A compound and use thereof

Abstract

The application discloses a compound and application thereof, and belongs to the technical field of biological pharmacy. The compound has a structure shown in formula (I), or a deuterium compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound has good PDE3 and / or PDE4 inhibiting effect, and is of great significance to the preparation of a medicine for PDE3 and / or PDE4 related diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biopharmaceutical, in particular to a compound and application thereof. BACKGROUND

[0002] Phosphodiesterases (PDEs) are a class of hydrolytic enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which play an important role in regulating cell activity. There are currently 11 known PDE families, among which PDE3 is mainly distributed in smooth muscle cells and is involved in regulating cardiac contractility and vascular smooth muscle, and inhibiting PDE3 can produce a relaxing effect on smooth muscle and bronchodilation. PDE4 is mainly distributed in various immune cells, airway epithelial cells and fibroblasts, and inhibiting PDE4 can cause an increase in cAMP levels in inflammatory cells and immune regulatory cells, thereby inhibiting the function of inflammatory cells and relaxing airway smooth muscle.

[0003] Chronic obstructive pulmonary disease (COPD) and asthma are common complex inflammatory diseases of the respiratory tract characterized by airway obstruction. Among the PDE inhibitors, only roflumilast has been approved for clinical treatment of COPD, but due to dose-dependent adverse reactions, its clinical use is limited. Due to the limitations of PDE3 or PDE4 inhibitors alone, dual PDE3 / PDE4 inhibition has become a new strategy for the targeted treatment of COPD and asthma. More and more experiments have confirmed that dual-target PDE3 / PDE4 inhibitors have a synergistic inhibitory effect, i.e., synergistic anti-inflammatory and bronchodilation effects. Ensifentrine (RPL554) is a new inhaled PDE3 / PDE4 inhibitor for the treatment of COPD and asthma, which has anti-inflammatory and bronchodilation effects, and is in the phase III clinical research stage. However, the data also show that its inhibitory activity on PDE4 is general, and the anti-inflammatory effect is not ideal. Therefore, it is necessary to develop a PDE3 / PDE4 dual-target inhibitor with good tolerance, a wide therapeutic window and high safety, or a PDE3 or PDE4 inhibitor with less side effects. SUMMARY

[0004] Therefore, the technical problem to be solved by the present application is to provide a compound and application thereof. The compound has good PDE3 and / or PDE4 inhibitory effect and can be used in the preparation of a medicament for treating a disease related to PDE3 and / or PDE4.

[0005] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0006] The present application provides a compound having the structure shown in formula (I), or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Among them, A 1 A 2 A is a nitrogen atom. 3 It consists of carbon atoms.

[0009] when It is a single key. When it is a double bond, R 2 Empty.

[0010] when It is a double bond. When it is a single bond, R 1 Empty.

[0011] R 1 R 2 R 6 R 7 Independent carbon atoms selected from hydrogen, substituted or unsubstituted, straight-chain or branched. 1～ C6 alkyl, substituted or unsubstituted C 2～ C6 alkenyl, substituted or unsubstituted C 2～ C6 ynyl group or C n H 2n R 8 .

[0012] n is an integer between 0 and 4.

[0013] R 8 Selected from substituted or unsubstituted 3- to 10-membered cycloalkyl groups, substituted or unsubstituted 4- to 10-membered heterocycloalkyl groups, substituted or unsubstituted 6- to 10-membered aryl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, -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 aR b , -S(O)2R a , -S(O)2NR a R b , -NR a S(O)2R b , -CN, -NH2, -CF3.

[0014] The 3-10 membered cycloalkyl group includes, but is not limited to, the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0015] 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, oxoazepanyl, 8-aza-bicyclo[3.2.1]octanyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 9-aza-bicyclo[3.3.1]nonanyl, dihydrofuranyl, imidazolinyl, tetrahydropyridinyl, dihydropyranyl, [1,2,4]triazolo[4,3-a]pyrazinyl, pyrroloimidazolyl, 2-keto-pyridinyl, 3-keto-pyridazinyl, and the like.

[0016] The 6-10 membered aryl group includes, but is not limited to, the following substituted or unsubstituted groups: phenyl or naphthyl.

[0017] The 5-10 membered heteroaryl group includes, but is not limited to, the following substituted or unsubstituted groups: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzofuranyl, benzopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophenyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, and the like.

[0018] R 3 , R 4 , and R 5 are independently selected from one or more of hydrogen, halogen, substituted or unsubstituted straight-chained or branched C 1～ C6alkyl.

[0019] The straight-chained or branched C 1～ C6alkyl is preferably one or more of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, neopentyl, i-pentyl, hexyl.

[0020] R a 、R b 、R c independently selected from hydrogen, deuterium, oxo, thioxo, halogen, amino, methylimino, methoxyimino, methylsulfonyl, hydroxyl, cyano, nitro, substituted or non-substituted linear or branched C 1～ C6alkyl, substituted or non-substituted C 1～ C4alkoxy, substituted or non-substituted C 2～ C6alkenyl, substituted or non-substituted C 2～ C6alkynyl, substituted or non-substituted 3-10 membered cycloalkyl, substituted or non-substituted 4-10 membered heterocycloalkyl, substituted or non-substituted 6-10 membered aryl, substituted or non-substituted 5-10 membered heteroaryl.

[0021] said C 1～ C4alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, and the like.

[0022] said C 1～ C6alkyl is as defined above, which is not repeated here.

[0023] said C 2～ C6alkenyl includes, but is not limited to, ethenyl, propenyl, 2-methylpropenyl, allyl, butenyl, 2-methylbutenyl, 2-ethylbutenyl, cyclopentenyl, cyclohexenyl, and the like.

[0024] said C 2～ C6alkynyl 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-hexynyl, 2-hexynyl, 3-hexynyl, 4-methyl-1-pentynyl, 3-methyl-1-pentynyl, 4-methyl-2-pentynyl, 2,2-dimethyl-1-butynyl, and the like.

[0025] said substituted or non-substituted 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl is as defined above, which is not repeated here.

[0026] E 1 selected from -(CH2) m - wherein m is 1, 2 or 3.

[0027] E 2 selected from -O-, -NH-, -S-, or -CR 9 R 10 -.

[0028] R 9 、R 10 independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted linear or branched C 1～ C6alkyl.

[0029] said C 1～ The preferred range of said C

[0030] or, R 6 and R 7 and the adjacent oxygen atom, phenyl carbon atom are linked to form a ring.

[0031] said ring is a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclyl.

[0032] said 5- or 6-membered monocyclic heterocyclyl can be further fused or spiro-fused with aryl, heteroaryl or heterocycloalkyl to form a fused ring group, a spiro ring group or a bridged ring group.

[0033] In the preferred embodiment of the present application, the substituents of the above-mentioned substituted 3-10 membered cycloalkyl, substituted 4-10 membered heterocycloalkyl, substituted 6-10 membered aryl, substituted 5-10 membered heteroaryl are selected from the group consisting of deuterium, oxo, thioxo, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted linear or branched C 1～ C6alkyl, substituted or unsubstituted C 3～ C 10 cycloalkyl, substituted or unsubstituted C 2～ C6alkenyl, substituted or unsubstituted C 2～ C6alkynyl, 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 NRa 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.

[0034] Preferably, in this invention, 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, hydroxyl, cyano, nitro, and C4. 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 CF3.

[0035] In a preferred embodiment of the application, the substituted C 2～ C6alkyl, substituted or unsubstituted C 1～ C6alkyl, substituted or unsubstituted C 2～ C6alkynyl, substituted or unsubstituted C 3～ C 10 cycloalkyl, C n H 2n ORa , -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 H2n one or more of CF3.

[0036] In preferred embodiments of the application, the substituted C 2～ substituents for C6alkynyl are selected from the group consisting of deuterium, oxo, thioxo, halogen, amino, hydroxy, cyano, nitro, substituted or non-substituted C 1～ substituents for C6alkyl are selected from the group consisting of deuterium, oxo, thioxo, halogen, amino, hydroxy, cyano, nitro, substituted or non-substituted C 2～ substituents for C6alkenyl are selected from the group consisting of deuterium, oxo, thioxo, halogen, amino, hydroxy, cyano, nitro, substituted or non-substituted C 3～ substituents for C6alkynyl are selected from the group consisting of deuterium, oxo, thioxo, halogen, amino, hydroxy, cyano, nitro, substituted or non-substituted 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)2Ra , -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 CF3.

[0037] In a preferred embodiment of the present application, R 6 and R 7 in formula (I) are independently selected from the group consisting of H, C 1～ and the adjacent oxygen atom, phenyl carbon atom are linked to form a 5- or 6-membered monocyclic heterocyclyl selected from the group consisting of 1,3-dioxolanyl or 1,4-dioxanyl.

[0038] In a preferred embodiment of the present application, the aryl fused or spiro-fused to the 5- or 6-membered monocyclic heterocyclyl is selected from the group consisting of substituted or unsubstituted phenyl or naphthyl.

[0039] In a preferred embodiment of the present application, the heteroaryl fused or spiro-fused to the 5- or 6-membered monocyclic heterocyclyl is selected from the group consisting of one or more of substituted or unsubstituted pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzofuranyl, benzopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophenyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

[0040] In a preferred embodiment of the present application, the heterocycloalkyl fused or spiro-fused to the 5- or 6-membered monocyclic heterocyclyl is selected from the group consisting of one or more of substituted or unsubstituted oxetanyl, azetidinyl, azepanyl, diazepanyl, oxazepanyl, 8-aza- bicyclo[3.2.1]octanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 9-aza-bicyclo[3.3.1]nonanyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, homopiperazinyl, quinuclidinyl, dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl, dihydropyranyl.

[0041] In a preferred embodiment of the present application, the substituents of the substituted 5- or 6-membered monocyclic heterocyclyl, substituted aryl, substituted heteroaryl, substituted heterocycloalkyl are independently selected from the group consisting of substituted or unsubstituted straight-chained or branched C 1～C6alkyl, substituted or unsubstituted C 1～ C4alkoxy, halogen, hydroxyl, nitro, cyano, amino, one or more of.

[0042] The above straight chain or branched C 1～ C6alkyl, C 1～ The range of C4alkoxy and the preferred range of its substituents are the same as above, which will not be repeated here.

[0043] In the present application, the above -C(O), -S(O), -S(O)2all represent the oxygen atom and the carbon atom, sulfur atom with double bond connection, wherein the horizontal line represents the connection position.

[0044] The above-mentioned pharmaceutically acceptable salt of the structure represented by formula (I) includes but is not limited to one or more of hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, trifluoroacetate.

[0045] Preferably, the compound has any one of the following structures, or its deuterium compound, or its stereoisomer, or its pharmaceutically acceptable salt:

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] The present application also provides a pharmaceutical composition comprising the above-mentioned compound and pharmaceutically acceptable adjuvant.

[0053] The adjuvant can be a carrier, vehicle, diluent or other adjuvant.

[0054] The present application also provides the use of the above-mentioned compound or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating PDE3 and / or PDE4 related disorders.

[0055] Preferably, the PDE3 and / or PDE4 related disorders are one or more of inflammation, bronchodilation, chronic obstructive pulmonary disease, asthma.

[0056] Compared with the prior art, the compound provided by the application and the application thereof have the structure shown in formula (I), or a deuterium compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound has good PDE3 and / or PDE4 inhibition effect, and is of great significance to the preparation of drugs for PDE3 and / or PDE4 related diseases. DETAILED DESCRIPTION

[0057] In order to further illustrate the application, the compound provided by the application and the application thereof are described in detail below in combination with examples.

[0058] The structure of the compound is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0059] The NMR determination is performed by using a (Bruker Avance NEO 400) nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0060] The LC-MS determination is performed by using a Shimadzu liquid chromatograph-mass spectrometer (Shimadzu LC-MS 2020 (ESI)), and the HPLC determination is performed by using a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-2030C 3D (Plus)).

[0061] The liquid phase preparation instrument uses a Shimadzu LC-20AP preparation chromatograph.

[0062] The thin layer chromatography silica gel plate uses a Yantai Xinuo Chemical Industry Co., Ltd. GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm. The column chromatography generally uses 200-300 mesh silica gel as a carrier.

[0063] The starting materials in the examples of the application are known and can be purchased on the market, or can be synthesized by using or according to the methods known in the art.

[0064] Unless otherwise specified, all the following reactions are performed under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is Celsius.

[0065] Synthesis of intermediate compounds in example 1(1)

[0066] 1) Synthesis of intermediate IM-01

[0067]

[0068] Step 1, synthesis of compound IM01B

[0069] 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 successively. The reaction solution was stirred at 50 °C for 2 hours. After the reaction was completed, the reaction solution was reduced to room temperature, and the precipitated solid was collected by filtration. The filter cake was dried to obtain IM01B (4.0 g). MS m / z (ESI): 225.1 [M+1] + .

[0070] Step 2, synthesis of compound IM01C

[0071] Sodium ethoxide ethanol solution (20 wt%, 32.5 g) was added to anhydrous ethanol (40 mL), and IM01B (4.0 g) and diethyl malonate (7.7 g) were added successively. The reaction solution was warmed to 80 °C and reacted for 16 hours. After the reaction was completed, ethanol was removed by concentration under reduced pressure. The residue was dissolved in water, and then dilute hydrochloric acid (2 M) was added dropwise to the resulting solution under ice bath to adjust pH = 2. The solid was collected by filtration, and the filter cake was dried to obtain IM01C (3.0 g). MS m / z (ESI): 315.0 [M+23] + .

[0072] Step 3, synthesis of compound IM01D

[0073] Compound IM01C (10.0 g) was added to phosphorus oxychloride (100 mL). The reaction mixture was stirred at 85 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature. Phosphorus oxychloride was removed by concentration under reduced pressure, and 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 obtain IM01D (11.0 g). 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 solution was reacted at 90 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain IM-01 (10.0 g). MS m / z (ESI): 392.2 [M+1] + .

[0076] 1H NMR (400 MHz, DMSO-d6) δ 9.42 (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 = 6.4 Hz, 2H), 3.89-3.80 (m, 6H), 2.92 (t, J = 6.5 Hz, 2H), 2.27 (s, 3H), 2.14 (s, 6H).

