0495] Example 62: Synthesis of Compound 65

[0496] Compound 65 (10 mg) was obtained by referring to the synthesis method of Example 48. MS m / z (ESI): 559.2 [M+1] + .

[0497] 1 H NMR (400MHz, DMSO-d6) δ9.54-9.39(m,1H),8.00-5.20(m,5H),4.15-4.03(m,3H),3.96-3.91(m,3H),3.73-3.54(m,4H),2.91-2.85(m,2H),2.74 -2.56(m,3H),2.29-2.26(m,3H),2.11(s,3H),2.05(s,3H),1.39-1.31(m,3H).

[0498] Example 63: Synthesis of Compound 66

[0499] Compound 66 (30 mg) was obtained by referring to the synthesis method of Example 11. MS m / z (ESI): 482.1 [M+1] + .

[0500] 1 H NMR (400MHz, DMSO-d6) δ6.97(s,1H),6.90-6.83(m,2H),6.79(s,1H),6.10(t,J=5.8Hz,1H),5.52(d,J=1.9Hz,1H),5.43(s,2 H), 4.17 (t, J = 6.5Hz, 2H), 3.93 (t, J = 6.1Hz, 2H), 3.81 (s, 3H), 3.65 (s, 3H), 2.91 (t, J = 5.9Hz, 2H), 2.26 (s, 3H), 2.08 (s, 3H).

[0501] Example 64: Synthesis of Compound 67

[0502] Compound 67 (25 mg) was obtained by referring to the synthesis method of Example 31. MS m / z (ESI): 561.1 [M+1] + .

[0503] 1 H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.26(s,1H),7.20-6.96(m,3H),6.77(s,2H),6.33(s,1H),5.58(s,1H),4.27(s,2H),4.06(s,2H),3.85(s,3 H),3.66-3.55(m,5H),3.47-3.39(m,2H),3.23-3.16(m,2H),3.03-2.88 (m,4H),2.32(s,3H),2.20(s,6H),1.90-1.81(m,2H),1.52-1.40(m,2H).

[0504] Example 65: Synthesis of Compound 68

[0505] Compound 68 (30 mg) was obtained by referring to the synthesis method of Example 36. MS m / z (ESI): 610.3 [M+1] + .

[0506] 1 H NMR(400MHz,DMSO-d6)δ7.59(s,1H),6.96(s,1H),6.85(s,2H),6.67(s,1H ),6.49(t,J=5.5Hz,1H),5.32(s,1H),4.27(s,6H),3.92-3.82(m,2H),3.80 (s,3H),3.70-3.64(m,1H),3.62(s,3H),3.48(q,J=6.4Hz,2H),2.88(t,J=5 .8Hz,2H),2.22(s,3H),1.97(s,6H),1.05-0.98(m,2H),0.97-0.89(m,2H).

[0507] Example 66: Synthesis of Compound 69

[0508] Step 1. Synthesis of Compound 69B

[0509] 69A (0.48 g) and triethylamine (0.66 g) were dissolved in dichloromethane (15 mL), followed by the slow dropwise addition of a solution of p-nitrophenyl chloroformate (1.0 g) in dichloromethane (25 mL) at room temperature. The reaction mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford 69B (0.8 g).

[0510] 1 H NMR (400MHz, CDCl3) δ8.38-8.22(m,2H),7.46-7.34(m,2H),5.18-5.01(m,1H),4.79-4. 68(m,1H),4.68-4.57(m,1H),4.53-4.37(m,2H),2.89-2.72(m,1H),2.72-2.55(m,1H).

[0511] Step 2, Synthesis of Compound 69C

[0512] 69B (50 mg) was added to tetrahydrofuran (5 mL), followed by compound 2 (85.8 mg) and triethylamine (180 mg). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 69C (30 mg). MS m / z (ESI): 549.2 [M+1] + .

[0513] Step 3, Synthesis of Compound 69

[0514] Compound 69C (80 mg) was added to 0.5 M sulfuric acid (2 mL). The reaction mixture was stirred at 60°C for 24 hours. After the reaction was complete, the reaction mixture was directly purified by reverse phase preparative chromatography to obtain compound 69 (15 mg).

[0515] MS m / z(ESI):567.2[M+1] + .

