3-benzimidazole-3-azabicyclo cyclohexane-2-ketone compound and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 3-benzimidazole-3-aza-bicyclohexyl-2-ketone compound and application of the 3-benzimidazole-3-aza-bicyclohexyl-2-ketone compound. The invention discloses a compound as shown in a formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, which can be used for preparing a glutamine cyclase (sQC / gQC) inhibitor, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof. A new medication choice is provided for clinical treatment of diseases (such as Alzheimer's disease) related to abnormal activity of glutamine cyclase.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a 3-benzimidazole-3-azabicyclohexane-2-one compound and its uses. Background Technology

[0002] Glutamine cyclase (QC) is an important post-translational modifying enzyme, primarily responsible for catalyzing the conversion of N-terminal glutamine and glutamate to pyroglutamate (pE). To date, two QC isoenzymes have been identified in humans: secretory glutamine cyclase (sQC) and Golgi-resident glutamine cyclase (gQC). They participate in the regulation of various physiological processes and are closely related to multiple diseases, including Alzheimer's disease (AD). Studies have shown that sQC / gQC mediates the truncation of Aβ pyroglutamate formation (pE-Aβ) and the maturation of chemokine ligand 2 (CCL2). Compared to the full-length unmodified Aβ peptide, pE-Aβ has been shown to have stronger neurotoxicity and aggregation, and can also interact with CCL2 to induce neuroinflammation, accelerating the progression of AD. Furthermore, sQC / gQC is also associated with Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, tumors, synovitis, gout, enteritis, rheumatoid arthritis, and other inflammatory diseases. Therefore, sQC / gQC is considered a drug target with application value.

[0003] Currently, various sQC / gQC inhibitors with different scaffolds have been reported, most of which involve metal coordination with zinc ions at the active site. Only one sQC / gQC inhibitor (PQ912) is in Phase II clinical trials as an anti-AD candidate. Therefore, there is still a need to develop novel sQC / gQC inhibitors with different scaffolds to provide more lead or candidate drugs for the development of innovative drugs targeting sQC / gQC-related diseases. Summary of the Invention

[0004] To address the problems of the prior art, the present invention provides a 3-benzimidazole-3-azabicyclohexane-2-one compound and its uses.

[0005] The compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof:

[0006]

[0007] in,

[0008] R1 is selected from H or hydroxyl groups;

[0009] R2 is selected from substituted or unsubstituted C6-C. 10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C3-C 10Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic alkyl groups, wherein the substituents are selected from halogens, hydroxyl groups, C1-C6 groups. 10 Alkyl, C6-C 10 Aryl, benzyl, C2-C 10 Ether group, -OR5, cyano group, amino group, 5-10 heteroaryl group, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C1-C 10 Haloalkyl, C1-C 10 Ester group, C1-C 10 Carboxyl group, C1-C 10 Acyl group, C1-C 10 amide group, C1-C 10 An amino group, or at least two substituents linked together, forms a C3-C group that is either substituted or unsubstituted with at least one R6 group. 10 Cycloalkyl, 5-10 membered heterocyclic alkyl groups substituted with at least one R6 or unsubstituted;

[0010] R3 and R4 are independently selected from H, halogens, and C1-C, respectively. 10 alkyl;

[0011] R5 is selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 Ether group, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic alkyl, substituted or unsubstituted C1-C 10 Ester group, substituted or unsubstituted C1-C 10 Carboxyl, substituted or unsubstituted C1-C 10 Acyl group, wherein the substituent is selected from halogen, benzyloxy group, C3-C group. 10 Cycloalkyl, -COR7, -COOR7, -CONHR7;

[0012] R6 is selected from halogens, hydroxyl groups, and C1-C. 10 Alkyl, C6-C 10 Aryl, benzyl, C2-C 10 Ether group, -OR5, cyano group, amino group, 5-10 heteroaryl group, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C1-C 10 Haloalkyl, C1-C 10 Ester group, C1-C 10 Carboxyl group, C1-C 10 Acyl group, C1-C 10 amide group, C1-C 10 amino group;

[0013] R7 is selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic alkyl groups, wherein the substituents are selected from C1-C2. 10 Alkyl, C1-C 10 Alkoxy, C6-C 10 Aryl.

[0014] Preferably, R2 is selected from phenyl, 9-membered heteroaryl, and C6 cycloalkyl groups substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from F, C1, hydroxyl, C1-C4 alkyl, phenyl, benzyl, C3 ether, and -OR5.

[0015] Alternatively, at least two substituents are linked together to form a 5-membered heterocyclic alkyl group that is substituted with 1-2 R6 groups or is unsubstituted;

[0016] R6 is selected from F.

[0017] Preferably, R5 is selected from C1-C3 alkyl, trifluoromethyl, phenyl, C3 ether, C6 cycloalkyl, 4-6 heterocyclic alkyl, C3 ester, C2 carboxyl, and C2 acyl groups, which are substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from F, benzyloxy, C3-C5 cycloalkyl, -COR7, -COOR7, and -CONHR7;

[0018] R7 is selected from C1-C3 alkyl, phenyl substituted with 1-2 substituents or unsubstituted, 5-membered heteroaryl substituted with 1-2 substituents or unsubstituted, C3 cycloalkyl, 5-6-membered heterocycloalkyl, wherein the substituent is selected from methyl, C1-C3 alkoxy, phenyl.

[0019] Preferably, R3 and R4 are independently selected from H, F, and methyl, respectively.

[0020] Preferably, the compound has the structural formula shown in Formula II:

[0021]

[0022] in,

[0023] R2 is selected from phenyl groups substituted with 1-2 substituents, or sulfur-containing 9-membered heteroaryl groups, wherein the substituents are selected from methyl groups, -OR5 groups;

[0024] R5 is selected from C1-C3 alkyl groups substituted or unsubstituted with 1-2 substituents, trifluoromethyl groups, and 4-6 heterocyclic alkyl groups substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from F, C3 cycloalkyl, -COR7, and -CONHR7.

[0025] R7 is selected from methyl, phenyl substituted with 1-2 substituents or unsubstituted, 5-membered heteroaryl substituted with 1-2 substituents or unsubstituted, C3 cycloalkyl, 5-6-membered heterocycloalkyl, wherein the substituent is selected from methyl, C1-C3 alkoxy, phenyl.