[0077] 2) Synthesis of intermediate IM-02

[0078]

[0079] Step 1, Synthesis of compound IM02B

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

[0081] Step 2, Synthesis of compound IM02C

[0082] A solution of lithium aluminum hydride in tetrahydrofuran (270 mL) was added into a three-necked flask under nitrogen atmosphere. IM02B (24.0 g) was dissolved in tetrahydrofuran (250 mL) and added into the three-necked flask dropwise 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 added slowly in sequence. An appropriate amount of anhydrous sodium sulfate was added and stirred 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 filtrate was combined and concentrated under reduced pressure. The obtained 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 solution was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated under reduced pressure. The obtained crude product was purified by 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] Sodium ethoxide ethanol solution (20%, 14.0 g) was added to anhydrous ethanol (20 mL), and IM02D (2.0 g) and diethyl malonate (3.4 g) were sequentially added thereto. The reaction solution was reacted at 80°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove ethanol. The residue was dissolved in water, and hydrochloric acid (2M) was added dropwise under ice bath to adjust pH until solid appeared. The precipitated solid was collected by filtration, and dried to obtain 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). The reaction mixture was stirred at 85°C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature. Phosphorus oxychloride was removed by concentration under reduced pressure, and the obtained residue was dissolved in dichloromethane (50 mL). The organic phase was washed with ice water (50 mL x 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 solution was reacted at 90°C for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by 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]

[0093] 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 successively. 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 chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 1 (120 mg). MS m / z (ESI): 445.2 [M+1] + .

[0094] 1 H NMR (400 MHz, CDCl3) δ 7.02 (s, 2H), 6.70 (s, 1H), 6.64 (s, 1H), 5.37 (d, J = 0.8 Hz, 1H), 4.16 (dt, J = 10.4, 6.7 Hz, 4H), 3.94-3.87 (m, 3H), 3.73 (d, J = 0.8 Hz, 3H), 2.96-2.85 (m, 4H), 2.34 (s, 3H), 2.17 (s, 6H).

[0095] Example 2

[0096] Synthesis of compound 2

[0097]

[0098] Step 1, Synthesis of compound 2A

[0099] 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 evaporated. 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] + .

[0100] Step 2, Synthesis of compound 2

[0101] 2A (800 mg) was dissolved in ethanol (10 mL), and hydrazine hydrate (212 mg) was added. The 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 and purified by a flash reverse-phase column to obtain compound 2 (300 mg). MS m / z (ESI): 435.2 [M+1] + .

[0102] 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 6.97 (s, 1H), 6.86 (s, 2H), 6.67 (s, 1H), 5.33 (s, 1H), 4.28 (t, J = 6.4 Hz, 2H), 3.91 (t, J = 5.9 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 3H), 3.04 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 5.8 Hz, 2H), 2.21 (s, 3H), 1.96 (s, 6H), 1.23 (s, 2H).

[0103] Example 3

[0104] Synthesis of compound 3

[0105]

[0106] 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 solution was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by a Flash reverse phase column to obtain compound 3 (10 mg, TFA salt). MS m / z (ESI): 477.2 [M+1] + .

[0107] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (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 = 5.9 Hz, 2H), 2.99 (s, 2H), 2.32 (s, 3H), 2.19 (s, 6H), 1.82 (s, 3H).

[0108] Example 4

[0109] Synthesis of compound 4

[0110]

[0111] 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 solution was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by a Flash reverse phase column to obtain compound 4 (10 mg, TFA salt). MS m / z (ESI): 513.2 [M+1] + .

[0112] 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.23 (t, J = 6.3 Hz, 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).

[0113] Example 5

[0114] Synthesis of compounds 5, 6

[0115]

[0116] Step 1, Synthesis of compound 5B

[0117] 5A (2.0 g) and triethylamine (2.08 g) were dissolved in anhydrous dichloromethane (20 mL) at 0 °C, and then a solution of p-toluenesulfonyl chloride (3.1 g) in dichloromethane (30 mL) was added dropwise. After the addition was completed, the reaction solution was stirred at 0 °C for 4 hours. After the reaction was completed, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain 5B (3.0 g). MS m / z (ESI): 301.1 [M+1] + .

[0118] Step 2, Synthesis of compounds 5C, 5D

[0119] 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 turn. The reaction solution was warmed 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 x 3). The combined organic phase was dried over sodium sulfate and concentrated to obtain the crude product. The crude product was purified by Flash reverse phase column to obtain 5C (0.45 g) and 5D (0.1 g). 5C and 5D: MS m / z (ESI): 520.2 [M+1] + .

[0120] Step 3, Synthesis of compound 5

[0121] Dissolve 5C (100 mg) in methanol (1.0 mL), add dilute hydrochloric acid (2 mol / L, 1.0 mL). The reaction liquid is stirred at room temperature for 2 hours. After the reaction is completed, the reaction liquid is concentrated to obtain the crude product. The crude product is purified by Flash reverse phase chromatographic column to obtain compound 5 (80 mg). MS m / z (ESI): 480.5 [M+1] + .

[0122] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (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 = 6.4 Hz, 2H), 3.85 (s, 3H), 3.70 (dd, J = 8.8, 3.4 Hz, 1H), 3.63 (s, 3H), 3.43-3.37 (m, 1H), 3.35-3.29 (m, 1H), 3.01 (t, J = 6.4 Hz, 2H), 2.33 (s, 3H), 2.20 (s, 6H), 2.05-1.95 (m, 1H), 1.87-1.76 (m, 1H).

[0123] Step 4, synthesis of compound 6

[0124] Dissolve 5D (50 mg) in methanol (0.5 mL), add dilute hydrochloric acid (2 mol / L, 0.50 mL). The reaction liquid is stirred at room temperature for 2 hours. After the reaction is completed, the reaction liquid is concentrated to obtain the crude product. The crude product is purified by Flash reverse phase chromatographic column to obtain compound 6 (40 mg). MS m / z (ESI): 480.2 [M+1] + .

[0125] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.07 (d, J = 1.8 Hz, 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 = 5.6 Hz, 1H), 4.53 (t, J = 5.7 Hz, 1H), 4.01 - 3.89 (m, 4H), 3.85 (d, J = 4.0 Hz, 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 = 5.3 Hz, 6H), 2.05 (s, 3H), 1.84 - 1.73 (m, 1H), 1.46 - 1.36 (m, 1H).

[0126] Example 6

[0127] Synthesis of compound 7

[0128]

[0129] 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 solution was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by a Flash reverse phase column to obtain compound 7 (10 mg). MS m / z (ESI): 492.3 [M+1] + .

[0130] 1 H NMR (400 MHz, DMSO-d6) δ 7.04 (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).

[0131] Example 7

[0132] Synthesis of compound 8

[0133]

[0134] Step 1, Synthesis of compound 8A

[0135] 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 was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction was concentrated, and the obtained crude product was purified by a Flash reverse phase column to obtain 8A (60 mg). MS m / z (ESI): 600.2 [M+1] + .

[0136] Step 2, synthesis of compound 8

[0137] 8A (60 mg) and methoxyamine hydrochloride (10 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (20 mg). The reaction was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction was concentrated, and the obtained crude product was purified by a Flash reverse phase column to obtain compound 8 (10 mg, TFA salt). MS m / z (ESI): 508.3 [M+1] + .

[0138] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (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 = 5.6 Hz, 2H), 4.06 (s, 2H), 3.85 (s, 3H), 3.64 (s, 3H), 3.55 - 3.52 (m, 3H), 3.51 (d, J = 6.2 Hz, 2H), 2.99 (s, 2H), 2.31 (s, 3H), 2.19 (s, 6H).

[0139] Example 8

[0140] Synthesis of compound 9

[0141]

[0142] Step 1, synthesis of compound 9B

[0143] 9A (10 g) was dissolved in tetrahydrofuran (100 mL), and the solution was cooled to -78 °C under nitrogen protection, followed by the dropwise addition of a tetrahydrofuran solution of diisopropyl amino lithium (2 M, 28.2 mL). After the dropwise addition was completed, the solution was continuously stirred at -78 °C for 1 hour, and then iodomethane (9.61 g) was added dropwise. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction was quenched by the dropwise addition of a saturated ammonium chloride solution (100 mL), and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The obtained organic phases were combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to obtain 9B (7.0 g).

[0144] 1 H NMR (400 MHz, CDC13) δ 6.91-6.85 (m, 3H), 3.87 (m, 7H), 1.64 (d, J = 7.3 Hz, 3H).

[0145] Step 2, synthesis of compound 9C

[0146] Dissolve 9B (5.0 g) in tetrahydrofuran (50 mL), add borane dimethyl sulfide solution (2 M, 26.1 mL), stir at 70 °C for 16 hours. After the reaction is completed, the temperature of the reaction solution is reduced to 0 °C, and methanol (5 mL) is added dropwise to quench the reaction. Then the reaction solution is concentrated to obtain 9C (5.0 g). MS m / z (ESI): 196.2 [M+1] + .

[0147] Step 3, synthesis of compound 9D

[0148] Dissolve 9C (1.0 g) in dichloroethane (20 mL), and add trimethylsilyl isocyanate (1.77 g). The reaction solution is stirred at 80 °C for 16 hours. After the reaction is completed, the reaction solution is reduced to room temperature, concentrated and dried in vacuum to obtain 9D (1.1 g). MS m / z (ESI): 239.0 [M+1] + .

[0149] Step 4, synthesis of compound 9E

[0150] Add sodium ethoxide ethanol solution (20%, 8.85 g) to anhydrous ethanol (10 mL), and then add 9D (1.25 g) and diethyl malonate (2.08 g) to the solution in sequence. The reaction solution is reacted at 80 °C for 16 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and ethanol is removed by concentration under reduced pressure. The residue is dissolved in water, and hydrochloric acid (2 M) is added dropwise under ice bath to adjust pH = 5. After filtration with diatomite, the filtrate is extracted with ethyl acetate (150 mL x 2), and then dried over anhydrous sodium sulfate. After filtration, the obtained residue is concentrated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 9E (1.2 g). MS m / z (ESI): 306.9 [M+1] + .

[0151] Step 5, synthesis of compound 9F

[0152] To phosphorus oxychloride (10 mL) was added compound 9E (1.1 g) under nitrogen atmosphere. The reaction was heated to 80 °C and stirred for 12 h. After the reaction was completed, the reaction was cooled to room temperature and concentrated under reduced pressure to remove phosphorus oxychloride. The residue was dissolved in dichloromethane (50 mL), washed with water (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give 9F (1.0 g). MS m / z (ESI): 307.0 [M+1] + .

[0153] Step 6, synthesis of compound 9G

[0154] To 9F (1.0 g) was added 2,4,6-trimethylaniline (2.23 g) in isopropanol (50 mL). The reaction was heated to 90 °C and stirred for 16 h. After the reaction was completed, the reaction was concentrated to give a crude product. The crude product was purified by silica gel column (dichloromethane / methanol = 10 / 1) to give 9G (0.8 g). MS m / z (ESI): 406.0 [M+1] + .

[0155] Step 7, synthesis of compound 9H

[0156] To 9G (300 mg) was added tert-butyl (2-hydroxyethyl)carbamate (173 mg) and cyanomethylidene tri-n-butylphosphonium (515 mg) in toluene (10 mL). The mixture was stirred at 120 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction was concentrated to give a crude product. The crude product was purified by silica gel column (dichloromethane / methanol = 10 / 1) to give 9H (210 mg). MS m / z (ESI): 549.5 [M+1] + .

[0157] Step 8, synthesis of compound 91

[0158] To 9H (100 mg) was added 4 M hydrochloric acid / dioxane solution (5 mL) and stirred at 25 °C for 1 h. After the reaction was completed, the reaction was concentrated to give 91 (90 mg). MS m / z (ESI): 449.1 [M+1] + .

[0159] Step 9, synthesis of compound 9

[0160] To 91 (100 mg) was added phenyl carbamate (46 mg) and triethylamine (68 mg) in dichloromethane (5 mL). The reaction was stirred at 25 °C for 16 h. After the reaction was completed, the reaction was concentrated to give a crude product. The crude product was purified by Flash reverse phase column to give compound 9 (40 mg). MS m / z (ESI): 492.0 [M+1] + .

[0161] 1 H NMR (400 MHz, DMSO-d6) δ 7.18 - 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 = 7.0 Hz, 3H).

[0162] Example 9

[0163] Synthesis of compound 10

[0164]

[0165] Compound 10 (25 mg) was obtained according to the synthetic procedure of Example 8. MS m / z (ESI): 506.1 [M+1] + .

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 1H), 7.07 (d, J = 4.8 Hz, 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 = 7.3 Hz, 3H).

[0167] Example 10

[0168] Synthesis of compound 11

[0169]

[0170] Compound 11 (60 mg) was obtained according to the synthetic procedure of Intermediate IM-01 and Example 8. MS m / z (ESI): 462.1 [M+1] + .

[0171] 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 7.19 (s, 1H), 7.07 (d, J = 14.5 Hz, 3H), 6.58 (s, 1H), 6.25 - 5.95 (m, 4H), 5.65 (s, 1H), 4.26 (t, J = 6.8 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 3.39 (d, J = 5.9 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 2.33 (s, 3H), 2.19 (s, 6H).

[0172] Example 11

[0173] Synthesis of compound 12

[0174]

[0175] Step 1, Synthesis of compound 12B

[0176] To a solution of 12A (5.2 g) and ammonium acetate (0.6 g) in nitromethane (50 mL) was stirred at 100 °C for 3 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4 / 1 ~ 3 / 2) to give 12B (6 g).

[0177] 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 13.5 Hz, 1H), 8.06 (d, J = 13.5 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.3, 1.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.82 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H).

[0178] Step 2, Synthesis of compound 12C

[0179] A solution of lithium aluminum hydride in tetrahydrofuran (60 mL, 1 mol / L) was added into a three-necked flask under nitrogen atmosphere. 12B (6.0 g) was dissolved in tetrahydrofuran (60 mL) and added into the flask dropwise at room temperature. After the addition was completed, the reaction solution was warmed 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 added slowly in sequence. An appropriate amount of anhydrous sodium sulfate was added and stirred 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 filtrate was combined and concentrated under reduced pressure. The obtained 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] + .

[0180] Step 3, synthesis of compound 12D

[0181] 12C (2.2 g) was dissolved in dichloroethane (20 mL) and trimethylsilyl isocyanate (3.9 g) was added. The reaction solution was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain 12D (2.0 g). MS m / z (ESI): 239.1 [M+1] + .

[0182] Step 4, synthesis of compound 12E

[0183] Sodium ethoxide ethanol solution (20%, 14.0 g) was added to anhydrous ethanol (20 mL), and 12D (2.0 g) and diethyl malonate (3.4 g) were added in sequence. The reaction solution was reacted at 80 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove ethanol. The residue was dissolved in water and hydrochloric acid (2M) was added dropwise under ice bath to adjust pH = 2 until solid appeared. The precipitated solid was collected by filtration and dried to obtain 12E (1.5 g). MS m / z (ESI): 307.1 [M+1] + .