[0516] 1H NMR (400MHz, DMSO-d6) δ7.22(t,J=5.8Hz,1H),6.96(s,1H),6.85(s,2H),6.66(s,1H),5.32( s,1H),4.61(d,J=5.3Hz,1H),4.35(t,J=5.0Hz,1H),4.24(t,J=6.3Hz,2H),3.91(t,J=6.0Hz ,2H),3.85-3.77(m,5H),3.71(s,1H),3.62(s,3H),3.49(q,J=6.0Hz,2H),3.39(q,J=6.2Hz, 2H),2.90(t,J=6.0Hz,2H),2.22(s,3H),1.97(s,6H),1.62-1.50(m,1H),1.50-1.36(m,1H).

[0517] Example 67: Synthesis of Compound 70

[0518] Referring to the synthetic method of Example 36, compound 70 (20 mg) was obtained.

[0519] MS m / z(ESI):578.3[M+1] + .

[0520] 1 H NMR (400MHz, DMSO-d6) δ7.12(s,2H),7.09(s,1H),6.96(s,1H),6.80(s,1H),5.61(s,1H),4.31(s,2H),4.08(t,J=6.3Hz,2H),3 .86(s,3H),3.80-3.74(m,1H),3.70-3.58(m,5H),3.57-3.23(m,7H),3.03-2.89(m,3H),2.32(s,3H),2.22(s,3H),2.21(s,3H).

[0521] Example 68: Synthesis of Compound 71

[0522] Referring to the synthetic method of Example 32, Compound 71 (3 mg) was obtained.

[0523] MS m / z(ESI):560.2[M+1] + .

[0524] 1H NMR (400MHz, CDCl3) δ6.98(s,2H),6.68(s,1H),6.65(s,1H),5.35(s,1H),4.20-4.00(m,6H),3.72(s,3H),3.65-3. 26(m,4H),2.88(t,J=6.4Hz,2H),2.86-2.34(m,6H),2.33(s,3H),2.17(s,6H),2.07(s,3H),1.47(t,J=7.0Hz,3H).

[0525] Example 69: Synthesis of Compounds 72 and 73

[0526] IM-02 (150 mg), 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (80 mg), and cyanomethylenetri-n-butylphosphine (268 mg) were dissolved in toluene (3 mL) in this order. The reaction mixture was stirred at reflux at 120°C under a nitrogen atmosphere for 2 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by reverse phase chromatography (acetonitrile / 0.1% trifluoroacetic acid) to obtain compound 72 (70.4 mg).

[0527] The above operation was followed by re-feeding, and the resulting crude product was purified by reverse phase chromatography (acetonitrile / 0.1% aqueous ammonia) to obtain compound 73 (40.8 mg).

[0528] Compound 72: MS m / z (ESI): 567.2 [M+1] + .

[0529] 1H NMR (400MHz, CDCl3) δ7.02(s,2H),6.71(s,1H),6.64(s,1H),5.42(s,1H),4.26-4.01(m,6H),3.72(s,3H),3.5 9-3.25(m,8H),3.13(t,J=5.8Hz,2H),2.95(t,J=6.2Hz,2H),2.34(s,3H),2.18(s,6H),1.49(t,J=7.0Hz,3H).

[0530] Compound 73: MS m / z (ESI): 567.2 [M+1] + .

[0531] 1H NMR (400MHz, DMSO-d6) δ6.94(s,1H),6.85(s,2H),6.66(s,1H),5.31(s,1H),4.26(t,J=6.9Hz,2H),4.06(q,J=6.9Hz,2H),3.91(t,J =6.1Hz,2H),3.62(s,3H),3.12-3.05(m,4H),3.04-2.98(m,4H),2.92-2.81(m,4H),2.21(s,3H),1.96(s,6H),1.33(t,J=6.9Hz,3H).

[0532] Example 70: Synthesis of Compound 74

[0533] Referring to the synthesis method of Example 32, compound 74 (13.5 mg) was obtained. MS m / z (ESI): 507.2 [M+1] + .

[0534] 1 H NMR (400MHz, CDCl3) δ6.97(s,2H),6.67(s,1H),6.64(s,1H),5.34(s,1H),5.26-4.98(m,1H),4.21- 4.07(m,4H),4.03-3.58(m,7H),3.56-2.42(m,6H),2.32(s,3H),2.14(s,6H),1.47(t,J=7.0Hz,3H).