[0026] Preferably, the structural formula of the compound is selected from:

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] The present invention also provides a method for preparing the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, comprising the following steps:

[0034]

[0035] Step 1: Compound e is reacted with 4-fluoro-1,2-dinitrobenzene to obtain compound f;

[0036] Step 2: Reduce compound f to obtain compound g;

[0037] Step 3: React compound g with triethyl orthoformate to obtain the compound shown in Formula I;

[0038] In step 1, the solvent for the reaction is selected from DMF;

[0039] And / or, in step 1, the reaction is carried out in the presence of a base, which is selected from at least one of potassium tert-butoxide and sodium hydride;

[0040] And / or, in step 1, the reaction temperature is 20-50℃;

[0041] And / or, in step 2, the solvent for the reaction is selected from a mixture of ethanol and water;

[0042] And / or, in step 2, the reaction is carried out under the action of a reducing agent, which is selected from iron;

[0043] And / or, in step 2, the reaction is carried out under the action of an acid, which is selected from ammonium chloride;

[0044] And / or, in step 2, the reaction temperature is 70-85℃;

[0045] And / or, in step 3, the solvent for the reaction is selected from acetonitrile;

[0046] And / or, in step 3, the reaction is carried out in the presence of a catalyst, which is selected from elemental iodine;

[0047] And / or, in step 3, the reaction temperature is 20-30℃.

[0048] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or deuterated compounds thereof, or solvates thereof, or crystal forms thereof, in the preparation of glutamine cyclase inhibitors.

[0049] Preferably, the glutamine cyclase inhibitor is a secretory glutamine cyclase inhibitor and / or a Golgi-resident glutamine cyclase inhibitor;

[0050] And / or, the glutamine cyclase inhibitor is a drug used to treat at least one of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, tumors, synovitis, gout, acute / chronic enteritis, rheumatoid arthritis, or inflammatory diseases.

[0051] The present invention also provides a pharmaceutical composition, which is a formulation made by adding pharmaceutically acceptable excipients to the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof as the active ingredient.

[0052] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0053] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0054] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0055] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a -C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1-C6 alkyl" refers to alkyl groups containing 1 to 6 carbon atoms.

[0056] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-C6 alkoxy groups.

[0057] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms, no heterocyclic atoms, and a single or multiple rings (including fused, bridged, and spirocyclic systems). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) applies when the linker is located on a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polycyclic bicyclic alkyl systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. Two such bicyclic alkyl polycyclic structures are illustrated and named below: Dicyclohexyl and Dicyclohexyl.

[0058] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0059] "Halogenated alkyl" refers to an alkyl group in which the hydrogen atom can be replaced by one or more halogen atoms. For example, C1-C6 halogenated alkyl refers to alkyl groups containing 1 to 6 carbon atoms in which the hydrogen atom is replaced by one or more halogen atoms.

[0060] "Heterocyclic" and "heterocyclic alkyl" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom and having a single ring; where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom.

[0061] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom and having a single ring; where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0062] "Alkoxy" refers to a group in which an alkyl group is attached to a linker site via an oxygen atom. For example, methoxy is -OCH3.

[0063] "Ether group" refers to a group that is connected to a carbon chain by a linking site, and the carbon chain contains at least one oxygen atom. For example, the diethyl ether group is -CH2OCH3.

[0064] "Ester group" refers to a group that is connected to a carbon chain via a linking site, and the carbon chain contains at least one ester bond (i.e., -COO-).

[0065] A "carboxyl group" is a group that is connected to a linking site through a carbon chain, and the carbon chain contains at least one -COOH group.

[0066] An acyl group is a group that is attached to a linker site via a carbonyl group (i.e., -CO-).

[0067] An "amide group" refers to a group that is connected to a carbon chain via a linking site, and the carbon chain contains at least one amide bond (i.e., -CONH-).

[0068] "Amino group" refers to a group that is connected to a linking site via a carbon chain or N, and the carbon chain contains at least one N.

[0069] “R a R b "Connected to form a ring" refers to R a and R b At least one atom in each is connected by a chemical bond, such that R a R b Together with the molecular backbone structure in which they reside, they form a ring structure.

[0070] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0071] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0072] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0073] This invention provides a new class of compounds represented by Formula I that exhibit good glutamine cyclase (sQC / gQC) inhibitory activity, providing a new drug option for the clinical treatment of diseases associated with abnormal glutamine cyclase activity (such as Alzheimer's disease).

[0074] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0075] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0076] In the following examples and experimental cases, reagents and raw materials not specifically described are all commercially available products. The specific structural formulas of compounds 1-89 in the following examples and experimental cases are shown in the Invention Content section.

[0077] Example 1: Synthesis of compounds 1-11, 13, 15-25, 28-32, 41-49, 57-60, 63-66 and 84

[0078]

[0079] Synthesis of compounds 1-11, 13, 15-25, 28-32, 41-49:

[0080] 1. Synthesis of Compound 1

[0081] Weigh 3-oxabicyclo[3.1.0]hexane-2,4-dione (a, 3.0 g, 26.8 mmol) and urea (b, 2.4 g, 40.1 mmol), place them in a dry sealed tube, add 15 mL of toluene, and then place the reaction system at 130 °C for 7 hours. After the reaction is complete as monitored by thin-layer chromatography (TLC), remove the toluene. Then extract with ethyl acetate (EA) and water (50 mL × 3), combine the organic layers, dry with anhydrous magnesium sulfate, remove the solvent by rotary evaporation, and then column chromatography (2% DCM / MeOH 300 mL) to give intermediate c (1.6 g, yield 53%, white solid).

[0082] Weigh 3-azabicyclo[3.1.0]hexane-2,4-dione (c, 1.0 g, 9 mmol) into a dry flask, dissolve it in ultra-dry tetrahydrofuran, pre-cool it at -78 °C under argon protection, slowly add phenyl magnesium bromide (1 M / L, 18 mL), and after the addition is complete, move to room temperature (25 °C, the same below) and stir the reaction. After 3 hours, the reaction is monitored by TLC to be complete. After quenching the reaction with saturated ammonium chloride solution, extract with EA and water (50 mL × 3), combine the organic layers, dry with anhydrous magnesium sulfate, remove the solvent by rotary evaporation, and then column chromatography (DCM 100 mL, 2% DCM / MeOH 200 mL) to give intermediate d (1602 mg, yield 94%, white solid).

[0083] Intermediate d (1602 mg, 8.5 mmol) was weighed into a dry reaction flask, dissolved in 10 mL of 1,2-dichloroethane and 6 mL of trifluoroacetic acid, and then triethylsilane (5914 mg, 50.9 mmol) was added. The reaction was carried out at 50 °C for 12 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and then extracted with EA and water (50 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation. The solution was then subjected to column chromatography (100 mL DCM, 2% DCM / MeOH 200 mL) to obtain intermediate e (1326 mg, 90% yield, white solid).