[0184] Step 5, synthesis of compound 12F

[0185] 12E (1.5 g) was added to phosphorus oxychloride (20 mL). The reaction mixture was stirred at 85 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature. Phosphorus oxychloride was removed by concentration under reduced pressure. The obtained residue was dissolved in dichloromethane (50 mL). The organic phase was washed with ice water (50 mL x 2), dried over anhydrous sodium sulfate and concentrated to obtain 12F (1.0 g). MS m / z (ESI): 307.1 [M+1] +.

[0186] Step 6, synthesis of compound 12G

[0187] Dissolve 12F (1.0 g) in isopropanol (20 mL), add 2,4,6-trimethylaniline (2.2 g). The reaction solution is reacted at 90 °C for 16 hours. After the reaction is completed, the reaction solution is concentrated, and the obtained crude product is purified by a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 12G (1.0 g). MS m / z (ESI): 406.1 [M+1] + .

[0188] Step 7, synthesis of compound 12H

[0189] Dissolve 12G (1.0 g) in toluene (10 mL), then add tert-butyl (2-hydroxyethyl)carbamate (0.6 g) and cyanomethylidene tri-n-butylphosphonium (1.8 g). The reaction solution is stirred at 120 °C for 2 hours under nitrogen atmosphere. After the reaction is completed, the reaction solution is concentrated. The obtained crude product is purified by a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 12H (0.5 g). MS m / z (ESI): 549.1 [M+1] + .

[0190] Step 8, synthesis of compound 12I

[0191] Dissolve 12H (200 mg) in 4M hydrochloric acid / dioxane solution (5 mL). The reaction solution is stirred at 25 °C for 1 hour. After the reaction is completed, the reaction solution is concentrated to obtain 12I (160 mg). MS m / z (ESI): 449.1 [M+1] + .

[0192] Step 9, synthesis of compound 12

[0193] Dissolve 12I (200 mg), phenyl carbamate (92 mg) and triethylamine (226 mg) in dichloromethane (5 mL). The reaction solution is stirred at 25 °C for 16 hours. After the reaction is completed, the reaction solution is concentrated. The obtained crude product is purified by a Flash reverse phase column to obtain compound 12 (20 mg). MS m / z (ESI): 492.1 [M+1] + .

[0194] 1H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 1H), 6.85 (s, 2H), 6.66 (s, 1H), 6.10 (t, J = 5.8 Hz, 1H), 5.45 (s, 2H), 5.29 (s, 1H), 4.18 (t, J = 6.7 Hz, 2H), 3.92 (t, J = 6.0 Hz, 2H), 3.87 - 3.82 (m, 2H), 3.80 (s, 3H), 3.35 (d, J = 6.6 Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H), 2.22 (s, 3H), 1.97 (s, 6H), 1.22 (t, J = 6.9 Hz, 3H).

[0195] Example 12

[0196] Synthesis of compound 13

[0197]

[0198] Compound 13 (150 mg) was obtained according to the synthetic procedure of Example 11. MS m / z (ESI): 476.2 [M+1] + .

[0199] 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (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 = 6.3 Hz, 2H), 3.39 (d, J = 5.8 Hz, 2H), 2.94 (t, J = 6.2 Hz, 2H), 2.33 (s, 3H), 2.19 (s, 6H).

[0200] Example 13

[0201] Synthesis of compound 14

[0202]

[0203] Compound 14 (20 mg) was obtained according to the synthetic procedure of Example 11. MS m / z (ESI): 492.1 [M+1] + .

[0204] 1H NMR (400 MHz, DMSO-d6) δ 6.94 (s, 1H), 6.85 (s, 2H), 6.66 (s, 1H), 6.10 (t, J = 5.9 Hz, 1H), 5.44 (s, 2H), 5.31 (s, 1H), 4.18 (t, J = 6.8 Hz, 2H), 4.06 (q, J = 6.9 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.62 (s, 3H), 3.39 - 3.34 (m, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.22 (s, 3H), 1.97 (s, 6H), 1.33 (t, J = 7.0 Hz, 3H).

[0205] Example 14

[0206] Synthesis of compound 15

[0207]

[0208] Step 1, Synthesis of compound 15B

[0209] Dissolve 15A (10.0 g) and ethyl 1,3-dioxoisoindoline-2-carboxylate (11.6 g) in methanol (10 mL), then slowly add triethylamine (2.2 g). The reaction solution is stirred at 25 °C for 12 hours. After the reaction is completed, the reaction solution is concentrated, and the crude product is purified by a Flash reverse-phase chromatographic column to obtain 15B (9.0 g). MS m / z (ESI): 284.2 [M+1] + .

[0210] Step 2, Synthesis of compound 15C

[0211] Dissolve 15B (10.0 g) and 2,2-dimethoxypropane (14.7 g) in toluene (100 mL), slowly add p-toluenesulfonic acid (0.3 g) under nitrogen protection, and stir at 120 °C for 2 hours. The reaction solution is reduced to room temperature, concentrated, and the crude product is purified by a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain 15C (8.0 g). MS m / z (ESI): 324.1 [M+1] + .

[0212] Step 3, Synthesis of compound 15D

[0213] Dissolve 15C (8.0 g) in a mixed solvent of dichloromethane / methanol (V / V = 1 / 1, 100 mL), then drop hydrazine hydrate (12.4 g). After the drop is completed, the reaction solution is stirred at 25 °C for 72 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated to obtain 15D (5.0 g). MS m / z (ESI): 194.1 [M+1]+ .

[0214] Step 4, synthesis of compound 15E

[0215] Dissolve 15D (5.0 g) in dichloroethane (50 mL), then add trimethylsilyl isocyanate (8.9 g). Stir the reaction solution at 80 °C for 16 hours. After the reaction is completed, cool the reaction solution to room temperature, and concentrate under reduced pressure. Purify the crude product by silica gel column (dichloromethane / methanol = 10 / 1) to obtain 15E (4.0 g). MS m / z (ESI): 237.1 [M+1] + .

[0216] Step 5, synthesis of compound 15F

[0217] Add sodium ethoxide ethanol solution (20%, 28.7 g) to anhydrous ethanol (50 mL), and then add 15E (4.0 g) and diethyl malonate (6.8 g) to the solution. Stir the reaction solution at 80 °C for 16 hours. After the reaction is completed, cool the reaction solution to room temperature, and concentrate under reduced pressure to remove ethanol. Dissolve the residue in water, and add hydrochloric acid (2 M) dropwise under ice bath to adjust the pH until solid appears. Collect the precipitated solid by filtration, and dry to obtain 15F (2.5 g). MS m / z (ESI): 305.1 [M+1] + .

[0218] Step 6, synthesis of compound 15G

[0219] Add 15F (2.4 g) to phosphorus oxychloride (20 mL). Stir the reaction mixture at 85 °C for 16 hours under nitrogen atmosphere. After the reaction is completed, cool the reaction solution to room temperature. Concentrate under reduced pressure to remove phosphorus oxychloride, and dissolve the obtained residue in dichloromethane (50 mL). Wash the organic phase with ice water (50 mL x 2), dry over anhydrous sodium sulfate, and concentrate to obtain 15G (2.4 g). MS m / z (ESI): 305.0 [M+1] + .

[0220] Step 7, synthesis of compound 15H

[0221] Dissolve 15G (1.0 g) in isopropanol (20 mL), and add 2,4,6-trimethylaniline (2.2 g). Stir the reaction solution at 90 °C for 16 hours. After the reaction is completed, concentrate the reaction solution. Purify the obtained crude product by silica gel column (dichloromethane / methanol = 10 / 1) to obtain 15H (0.8 g). MS m / z (ESI): 404.2 [M+1] + .

[0222] Step 8, synthesis of compound 15I

[0223] Step 9, synthesis of compound 15J + .

[0224] Step 9, synthesis of compound 15J

[0225] Step 9, synthesis of compound 15J + .

[0226] Step 10, synthesis of compound 15

[0227] Step 10, synthesis of compound 15 + .

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 6.2 Hz, 3H), 6.66 (s, 1H), 6.10 (t, J = 5.8 Hz, 1H), 5.44 (s, 2H), 5.26 (s, 1H), 4.17 (t, J = 6.8 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.35 (d, J = 7.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.23 (s, 3H), 1.95 (s, 6H), 1.61 (s, 6H).

[0229] Example 15

[0230] Synthesis of compound 16

[0231]

[0232] Step 1, synthesis of compound 16B

[0233] IM-01 (500 mg) was added to toluene (10 mL), followed by the addition of tert-butyl (2-hydroxyethyl)(methyl)carbamate (338 mg) and cyanomethylidene tri-n-butylphosphonium (1.50 g). The mixture was stirred at 120 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain 16B (250 mg). MS m / z (ESI): 549.1 [M+1] + .

[0234] Step 2, synthesis of compound 16

[0235] 16B (200 mg) was added to 4M hydrochloric acid / dioxane solution (2 mL). The reaction solution was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain compound 16 (170 mg). MS m / z (ESI): 449.0 [M+1] + .

[0236] 1 H NMR (400 MHz, DMSO-d6) d 7.05 (d, J = 3.3 Hz, 3H), 6.76 (s, 1H), 5.54 (s, 1H), 4.57 - 4.51 (m, 2H), 4.03 (t, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.63 (s, 3H), 3.35 - 3.29 (m, 2H), 2.98 (t, J = 6.3 Hz, 2H), 2.66 (s, 3H), 2.29 (s, 3H), 2.13 (s, 6H).

[0237] Example 16

[0238] Synthesis of compounds 17, 18

[0239]

[0240] 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 by silica gel column (dichloromethane / methanol = 20 / 1) to obtain compound 17 (15 mg) and compound 18 (60 mg).

[0241] Compound 17, MS m / z (ESI): 478.3 [M+1] + .

[0242] 1H NMR (400 MHz, DMSO-d6) δ 6.95 (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 = 5.8 Hz, 2H), 3.80 (s, 3H), 3.61 (s, 3H), 2.90 (t, J = 5.8 Hz, 2H), 2.22 (s, 3H), 1.96 (s, 6H), 1.85 - 1.75 (m, 2H), 1.17 (s, 6H).

[0243] Compound 18, MS m / z (ESI): 478.2 [M+1] + .

[0244] 1 H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H), 6.69 (s, 1H), 6.63 (s, 1H), 5.32 (s, 1H), 4.14 (t, J = 6.4 Hz, 2H), 4.01 - 3.95 (m, 2H), 3.90 (s, 3H), 3.72 (s, 3H), 2.89 (t, J = 6.3 Hz, 2H), 2.33 (s, 3H), 2.16 (s, 6H), 1.97 - 1.89 (m, 2H), 1.25 (s, 6H).

[0245] Example 17

[0246] Synthesis of compound 19

[0247]

[0248] Step 1, synthesis of compound 19B

[0249] Dissolve 19A (10.0 g) in tetrahydrofuran (175 mL), then add triethylamine (7.3 mL). Cool the resulting mixture to -10 °C, then add ethyl chloroformate (5.0 mL) dropwise. After the reaction solution is stirred at -10 °C for 20 minutes, add a solution of concentrated aqueous ammonia (105 mL) in tetrahydrofuran (105 mL). Continue stirring the reaction mixture at -10 °C for 30 minutes, then stir at room temperature for 90 minutes. After the reaction is completed, concentrate the reaction mixture under reduced pressure, extract the residue with dichloromethane (100 mL x 3). After the organic phases are combined, wash with saturated aqueous sodium bicarbonate and brine, dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure to obtain 19B (9.0 g). MS m / z (ESI): 210.1 [M+1] + .

[0250] Step 2, synthesis of compound 19C

[0251] Lithium aluminum tetrahydride (1.81 g) was added into a flask under nitrogen atmosphere, and anhydrous tetrahydrofuran (80 mL) was added slowly. 19B (5.0 g) was dissolved in anhydrous tetrahydrofuran (180 mL), and the solution was added dropwise into the flask slowly at 0°C. After the addition was completed, the reaction solution was warmed 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 added slowly in this order. 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 then filtered. The filtrate was combined and concentrated under reduced pressure, and the resulting crude product was purified by a silica gel column (dichloromethane / methanol = 24 / 1) to obtain 19C (3.5 g). MS m / z (ESI): 196.1 [M+1] + .

[0252] Step 3, synthesis of compound 19D

[0253] 19C (2.0 g) was dissolved in 1,2-dichloroethane (30 mL), and trimethylsilyl isocyanate (2.94 g) was added. The reaction solution was stirred at 85°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 19D (2.1 g). MS m / z (ESI): 239.1 [M+1] + .

[0254] Step 4, synthesis of compound 19E

[0255] Sodium ethoxide ethanol solution (20%, 14.0 g) was added to anhydrous ethanol (20 mL), and 19D (2.0 g) and diethyl malonate (3.4 g) were added in this order. The reaction solution was reacted at 80°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, and ethanol was removed by concentration under reduced pressure. The residue was dissolved in water, and hydrochloric acid (2M) was added dropwise under ice bath to adjust the pH, until a solid was precipitated. The precipitated solid was collected by filtration, and dried to obtain 19E (1.5 g). MS m / z (ESI): 307.2 [M+1] + .

[0256] Step 5, synthesis of compound 19F

[0257] 19E (1.4 g) was added to phosphorus oxychloride (20 mL). The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature. Phosphorus oxychloride was removed by concentration under reduced pressure, and the 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 give 19F (1.4 g). MS m / z (ESI): 307.1 [M+1] + .

[0258] Step 6, Synthesis of Compound 19G

[0259] 19F (1.4 g) was dissolved in isopropanol (20 mL), and 2,4,6-trimethylaniline (1.85 g) was added. The reaction mixture was reacted at 90 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 14 / 1) to obtain 19G (160 mg). MS m / z (ESI): 406.1 [M+1] + .

[0260] Step 7, Synthesis of compound 19H

[0261] 19G (140 mg) was added to toluene (5 mL), followed by 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 protection. After the reaction was complete, the mixture was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 24 / 1) to give 19H (140 mg). MS m / z (ESI): 549.3 [M+1] + .

[0262] Step 8, Synthesis of Compound 19I

[0263] 19H (140 mg) was dissolved in a 4 M, 2 mL solution of 1,4-dioxane hydrogen chloride 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 give 19I (125 mg). MS m / z (ESI): 449.1 [M+1] + .

[0264] Step 9, Synthesis of Compound 19

[0265] Compound 19 was prepared according to the procedures described in Example 1. MS m / z (ESI): 492.3 [M+1] + .