[0535] Example 71: Synthesis of Compound 75

[0536] Step 1. Synthesis of Compound 75A

[0537] IM-02 (250 mg) was dissolved in toluene (5 mL), and tert-butyl-(2-iodoethoxy)dimethylsilane (163 mg) and cyanomethylenetri-n-butylphosphine (446 mg) were added sequentially. Under a nitrogen atmosphere, the mixture was heated to 120°C and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to obtain 75A (190 mg). MS m / z (ESI): 564.2 [M+1] + .

[0538] Step 2, Synthesis of Compound 75

[0539] 75A (200 mg) was dissolved in dichloromethane (3 mL), and pyridine hydrofluoride solution (0.75 mL) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute it, and saturated sodium bicarbonate solution was added dropwise to quench it. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to obtain compound 75 (97 mg). MS m / z (ESI): 450.2 [M+1] + .

[0540] 1 H NMR(400MHz,Chloroform-d)δ7.27(d,J=1.5Hz,1H),7.00(s,2H),6.72-6.63(m,2H),5.36(s,1H),4.19-4.09(m,4H),4. 05-3.98(m,2H),3.93-3.85(m,2H),3.72(s,3H),2.89(t,J=6.3Hz,2H),2.34(s,3H),2.20(s,6H),1.48(t,J=7.0Hz,3H).

[0541] Example 72: Synthesis of Compound 76

[0542] Step 1. Synthesis of Compound 76A

[0543] IM-02 (1.5 g) was dissolved in N,N-dimethylformamide (20 mL), and tert-butyl bromoacetate (5.05 g), potassium carbonate (4.6 g), and sodium iodide (3.33 g) were added sequentially. The mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase chromatography to obtain 76A (300 mg). MS m / z (ESI): 520.5 [M+1] + .

[0544] Step 2, Synthesis of Compound 76

[0545] 76A (250 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The product was purified by reverse phase chromatography to obtain compound 76 (134 mg). MS m / z (ESI): 464.3 [M+1] + .

[0546] 1H NMR (400MHz, DMSO-d6) δ7.07-6.92(m,3H),6.66-6.45(m,1H),5.36(s,1H),4.59-4.23(m,2H),4.15-4.03(m,2H),3. 94(t,J=6.3Hz,2H),3.88-3.55(m,3H),2.96-2.82(m,2H),2.35-2.24(m,3H),2.22-2.08(m,6H),1.41-1.27(m,3H).

[0547] Example 73: Synthesis of Compound 77

[0548] Referring to the synthetic method of Example 45, Compound 77 (70 mg) was obtained.

[0549] MS m / z(ESI):570.3[M+1] + .

[0550] 1 H NMR (400MHz, DMSO-d6) δ7.78 (s, 1H), 7.26 (s, 1H), 7.12 (d, J = 3.6Hz, 2H), 7.04 (s,1H),5.93(s,1H),4.84(d,J=8.1Hz,1H),4.60-4.52(m,1H),4.50-4.42(m, 1H),4.21-4.07(m,4H),3.75(s,3H),3.62-3.52(m,1H),3.41-3.33(m,1H),3. 01(s,2H),2.33(s,3H),2.29(s,3H),2.28-2.24(m,6H),1.36(t,J=6.9Hz,3H).

[0551] Example 74: Synthesis of Compounds 78 and 79

[0552] Step 1. Synthesis of Compound 78B

[0553] 78A (900 mg) and triethylamine (1076 mg) were added to a tetrahydrofuran (10 mL) solution and stirred for 5 minutes before adding di-tert-butyl dicarbonate (2110 mg). The reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1-3 / 2) to obtain 78B (1400 mg). MS m / z (ESI): 230.1 [M-56+1] + .

[0554] Step 2, Synthesis of Compound 78C

[0555] Under a nitrogen atmosphere, a tetrahydrofuran solution of lithium aluminum tetrahydride (12 mL, 1 mol / L) was added to a three-necked flask. 78B (1.4 g) was dissolved in tetrahydrofuran (15 mL) and slowly added dropwise to the three-necked flask at room temperature. After the addition was complete, the reaction solution was heated to 25°C and stirred for 3 hours. After the reaction was complete, water (1 mL), 15% aqueous sodium hydroxide solution (1 mL), and water (3 mL) were slowly added in sequence to quench the reaction. Anhydrous sodium sulfate was added and stirring continued for 20 minutes. The mixture was filtered and the filtrate was collected. The filter cake was stirred in a mixed solvent of dichloromethane / methanol (10 / 1) for 20 minutes and filtered again. The filtrates were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 93 / 7) to obtain 78C (1.0 g). MS m / z (ESI): 188.1 [M-56+1] + .