[0084] Intermediate e (1326 mg, 7.7 mmol) was weighed into a dry reaction flask, dissolved in dry DMF, and 4-fluoro-1,2-dinitrobenzene (1426 mg, 7.7 mmol) and potassium tert-butoxide (1032 mg, 9.2 mmol) were added. The mixture was stirred at room temperature (25 °C). After 1 hour, the reaction was monitored by TLC to ensure complete reaction. The mixture was extracted with EA and water (50 mL × 4), washed with saturated brine (100 mL × 3), and the organic layers were combined. After drying with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation, followed by column chromatography (20% PE / EA 100 mL, 30% PE / EA 100 mL, 50% PE / EA 200 mL) to give intermediate f (512 mg, yield 20%, yellow viscous liquid).

[0085] Intermediate f (512 mg, 1.5 mol) was dissolved in 6 mL of EtOH and 3 mL of H2O. Iron powder (846 mg, 15.1 mmol) and ammonium chloride (121 mg, 2.3 mmol) were added, and the reaction was carried out at 80 °C. After 0.5 hours, the reaction was monitored by TLC until it was complete. The mixture was filtered while hot, washed with methanol, and the solvent was removed by rotary evaporation. After drying, column chromatography was performed (1% DCM / MeOH 100 mL, 2% DCM / MeOH 100 mL, 3% DCM / MeOH 200 mL) to obtain intermediate g (176 mg, yield 43%, grayish-brown solid).

[0086] Intermediate g (176 mg, 0.6 mmol) was dissolved in dry acetonitrile, and triethyl orthoformate (112 mg, 0.8 mmol) and elemental iodine (16 mg, 0.1 mmol) were added and stirred at room temperature. After half an hour, the reaction was monitored by TLC until it was complete. The solvent was removed by rotary evaporation, and column chromatography (1% DCM / MeOH 100 mL, 2% DCM / MeOH 100 mL, 3% DCM / MeOH 200 mL) was performed to give product 1 (142 mg, yield 78%, grayish-yellow solid). 1 H NMR(400MHz,DMSO-d6)δ12.31(s br,1H),8.11(s,1H),7.45(s,1H),7.41(d,J=8.1Hz,1H),7.22(dd,J=11.6,3.5Hz,2H),7.20(s,2H),7.17-7.07(m,2H),5.79(d, J=6.1Hz,1H),2.43-2.32(m,1H),2.14(ddd,J=8.9,6.1,3.1Hz,1H),0.96(dd,J=7.6,4.2Hz,1H),0.88(td,J=8.1,4.7Hz,1H)ppm.

[0087] 2. Synthesis of compounds 2-11, 13, 15-25, 28, 29, 32, 41, 42, 57-60, 63-66 and 84

[0088] Following the synthetic method of compound 1, the phenyl Grignard reagents were replaced with: 4-fluorophenyl Grignard reagent (2), 4-tert-butylphenyl Grignard reagent (3), 4-chlorophenyl Grignard reagent (4), 3-methylphenyl Grignard reagent (5), 4-methylphenyl Grignard reagent (6), 3-methoxyphenyl Grignard reagent (7), 2-methoxyphenyl Grignard reagent (8), 3-fluorophenyl Grignard reagent (9), 4-methoxyphenyl Grignard reagent (10), 2,5-dimethylphenyl Grignard reagent (11), 3, 5-Dimethylphenyl Grignard reagent (13), 3,5-Dimethoxyphenyl Grignard reagent (15), 4-Ethoxyphenyl Grignard reagent (16), 4-Phenylenephenyl Grignard reagent (17), 4-Propylphenyl Grignard reagent (18), Benzo[d][1,3]diazole-5-yl Grignard reagent (19), 3,4-Dimethoxyphenyl Grignard reagent (20), 2,3-Dimethoxyphenyl Grignard reagent (21), 4-Isopropylphenyl Grignard reagent (22), 2-Methyl-4-methoxyphenyl Grignard reagent Grignard reagent (23), 4-trifluoromethoxyphenyl Grignard reagent (24), 2,5-dimethoxyphenyl Grignard reagent (25), 4-phenoxyphenyl Grignard reagent (28), 4-methoxyethylphenyl Grignard reagent (29), 2,2-difluorobenzo[d][1,3]diazole-5-yl Grignard reagent (32), benzyl Grignard reagent (41), cyclohexyl Grignard reagent (42), 2,4-dimethoxyphenyl Grignard reagent (57), 4-propoxyphenyl Grignard reagent (58), benzo[d][ Compounds 1-11, 13, 15-25, 28, 29, 32, 41, 42, 57-60, 63-66 and 84 were prepared from diazole-4-kigrünster reagent (59), benzothiophene-3-kigrünster reagent (60), benzothiophene-2-kigrünster reagent (63), benzothiophene-5-kigrünster reagent (64), benzothiophene-4-kigrünster reagent (65), benzofuran-5-kigrünster reagent (66)-(3-(benzyloxy)propoxy)-4-kigrünster reagent.

[0089] Product characterization:

[0090] Compound 2: 11H NMR (400 MHz, DMSO-d6) δ 12.35 (s br, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.26 (dd, J = 8.1, 5.7 Hz, 2H), 7.09 (s, 1H), 7.04 (t, J = 8.7 Hz, 2H), 5.81 (d, J = 6.0 Hz, 1H), 2.43 - 2.27 (m, 1H), 2.22 - 2.09 (m, 1H), 0.98 (d, J = 7.4 Hz, 1H), 0.89 (td, J = 8.0, 4.9 Hz, 1H) ppm. HRMS m / z: calcd for C 18 H 14 FN3O [M+H] + 308.1194, found 308.1192.

[0091] Compound 3: 1 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s br, 1H), 8.13 (s, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.4 Hz, 3H), 5.76 (d, J = 6.1 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.13 (ddd, J = 9.1, 6.1, 3.1 Hz, 1H), 1.18 (s, 9H), 0.94 (dd, J = 7.6, 4.2 Hz, 1H), 0.87 (td, J = 8.1, 4.6 Hz, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.62, 149.81, 142.93, 137.01, 126.80, 125.50, 61.74, 34.58, 31.53, 21.79, 20.16, 9.10 ppm. HRMS m / z: calcd for C22H23N3O [M+H] + 346.1914, found 346.1911.

[0092] Compound 4: 11H NMR (400 MHz, DMSO-d6) δ 12.35 (s br, 1H), 8.13 (d, J = 4.1 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.25 - 7.22 (m, 2H), 7.10 (d, J = 8.3 Hz, 1H), 5.81 (t, J = 7.1 Hz, 1H), 2.43 - 2.30 (m, 1H), 2.15 (ddd, J = 9.1, 6.1, 3.1 Hz, 1H), 0.96 (dd, J = 7.7, 4.3 Hz, 1H), 0.93 - 0.83 (m, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.41, 143.00, 139.11, 132.20, 129.10, 128.71, 61.34, 55.37, 21.75, 19.76, 8.88 ppm. HRMS m / z: calcd for C 18 H 14 ClN3O [M + H] + 324.0898, found 324.0893.