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 6.93 (s, 1H), 6.81 (s, 2H), 6.68 (d, J = 1.5 Hz, 1H), 6.09 (t, J = 5.3 Hz, 1H), 5.45 (s, 2H), 4.93 (d, J = 1.6 Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.78 (d, J = 1.5 Hz, 3H), 3.66 (d, J = 1.6 Hz, 3H), 3.37 (s, 2H), 3.32 (d, J = 2.1 Hz, 4H), 2.67 (s, 2H), 2.18 (s, 3H), 1.98 (s, 6H).

[0267] Example 18

[0268] Synthesis of compound 20

[0269]

[0270] Step 1, synthesis of compound 20B

[0271] Sodium hydride (0.85 g) was added to a solution of 20A (4 g) in tetrahydrofuran (130 mL) at 0 °C. After the addition was completed, the reaction was stirred at room temperature for 30 minutes, then (2-bromoethyl) tert-butyl carbamate (8.4 g) was added. The reaction was heated to 40 °C for 3 hours. After the reaction was completed, the reaction was added to ice water, extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a crude product, which was purified by silica gel column (petroleum ether / ethyl acetate = 4 / 1) to give 20B (7.9 g). MS m / z (ESI): 314.0 [M+1] + .

[0272] Step 2, synthesis of compound 20C

[0273] 20B (7.9 g) was dissolved in dichloromethane (80 mL), and trifluoroacetic acid (26 mL) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated to give 20C (9.5 g). MS m / z (ESI): 213.7 [M+1] +.

[0274] Step 3, synthesis of compound 20D

[0275] Dissolve 20C (9.0 g) in 1,2-dichloroethane (250 mL), add trimethylsilyl isocyanate (16.6 g), replace nitrogen, and heat the reaction at 90 °C for 4 h. After the reaction is completed, cool the reaction to room temperature and concentrate to give a crude product. The crude product is slurried with methyl tert-butyl ether to give 20D (3.7 g). MS m / z (ESI): 256.9 [M+1] + .

[0276] Step 4, synthesis of compound 20E

[0277] Dissolve 20D (3.0 g) in ethanol (80 mL), add diethyl malonate (4.7 g) and sodium ethoxide (4.0 g), and heat the reaction under reflux for 18 h. After the reaction is completed, cool the reaction to room temperature, concentrate, dissolve in water, and adjust the pH to 5 with dilute hydrochloric acid. Filter, and extract the filtrate with ethyl acetate. Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate the organic phase to give 20E (1.0 g). MS m / z (ESI): 324.9 [M+1] + .

[0278] Step 5, synthesis of compound 20F

[0279] Dissolve 20E (700 mg) in phosphorus oxychloride (37 mL), and heat the reaction at 70 °C for 2 h. After the reaction is completed, cool the reaction to room temperature, quench by dropwise addition to ice water, and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate the organic phase to give a crude product. Purify the crude product by silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to give 20F (230 mg). MS m / z (ESI): 324.8 [M+1] + .

[0280] Step 6, synthesis of compound 20G

[0281] Dissolve 20F (220 mg) and 2,4,6-trimethylaniline (458 mg) in propylene glycol (7 mL), and heat the reaction at 90 °C for 10 h. After the reaction is completed, cool the reaction to room temperature, and concentrate to give a crude product. Purify the crude product by silica gel column (dichloromethane / methanol = 10 / 1) to give 20G (211 mg). MS m / z (ESI): 424.2 [M+1] + .

[0282] Step 7, synthesis of compound 20H

[0283] Dissolve 20G (210 mg), (2-hydroxyethyl)carbamic acid tert-butyl ester (104 mg) and cyano methylene tri-n-butyl phosphonium (359 mg) in toluene (5 mL), heat the reaction at 120 °C for 4 hours after nitrogen replacement. After the reaction is completed, concentrate the reaction to get the crude product. Purify the crude product by silica gel column (dichloromethane / methanol = 10 / 1) to get 20H (235 mg). MS m / z (ESI): 567.2 [M+1] + .

[0284] Step 8, synthesis of compound 20I

[0285] Dissolve 20H (235 mg) in hydrochloric acid 1.4-dioxane solution (4 M, 2.5 mL), react at 25 °C for 2 hours. After the reaction is completed, concentrate the reaction to get 20I (239 mg). MS m / z (ESI): 467.2 [M+1] + .

[0286] Step 9, synthesis of compound 20

[0287] Dissolve 20I (200 mg) in dichloromethane (3 mL), add phenyl carbamate (59 mg) and triethylamine (130 mg), react at 25 °C for 3 hours after nitrogen replacement. After the reaction is completed, concentrate the reaction to get the crude product. Purify the crude product by silica gel column (dichloromethane / methanol = 10 / 1) to get compound 20 (150 mg). MS m / z (ESI): 509.9 [M+1] + .

[0288] 1 H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 1H), 6.85 (s, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 6.11 (t, J = 5.7 Hz, 1H), 5.46 (s, 2H), 4.94 (s, 1H), 4.64 - 4.57 (m, 1H), 4.20 (q, J = 6.5 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.36 (q, J = 6.4 Hz, 2H), 3.24 - 2.96 (m, 4H), 2.17 (s, 3H), 2.05 (s, 3H), 1.90 (s, 3H).

[0289] Example 19

[0290] Synthesis of compound 21

[0291]

[0292] Compound 20 (50 mg) was dissolved in dichloromethane (1 mL), m-chloroperoxybenzoic acid (101 mg) was added at 0 °C, then warmed to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the crude product was purified by a Flash reverse phase chromatographic column to obtain compound 21 (10 mg). MS m / z (ESI): 541.9 [M+1] + .

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 7.41 (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 = 9.6 Hz, 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).

[0294] Example 20

[0295] Synthesis of compound 22

[0296]

[0297] Compound 22 (57 mg) was obtained according to the synthetic method of Example 19. MS m / z (ESI): 494.3 [M+1] + .

[0298] 1 H NMR (400 MHz, DMSO-d6) δ 7.06 (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 = 5.0 Hz, 2H), 4.28 - 4.24 (m, 2H), 4.22 (d, J = 4.9 Hz, 2H), 3.82 (s, 3H), 3.67 (s, 3H), 3.40 (d, J = 6.1 Hz, 2H), 2.29 (s, 3H), 2.20 (s, 6H).

[0299] Example 21

[0300] Synthesis of compound 23

[0301]

[0302] Step 1, synthesis of compound 23B

[0303] Sodium azide (4.6 g) was added slowly to a solution of 23A (10.0 g) in N,N- dimethylformamide (100 mL). The reaction was stirred at 25 °C for 16 h. After the reaction was completed, water (200 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give 23B (11 g).

[0304] Step 2, synthesis of compound 23C

[0305] Sodium ethoxide ethanol solution (20%, 104 g) was added to anhydrous ethanol (100 mL), and 23B (10.0 g) and diethyl malonate (25.0 g) were added sequentially. The reaction was stirred at 80 °C for 16 h. After the reaction was completed, the reaction 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 under ice bath to adjust pH = 2. The precipitated solid was collected by filtration and dried to give 23C (12 g). MS m / z (ESI): 278.1 [M+1] + .

[0306] Step 3, synthesis of compound 23D

[0307] 23C (12.0 g) was added to N,N-dimethylformamide (120 mL), followed by the addition of benzyl bromide (11.1 g) and potassium carbonate (12.0 g). The reaction mixture was stirred at 25 °C for 16 h. After the reaction was completed, water (200 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give 23D (10 g). MS m / z (ESI): 368.1 [M+1]+.

[0308] Step 4, synthesis of compound 23E

[0309] 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 h. After the reaction was completed, the reaction was cooled to room temperature and the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by flash reverse-phase chromatography to give 23E (3.0 g). MS m / z (ESI): 248.1 [M+1] + .

[0310] Step 5, synthesis of compound 23F

[0311] 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] + .

[0312] Step 6: Synthesis of compound 23G

[0313] 23F (2.6 g) was added to an ethanolic solution of sodium hydroxide (5 M, 20 mL). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and diluted with water. The pH was adjusted to 2 with 1 M dilute hydrochloric acid, and the resulting solution was purified by Flash reversed-phase chromatography to obtain 23G (800 mg). MS m / z (ESI): 234.1 [M+1]+.

[0314] Step 7, Synthesis of compound 23H

[0315] 23G (50 mg) and a small amount of N,N-dimethylformamide were added to dichloromethane (5 mL), followed by the dropwise addition of oxaloyl chloride (32 mg) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated to give 23H (60 mg).

[0316] Step 8, Synthesis of Compound 23I

[0317] 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 complete, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 23I (70 mg). MS m / z (ESI): 664.3 [M+1] + .

[0318] Step 9, Synthesis of Compound 23

[0319] Compound 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 for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by Flash reversed-phase chromatography to give compound 23 (5 mg). MS m / z (ESI): 574.3 [M+1] + .

[0320] 1H NMR (400 MHz, DMSO-d6) δ 14.65 (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), 4.12 (d, J = 6.5 Hz, 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 = 6.9 Hz, 3H).

[0321] Example 22

[0322] Synthesis of compound 24

[0323]

[0324] Compound 24 (15 mg) was obtained according to the synthetic procedure of Example 11. MS m / z (ESI): 554.2 [M+1] + .

[0325] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.33 (m, 5H), 7.08 (s, 1H), 6.86 (s, 2H), 6.70 (s, 1H), 6.10 (t, J = 5.6 Hz, 1H), 5.44 (s, 2H), 5.33 (s, 1H), 5.14 (s, 2H), 4.18 (t, J = 6.6 Hz, 2H), 3.92 (t, J = 5.7 Hz, 2H), 3.63 (s, 3H), 3.35 (d, J = 6.4 Hz, 2H), 2.88 (s, 2H), 2.22 (s, 3H), 1.97 (s, 6H).

[0326] Example 23

[0327] Synthesis of compound 25

[0328]

[0329] Step 1, Synthesis of compound 25A

[0330] Compound 24H (600 mg) was dissolved in methanol (10 mL), then palladium on carbon (100 mg) was added. The reaction was stirred at room temperature for 16 hours under hydrogen atmosphere. After the reaction was completed, it 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] +.

[0331] Step 2, synthesis of compound 25B

[0332] 25A (200 mg), 3-hydroxytetrahydrofuran (51 mg) and cyanomethylidene tri-n- butylphosphonium (278 mg) were dissolved in toluene (5 mL). The reaction was stirred at 120 °C under nitrogen atmosphere for 6 hours. After the reaction was completed, the reaction was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (dichloromethane / methanol = 24 / 1) to obtain 25B (100 mg). MS m / z (ESI): 591.3 [M+1] + .

[0333] Step 3, synthesis of compound 25C

[0334] 25B (100 mg) was added to hydrochloric acid / dioxane solution (4 M, 2 mL). The reaction was stirred at 25 °C for 4 hours. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain 25C (90 mg). MS m / z (ESI): 491.2 [M+1] + .

[0335] Step 4, synthesis of compound 25

[0336] 25C (90 mg), phenyl carbamate (38 mg) and triethylamine (93 mg) were added to dichloromethane (2 mL). The reaction was stirred at 25 °C for 4 hours. After the reaction was completed, the reaction was concentrated under reduced pressure. The obtained crude product was purified by Flash reverse phase column to obtain compound 25 (20 mg). MS m / z (ESI): 534.3 [M+1] + .

[0337] 1 H NMR (400 MHz, DMSO-d6) δ 6.94 (s, 1H), 6.85 (s, 2H), 6.68 (s, 1H), 6.10 (t, J = 5.5 Hz, 1H), 5.45 (s, 2H), 5.32 (s, 1H), 5.06 (s, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.94 - 3.89 (m, 2H), 3.88 - 3.70 (m, 4H), 3.62 (s, 3H), 3.35 (d, J = 6.3 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.28 - 2.18 (m, 4H), 1.97 (s, 6H), 1.93 (s, 1H).

[0338] Example 24

[0339] Synthesis of compound 26

[0340]

[0341] Step 1, synthesis of compound 26A

[0342] Dissolve 25A (800 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (537 mg) in acetonitrile (10 mL), then add cesium carbonate (601 mg). The reaction mixture is stirred at 80 °C under nitrogen atmosphere for 10 hours. After the reaction is completed, the reaction solution is cooled to room temperature. After dilution with water (50 mL), it is extracted with ethyl acetate (50 mL x 3). The combined organic phase is washed with saturated brine and concentrated under reduced pressure to obtain the crude product. The crude product is purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 26A (180 mg). MS m / z (ESI): 603.3 [M+1] + .

[0343] Step 2, synthesis of compound 26B

[0344] Dissolve 26A (180 mg) in hydrochloric acid / dioxane solution (4 M, 4 mL). The reaction solution is stirred at 25 °C for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain 26B (150 mg). MS m / z (ESI): 503.2 [M+1] + .

[0345] Step 3, synthesis of compound 26C

[0346] Dissolve 26B (100 mg) in dichloromethane (2 mL), then add triethylamine (88 mg) and 23H (44 mg). The reaction solution is stirred at room temperature for 4 hours. After the reaction is completed, it is concentrated under reduced pressure to obtain the crude product. The crude product is purified by silica gel column (dichloromethane / methanol = 20 / 1) to obtain 26C (70 mg). MS m / z (ESI): 718.3 [M+1] + .

[0347] Step 4, synthesis of compound 26

[0348] Dissolve 26C (67 mg) in methanol (1 mL), then add palladium on carbon (30 mg) and palladium hydroxide on carbon (30 mg). The reaction solution is heated to 30 °C and stirred for 4 hours under hydrogen atmosphere. After the reaction is completed, it is filtered and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is purified by Flash reverse phase column to obtain compound 26 (27.5 mg). MS m / z (ESI): 628.3 [M+1] + .

[0349] 1H NMR (400 MHz, DMSO-d6) δ 14.66 (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 = 8.5 Hz, 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).

[0350] Example 25

[0351] Synthesis of compound 27

[0352]

[0353] Compound 27 (6.5 mg) was obtained according to the synthetic procedure of Example 24. MS m / z (ESI): 600.3 [M+1] + .

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 14.67 (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 = 6.8 Hz, 5H), 3.70 (d, J = 5.8 Hz, 2H), 3.66 (s, 3H), 2.94 (t, J = 6.1 Hz, 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).

[0355] Example 26

[0356] Synthesis of compound 28

[0357]

[0358] Compound 28 (12 mg) was obtained according to the synthetic procedure of Example 24. MS m / z (ESI): 604.3 [M+1] + .

[0359] 1H NMR (400 MHz, DMSO-d6) δ 14.67 (s, 1H), 10.58 (s, 1H), 8.31 (s, 1H), 7.11 (d, J = 6.6 Hz, 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).