[0556] Step 3. Synthesis of Compound 78D

[0557] 78C (1.0 g) and p-toluenesulfonyl chloride (1.3 g) were dissolved in dichloromethane (10 mL), triethylamine (1.0 g) was added, and the mixture was stirred at 25°C for 2 hours. After the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 78D (800 mg). MS m / z (ESI): 342.1 [M-56+1] + .

[0558] Step 4. Synthesis of Compounds 78E and 79A

[0559] 78D (800 mg), IM-02 (1221 mg), potassium carbonate (1387 mg) and sodium iodide (903 mg) were added to 2-butanone (20 mL). The reaction solution was stirred at 85°C for 72 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compounds 78E (500 mg) and 79A (500 mg). 78E: MS m / z (ESI): 631.2 [M+1] + .79A: MS m / z (ESI): 631.3[M+1] + .

[0560] Step 5. Synthesis of Compound 78

[0561] 78E (100 mg) was added to a 1 / 2, 5 mL mixture of trifluoroacetic acid and dichloromethane. The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse phase chromatography to obtain compound 78 (10 mg). MS m / z (ESI): 531.2 [M+1] + .

[0562] 1 H NMR(400MHz, CDCl3)δ7.05(s,1H),7.03(s,1H),6.70(s,1H),6.63(s,1H),5.43(s,1H),4.61-4.38(m,1H), 4.23-3.99(m,5H),3.72(s,4H),2.92(s,2H),2.47-2.29(m,4H),2.28-2.07(m,7H),1.48(t,J=6.9Hz,3H).

[0563] Step 6. Synthesis of Compound 79

[0564] 79A (20 mg) was added to a 1 / 2, 5 mL mixture of trifluoroacetic acid and dichloromethane. The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse phase chromatography to afford compound 79 (5 mg). MS m / z (ESI): 531.3 [M+1] + .

[0565] 1H NMR(400MHz,DMSO-d6)δ7.03(s,3H),6.74(s,1H),5.48(s,1H),4.54–4.18(m,4H),4.17-3.93 (m,5H),3.64(s,3H),2.96(t,J=6.2Hz,2H),2.29(s,3H),2.10(s,6H),1.34(t,J=6.9Hz,3H).

[0566] Example 75: Synthesis of Compound 80

[0567] Step 1. Synthesis of Compound 80A

[0568] IM-02 (300 mg) was added to toluene (10 mL), followed by 2,2-dimethyl-1,3-dioxan-5-ol (147 mg) and cyanomethylenetri-n-butylphosphine (536 mg). The reaction mixture was stirred at 120°C for 2 hours under nitrogen. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to yield 80A (100 mg). MS m / z (ESI): 520.2 [M+1]+.

[0569] Step 2, Synthesis of Compound 80

[0570] 80A (50 mg) was added to acetic acid (5 mL). The reaction mixture was stirred at 25°C for 48 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse phase chromatography to obtain compound 80 (10 mg). MS m / z (ESI): 480.3 [M+1] + .

[0571] 1 H NMR(400MHz,Chloroform-d)δ7.00(s,2H),6.69(s,1H),6.59(s,1H),5.30(s,1H),4.36-4.27(m,2H),4.17-4.10(m,4H),4 .08-4.02(m,2H),3.70(s,3H),3.68-3.64(m,1H),2.90(t,J=6.4Hz,2H),2.33(s,3H),2.18(s,6H),1.48(t,J=7.0Hz,3H).

[0572] Example 76: Synthesis of Compound 81

[0573] Referring to the synthesis method of Example 29, Compound 81 (30 mg) was obtained.

[0574] MS m / z(ESI):463.3[M+1] + .

[0575] 1 H NMR(400MHz, CDCl3)δ8.97(s,3H),7.03(s,2H),6.70(s,1H),6.63(s,1H),5.42(s,1H),4.14-4.12(m,4H), 4.02(s,2H),3.72(s,3H),3.26(s,2H),2.92(s,2H),2.35(s,3H),2.23-2.07(s,8H),1.48(t,J=6.5Hz,3H).