[0093] Compound 5: 1 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s br, 1H), 8.12 (s, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.93 (t, J = 8.0 Hz, 2H), 5.75 (s, 1H), 2.35 (dt, J = 10.5, 6.2 Hz, 1H), 2.20 (s, 3H), 2.17 - 2.06 (m, 1H), 0.95 (dt, J = 9.9, 5.0 Hz, 1H), 0.93 - 0.80 (m, 1H) ppm. HRMS m / z: calcd for C 19 H 17 N3O [M + H] + 304.1444, found 304.1439.

[0094] Compound 6: 11H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.11 (dd, J = 8.7, 2.0 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 5.74 (d, J = 5.9 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.16 (s, 3H), 2.12 (ddd, J = 9.0, 6.1, 3.0 Hz, 1H), 0.95 (dd, J = 7.6, 4.2 Hz, 1H), 0.87 (td, J = 8.1, 4.7 Hz, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.50, 142.84, 136.95, 136.71, 132.59, 129.29, 127.12, 119.15, 115.17, 111.00, 61.84, 21.71, 21.01, 20.01, 8.94 ppm. HRMS m / z: calcd for C 19 H 17 N3O [M + H] + 304.1444, found 304.1439.

[0095] Compound 7: 1 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.76 (dd, J = 5.0, 3.0 Hz, 2H), 6.73 - 6.68 (m, 1H), 5.76 (d, J = 6.1 Hz, 1H), 3.64 (s, 3H), 2.43 - 2.33 (m, 1H), 2.13 (ddd, J = 9.1, 6.1, 3.1 Hz, 1H), 0.97 (dd, J = 7.7, 4.3 Hz, 1H), 0.88 (ddd, J = 18.7, 9.3, 5.7 Hz, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.52, 159.61, 142.87, 141.66, 132.69, 129.78, 119.38, 119.13, 113.16, 112.70, 61.88, 55.35, 21.69, 19.89, 9.03 ppm. HRMS m / z: calcd for C 19 H 17 N3O2 [M + H] +320.1394, found 320.1390.

[0096] Compound 8: 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.44 (dd, J = 5.1, 3.2 Hz, 2H), 7.17 - 7.07 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.78 (dd, J = 7.5, 1.4 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 5.98 (d, J = 6.0 Hz, 1H), 3.89 (s, 3H), 2.43 (ddd, J = 11.9, 8.3, 5.3 Hz, 1H), 2.20 - 2.06 (m, 1H), 0.88 (ddd, J = 12.6, 8.8, 4.6 Hz, 1H), 0.79 (dd, J = 7.8, 4.1 Hz, 1H) ppm. 13 C NMR (101 MHz, DMSO-d6) δ 174.72, 157.07, 142.89, 132.74, 128.47, 127.54, 127.24, 120.40, 118.57, 111.24, 56.47, 56.13, 21.64, 18.53, 9.21 ppm. HRMS m / z: calcd for C 19 H 17 N3O2 [M + H] + 320.1394, found 320.1388.

[0097] Compound 9: 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s br, 1H), 8.13 (s, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.25 (t, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.09 - 7.03 (m, 2H), 7.01 - 6.88 (m, 1H), 5.82 (d, J = 6.1 Hz, 1H), 2.45 - 2.35 (m, 1H), 2.15 (ddd, J = 9.0, 6.1, 3.1 Hz, 1H), 1.01 (dd, J = 7.7, 4.3 Hz, 1H), 0.95 - 0.84 (m, 1H) ppm. 13C NMR(101MHz,DMSO-d6)δ174.46,163.77,161.35,143.45,132.26,130.65(d,J=8.2 Hz),123.35,118.93,114.80,114.58,114.01,61.48,21.70,19.74,8.91ppm.HRMS m / z:calcd for C 18 H 14 FN3O[M+H] + 308.1194, found 308.1188.

[0098] Compound 10: 1 H NMR(400MHz,DMSO-d6)δ12.36(s br,1H),8.13(s,1H),7.44(d,J=1.8Hz,1H),7.41(d,J=8.7Hz,1H),7.13(d,J=8.7Hz,2H),7.10(dd,J=8.7,1.9Hz,1H),6.81-6.74(m,2H),5.73 (d,J=6.0Hz,1H),3.65(s,3H),2.34(dtd,J=7.6,6.1,4.3Hz,1H),2.12(ddd,J=9.0,6.1,3.1Hz,1H),1.01-0.94(m,1H),0.93-0.84(m,1H)ppm.

[0099] Compound 11: 1 H NMR(400MHz,DMSO-d6)δ12.33(s br,1H),8.12(s,1H),7.47(d,J=1.7Hz,1H),7.43(d,J=8.7Hz,1H),7.13(dd,J=8.7,1.9Hz,1H),7.01(d,J=7.7Hz,1H),6.82(d,J=6.8Hz,1H) HRMS m / z:calcdfor C 20 H 19 N3O[M+H] + 318.1601, found 318.1597.

[0100] Compound 13: 11H NMR (400 MHz, DMSO-d6) δ 12.33 (s br, 1H), 8.12 (s, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.12 (dd, J = 8.7, 1.8 Hz, 1H), 6.80 (s, 2H), 6.76 (s, 1H), 5.69 (d, J = 6.1 Hz, 1H), 2.38 - 2.29 (m, 1H), 2.14 (s, 6H), 2.11 (dd, J = 6.0, 3.1 Hz, 1H), 0.97 (dd, J = 7.7, 4.2 Hz, 1H), 0.87 (td, J = 8.1, 4.7 Hz, 1H) ppm. HRMS m / z: calcd for C 20 H 19 N3O [M+H] + 318.1601, found 318.1606.

[0101] Compound 15: 1 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.32 (d, J = 2.2 Hz, 2H), 6.25 (t, J = 2.2 Hz, 1H), 5.69 (d, J = 6.2 Hz, 1H), 3.63 (s, 6H), 2.40 (dtd, J = 7.6, 6.1, 4.3 Hz, 1H), 2.17 (ddd, J = 9.1, 6.1, 3.2 Hz, 1H), 1.08 (dd, J = 7.8, 4.5 Hz, 1H), 0.99 (td, J = 8.1, 5.0 Hz, 1H) ppm. 13 13C NMR (101 MHz, CD3OD) δ 176.33, 160.98, 142.02, 140.92, 132.61, 119.21, 114.62, 110.45, 104.84, 98.76, 63.12, 54.28, 21.08, 19.18, 8.39 ppm. HRMS m / z: calcd for C 20 H 19 N3O3 [M+H] + 350.1499, found 350.1499.