[0360] Example 27

[0361] Synthesis of compound 29

[0362]

[0363] Step 1, Synthesis of compound 29B

[0364] Dissolve 29A (200 mg) in dichlorosulfoxide (5 mL), heat the reaction at 80 °C for 2 hours under nitrogen protection. After the reaction is completed, the reaction solution is directly rotary evaporated to obtain 29B (215 mg).

[0365] Step 2, Synthesis of compound 29

[0366] Dissolve 29B (215 mg) in dichloromethane (10 mL), add 14B (548 mg) and triethylamine (370 mg), and react at 25 °C for 18 hours after nitrogen replacement. After the reaction is completed, the reaction solution is concentrated to obtain a crude product. The crude product is purified by silica gel column (petroleum ether / ethyl acetate = 1 / 4) to obtain compound 29 (476 mg). MS m / z (ESI): 588.2 [M+1] + .

[0367] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J = 5.8 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J = 5.1 Hz, 1H), 6.94 (s, 1H), 6.84 (s, 2H), 6.67 (s, 1H), 5.33 (s, 1H), 4.36 (t, J = 5.8 Hz, 2H), 4.05 (p, J = 6.3 Hz, 2H), 3.89 (t, J = 5.9 Hz, 2H), 3.78 - 3.67 (m, 2H), 3.62 (s, 3H), 2.86 (d, J = 6.0 Hz, 2H), 2.21 (s, 3H), 1.95 (s, 6H), 1.33 (t, J = 6.9 Hz, 3H).

[0368] Example 28

[0369] Synthesis of compound 30

[0370]

[0371] 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 the reaction was heated at 80 °C for 18 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by flash reverse-phase chromatography column to give compound 30 (14 mg). MS m / z (ESI): 570.0 [M+1] + .

[0372] 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.81 (s, 1H), 7.45 (d, J = 6.7 Hz, 1H), 7.12 (s, 2H), 7.07 (s, 1H), 6.78 (s, 1H), 6.63 (s, 1H), 6.38 (d, J = 6.6 Hz, 1H), 5.59 (s, 1H), 4.47 (s, 2H), 4.15 - 4.09 (m, 2H), 4.02 (s, 2H), 3.69 (d, J = 5.1 Hz, 2H), 3.65 (s, 3H), 2.95 (s, 2H), 2.32 (s, 3H), 2.19 (s, 6H), 1.35 (t, J = 6.9 Hz, 3H).

[0373] Example 29

[0374] Synthesis of compound 31

[0375]

[0376] Step 1, Synthesis of compound 31A

[0377] IM-02 (500 mg) was added to toluene (5 mL), followed by the addition of tert-butyl (3-hydroxycyclobutyl)carbamate (346 mg) and cyanomethylidene tri-n-butylphosphonium (890 mg). The reaction solution was stirred at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained crude product was purified by silica gel column (dichloromethane / methanol = 24 / 1) to give 31A (200 mg). MS m / z (ESI): 575.4 [M+1] + .

[0378] Step 2, Synthesis of compound 31B

[0379] To a solution of 31A (200 mg) in hydrochloric acid / dioxane (4 M, 4 mL) was added. The reaction was stirred at 25 °C for 2 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by flash reverse phase column to give 31B (120 mg). MS m / z (ESI): 475.3 [M+1] + .

[0380] Step 3, synthesis of compound 31C

[0381] To a solution of 31B (120 mg) in dichloromethane (2 mL) was added triethylamine (128 mg) and 23H (64 mg). The reaction was stirred at room temperature for 4 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (dichloromethane / methanol = 20 / 1) to give 31C (120 mg). MS m / z (ESI): 690.3 [M+1] + .

[0382] Step 4, synthesis of compound 31

[0383] To a solution of 31C (90 mg) in methanol (2 mL) was added palladium on carbon (18 mg) and palladium hydroxide on carbon (18 mg). The reaction was heated to 30 °C and stirred for 14 h under hydrogen atmosphere. After the reaction was completed, the reaction was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash reverse phase column to give compound 31 (7 mg). MS m / z (ESI): 600.3 [M+1] + .

[0384] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 8.3 Hz, 1H), 6.94 (s, 1H), 6.86 (s, 2H), 6.64 (s, 1H), 5.32 (s, 1H), 5.25 - 5.15 (m, 1H), 4.25 (dd, J = 15.9, 8.0 Hz, 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 = 6.0 Hz, 2H), 2.82-2.75 (m, 2H), 2.22 (s, 3H), 1.98 (d, J = 3.9 Hz, 6H), 1.33 (t, J = 7.0 Hz, 3H).

[0385] Example 30

[0386] Synthesis of compound 32

[0387]

[0388] Step 1, synthesis of compound 32A

[0389] IM-01 (200 mg) was added to toluene (5 mL), followed by the addition of tert-butyl 3-hydroxyazetidine-1-carboxylate (133 mg) and cyanomethylidene tri-n-butylphosphonium (370 mg). The mixture was stirred at 120 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution 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 32A (100 mg). MS m / z (ESI): 547.2 [M+1] + .

[0390] Step 2, synthesis of compound 32B

[0391] 32A (100 mg) was added to dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (1 ml). The reaction solution was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution 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] + .

[0392] Step 3, synthesis of compound 32

[0393] 32B (70 mg) was added to dichloromethane (2 mL), followed by the addition of phenyl carbamate (32 mg) and triethylamine (79 mg) in sequence. 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 column to obtain compound 32 (30 mg). MS m / z (ESI): 490.2 [M+1] + .

[0394] 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 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 = 6.2 Hz, 2H), 2.34 - 2.26 (m, 3H), 2.13 - 1.99 (m, 6H).

[0395] Example 31

[0396] Synthesis of compound 33

[0397]

[0398] Step 1. Synthesis of compound 33A

[0399] Compound 33B (0.62 g) was obtained by the same procedure as described in Example 1, Step 1 using compound 33A (1.0 g), p-nitrophenyl chloroformate (1.26 g) and N,N-diisopropyl ethylamine (3.36 g). MS m / z (ESI): 358.0 [M+1] + .

[0400] Step 2. Synthesis of compound 33

[0401] Compound 33 (25 mg) was obtained by the same procedure as described in Example 1, Step 2 using compound 2 (100 mg) and 33B (90 mg). MS m / z (ESI): 653.0 [M+1] + .

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.32 (s, 1H), 7.11 (d, J = 7.1 Hz, 3H), 6.79 (s, 1H), 5.60 (s, 1H), 4.78 (s, 2H), 4.36 (s, 2H), 4.17 (t, J = 5.0 Hz, 2H), 3.88 - 3.79 (m, 7H), 3.65 (s, 3H), 3.50 (d, J = 5.2 Hz, 2H), 2.93 (t, J = 6.2 Hz, 2H), 2.33 (s, 3H), 2.20 (s, 6H).

[0403] Example 32

[0404] Synthesis of compound 34

[0405]

[0406] Step 1. Synthesis of compound 34A

[0407] IM-01 (2.0 g) was dissolved in N,N-dimethylformamide (20 mL), 2-bromo-1,1- dimethoxyethane (6.0 g), potassium carbonate (6.3 g) and sodium iodide (4.59 g) were added successively. The reaction mixture was stirred at 83 °C for 72 h under nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with ethyl acetate (70 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4 / 1 ~ 3 / 2) to give 34A (150 mg). MS m / z (ESI): 480.2 [M+1] + .

[0408] Step 2, synthesis of compound 34B

[0409] 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 h under nitrogen atmosphere. After the reaction was completed, the pH of the reaction mixture was adjusted to 7-8 by adding saturated sodium carbonate aqueous solution, and then the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 34B (100 mg). MS m / z (ESI): 434.1 [M+1] + .

[0410] Step 3, synthesis of compound 34

[0411] 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 h under nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, and then sodium borohydride (44 mg, 1.15 mmol) and methanol (0.5 mL) were added, and the reaction mixture was stirred at 78 °C for another 12 h. The reaction mixture was quenched with water and concentrated under reduced pressure. The residue was dissolved in ethanol (1 mL), and then palladium on carbon (10 mg) was added. The reaction mixture was stirred at room temperature for 10 h under hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash reverse-phase chromatography column to give compound 34 (15 mg). MS m / z (ESI): 610.2 [M+1] + .

[0412] 1H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 1H), 6.85 (s, 2H), 6.66 (s, 1H), 5.32 (s, 1H), 4.35 (t, J = 6.5 Hz, 2H), 4.15 (t, J = 5.3 Hz, 2H), 4.00 (s, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.61 (s, 3H), 3.08 (t, J = 5.4 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.22 (s, 3H), 1.94 (s, 6H).

[0413] Example 33

[0414] Synthesis of compound 35

[0415]

[0416] Step 1, Synthesis of compound 35A

[0417] IM-01 (1.0 g) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (590 mg) were dissolved in toluene (10 mL), and cyanomethylidene tri-n-butylphosphonium (1.9 g) was added. The reaction was heated to 120 °C for 10 hours under nitrogen atmosphere. 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] + .

[0418] Step 2, Synthesis of compound 35B

[0419] 35A (500 mg) was added to a hydrochloric acid solution in dioxane (4 M, 5 mL). The reaction was reacted at 25 °C for 1 hour. After the reaction was completed, the reaction was directly spin-dried to obtain 35B (0.42 g). MS m / z (ESI): 461.3 [M+1] + .

[0420] Step 3, Synthesis of compound 35C

[0421] 35B (110 mg) and 23H (50 mg) were dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (51 mg) was added. The reaction was reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained crude product was purified by thin layer preparative chromatography (dichloromethane / methanol = 60 / 1) to obtain 35C (80 mg). MS m / z (ESI): 676.2 [M+1] + .

[0422] Step 4, synthesis of compound 35

[0423] Compound 35 (17 mg) was obtained from 35C (80 mg) by the similar procedure as described in Step 3. MS m / z (ESI): 586.3 [M+1] + .

[0424] 1 H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J = 3.5 Hz, 1H), 6.85 (s, 2H), 6.64 (d, J = 7.9 Hz, 1H), 6.13 - 6.02 (m, 1H), 5.33 (d, J = 10.3 Hz, 1H), 4.38 - 4.04 (m, 1H), 4.01 - 3.52 (m, 15H), 2.90 (q, J = 5.9 Hz, 2H), 2.81 - 2.72 (m, 1H), 2.21 (s, 4H), 2.03 - 1.85 (m, 6H).

[0425] Example 34, synthesis of compound 36

[0426]

[0427] Step 1, synthesis of compound 36B

[0428] Compound 36B (100 mg) was obtained from 36A (100 mg) by the similar procedure as described in Step 1. MS m / z (ESI): 167.1 [M+1] + .

[0429] Step 2, synthesis of compound 36C

[0430] Compound 36C (40 mg) was obtained from 36B (100 mg) by the similar procedure as described in Step 2. MS m / z (ESI): 153.2 [M+1]+ .

[0431] Step 3, synthesis of compound 36

[0432] Compound 36C (10 mg) was dissolved in N,N-dimethylformamide (2 mL), then HATU (26 mg) and diisopropylethylamine (22 mg) were added. The reaction was stirred at room temperature for 0.5 h, then compound 2 (25 mg) was added. The reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction was diluted with ethyl acetate to 100 mL, then washed with water (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure. The crude product was purified by thin layer preparative chromatography (dichloromethane / methanol = 25 / 1) to obtain compound 36 (15 mg). MS m / z (ESI): 569.2 [M+1] + .

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (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 = 6.7 Hz, 2H), 4.08 (t, J = 7.1 Hz, 2H), 3.92 (t, J = 6.2 Hz, 2H), 3.81 (s, 3H), 3.68 - 3.54 (m, 5H), 2.93 - 2.87 (m, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.49 - 2.41 (m, 2H), 2.22 (s, 3H), 1.97 (s, 6H).

[0434] Example 35

[0435] Synthesis of compound 37

[0436]

[0437] Compound 37 (20 mg) was obtained according to the synthetic method of Example 23. MS m / z (ESI): 547.3 [M+1] + .

[0438] 1H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J = 5.1 Hz, 3H), 6.66 (s, 1H), 6.10 (t, J = 5.7 Hz, 1H), 5.44 (s, 2H), 5.31 (s, 1H), 4.88 (s, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.91 (d, J = 6.1 Hz, 2H), 3.61 (s, 3H), 3.39 - 3.33 (m, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.77 (m, 1H), 2.68 - 2.54 (m, 2H), 2.37 - 2.27 (m, 2H), 2.23 (d, J = 9.9 Hz, 6H), 1.97 (s, 6H), 1.79 - 1.69 (m, 1H).

[0439] Example 36

[0440] Synthesis of compound 38

[0441]

[0442] Compound 38A (15 mg), N,N'-carbonyldiimidazole (22 mg) and triethylamine (46 mg) were dissolved into dichloromethane (5 mL). After the reaction solution was stirred at 25 °C for 2 hours, compound 2 (50 mg) was added. The reaction solution continued to be stirred at 25 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained crude product was purified by a Flash reverse phase column to obtain compound 38 (5 mg). MS m / z (ESI): 591.2 [M+1] + .

[0443] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (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 = 6.3 Hz, 4H), 3.37 - 3.29 (m, 2H), 3.11 (s, 2H), 3.09 - 2.96 (m, 4H).

[0444] Example 37

[0445] Synthesis of compound 39

[0446]

[0447] Compound 39A (79 mg), compound 2 (150 mg), N, N, N', N'-tetramethylchloroformamidium hexafluorophosphate (145 mg) and N-methylimidazole (85 mg) were dissolved in 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 a flash reverse-phase chromatographic column to obtain compound 39 (30 mg). MS m / z (ESI): 570.7 [M+1] + .

[0448] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J = 7.3, 2.1 Hz, 1H), 8.04 (dd, J = 6.5, 2.1 Hz, 1H), 7.08 (s, 2H), 7.04 (s, 1H), 6.76 (s, 1H), 6.50 (t, J = 6.9 Hz, 1H), 5.53 (s, 1H), 4.40 (t, J = 6.2 Hz, 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).

[0449] Example 38

[0450] Synthesis of compound 40

[0451]

[0452] Step 1, Synthesis of compound 40B

[0453] 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 aqueous solution was added. After the reaction solution was stirred for 10 minutes, iodoethane (2.47 g) was added dropwise. The reaction solution was stirred at 70 °C for 20 hours under a sealed condition. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water, and adjusted to pH = 2-3 with 1M dilute hydrochloric acid, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by a silica gel column (dichloromethane / methanol = 10 / 1) to obtain 40B (0.35 g), yield: 12%. MS m / z (ESI): 168.0 [M+1]+.

[0454] Step 2, Synthesis of compound 40

[0455] Compound 40B (46 mg), compound 2 (80 mg), N, N, N', N'-tetramethylchloroformamidium hexafluorophosphate (78 mg) and N-methylimidazole (45 mg) were dissolved in N, N-dimethylformamide (1.5 mL). The reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was purified by Flash reverse-phase column to give compound 40 (15 mg). MS m / z (ESI): 584.3 [M+1] + .