[0576] Example 77: Synthesis of Compound 82

[0577] Step 1. Synthesis of Compound 82A

[0578] Compound 61 (60 mg) was dissolved in N,N-dimethylformamide (2 mL), and HATU (72 mg) and diisopropylethylamine (41 mg) were added sequentially. After stirring for 15 minutes, (2-aminoethoxy)(tert-butyl)dimethylsilane (26 mg) was added. Stirring was continued for 3 hours. After the reaction was complete, water (1 mL) was added to quench the mixture. The reaction solution was purified by reverse phase chromatography to yield 82A (40 mg). MS m / z (ESI): 635.2 [M+1]+.

[0579] Step 2, Synthesis of Compound 82

[0580] 82A (45 mg) was dissolved in dichloromethane (3 mL) and hydrofluoric acid-pyridine solution (105 mg) was added at 0°C. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 1 hour. After the reaction was completed, saturated aqueous sodium bicarbonate solution (3 mL) was added to quench the reaction. Dichloromethane (20 mL) was added to dilute the mixture, the liquids were separated, and the organic phase was concentrated to obtain a crude product. The crude product was purified by reverse phase chromatography to obtain compound 82 (15.2 mg).

[0581] MS m / z(ESI):521.3[M+1] + .

[0582] 1H NMR(400MHz,Chloroform-d)δ9.25(s,1H),7.00(s,2H),6.70(s,1H),6.65(s,1H),5.41(s,1H),4.32-4.08(m,4H),4.03(t,J=6.5Hz,2H),3.91- 3.81(m,2H),3.72(s,3H),3.48(q,J=4.7Hz,2H),2.91(t,J=6.5Hz,2H), 2.77(t,J=6.4Hz,2H),2.34(s,3H),2.13(s,6H),1.48(t,J=7.0Hz,3H).

[0583] Example 78: Synthesis of Compound 83

[0584] Referring to the synthetic method of Example 46, compound 83 (15 mg) was obtained.

[0585] MS m / z(ESI):592.2[M+1] + .

[0586] 1 H NMR(400MHz,Chloroform-d)δ7.01(s,2H),6.70(s,1H),6.63(s,1H),5.40(s,1H),4.29-4.03(m,8H),3.93-3.83(m,3H),3.79-3.65(m,5H) ,3.65-3.57(m,1H),3.53-3.42(m,3H),3.13-3.00(m,1H),2.95-2.85 (m,2H),2.34(s,3H),2.16(s,3H),2.14(s,3H),1.48(t,J=7.0Hz,3H).

[0587] Example 79: Synthesis of Compound 84

[0588] Referring to the synthetic method of Example 43, compound 84 (10 mg) was obtained.

[0589] MS m / z(ESI):492.2[M+1] + .

[0590] 1H NMR(400MHz,Chloroform-d)δ6.99(s,2H),6.69(s,1H),6.65(s,1H),5.36(s,1H),4.18-4.08(m,4H),3.92(s ,2H),3.72(s,3H),3.53-3.43(m,2H),2.90(t,J=6.3Hz,2H),2.33(s,3H),2.15(s,6H),1.48(t,J=7.0Hz,3H).

[0591] Example 80: Synthesis of Compound 85

[0592] Referring to the synthesis method of Example 7, compound 85 (61 mg) was obtained.

[0593] MS m / z(ESI):522.2[M+1] + .

[0594] 1 H NMR(400MHz,Chloroform-d)δ7.81(s,1H),6.99(s,2H),6.73(s,1H),6.61(s,1H),5.55(s,1H),4.67(s,2H),4.25-4.12 (m,4H),3.85(s,2H),3.72(s,3H),3.68(s,3H),3.01(t,J=6.4Hz,2H),2.33(s,3H),2.22(s,6H),1.50(t,J=7.0Hz,3H).

[0595] Example 81: Synthesis of Compound 86

[0596] Referring to the synthesis method of Example 7, compound 86 (15 mg) was obtained.

[0597] MS m / z(ESI):522.2[M+1] + .

[0598] 1 H NMR(400MHz,Chloroform-d)δ6.99(s,2H),6.68(s,1H),6.64(s,1H),5.36(s,1H),4.18-4.06(m,6H),3.73(s ,3H),3.71(s,3H),3.58-3.51(m,2H),2.89(t,J=6.4Hz,2H),2.33(s,3H),2.15(s,6H),1.47(t,J=7.0Hz,3H).