[0102] Compound 16: 11H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.4 Hz, 3H), 6.74 (d, J = 8.5 Hz, 2H), 5.71 (d, J = 6.0 Hz, 1H), 3.89 (q, J = 6.9 Hz, 2H), 2.33 (td, J = 11.1, 6.4 Hz, 1H), 2.21 - 2.07 (m, 1H), 1.23 (t, J = 6.9 Hz, 3H), 0.97 (dd, J = 7.4, 3.8 Hz, 1H), 0.93 - 0.84 (m, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.47, 158.09, 142.83, 132.56, 131.64, 128.35, 119.23, 114.57, 63.30, 61.57, 21.62, 20.11, 15.10, 8.94 ppm. HRMS m / z: calcd for C 20 1 19 1 + N3O2 [M + H]

[0103] Compound 17: 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 8.4 Hz, 3H), 7.45 (d, J = 8.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.34 - 7.26 (m, 3H), 7.17 (dd, J = 8.7, 1.5 Hz, 1H), 5.87 (d, J = 6.1 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.21 - 2.12 (m, 1H), 1.01 (dd, J = 7.5, 3.9 Hz, 1H), 0.91 (td, J = 8.1, 4.7 Hz, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.54, 142.95, 140.13, 139.48, 139.29, 132.50, 129.31, 127.82, 127.78, 127.06, 127.02, 119.03, 61.69, 21.81, 20.00, 9.05 ppm.

[0104] Compound 18: 11H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.09 (s, 1H), 7.02 (d, J = 8.0 Hz, 2H), 5.76 (d, J = 6.1 Hz, 1H), 2.41 (t, J = 7.6 Hz, 2H), 2.38 - 2.31 (m, 1H), 2.13 (ddd, J = 8.9, 6.1, 3.1 Hz, 1H), 1.55 - 1.43 (m, 2H), 0.99 - 0.93 (m, 1H), 0.88 (td, J = 8.2, 4.7 Hz, 1H), 0.82 (t, J = 7.3 Hz, 3H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.56, 142.82, 141.43, 137.21, 132.72, 128.65, 127.06, 119.26, 115.18, 110.95, 61.81, 37.33, 24.36, 21.74, 20.09, 14.24, 9.01 ppm.

[0105] Compound 19: 1 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s br, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 8.6, 1.3 Hz, 1H), 6.79 (d, J = 0.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.90 (d, J = 6.8 Hz, 2H), 5.70 (d, J = 6.0 Hz, 1H), 2.37 - 2.24 (m, 1H), 2.17 - 2.05 (m, 1H), 1.07 - 1.00 (m, 1H), 0.88 (td, J = 8.1, 4.8 Hz, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.44, 147.66, 146.75, 133.82, 132.39, 120.66, 119.14, 108.45, 107.64, 101.31, 61.72, 55.40, 21.52, 20.04, 8.84 ppm.

[0106] Compound 20: 11H NMR (400 MHz, DMSO-d6) δ 12.44 (s br, 1H), 8.16 (s, 1H), 7.46 (s, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.82 (s, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 5.71 (d, J = 5.8 Hz, 1H), 3.64 (d, J = 8.6 Hz, 6H), 2.34 (s, 1H), 2.12 (s, 1H), 1.02 (d, J = 2.6 Hz, 1H), 0.95 - 0.81 (m, 1H) ppm.

[0107] Compound 21: 1 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s br, 1H), 8.15 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.11 (dd, J = 8.7, 1.6 Hz, 1H), 6.86 - 6.81 (m, 1H), 6.78 (t, J = 7.9 Hz, 1H), 6.43 (dd, J = 7.6, 1.1 Hz, 1H), 6.01 (d, J = 6.1 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.38 (dt, J = 12.0, 6.2 Hz, 1H), 2.17 - 2.08 (m, 1H), 0.92 - 0.84 (m, 2H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.53, 152.58, 146.65, 142.91, 133.14, 132.62, 123.97, 119.24, 118.65, 112.03, 61.04, 56.59, 56.03, 21.61, 19.09, 8.99 ppm.

[0108] Compound 22: 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.44 (dd, J = 17.4, 5.0 Hz, 2H), 7.16 - 7.07 (m, 3H), 6.99 (d, J = 8.0 Hz, 2H), 5.76 (d, J = 6.0 Hz, 1H), 2.38 - 2.33 (m, 1H), 2.31 (d, J = 7.0 Hz, 2H), 2.17 - 2.10 (m, 1H), 1.79 - 1.66 (m, 1H), 0.96 (dd, J = 7.3, 3.8 Hz, 1H), 0.93 * 0.84 (m, 1H), 0.78 (d, J = 6.6 Hz, 6H) ppm. 1313C NMR (101 MHz, DMSO-d6) δ 174.56, 142.86, 140.42, 137.26, 132.60, 129.26, 126.96, 119.10, 61.84, 44.65, 29.90, 22.69, 22.63, 21.74, 20.07, 9.02 ppm.

[0109] Compound 23: 1 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s br, 1H), 8.14 (s, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.11 (dd, J = 8.7, 1.9 Hz, 1H), 6.71 (dd, J = 6.8, 6.0 Hz, 2H), 6.47 (dd, J = 8.6, 2.6 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 3.61 (s, 3H), 2.48 (s, 3H), 2.46*2.39 (m, 1H), 2.13 (ddd, J = 7.7, 6.3, 3.8 Hz, 1H), 0.89*0.80 (m, 2H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.52, 158.22, 142.85, 136.94, 132.61, 129.65, 127.58, 118.76, 116.42, 111.06, 58.23, 55.23, 21.70, 19.35, 18.16, 8.90 ppm.

[0110] Compound 24: 1 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.15 (dd, J = 8.7, 1.8 Hz, 1H), 5.89 (d, J = 6.1 Hz, 1H), 2.48*2.35 (m, 1H), 2.18 (ddd, J = 8.9, 6.2, 3.1 Hz, 1H), 0.98 (dd, J = 7.5, 4.1 Hz, 1H), 0.91 (td, J = 8.0, 4.8 Hz, 1H) ppm. 1313C NMR (101 MHz, DMSO-d6) δ 174.51, 147.80, 142.96, 139.47, 137.82, 135.40, 132.41, 129.05, 121.27, 119.12, 115.26, 111.09, 61.21, 21.80, 19.88, 8.91 ppm.

[0111] Compound 25: 1 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.15 (dd, J = 8.7, 2.0 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.67 (dd, J = 8.9, 3.1 Hz, 1H), 6.33 (d, J = 3.0 Hz, 1H), 5.96 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 3.47 (s, 3H), 2.42 (dq, J = 7.4, 6.2 Hz, 1H), 2.16 - 2.07 (m, 1H), 0.97 * 0.79 (m, 2H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.73 (s), 153.10, 151.15, 142.78, 137.16, 135.02, 133.14, 128.69, 119.22, 115.41, 114.02, 112.14, 110.31, 56.58, 56.56, 55.46, 21.55, 18.52, 9.18 ppm.