[0456] 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (t, J = 5.6 Hz, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 6.5 Hz, 1H), 6.96 (s, 1H), 6.84 (s, 2H), 6.67 (s, 1H), 6.51 (t, J = 6.8 Hz, 1H), 5.32 (s, 1H), 4.34 (t, J = 6.1 Hz, 2H), 4.02 (q, J = 6.9 Hz, 2H), 3.89 (t, J = 5.5 Hz, 2H), 3.80 (s, 3H), 3.76 - 3.68 (m, 2H), 3.62 (s, 3H), 2.89 (t, J = 5.3 Hz, 2H), 2.21 (s, 3H), 1.93 (s, 6H), 1.24 (t, J = 7.0 Hz, 3H).

[0457] Example 39

[0458] Synthesis of compound 41

[0459]

[0460] Step 1, Synthesis of compound 41A

[0461] Compound 40A (1.4 g) was dissolved in anhydrous ethanol (50 mL), then sulfuric chloride (1 mL) was added. The reaction was reacted at 90 °C for 1 h. After the reaction was completed, the reaction was concentrated under reduced pressure, and the obtained crude product was purified by Flash reverse-phase column to give compound 41A (0.3 g). MS m / z (ESI): 168.1 [M+1] + .

[0462] Step 2, Synthesis of compound 41B

[0463] Compound 41B (0.3 g) was obtained. MS m / z (ESI): 207.9 [M+1]+.

[0464] Step 3, synthesis of compound 41C

[0465] Compound 41B (300 mg) was dissolved in ethanol (10 mL), and water (2 mL) and sodium hydroxide (116 mg) were added successively. The reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, water (10 mL) was added for dilution, and methyl tert-butyl ether was used for extraction. The aqueous phase was adjusted to pH = 2-3 with 1M hydrochloric acid aqueous solution, and ethyl acetate (30 mL x 3) was continuously added for extraction. After the organic phases were combined, they were concentrated, and the residue was purified by a Flash reverse-phase chromatographic column, and compound 41C (30 mg) was obtained after freeze-drying. MS m / z (ESI): 179.9 [M+1] + .

[0466] Step 4, synthesis of compound 41

[0467] Compound 41C (30 mg) was dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (70 mg), N-methylimidazole (41 mg) and compound 2 (109 mg) were added successively. The reaction solution was reacted at 25°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was purified by a Flash reverse-phase chromatographic column, and compound 41 (9 mg) was obtained after freeze-drying. MS m / z (ESI): 596.3 [M+1] + .

[0468] 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.09 (s, 1H), 8.27 (dd, J = 7.2, 2.1 Hz, 1H), 7.95 (dd, J = 6.7, 2.0 Hz, 1H), 7.10 (d, J = 12.1 Hz, 3H), 6.78 (s, 1H), 6.44 (t, J = 7.0 Hz, 1H), 5.57 (s, 1H), 4.40 (t, J = 6.6 Hz, 2H), 4.06 (s, 2H), 3.85 (s, 3H), 3.78 (d, J = 6.4 Hz, 2H), 3.64 (s, 3H), 3.43 (td, J = 7.5, 3.7 Hz, 1H), 2.99 (t, J = 6.5 Hz, 2H), 2.32 (s, 3H), 2.17 (s, 6H), 1.05 (q, J = 7.3 Hz, 2H), 0.94 - 0.87 (m, 2H).

[0469] Example 40

[0470] Synthesis of compound 42

[0471]

[0472] Step 1, Synthesis of compound 42A

[0473] 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 into 2-butanone (20 mL). Stirring at 85 °C for 16 hours. After the reaction was completed, concentrated under reduced pressure. The crude product was purified by silica gel column (dichloromethane / methanol = 20 / 1) to obtain 42A (200 mg). MS m / z (ESI): 579.3 [M+1] + .

[0474] Step 2, Synthesis of compound 42

[0475] 42A (120 mg) was dissolved in ethanol (10 mL), and hydrazine hydrate (31 mg) was added. Stirring at 85 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Flash reverse phase column to obtain compound 42 (90 mg). MS m / z (ESI): 449.3 [M+1] + .

[0476] 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 2H), 7.10 (s, 2H), 6.98 (s, 1H), 6.60 (s, 1H), 5.27 (s, 1H), 4.07 (d, J = 7.0 Hz, 2H), 3.98 - 3.90 (m, 4H), 3.59 (s, 3H), 3.10 (d, J = 6.6 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H), 2.31 (s, 3H), 2.11 (s, 6H), 1.33 (t, J = 6.9 Hz, 3H).

[0477] Example 41

[0478] Synthesis of compound 43

[0479]

[0480] Step 1, Synthesis of compound 43A

[0481] 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 was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the obtained crude product was purified by a Flash reverse phase column to obtain 43A (40 mg). MS m / z (ESI): 664.3 [M+1] + .

[0482] Step 2, Synthesis of compound 43

[0483] 43A (40 mg), palladium on carbon (40 mg) and palladium hydroxide on carbon (40 mg) were added to methanol (10 mL). The reaction mixture was stirred at 30 °C for 2 hours under hydrogen atmosphere. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by a Flash reverse phase column to obtain compound 43 (15 mg). MS m / z (ESI): 574.2 [M+1] + .

[0484] 1 H NMR (400 MHz, CDCl3) δ 6.99 (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 = 6.3 Hz, 2H), 2.33 (s, 3H), 2.15 (s, 6H), 1.48 (t, J = 7.0 Hz, 3H).

[0485] Example 42

[0486] Synthesis of compound 44

[0487]

[0488] Referring to the synthesis method of Example 40 and Example 41, compound 44 (10 mg) was obtained. MS m / z (ESI): 560.2 [M+1] + .

[0489] 1 H NMR (400 MHz, CDCl3) δ 7.00 (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 = 4.8 Hz, 2H), 3.72 (s, 3H), 2.95 (s, 2H), 2.33 (s, 3H), 2.16 (s, 6H).

[0490] Example 43

[0491] Synthesis of compound 45

[0492]

[0493] 44B (50 mg) and phenyl carbamate (16 mg) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (23 mg). The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by a Flash reverse phase column to obtain compound 45 (10 mg). MS m / z (ESI): 478.2 [M+1] + .

[0494] 1 H NMR (400 MHz, CDCl3) δ 7.01 (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 = 6.6 Hz, 2H), 2.94 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 2.15 (s, 6H).

[0495] Example 44

[0496] Synthesis of compound 46

[0497]

[0498] To a solution of 44B (50 mg), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (26 mg), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (48 mg) and N-methylimidazole (28 mg) in N,N-dimethylformamide (2 mL) was stirred at 25 °C for 16 h. After the reaction was completed, the reaction solution was purified by flash reverse phase chromatography to give compound 46 (5 mg). MS m / z (ESI): 570.2 [M+1] + .

[0499] 1 H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.43 (d, J = 5.4 Hz, 1H), 7.50 (d, J = 6.6 Hz, 1H), 6.96 (s, 2H), 6.69 (s, 1H), 6.64 (s, 1H), 6.34 (t, J = 6.9 Hz, 1H), 5.38 (s, 1H), 4.18 (t, J = 6.3 Hz, 2H), 4.12 - 4.06 (m, 2H), 3.90 (s, 3H), 3.80 (dd, J = 15.0, 5.9 Hz, 2H), 3.72 (s, 3H), 3.62 (s, 3H), 2.90 (t, J = 6.4 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 6H).

[0500] Example 45

[0501] Synthesis of compound 47

[0502]

[0503] Step 1, Synthesis of compound 47A

[0504] To a solution of 4-benzyloxy-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (50 mg) in N,N-dimethylformamide (4 mL) was added HATU (170 mg) and diisopropylethylamine (93 mg) and stirred for 0.5 h. To the reaction solution was added 32B (80 mg) and stirred for 3 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate to 50 mL, washed with water (30 mL x 3) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a crude product. Purification by preparative plate separation gave 47A (100 mg). MS m / z (ESI): 662.3 [M+1] + .

[0505] Step 2, Synthesis of compound 47

[0506] Compound 47 was prepared according to the procedures described in Example 1. MS m / z (ESI): 572.2 [M+1] + .

[0507] 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 7.26 (s, 1H), 7.10 (d, J = 5.1 Hz, 2H), 7.06 (s, 1H), 5.94 (s, 1H), 4.83 (d, J = 9.4 Hz, 1H), 4.57 (t, J = 11.0 Hz, 1H), 4.43 (dd, J = 11.8, 7.5 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.87 (d, J = 11.3 Hz, 6H), 3.75 (s, 3H), 3.59 (dd, J = 13.9, 7.3 Hz, 1H), 3.41 - 3.35 (m, 1H), 2.35 - 2.24 (m, 9H).

[0508] Example 46

[0509] Synthesis of compound 48

[0510]

[0511] Compound 48 was prepared according to the procedures described in Example 1. MS m / z (ESI): 578.3 [M+1] + .

[0512] 1H NMR (400 MHz, CDC13) δ 7.01 (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 = 5.6 Hz, 2H), 3.75 (d, J = 6.1 Hz, 1H), 3.72 (s, 3H), 3.52-3.47 (m, 5H), 3.12-3.02 (m, 1H), 2.92 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 2.14-2.17 (m, 6H).

[0513] Example 47

[0514] Synthesis of compound 49

[0515]

[0516] Step 1, Synthesis of compound 49B

[0517] Triphenylmethyl chloride (1368 mg) and 1H-imidazole-5-carboxylic acid 49A (500 mg) were dissolved in N,N-dimethylformamide (10 mL), and then pyridine (0.5 mL) was added. The mixture was warmed to 50°C and stirred for 6 hours under nitrogen protection. 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 x 3) to obtain 49B (400 mg). MS m / z (ESI): 709.2 [2M+1] + .

[0518] Step 2, Synthesis of compound 49C

[0519] 49B (90 mg) was dissolved in N,N-dimethylformamide (10 mL), and HATU (220 mg) and diisopropylethylamine (119 mg) were added in turn. After stirring for 15 minutes, 32B (100 mg) was added. After stirring for 3 hours, the reaction was completed, water (20 mL) was added for dilution, and ethyl acetate (15 mL x 3) was extracted. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 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] + .

[0520] Step 3, Synthesis of compound 49

[0521] Compound 49 was dissolved in trifluoroacetic acid in dichloromethane solution (5%, 10 mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated, and the crude product was purified by thin layer chromatography to give compound 49 (18 mg). MS m / z (ESI): 541.0 [M+1] + .

[0522] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.41 - 8.02 (m, 1H), 7.74 (t, J = 6.2 Hz, 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), 3.70 - 3.59 (m, 1H), 3.40 - 3.28 (m, 1H), 3.01 (t, J = 6.6 Hz, 2H), 2.40 - 2.09 (m, 9H).

[0523] Example 48

[0524] Synthesis of compound 50

[0525]

[0526] Compound 50A (19 mg) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of HATU (138 mg) and diisopropylethylamine (75 mg). After stirring for 0.5 hours, 32B (65 mg) was added. After stirring for 4 hours, the reaction was purified by flash reverse-phase chromatography to give compound 50 (10 mg). MS m / z (ESI): 556.3 [M+1] + .

[0527] 1H NMR (400 MHz, DMSO-d6) δ 7.11 (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 = 6.4 Hz, 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 = 6.3 Hz, 2H), 2.41 (d, J = 5.8 Hz, 3H), 2.34 - 2.28 (m, 3H), 2.12 - 2.02 (m, 6H).

[0528] Example 49

[0529] Synthesis of compound 51

[0530]

[0531] Compound 51 (20 mg) was obtained according to the synthetic procedure of Example 48. MS m / z (ESI): 543.3 [M+1] + .

[0532] 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.20 (t, J = 5.9 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 3.2 Hz, 3H), 6.09 (s, 1H), 4.83 (d, J = 9.5 Hz, 1H), 4.60 (t, J = 11.1 Hz, 1H), 4.40 (dd, J = 11.8, 6.9 Hz, 1H), 4.12 (dd, J = 11.7, 5.8 Hz, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.72 - 3.66 (m, 1H), 3.41 (dd, J = 7.9, 5.1 Hz, 1H), 3.01 (t, J = 6.2 Hz, 2H), 2.30 (s, 6H), 2.24 (s, 3H).

[0533] Example 50

[0534] Synthesis of compound 52

[0535]

[0536] Compound 52 was obtained by the same method with 14B (100 mg), 1-methyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid (39 mg), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (71 mg) and N-methylimidazole (42 mg) in N,N-dimethylformamide (2 mL). The reaction solution was stirred at 25 °C for 16 h. After the reaction was completed, the reaction solution was purified by a flash reverse-phase chromatographic column to obtain compound 52 (10 mg). MS m / z (ESI): 584.3 [M+1] + .

[0537] 1 H NMR (400 MHz, CDC13) δ 10.32 (s, 1H), 8.43 - 8.32 (m, 1H), 7.58 (dd, J = 6.5, 1.9 Hz, 1H), 7.01 (s, 2H), 6.73 (s, 1H), 6.69 (s, 1H), 6.36 (t, J = 6.9 Hz, 1H), 5.61 (s, 1H), 4.71 (d, J = 6.0 Hz, 2H), 4.16 (q, J = 6.8 Hz, 4H), 3.93 (d, J = 6.1 Hz, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 2.98 (t, J = 6.2 Hz, 2H), 2.34 (s, 3H), 2.25 (s, 6H), 1.49 (t, J = 7.0 Hz, 3H).

[0538] Example 51

[0539] Synthesis of compound 53, 54

[0540]

[0541] 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 h. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by a silica gel column (dichloromethane / methanol = 20 / 1) to obtain compound 53 (5 mg), compound 54 (15 mg).

[0542] Compound 53: MS m / z (ESI): 492.3 [M+1] + .

[0543] 1H NMR (400 MHz, CDC13) δ 6.99 (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 = 6.2 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 6H), 1.96 - 1.89 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H), 1.26 (s, 6H).

[0544] Compound 54: MS m / z (ESI): 492.2 [M+1] + .

[0545] 1 H NMR (400 MHz, DMSO-d6) δ 6.94 (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 = 6.9 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.62 (s, 3H), 2.88 (t, J = 5.9 Hz, 2H), 2.22 (s, 3H), 1.96 (s, 6H), 1.85 -

[0546] 1.76 (m, 2H), 1.33 (t, J = 6.9 Hz, 3H), 1.17 (s, 6H).