[0599] Example 82: Synthesis of Compound 87

[0600] Referring to the synthetic method of Example 15, compound 87 (30 mg) was obtained.

[0601] MS m / z(ESI):463.3[M+1] + .

[0602] 1 H NMR(400MHz,DMSO-d6)δ7.96(s,3H),7.31–7.02(m,4H),6.75(s,1H),5.53(s,1H),4.27(t,J=6.9Hz,2H),4.14-4.09(m,2H), 4.08-4.01(m,2H),3.64(s,3H),3.06-2.90(m,4H),2.32(s,3H),2.23-2.10(m,6H),2.09-2.02(m,2H),1.35(t,J=6.9Hz,3H).

[0603] Experimental Example 1: Performance Test Experiment 1 - Inhibitory Activity on PDE3A and PDE4B1 Enzymes

[0604] 1. Main reagents, consumables and instruments for in vitro detection of inhibitory activity: see Table 1 and Table 2

[0605] Table 1 Main reagents and consumables for in vitro detection of inhibitory activity

[0606] Table 2 Main instruments for in vitro detection of inhibitory activity

[0607] 2. Preparation of experimental buffer

[0608] Reaction buffer (5×): 50 mM Tris-HCl (buffer), 50 mM MgCl 2 , 0.5% BSA, 0.25% Tween-20, pH 7.4, stored at -20°C.

[0609] 3. Experimental steps

[0610] 1) Prepare the test sample and reference substance to a certain concentration with DMSO, and dilute the reaction buffer from 5× to 1× with ultrapure water.

[0611] 2) Use Bravo to perform a gradient dilution of the test sample and the control, and transfer 1 μL to the assay plate (Optiplate-384 assay plate) according to the experimental plate compound distribution map designed before the experiment. The low control is the starting concentration of the control sample gradient dilution, and the high control is 1% DMSO-reaction buffer.

[0612] 3) Dilute the enzyme to the specified concentration with 1× reaction buffer and transfer 4 μL to the assay plate. After centrifugation, seal the 384-well low dead volume microplate with sealing film and incubate in a 23°C incubator for 15 minutes.

[0613] 4) Dilute the substrate cyclic adenosine monophosphate (cAMP) to the specified concentration with 1× reaction buffer and transfer 5 μL to the assay plate. After centrifugation, cover the plate with film again and incubate in a 23°C incubator for 60 minutes (PDE3A) or 10 minutes (PDE4B1).

[0614] 5) Add 5 μL AMP-Glo ​​to the assay plate TM After centrifugation, the plate was sealed with a sealing film and incubated in a 23°C incubator for 60 minutes.

[0615] 6) According to AMP-Glo TM Prepare the assay solution according to the instructions of the Assay Kit and add 10 μL to the assay plate. After centrifugation, cover the plate with sealing film and incubate in a 23°C incubator for 60 minutes.

[0616] 7) Read the plate using a multi-function plate reader.

[0617] 4. Result analysis:

[0618] The formula for calculating the % Inhibition of the sample well is: % Inhibition = 100% - (sample well signal value - low control signal value) / (high control signal value - low control signal value) * 100%

[0619] The “log (antagonist) vs. response—Variable slope” model in GraphPad Prism 5.0 was used for fitting and IC50 was calculated.

[0620] 5. The experimental results are shown in Table 3:

[0621] Table 3 In vitro PDE3 and PDE4 inhibition test results of compounds

[0622] Experimental Example 2: Performance Test Experiment 1 - Inhibitory Activity on CYP (Cytochrome Peptide)

[0623] 1. Experimental steps

[0624] 1.1 Prepare the test compound and standard inhibitor working solutions (100×);

[0625] 1.2 Take the microsomes out of the -80°C freezer, thaw on ice, label with the date, and return to the freezer immediately after use;

[0626] 1.3 Add 20 μL of substrate solution to the corresponding wells and add 20 μL of PB (phosphate buffer) to the blank wells;

[0627] 1.4 Add 2 μL of test compound and positive control working solution to the corresponding wells. Add 2 μL of solvent to the wells without inhibitor and blank wells.

[0628] 1.5 Prepare HLM working solution (human liver microsome solution);

[0629] 1.6 Add 158 μL of HLM working solution to all wells of the culture plate;

[0630] 1.7 Preheat the plate in a 37°C water bath for approximately 10 minutes.