[0112] Compound 28: 1 1H NMR (400 MHz, DMSO-d6) δ.18 (s, 1H), 7.46 (dd, J = 14.4, 4.9 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 7.2 Hz, 2H), 6.94 (d, J = 7.8 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 5.79 (d, J = 6.0 Hz, 1H), 2.44 - 2.29 (m, 1H), 2.24 - 2.08 (m, 1H), 0.99 (d, J = 3.4 Hz, 1H), 0.91 (td, J = 8.0, 4.8 Hz, 1H) ppm. 1313C NMR (101 MHz, DMSO-d6) δ 174.53, 156.58, 156.48, 142.95, 134.75, 132.40, 130.52, 128.82, 124.16, 119.52, 119.17, 118.32, 61.51, 21.73, 20.08, 8.97 ppm.

[0113] Compound 29: 1 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.49 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 8.7, 1.3 Hz, 1H), 7.09 (dd, J = 19.5, 8.0 Hz, 4H), 5.77 (d, J = 6.0 Hz, 1H), 3.44 (t, J = 6.8 Hz, 2H), 3.17 (s, 3H), 2.67 (t, J = 6.7 Hz, 2H), 2.42 - 2.30 (m, 1H), 2.19 - 2.05 (m, 1H), 0.96 (d, J = 3.3 Hz, 1H), 0.92 - 0.82 (m, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.59, 142.76, 138.43, 137.56, 137.69, 134.90, 132.90, 129.18, 127.04, 119.47, 115.16, 110.90, 72.92, 61.78, 58.18, 35.29, 21.76, 20.09, 9.01 ppm.

[0114] Compound 30: 1 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.10 (dd, J = 8.7, 1.9 Hz, 3H), 6.74 (d, J = 8.7 Hz, 2H), 5.72 (d, J = 6.0 Hz, 1H), 3.67 (d, J = 7.0 Hz, 2H), 2.39 * 2.27 (m, 1H), 2.11 (ddd, J = 8.9, 6.1, 3.1 Hz, 1H), 1.19 - 1.04 (m, 1H), 0.97 (dd, J = 7.5, 4.1 Hz, 1H), 0.93 - 0.81 (m, 1H), 0.56 * 0.44 (m, 2H), 0.30 - 0.16 (m, 2H) ppm. 13CNMR(101MHz,DMSO-d6)δ174.47,158.17,142.87,132.50,131.59,128.33, 119.21,114.58,111.16,72.28,61.55,21.63,20.10,10.56,8.91,3.51ppm.

[0115] Compound 31: 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.43(dd,J=10.7,5.1Hz,2H),7.18-7.04(m,3H),6.77(d,J=8.7Hz,2H),5.72(d,J=6.0Hz,1H ),4.01-3.91(m,2H),3.60-3.52(m,2H),3.24(s,3H),2.38-2.27(m,1H),2.12(ddd,J=8.9,6.2,3.0Hz,1H),1.03-0.77(m,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ174.49,158.02,142.89,132.47,131.87,128.37,119.16,114.60,70.79,67.14,61.54,58.54,21.64,20.10,8.93ppm.

[0116] Compound 32: 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.53(d,J=1.6Hz,1H),7.46(d,J=8.6Hz,1H),7.34(d,J=1.3Hz,1H),7.26(d,J=8.3Hz,1H),7.18-7.09(m, 2H),5.85(d,J=6.0Hz,1H),2.38(dq,J=7.3,6.1Hz,1H),2.17(ddd,J=8.9,6.1,3.0Hz,1H),1.16-1.07(m,1H),0.89(tt,J=13.8,7.0Hz,1H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.43,143.20,143.05,142.22,137.18,132.09,131.52 ,123.43,119.14,115.27,111.48,110.24,109.09,61.57,21.68,19.93,8.74ppm.

[0117] Compound 41:1 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.30 (dd, J = 14.5, 7.6 Hz, 3H), 7.24 (dd, J = 12.6, 5.3 Hz, 2H), 7.19 - 7.14 (m, 1H), 4.70 - 4.60 (m, 1H), 2.76 (dd, J = 13.0, 3.7 Hz, 1H), 2.49 - 2.38 (m, 1H), 1.99 - 1.91 (m, 1H), 1.80 - 1.69 (m, 1H), 1.18 (t, J = 7.1 Hz, 1H), 1.05 - 1.01 (m, 1H) ppm.

[0118] Compound 42: 1 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.60 (dd, J = 30.1, 7.6 Hz, 1H), 7.39 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.30 (s, 1H), 2.01 - 1.95 (m, 1H), 1.90 (d, J = 5.7 Hz, 1H), 1.57 (s, 4H), 1.16 - 1.00 (m, 6H), 0.98 (s, 1H), 0.85 - 0.75 (m, 1H) ppm.

[0119] Compound 57: 1 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s br, 1H), 8.14 (s, 1H), 7.44 - 7.41 (m, 2H), 7.07 (dd, J = 8.7, 1.7 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.24 (dd, J = 8.5, 2.3 Hz, 1H), 5.89 (d, J = 6.0 Hz, 1H), 3.87 (s, 3H), 3.64 (s, 3H), 2.42 - 2.31 (m, 1H), 2.13 - 2.03 (m, 1H), 0.86 (td, J = 8.1, 4.6 Hz, 1H), 0.78 (dd, J = 7.7, 4.0 Hz, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.67, 170.83, 159.87, 158.03, 142.89, 132.69, 127.87, 119.64, 118.59, 104.60, 98.88, 60.24, 56.17, 55.47, 21.61, 18.77, 9.19 ppm. HRMS m / z: calcd for C 20H 19 N3O3[M+H] + 350.1499, found 350.1493.

[0120] Compound 58: 1 H NMR(400MHz, DMSO-d6) δ 12.37(s br, 1H), 8.14(s, 1H), 7.43(dd, J=9.8, 5.1Hz, 2H), 7.19 - 7.05(m, 3H), 6.75(d, J=8.6Hz, 2H), 5.72(d, J=6.0Hz, 1H), 3.79(t, J=6.5Hz, 2H), 2.39 - 2.25(m, 1H), 2.12(ddd, J=8.9, 6.2, 3.0Hz, 1H), 1.73 - 1.55(m, 2H), 0.97(dd, J=7.5, 4.0Hz, 1H), 0.93 - 0.82(m, 4H) ppm. 13 C NMR(101MHz, DMSO-d6) δ 174.46, 158.23, 142.90, 132.42, 131.64, 128.34, 119.12, 114.57, 69.20, 61.55, 22.47, 21.64, 20.10, 10.84, 8.92 ppm. HRMS m / z: calcd for C 21 H 21 N3O2[M+H] + 348.1707, found 348.1708.