[0547] Example 52

[0548] Synthesis of compound 55

[0549]

[0550] Step 1, synthesis of compound 55B

[0551] 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 solution was stirred at room temperature for 10 hours. After the reaction was completed, water (1 mL) was added to quench the reaction, and the resulting solution was purified by a Flash reverse-phase chromatographic column to obtain 55B (2.0 g). MS m / z (ESI): 236.1 [M+1] + .

[0552] Step 2, synthesis of compound 55C

[0553] Dissolve 55B (500 mg) in tetrahydrofuran / water (V / V = 1 / 1, 10 mL) solution, then add lithium hydroxide (152 mg). The reaction solution is reacted at 25 °C for 6 hours. After the reaction is completed, concentrate under reduced pressure, extract with diethyl ether (3 mL), then adjust pH = 2-3 with 1M dilute hydrochloric acid. Filter, collect the precipitated solid, and dry under vacuum to obtain 55C (220 mg). MS m / z (ESI): 222.2 [M+1] + .

[0554] Step 3, synthesis of compound 55

[0555] Dissolve 55C (51 mg) in N,N-dimethylformamide (2 mL), then add HATU (102 mg), diisopropylethylamine (53 mg) in turn. The reaction solution is stirred at room temperature for 15 minutes, then add compound 2 (90 mg). The reaction solution is continuously stirred at room temperature for 3 hours, then add water (0.1 mL) to quench after the reaction is completed. The obtained solution is purified by a reverse phase chromatographic column to obtain compound 55 (22.45 mg). MS m / z (ESI): 638.2 [M+1]+.

[0556] 1 H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.55 (s, 1H), 7.46 (d, J = 6.8 Hz, 1H), 6.85 (s, 2H), 6.71 (s, 1H), 6.66 (s, 1H), 6.43 (t, J = 6.8 Hz, 1H), 5.46 (s, 1H), 4.68 (q, J = 8.5 Hz, 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).

[0557] Example 53

[0558] Synthesis of compound 56

[0559]

[0560] Refer to the synthesis method of Example 48 to obtain compound 56 (18 mg). MS m / z (ESI): 542.2 [M+1] + .

[0561] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (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 = 6.9 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H).

[0562] Example 54

[0563] Synthesis of compound 57

[0564]

[0565] Compound 57 (30 mg) was obtained according to the synthetic procedure of Example 30. MS m / z (ESI): 504.3 [M+1] + .

[0566] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (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 = 6.9 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H).

[0567] Example 55

[0568] Synthesis of compound 58

[0569]

[0570] Step 1, Synthesis of compound 58A

[0571] IM-02 (500 mg) was dissolved in acetonitrile (30 mL), then compound 5B (667 mg), potassium carbonate (1.2 g) and potassium iodide (1.02 g) were added successively. The reaction was carried out at 80 °C for 72 h. After the reaction was completed, water (80 mL) was added for dilution, and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by flash reverse phase chromatography column to obtain 58A (180 mg). MS m / z (ESI): 534.3 [M+1] + .

[0572] Step 2, synthesis of compound 58

[0573] 58A (100 mg) was dissolved in water (5 mL), then 2M hydrochloric acid methanol solution (5 mL) was added, and stirred at room temperature for 2 h. After the reaction was completed, saturated sodium bicarbonate was added to adjust pH = 7-9. The precipitated solid was filtered to obtain the crude product, which was purified by reverse phase chromatography column to obtain compound 58 (38 mg). MS m / z (ESI): 494.2 [M+1] + .

[0574] 1 H NMR (400 MHz, Chloroform-d & D20) d 7.02 (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 = 6.4 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 1.80 - 1.58 (m, 2H), 1.48 (t, J = 7.0 Hz, 3H).

[0575] 1.58 (m, 2H), 1.48 (t, J = 7.0 Hz, 3H).

[0576] Example 56

[0577] Synthesis of compound 59

[0578]

[0579] Step 1, synthesis of compound 59B

[0580] Dissolve 59A (200 mg) in N,N-dimethylformamide (5 mL), and add potassium carbonate (247 mg) and iodomethane (253 mg) in sequence. Stir the reaction mixture at 25 °C for 16 hours. After the reaction is completed, dilute with water (10 mL) and extract with ethyl acetate (20 mL x 3). Wash the combined organic phase with saturated brine (10 mL), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the obtained crude product by flash reverse-phase chromatography to obtain 59B (80 mg). MS m / z (ESI): 182.7 [M+1] + .

[0581] Step 2, synthesis of compound 59C

[0582] Dissolve 59B (200 mg) in tetrahydrofuran / water (1 / 1, 10 mL), and then add lithium hydroxide (53 mg). Stir the reaction solution at 45 °C for 2 hours. After the reaction is completed, concentrate under reduced pressure, dilute the residue with water, and adjust the pH to 2 with 1M dilute hydrochloric acid. Collect the precipitated solid by filtration, wash with water, and freeze-dry to obtain 59C (80 mg). MS m / z (ESI): 155.1 [M+1] + .

[0583] Step 3, synthesis of compound 59

[0584] Dissolve 59C (18 mg), compound 2 (50 mg), HATU (106 mg), and diisopropylethylamine (43 mg) in N,N-dimethylformamide (2 mL). Stir the reaction solution at 25 °C for 16 hours. After the reaction is completed, purify the reaction solution by flash reverse-phase chromatography to obtain compound 59 (10.2 mg). MS m / z (ESI): 585.2 [M+1] + .

[0585] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (t, J = 6.0 Hz, 1H), 8.13 (d, J = 4.2 Hz, 1H), 8.04 (d, J = 4.2 Hz, 1H), 6.94 (s, 1H), 6.84 (s, 2H), 6.67 (s, 1H), 5.32 (s, 1H), 4.36 (t, J = 6.2 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.82 -

[0586] 3.68 (m, 5H), 3.62 (s, 3H), 2.87 (t, J = 6.2 Hz, 2H), 2.21 (s, 3H), 1.94 (s, 6H), 1.33 (t, J = 7.0 Hz, 3H).

[0587] Example 57

[0588] Synthesis of compound 60

[0589]

[0590] Step 1, Synthesis of compound 60A

[0591] Dissolve IM-02 (1.0 g) in toluene (20 mL), then add 3-(tert-butyldimethylsilyloxy)propanol (0.71 g) and cyano methylene tri-n-butyl phosphonium (1.81 g). Heat to 120 °C under nitrogen atmosphere, stir for 2 hours. After the reaction is completed, concentrate under reduced pressure, the obtained crude product is purified by Flash reverse phase chromatography column to obtain 60A (280 mg). MS m / z (ESI): 578.3 [M+1] + .

[0592] Step 2, Synthesis of compound 60

[0593] Dissolve 60A (600 mg) in dichloromethane (10 mL), slowly add hydrogen fluoride-pyridine solution (617 mg). The reaction solution is stirred at room temperature for 1 hour. After the reaction is completed, quench with saturated sodium bicarbonate (2 mL), extract with dichloromethane (15 mL x 3). The organic phase is combined, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained residue is purified by Flash reverse phase chromatography column to obtain compound 60 (300 mg). MS m / z (ESI): 464.2 [M+1] + .

[0594] 1 H NMR (400 MHz, Chloroform-d) δ 7.01 (s, 2H), 6.69 (s, 1H), 6.63 (s, 1H), 5.33 (s, 1H), 4.21-4.08 (m, 4H), 3.99 (t, J = 6.1 Hz, 2H), 3.80-3.73 (m, 2H), 3.71 (s, 3H), 2.89 (t, J = 6.5 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 6H), 1.80 (p, J = 5.7 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H).

[0595] Example 58

[0596] Synthesis of compound 61

[0597]

[0598] Step 1, Synthesis of compound 61A

[0599] 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 h. After the reaction was completed, water (0.5 mL) was added to quench the reaction, and the reaction solution was purified by a Flash reverse-phase chromatographic column to obtain 61A (200 mg). MS m / z (ESI): 462.1 [M+1]+.

[0600] Step 2, synthesis of compound 61

[0601] 61A (200 mg) was dissolved in acetonitrile / tert-butanol / water (2 / 2 / 1, 10 mL), followed by the sequential addition of sodium phosphate monobasic (182.0 mg) and sodium chlorite (117.5 mg). The reaction mixture was stirred at 25 °C for 1 h. After the reaction was completed, saturated sodium thiosulfate solution (0.5 mL) was added to quench the reaction. The reaction solution was purified by a Flash reverse-phase chromatographic column to obtain compound 61 (17 mg). MS m / z (ESI): 478.1 [M+1] + .

[0602] 1 H NMR (400 MHz, Chloroform-d & D20) d 7.01 (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 = 7.4 Hz, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 6H), 1.48 (t, J = 7.0 Hz, 3H).

[0603] Example 59

[0604] Synthesis of compound 62

[0605]

[0606] Compound 62 (10 mg) was obtained according to the synthetic method of Example 48. MS m / z (ESI): 544.2 [M+1] + .

[0607] 1H NMR (400 MHz, Chloroform-d) δ 9.02 (s, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.10 (d, J = 7.8 Hz, 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 = 6.5 Hz, 2H), 3.71 (s, 3H), 2.89 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 2.17 (s, 6H), 1.47 (t, J = 7.0 Hz, 3H).

[0608] Example 60

[0609] Synthesis of compound 63

[0610]

[0611] Compound 63 (10 mg) was obtained according to the synthetic procedure of Example 48. MS m / z (ESI): 554.2 [M+1] + .

[0612] 1 H NMR (400 MHz, Chloroform-d) δ 9.02 (s, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.10 (d, J = 7.8 Hz, 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 = 6.5 Hz, 2H), 3.71 (s, 3H), 2.89 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 2.17 (s, 6H), 1.47 (t, J = 7.0 Hz, 3H).

[0613] Example 61

[0614] Synthesis of compound 64

[0615]

[0616] Compound 64 (24 mg) was obtained according to the synthetic procedure of Example 48. MS m / z (ESI): 544.3 [M+1] + .

[0617] 1H NMR (400 MHz, DMSO-d6) δ 15.83 - 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).

[0618] Example 62

[0619] Synthesis of compound 65

[0620]

[0621] Compound 65 (10 mg) was obtained according to the synthetic procedure of Example 48. MS m / z (ESI): 559.2 [M+1] + .

[0622] 1 H NMR (400 MHz, DMSO-d6) δ 9.54 - 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).

[0623] Example 63

[0624] Synthesis of compound 66

[0625]

[0626] Compound 66 (30 mg) was obtained according to the synthetic procedure of Example 11. MS m / z (ESI): 482.1 [M+1] + .

[0627] 1H NMR (400 MHz, DMSO-d6) δ 6.97 (s, 1H), 6.90 - 6.83 (m, 2H), 6.79 (s, 1H), 6.10 (t, J = 5.8 Hz, 1H), 5.52 (d, J = 1.9 Hz, 1H), 5.43 (s, 2H), 4.17 (t, J = 6.5 Hz, 2H), 3.93 (t, J = 6.1 Hz, 2H), 3.81 (s, 3H), 3.65 (s, 3H), 2.91 (t, J = 5.9 Hz, 2H), 2.26 (s, 3H), 2.08 (s, 3H).

[0628] Example 64

[0629] Synthesis of compound 67

[0630]

[0631] Compound 67 (25 mg) was obtained according to the synthetic procedure of Example 31. MS m / z (ESI): 561.1 [M+1] + .

[0632] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (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, 3H), 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).

[0633] Example 65

[0634] Synthesis of compound 68

[0635]

[0636] Compound 68 (30 mg) was obtained according to the synthetic procedure of Example 36. MS m / z (ESI): 610.3 [M+1] + .

[0637] 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 6.96 (s, 1H), 6.85 (s, 2H), 6.67 (s, 1H), 6.49 (t, J = 5.5 Hz, 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 = 6.4 Hz, 2H), 2.88 (t, J = 5.8 Hz, 2H), 2.22 (s, 3H), 1.97 (s, 6H), 1.05 - 0.98 (m, 2H), 0.97 - 0.89 (m, 2H).

[0638] Example 66

[0639] Synthesis of compound 69

[0640]

[0641] Step 1, Synthesis of compound 69B

[0642] Compound 69A (0.48 g) and triethylamine (0.66 g) were dissolved in dichloromethane (15 mL), then a solution of p-nitrophenyl chloroformate (1.0 g) in dichloromethane (25 mL) was added dropwise slowly at room temperature. The reaction was reacted at room temperature for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 69B (0.8 g).

[0643] 1 H NMR (400 MHz, CDCl3) δ 8.38 - 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).

[0644] Step 2, Synthesis of compound 69C

[0645] Compound 69B (50 mg) was added to tetrahydrofuran (5 mL), and compound 2 (85.8 mg) and triethylamine (180 mg) were added in turn. The reaction was stirred at 25°C for 12 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the obtained crude product was purified by thin layer preparative chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 69C (30 mg). MS m / z (ESI): 549.2 [M+1] + .

[0646] Step 3, synthesis of compound 69

[0647] Compound 69C (80 mg) was added to 0.5 M sulfuric acid (2 mL). The reaction was stirred at 60 °C for 24 h. After the reaction was completed, the reaction was directly purified by reverse phase preparative chromatography to give compound 69 (15 mg). MS m / z (ESI): 567.2 [M+1] + .

[0648] 1 H NMR (400 MHz, DMSO-d6) δ 7.22 (t, J = 5.8 Hz, 1H), 6.96 (s, 1H), 6.85 (s, 2H), 6.66 (s, 1H), 5.32 (s, 1H), 4.61 (d, J = 5.3 Hz, 1H), 4.35 (t, J = 5.0 Hz, 1H), 4.24 (t, J = 6.3 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.85 - 3.77 (m, 5H), 3.71 (s, 1H), 3.62 (s, 3H), 3.49 (q, J = 6.0 Hz, 2H), 3.39 (q, J = 6.2 Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H), 2.22 (s, 3H), 1.97 (s, 6H), 1.62 - 1.50 (m, 1H), 1.50 - 1.36 (m, 1H).

[0649] Example 67

[0650] Synthesis of compound 70

[0651]

[0652] Compound 70 (20 mg) was obtained according to the synthetic procedure of Example 36. MS m / z (ESI): 578.3 [M+1] + .

[0653] 1 H NMR (400 MHz, DMSO-d6) δ 7.12 (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 = 6.3 Hz, 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).

[0654] Example 68

[0655] Synthesis of compound 71

[0656]

[0657] Referring to the synthetic method of Example 32, compound 71 (3 mg) was obtained. MS m / z (ESI): 560.2 [M+1] + .

[0658] 1 H NMR (400 MHz, CDC13) δ 6.98 (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 = 6.4 Hz, 2H), 2.86 - 2.34 (m, 6H), 2.33 (s, 3H), 2.17 (s, 6H), 2.07 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H).