[0631] 1.8 Prepare NADPH (nicotinamide adenosine denucleotide hydro-phosphoric acid, referred to as reduced coenzyme II) cofactor solution;

[0632] 1.9 Add 20 μL of NADPH cofactor to all incubation wells;

[0633] 1.10 Mix and incubate all CYPs in a 37°C water bath for 10 minutes;

[0634] 1.11 At the specified time point, stop the reaction by adding 400 μL of cold stop solution;

[0635] 1.12 Centrifuge the sample at 4000 rpm for 20 minutes to precipitate the protein;

[0636] 1.13 Transfer 200 μL of supernatant into 100 μL of HPLC water and shake for 10 minutes;

[0637] 1.14 The samples were analyzed by LC / MS / MS.

[0638] 2. Experimental data analysis

[0639] XL Fit or SigmaPlot was used to plot the percentage of control compound versus test compound concentration and perform nonlinear regression analysis on the data.

[0640] IC50 values ​​were determined using a 3- or 4-parameter logistic equation. When the percent inhibition at the highest concentration (50 μM) was less than 50%, the IC50 value was reported as ">50 μM"

[0641] 3. The experimental results are shown in the table below:

[0642] Table 4 In vitro CYP inhibition test results of compounds

[0643] The results in Table 4 show that compared with Ensifentrine, some compounds of the present invention have no inhibitory effect on CYP (cytochrome enzyme).

[0644] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound, characterized in that Having the structure represented by formula (I), or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Among them, A 1 , A 2 is a nitrogen atom, A 3 is a carbon atom; when is a single bond, When it is a double bond, R 2 is empty; when is a double bond, When it is a single bond, R 1 is empty; R 1 , R 2 , R 6 , R 7 independently selected from hydrogen, substituted or unsubstituted straight or branched C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl or C n H 2n R 8 ; n is selected from an integer between 0 and 6; R 8 is selected from substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR a 、-OC(O)R a 、-OC(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a R b 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b C n H 2n R c 、-SR a 、-S(O)R a 、-S(O)NR a R b 、-S(O)2R a 、-S(O)2NR a R b 、-NR a S(O)2R b , -CN, -NH2, -CF3; R 3 , R 4 and R 5 Independently selected from one or more of hydrogen, halogen, substituted or unsubstituted straight chain or branched C1-C6 alkyl; R a , R b , R c independently selected from one or more of hydrogen, deuterium, oxo, thioxo, halogen, amino, methylimino, methoxyimino, mesyl, hydroxyl, cyano, nitro, substituted or unsubstituted straight or branched C1-C6 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; E 1 Selected from -(CH2) m -, where m is 1, 2 or 3; E 2 Selected from -O-, -NH-, -S-, or -CR 9 R 10 -; R 9 , R 10 Independently selected from one or more of hydrogen, deuterium, substituted or unsubstituted straight chain or branched C1-C6 alkyl; Or, R 6 and R 7 and adjacent oxygen atoms and phenyl carbon atoms are connected to form a ring; The ring is a substituted or unsubstituted 5-membered or 6-membered monocyclic heterocyclic group; The 5-membered or 6-membered monocyclic heterocyclic group may be further fused or spiro-fused with an aryl group, a heteroaryl group or a heterocycloalkyl group to form a fused ring group, a spiro ring group or a bridged ring group.

2. The compound according to claim 1, characterized in that The substituents of the substituted 3-10 membered cycloalkyl, substituted 4-10 membered heterocycloalkyl, substituted 6-10 membered aryl, substituted 5-10 membered heteroaryl are selected from deuterium, oxo, thio, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted straight or branched C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C n H 2n OR a , -C n H 2n OC(O)R a , -C n H 2n OC(O)NR a R b , -C n H 2n C(O)R a , -C n H 2n C(O)OR a , -C n H 2n C(O)NR a R b , -C n H 2n NR a R b , -C n H 2n NR a C(O)R b , -C n H 2n NR a C(O)OR b , -C n H 2n NR a C(O)NR b C n H 2n R c , -C n H 2n SR a , -C n H 2n S(O)R a , -C n H 2n S(O)NR a R b , -C n H 2n S(O)2R a , -C n H 2n S(O)2NR a R b , -C n H 2n NR a S(O)2R b , -C n H 2n CN, -C n H 2n NH2, -C n H 2n One or more of CF3.