[0121] Compound 59: 1 H NMR(400MHz, DMSO-d6) δ 8.17(s, 1H), 7.54 - 7.43(m, 2H), 7.14(d, J=8.6Hz, 1H), 6.72(d, J=7.4Hz, 1H), 6.67 - 6.54(m, 2H), 6.04(s, 1H), 5.94(s, 1H), 5.83(d, J=6.0Hz, 1H), 2.37(dd, J=10.9, 6.0Hz, 1H), 2.19 - 2.09(m, 1H), 1.09(d, J=3.4Hz, 1H), 1.01 - 0.88(m, 1H) ppm. 1313C NMR (101 MHz, DMSO-d6) δ 174.25, 147.40, 144.90, 142.95, 132.36, 121.84, 121.79, 120.69, 118.93, 107.90, 101.29, 57.81, 21.45, 18.75, 9.11 ppm. HRMS m / z: calcd for C 19 H 15 N3O3 [M + H] + 334.1186, found 334.1185.

[0122] Compound 60: 1 1H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.13 (t, J = 11.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.32 (d, J = 6.0 Hz, 1H), 2.59 (dt, J = 12.3, 6.3 Hz, 1H), 2.21 (dt, J = 9.9, 5.6 Hz, 1H), 1.02 - 0.88 (m, 2H) ppm. 13 ⏎ 13C NMR (101 MHz, DMSO-d6) δ 174.45, 139.97, 137.97, 134.58, 132.75, 125.12, 124.80, 123.67, 123.39, 122.20, 118.85, 115.44, 111.06, 57.52, 22.12, 18.93, 10.14 ppm. HRMS m / z: calcd for C ⏎ 20 H 15 N3OS [M + H] + 346.1009, found 346.1003.

[0123] Compound 63: 1 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.37 (s, 1H), 7.31 - 7.21 (m, 2H), 7.13 (d, J = 7.5 Hz, 1H), 6.15 (d, J = 5.8 Hz, 1H), 2.49 - 2.43 (m, 1H), 2.21 (dd, J = 11.4, 6.1 Hz, 1H), 1.17 (t, J = 6.7 Hz, 2H) ppm.13 CNMR(101MHz, DMSO-d6) δ 174.13, 143.94, 143.09, 139.03, 138.98, 131.98, 124.82, 124.79, 123.85, 123.75, 122.81, 119.81, 59.24, 21.49, 19.63, 10.57 ppm.

[0124] Compound 64: 1 H NMR(400MHz, DMSO-d6) δ 8.16(s, 1H), 7.84(d, J = 8.3Hz, 1H), 7.72(s, 1H), 7.69(d, J = 5.4Hz, 1H), 7.52(s, 1H), 7.41(d, J = 8.7Hz, 1H), 7.33(d, J = 5.3Hz, 1H), 7.24(d, J = 8.2Hz, 1H), 7.17(d, J = 8.6Hz, 1H), 5.94(d, J = 5.9Hz, 1H), 2.42(s, 1H), 2.18(d, J = 5.7Hz, 1H), 1.14 - 0.82(m, 2H) ppm. 13 C NMR(101MHz, DMSO-d6) δ 174.55, 142.93, 139.86, 138.47, 136.35, 132.46, 128.37, 124.28, 123.72, 122.90, 122.20, 119.02, 62.05, 21.86, 20.20, 9.01 ppm.

[0125] Compound 65: 1 H NMR(400MHz, DMSO-d6) δ 8.15(s, 1H), 7.95(d, J = 5.5Hz, 1H), 7.89(d, J = 5.5Hz, 1H), 7.80(d, J = 8.1Hz, 1H), 7.51(d, J = 1.2Hz, 1H), 7.43(d, J = 8.7Hz, 1H), 7.18(dd, J = 8.7, 1.6Hz, 1H), 7.11(t, J = 7.7Hz, 1H), 6.88(d, J = 7.3Hz, 1H), 6.47(d, J = 6.1Hz, 1H), 2.56(dd, J = 11.7, 5.9Hz, 1H), 2.21(dd, J = 11.6, 6.1Hz, 1H), 0.88(dd, J = 8.6, 4.3Hz, 2H) ppm. 13CNMR(101MHz,DMSO-d6)δ174.57,142.96,140.05,137.69,134.60,132.73,12 8.35,124.46,122.03,121.91,121.72,118.53,59.62,22.04,19.33,9.44ppm.

[0126] Compound 66: 1 H NMR(400MHz,DMSO-d6)δ12.47(s br,1H),8.12(s,1H),7.91(s,1H),7.49(d,J=4.9Hz,2H),7.43(dd,J=13.7,8.6Hz,2H),7.17(dd,J=18.2,8.5Hz,2H), 6.84(s,1H),5.92(d,J=6.0Hz,1H),2.40(s,1H),2.17(d,J=5.7Hz,1H),1.04(d,J=3.2Hz,1H),0.98-0.83(m,1H)ppm.

[0127] Synthesis of compound 45: Compound 45 was synthesized by replacing 3-oxabicyclo[3.1.0]hexane-2,4-dione with 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione, following the same method as compound 1. 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.52(d,J=2.1Hz,1H),7.51(d,J=4.4Hz,1H),7.19(d,J=1.6Hz,1H),7.18-7.14(m,2 H),7.13-7.07(m,3H),5.92(d,J=6.6Hz,1H),2.33(t,J=6.7Hz,1H),2.00(d,J=6.7Hz,1H),1.07(s,3H),1.04(s,3H)ppm. 13 C NMR (101MHz, DMSO-d6) δ172.72,143.00,138.93,133.26,128.26,127.53,126. 87,118.65,115.54,110.26,61.28,32.87,30.41,27.15,23.36,17.31ppm.HRMS m / z:calcd for C 20 H 19 N3O[M+H] + 318.1601, found 318.1593.

[0128] Synthesis of Compound 46: Compound 46 was synthesized by replacing 3-oxabicyclo[3.1.0]hexane-2,4-dione with 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione and 4-methoxyphenyl Grignard reagent with phenyl Grignard reagent, following the same method as Compound 1. 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.54(d,J=8.7Hz,1H),7.51(d,J=1.2Hz,1H),7.18(dd,J=8.7,1.6Hz,1H),7.01(d,J=8.6Hz,2H) ,6.74(d,J=8.7Hz,2H),5.85(d,J=6.5Hz,1H),3.64(s,3H),2.28(t,J=6.6Hz,1H),1.99(d,J=6.6Hz,1H),1.07(d,J=20.1Hz,6H)ppm. 13 C NMR(101MHz,DMSO-d6)δ172.72,158.14,142.86,133.50,130.40,128.71,119.1 1,115.48,113.73,110.20,60.93,55.34,32.81,30.48,27.17,23.34,17.39ppm.