[0659] Example 69

[0660] Synthesis of compound 72, 73

[0661]

[0662] IM-02 (150 mg), 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (80 mg) and cyano-methylidene tri-n-butylphosphonium (268 mg) were dissolved in toluene (3 mL) in turn. The reaction solution was stirred at 120 °C under nitrogen atmosphere for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was purified by a reverse phase column (acetonitrile / 0.1% trifluoroacetic acid) to obtain compound 72 (70.4 mg).

[0663] The obtained crude product was purified by a reverse phase column (acetonitrile / 0.1% ammonia water) according to the above operation to obtain compound 73 (40.8 mg).

[0664] Compound 72: MS m / z (ESI): 567.2 [M+1] + .

[0665] 1H NMR (400 MHz, CDC13) δ 7.02 (s, 2H), 6.71 (s, 1H), 6.64 (s, 1H), 5.42 (s, 1H), 4.26 - 4.01 (m, 6H), 3.72 (s, 3H), 3.59 - 3.25 (m, 8H), 3.13 (t, J = 5.8 Hz, 2H), 2.95 (t, J = 6.2 Hz, 2H), 2.34 (s, 3H), 2.18 (s, 6H), 1.49 (t, J = 7.0 Hz, 3H).

[0666] Compound 73: MS m / z (ESI): 567.2 [M+1] + .

[0667] 1 1H NMR (400 MHz, DMSO-d6) δ 6.94 (s, 1H), 6.85 (s, 2H), 6.66 (s, 1H), 5.31 (s, 1H), 4.26 (t, J = 6.9 Hz, 2H), 4.06 (q, J = 6.9 Hz, 2H), 3.91 (t, J = 6.1 Hz, 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 = 6.9 Hz, 3H).

[0668] Example 70

[0669] Synthesis of Compound 74

[0670]

[0671] Compound 74 (13.5 mg) was obtained according to the synthetic procedure of Example 32. MS m / z (ESI): 507.2 [M+1] + .

[0672] 1 1H NMR (400 MHz, CDC13) δ 6.97 (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 = 7.0 Hz, 3H).

[0673] Example 71

[0674] Synthesis of Compound 75

[0675]

[0676] Step 1, synthesis of compound 75A

[0677] Dissolve IM-02 (250 mg) in toluene (5 mL), add tert-butyl-(2-iodoethoxy)dimethylsilane (163 mg) and cyanomethylidene tri-n-butylphosphonium (446 mg) successively. Heat the mixture to 120 °C under nitrogen atmosphere and stir for 2 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure. Purify the crude product by reverse phase column to obtain 75A (190 mg). MS m / z (ESI): 564.2 [M+1] + .

[0678] Step 2, synthesis of compound 75

[0679] Dissolve 75A (200 mg) in dichloromethane (3 mL), and add hydrofluoric acid pyridine solution (0.75 mL) dropwise. Stir the reaction solution at room temperature for 2 hours. After the reaction is completed, dilute with dichloromethane, and quench with saturated sodium bicarbonate solution dropwise. Collect the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by reverse phase column to obtain compound 75 (97 mg). MS m / z (ESI): 450.2 [M+1] + .

[0680] 1 H NMR (400 MHz, Chloroform-d) δ 7.27 (d, J = 1.5 Hz, 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 = 6.3 Hz, 2H), 2.34 (s, 3H), 2.20 (s, 6H), 1.48 (t, J = 7.0 Hz, 3H).

[0681] Example 72

[0682] Synthesis of compound 76

[0683]

[0684] Step 1, synthesis of compound 76A

[0685] 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 successively. The mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the crude product was obtained by concentration under reduced pressure. The crude product was purified by a reverse phase column to obtain 76A (300 mg). MS m / z (ESI): 520.5 [M+1] + .

[0686] Step 2, synthesis of compound 76

[0687] 76A (250 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the crude product was obtained by concentration under reduced pressure. Purification by a reverse phase column gave compound 76 (134 mg). MS m / z (ESI): 464.3 [M+1] + .

[0688] 1 H NMR (400 MHz, DMSO-d6) d 7.07 - 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 = 6.3 Hz, 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).

[0689] Example 73

[0690] Synthesis of compound 77

[0691]

[0692] Compound 77 (70 mg) was obtained according to the synthetic method of Example 45. MS m / z (ESI): 570.3 [M+1] + .

[0693] 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.26 (s, 1H), 7.12 (d, J = 3.6 Hz, 2H), 7.04 (s, 1H), 5.93 (s, 1H), 4.84 (d, J = 8.1 Hz, 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 = 6.9 Hz, 3H).

[0694] Example 74

[0695] Synthesis of compound 78, 79

[0696]

[0697] Step 1, synthesis of compound 78B

[0698] 78A (900 mg) and triethylamine (1076 mg) were added into tetrahydrofuran (10 mL), after stirring for 5 minutes, di-tert-butyl dicarbonate (2110 mg) was added. 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 ethyl acetate (10 mL x 3) was extracted. The organic phase was combined and washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure, the obtained 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] + .

[0699] Step 2, synthesis of compound 78C

[0700] A solution of lithium aluminum hydride in tetrahydrofuran (12 mL, 1 mol / L) was added into a flask under nitrogen atmosphere. 78B (1.4 g) was dissolved in tetrahydrofuran (15 mL) and added into the flask dropwise at room temperature. After the addition was completed, the reaction solution was warmed to 25 °C and stirred for 3 hours. After the reaction was completed, water (1 mL), 15% sodium hydroxide aqueous solution (1 mL), and water (3 mL) were added sequentially to quench the reaction. Anhydrous sodium sulfate was added and stirred for 20 minutes. The filtrate was collected by filtration, and the filter cake was stirred in a mixed solvent of dichloromethane / methanol (10 / 1) for 20 minutes and then filtered again. The filtrate was combined and concentrated under reduced pressure. The resulting 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] + .

[0701] Step 3, synthesis of compound 78D

[0702] 78C (1.0 g) and p-toluenesulfonyl chloride (1.3 g) were dissolved in dichloromethane (10 mL), and triethylamine (1.0 g) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, 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] + .

[0703] Step 4, synthesis of compounds 78E, 79A

[0704] 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, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried with 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] + .

[0705] Step 5, synthesis of compound 78

[0706] Compound 78 was prepared according to the procedures described in Example 1. Step 1, synthesis of compound 78A + .

[0707] 1 H NMR (400 MHz, CDC13) δ 7.05 (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 = 6.9 Hz, 3H).

[0708] Step 6, synthesis of compound 79

[0709] Compound 79 was prepared according to the procedures described in Example 1. Step 1, synthesis of compound 79A + .

[0710] 1 H NMR (400 MHz, DMSO-d6) δ 7.03 (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 = 6.2 Hz, 2H), 2.29 (s, 3H), 2.10 (s, 6H), 1.34 (t, J = 6.9 Hz, 3H).

[0711] Example 75

[0712] Synthesis of compound 80

[0713]

[0714] Step 1, synthesis of compound 80A

[0715] IM-02 (300 mg) was added to toluene (10 mL), followed by 2,2-dimethyl-1,3-dioxane-5-ol (147 mg) and cyano-methylidene tri-n-butylphosphonium (536 mg). The reaction was stirred at 120 °C for 2 hours under nitrogen. After the reaction was completed, the reaction was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain 80A (100 mg). MS m / z (ESI): 520.2 [M+1]+.

[0716] Step 2, synthesis of compound 80

[0717] 80A (50 mg) was added to acetic acid (5 mL). The reaction was stirred at 25 °C for 48 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the obtained crude product was purified by reverse phase column chromatography to obtain compound 80 (10 mg). MS m / z (ESI): 480.3 [M+1] + .

[0718] 1 H NMR (400 MHz, Chloroform-d) δ 7.00 (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 = 6.4 Hz, 2H), 2.33 (s, 3H), 2.18 (s, 6H), 1.48 (t, J = 7.0 Hz, 3H).

[0719] Example 76

[0720] Synthesis of compound 81

[0721]

[0722] Compound 81 (30 mg) was obtained according to the synthetic method of Example 29. MS m / z (ESI): 463.3 [M+1] + .

[0723] 1H NMR (400 MHz, CDC13) δ 8.97 (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 = 6.5 Hz, 3H).

[0724] Example 77

[0725] Synthesis of compound 82

[0726]

[0727] Step 1, Synthesis of compound 82A

[0728] Compound 61 (60 mg) was dissolved in N,N-dimethylformamide (2 mL), and HATU (72 mg) and diisopropylethylamine (41 mg) were added successively. After stirring for 15 min, (2-aminoethoxy)(tert-butyl)dimethylsilane (26 mg) was added. Stirring was continued for 3 h, and after the reaction was completed, water (1 mL) was added for quenching. The reaction solution was purified by a reverse-phase chromatographic column to give 82A (40 mg). MS m / z (ESI): 635.2 [M+1]+.

[0729] Step 2, Synthesis of compound 82

[0730] Compound 82A (45 mg) was dissolved in dichloromethane (3 mL), and a hydrofluoric acid-pyridine solution (105 mg) was added at 0°C. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 1 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution (3 mL) was added for quenching. Dilution with dichloromethane (20 mL) was followed by separation, and the organic phase was concentrated to give a crude product, which was purified by a reverse-phase chromatographic column to give compound 82 (15.2 mg). MS m / z (ESI): 521.3 [M+1] + .

[0731] 1H NMR (400 MHz, Chloroform-d) δ 7.01 (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 = 7.0 Hz, 3H).

[0732] Example 78

[0733] Synthesis of compound 83

[0734]

[0735] Compound 83 (15 mg) was obtained according to the synthetic procedure of Example 46. MS m / z (ESI): 592.2 [M+1] + .

[0736] 1 H NMR (400 MHz, Chloroform-d) δ 7.01 (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 = 7.0 Hz, 3H).

[0737] Example 79

[0738] Synthesis of compound 84

[0739]

[0740] Compound 84 (10 mg) was obtained according to the synthetic procedure of Example 43. MS m / z (ESI): 492.2 [M+1] + .

[0741] 1H NMR (400 MHz, Chloroform-d) δ 7.81 (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 = 6.4 Hz, 2H), 2.33 (s, 3H), 2.22 (s, 6H), 1.50 (t, J = 7.0 Hz, 3H).

[0742] Example 80

[0743] Synthesis of compound 85

[0744]

[0745] Compound 85 (61 mg) was obtained according to the synthetic procedure of Example 7. MS m / z (ESI): 522.2 [M+1] + .

[0746] 1 H NMR (400 MHz, Chloroform-d) δ 7.81 (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 = 6.4 Hz, 2H), 2.33 (s, 3H), 2.22 (s, 6H), 1.50 (t, J = 7.0 Hz, 3H).

[0747] Example 81

[0748] Synthesis of compound 86

[0749]

[0750] Compound 86 (15 mg) was obtained according to the synthetic procedure of Example 7. MS m / z (ESI): 522.2 [M+1] + .

[0751] 1H NMR (400 MHz, Chloroform-d) δ 6.99 (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 = 6.4 Hz, 2H), 2.33 (s, 3H), 2.15 (s, 6H), 1.47 (t, J = 7.0 Hz, 3H).

[0752] Example 82

[0753] Synthesis of compound 87

[0754]

[0755] Referring to the synthesis method of Example 15, compound 87 (30 mg) was obtained. MS m / z (ESI): 463.3 [M+1] + .

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 3H), 7.31 - 7.02 (m, 4H), 6.75 (s, 1H), 5.53 (s, 1H), 4.27 (t, J = 6.9 Hz, 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 = 6.9 Hz, 3H).

[0757] Performance test experiment

[0758] In vitro detection of the inhibitory activity of the above-mentioned compounds prepared by the present application on PDE3A enzyme and PDE4B1 enzyme

[0759] Table 1 Main reagents and consumables for in vitro detection of inhibitory activity

[0760]

[0761] Table 2 Main instruments for in vitro detection of inhibitory activity

[0762]

[0763] Preparation of experimental buffer

[0764] Reaction Buffer (5x): 50 mM Tris-HCl, 50 mM MgCl2, 0.5% BSA, 0.25% Tween-20, pH 7.4, stored at -20°C.

[0765] Experimental Procedure

[0766] 1) Prepare test samples and controls to a certain concentration with DMSO, dilute reaction buffer from 5x to lx with ultrapure water.

[0767] 2) Gradient dilute test samples and controls with Bravo, and transfer 1 μL to the assay plate (Optiplate-384 assay plate) according to the experimental plate compound distribution diagram designed before the experiment. The Low control is the starting concentration of the gradient dilution of the control, and the High control is 1% DMSO-reaction buffer

[0768] 3) Dilute the enzyme to the specified concentration with 1x reaction buffer, and transfer 4 μL to the assay plate. After centrifugation, seal the 384-well plate with a plate sealing film, and then incubate in a constant temperature incubator at 23°C for 15 minutes.

[0769] 4) Dilute the substrate cAMP to the specified concentration with 1x reaction buffer, and transfer 5 μL to the assay plate. After centrifugation, cover the plate sealing film again and incubate in a constant temperature incubator at 23°C for 60 minutes (PDE3A) or 10 minutes (PDE4B1).

[0770] 5) Add 5 μL AMP-Glo TM Reagent I in the Assay kit, cover the plate sealing film after centrifugation and incubate in a constant temperature incubator at 23°C for 60 minutes.

[0771] 6) Configure the detection solution according to the instructions of the AMP-Glo TM Assay kit, and add 10 μL to the assay plate. After centrifugation, cover the plate sealing film and continue to incubate in a constant temperature incubator at 23°C for 60 minutes.

[0772] 7) Read with EnVision.

[0773] Result analysis:

[0774] Sample well % Inhibition calculation formula: % Inhibition = 100% - (sample well signal value - Low control signal value) / (High control signal value - Low control signal value) * 100%

[0775] IC50values were calculated using the "log(antagonist) vs. response - Variable slope" model in GraphPad Prism 5.0.

[0776] The results of the experiments are shown in the table below:

[0777] Table 3. Results of in vitro screening test of compounds

[0778]

[0779]

[0780] The above description of the embodiments is only used to help understand the method of the present application and its core idea. It should be noted that, for those skilled in the art, without departing from the principles of the present application, some improvements and modifications can be made to the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A compound, characterized in that, The compound has any one of the following structures, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 。 2. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

3. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the manufacture of a medicament for treating a PDE3 and / or PDE4 related disorder.

4. Use according to claim 3, characterized in that, The PDE3 and / or PDE4 related disorder is one or more of inflammation, bronchodilation, chronic obstructive pulmonary disease, and asthma.

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