3. The compound according to claim 1, characterized in that The substituents of the substituted straight-chain or branched C1-C6 alkyl and substituted C1-C4 alkoxy are selected from deuterium, oxo, thio, halogen, hydroxyl, cyano, nitro, C n H 2n OR a , -C n H 2n OC(O)R a , -C n H 2n OC(O)NR a R b , -C n H 2n C(O)R a , -C n H 2n C(O)OR a , -C n H 2n C(O)NR a R b , -C n H 2n NR a R b , -C n H 2n NR a C(O)R b , -C n H 2n NR a C(O)OR b , -C n H 2n NR a C(O)NR b C n H 2n R c , -C n H 2n SR a , -C n H 2n S(O)R a , -C n H 2n S(O)NR a R b , -C n H 2n S(O)2R a , -C n H 2n S(O)2NR a R b , -C n H 2n NR a S(O)2R b , -C n H 2n CN, -C n H 2n NH2, -C n H 2n One or more of CF3; The substituent of the substituted C2-C6 alkenyl is selected from deuterium, oxo, thio, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C 10 Cycloalkyl, C n H 2n OR a , -C n H 2n OC(O)R a , -C n H 2n OC(O)NR a R b , -C n H 2n C(O)R a , -C n H 2n C(O)OR a , -C n H 2n C(O)NR a R b , -C n H 2n NR a R b , -C n H 2n NR a C(O)R b , -C n H 2n NR a C(O)OR b , -C n H 2n NR a C(O)NR b C n H 2n R c , -C n H 2n SR a , -C n H 2n S(O)R a , -C n H 2n S(O)NR a R b , -C n H 2n S(O)2R a , -C n H 2n S(O)2NR a R b , -C n H 2n NR a S(O)2R b , -C n H 2n CN, -C n H 2n NH2, -C n H 2n One or more of CF3; The substituent of the substituted C2-C6 alkynyl is selected from deuterium, oxo, thio, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -C n H 2n OR a , -C n H 2n OC(O)R a , -C n H 2n OC(O)NR a R b , -C n H 2n C(O)R a , -C n H 2n C(O)OR a , -C n H 2n C(O)NR a R b , -C n H 2n NR a R b , -C n H 2n NR a C(O)R b , -C n H 2n NR a C(O)OR b , -C n H 2n NR a C(O)NR b C n H 2n R c , -C n H 2n SR a , -C n H 2n S(O)R a , -C n H 2n S(O)NR a R b , -C n H 2n S(O)2R a , -C n H 2n S(O)2NR a R b , -C n H 2n NR a S(O)2R b , -C n H 2n CN, -C n H 2n NH2, -C n H 2n One or more of CF3.

4. The compound according to claim 1, characterized in that In the formula (I), R 6 and R 7 The 5-membered or 6-membered monocyclic heterocyclic group formed by connecting adjacent oxygen atoms and phenyl carbon atoms is selected from 1,3-dioxolyl or 1,4-dioxaneyl.

5. The compound according to claim 1, characterized in that The aryl group fused or spiro-coupled to the 5-membered or 6-membered monocyclic heterocyclic group is selected from substituted or unsubstituted phenyl or naphthyl; The heteroaryl group fused or spiro with the 5-membered or 6-membered monocyclic heterocyclic group is selected from one or more of substituted or unsubstituted pyridyl, indolyl, quinoxalyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl; The heterocycloalkyl group fused or spiro to the 5-membered or 6-membered monocyclic heterocyclic group is selected from substituted or unsubstituted oxetanyl, azetidinyl, azepanyl, diazepanyl, oxazepanyl, 8-aza-bicyclo[3.2.1]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, One or more of pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, homopiperazinyl, quinuclidine, dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl, and dihydropyranyl.

6. The compound according to claim 1, characterized in that The substituents of the substituted 5-membered or 6-membered monocyclic heterocyclic group, substituted aryl, substituted heteroaryl, and substituted heterocycloalkyl are independently selected from one or more of substituted or unsubstituted straight-chain or branched C1-C6 alkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, hydroxyl, nitro, cyano, and amino.

7. The compound according to claim 1, characterized in that The compound has any of the following structures, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

8. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable auxiliary material.

9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating a disease associated with PDE3 and / or PDE4.

10. The use according to claim 9, characterized in that: The PDE3 and / or PDE4 related disorders are one or more of inflammation, bronchiectasis, chronic obstructive pulmonary disease, and asthma.

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