[0129] Synthesis of Compound 47: Compound 47 was synthesized by replacing 3-oxabicyclo[3.1.0]hexane-2,4-dione with 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione and 3-methoxyphenyl Grignard reagent with phenyl Grignard reagent, following the same method as Compound 1. 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.52(d,J=8.7Hz,1H),7.50(d,J=1.7Hz,1H),7.18(dd,J=8.7,1.9Hz,1H),7.09(t,J=7.8Hz,1H),6. 68(dd,J=7.5,5.6Hz,3H),5.88(d,J=6.6Hz,1H),3.57(s,3H),2.33(t,J=6.6Hz,1H),2.00(d,J=6.7Hz,1H),1.09(s,3H),1.04(s,3H)ppm. 13C NMR(101MHz,DMSO-d6)δ172.70,159.13,143.04,140.54,133.29,129.35,119.8 5,118.79,113.83,111.82,61.19,55.21,32.78,30.29,27.17,23.38,17.39ppm.

[0130] Synthesis of Compound 48: Compound 48 was synthesized by replacing 3-oxabicyclo[3.1.0]hexane-2,4-dione with 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione and 2-methoxyphenyl Grignard reagent with phenyl Grignard reagent, following the same method as Compound 1. 1 H NMR(400MHz,DMSO-d6)δ12.36(s br,1H),8.16(s,1H),7.48(d,J=10.4Hz,2H),7.12(dd,J=13.5,7.5Hz,2H),7.02(d,J=8.2Hz,1H),6.66(d,J=7.3Hz,1H),6.57 (t,J=7.4Hz,1H),5.93(d,J=6.2Hz,1H),3.91(s,3H),2.34(t,J=6.5Hz,1H),1.95(d,J=6.7Hz,1H),1.04(d,J=26.7Hz,6H)ppm. 13 C NMR(101MHz,DMSO-d6)δ172.94,157.34,142.99,133.11,128.17,126.00,11 9.55,118.26,111.42,57.46,56.12,32.60,28.74,27.30,23.43,17.19ppm.

[0131] Synthesis of Compound 49: Compound 49 was synthesized by replacing 3-oxabicyclo[3.1.0]hexane-2,4-dione with 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione and 3,4-dimethoxyphenyl Grignard reagent with phenyl Grignard reagent, following the same method as Compound 1. 1H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.52(d,J=8.6Hz,1H),7.47(d,J=1.5Hz,1H),7.16(dd,J=8.6,1.8Hz,1H),6.72(d,J=8.7Hz,2H),6.54(d d,J=8.3,1.5Hz,1H),5.81(d,J=6.4Hz,1H),3.63(s,3H),3.51(s,3H),2.28(t,J=6.6Hz,1H),2.01-1.96(m,1H),1.14(s,3H),1.06(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ172.66,148.45,147.68,143.06,133.24,130.84,119.84,1 19.16,111.80,111.49,61.28,55.73,55.65,32.76,30.31,27.22,23.29,17.51ppm.

[0132] Example 2: Synthesis of compounds 12, 14, 26-27, 50-51, 61-62

[0133]

[0134] Synthesis of compound 12: Compound 7 (208 mg, 0.7 mmol) was dissolved in 1 mL of dry dichloromethane, pre-cooled at 0 °C, and 0.25 mL of boron tribromide (1 M / L DCM) solution was added. The mixture was then moved to room temperature for reaction. After 1 hour, the reaction was monitored by TLC until it was complete. The reaction was quenched with 6 mL of methanol, and then subjected to rotary cyclohexane chromatography (100 mL of 2% DCM / MeOH, 100 mL of 3% DCM / MeOH, 100 mL of 5% DCM / MeOH, and 100 mL of 10% DCM / MeOH) to give compound 12 (195 mg, 98% yield, purple-pink solid). 1 HNMR(400MHz,DMSO-d6)δ9.46(s,1H),9.32(s br,1H),7.72(dd,J=9.3,5.3Hz,2H),7.45(dd,J=9.0,1.9Hz,1H),7.01(dd,J=8.3,7.6Hz,1H),6.67-6.50( m,3H),5.78(d,J=6.1Hz,1H),2.45-2.35(m,1H),2.19(ddd,J=8.2,6.1,3.9Hz,1H),1.02-0.89(m,2H)ppm. 13CNMR(101MHz,DMSO-d6)δ174.79,157.83,141.40,140.81,136.27,130.93,129.89,1 27.65,122.09,117.70,114.70,114.01,108.67,61.53,21.66,20.21,9.20ppm.HRMS m / z:calcdfor C 18 H 15 FN3O2[M+H] + 306.1237, found 306.1230.

[0135] Synthesis of compound 14: Compound 8 was demethylated using the same method as that used to synthesize compound 7 to obtain target compound 14. 1 HNMR(400MHz,DMSO-d6)δ9.86(s br,1H),9.49(s,1H),7.74(d,J=0.6Hz,1H),7.72(d,J=5.6Hz,1H),7.42(dd,J=9.1,1.8Hz,1H),6.98(td,J=8.1,1.6Hz,1H),6.87(d,J=8.0Hz ,1H),6.65(dd,J=7.6,1.4Hz,1H),6.51(t,J=7.4Hz,1H),6.01(d,J=6.0Hz,1H),2.51-2.46(m,1H),2.25-2.12(m,1H),1.01-0.82(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.99,155.26,141.35,136.41,130.97,128.36,127.56,127.1 9,125.22,121.80,119.12,115.59,114.65,108.33,56.41,21.61,18.83,9.30ppm.HRMS m / z:calcd for C 18 H 15 N3O2[M+H] + 306.1237, found 306.1232.

[0136] Synthesis of compound 26: Compound 10 was demethylated using the same method as that used to synthesize compound 7 to obtain target compound 26. 1HNMR (400MHz, DMSO-d6) δ9.55(s,1H),7.73(d,J=1.3Hz,1H),7.71(d,J=9.0Hz,1H),7.44(dd,J=8.9,1.6Hz,1H),7.02(d,J=8.5Hz, 2H),6.62(d,J=8.4Hz,2H),5.77(s,1H),2.43-2.33(m,1H),2.21-2.13(m,1H),1.11-1.00(m,1H),0.94(td,J=8.1,4.7Hz,1H)ppm. 13 C NMR (101MHz, DMSO-d6) δ157.05,141.33,128.32,122.58,115.66,114.49,109.15,61.39,21.55,20.47,9.02ppm.

[0137] Synthesis of compound 27: Compound 25 was demethylated using the same method as that used to synthesize compound 7 to obtain target compound 27. 1 HNMR(400MHz,DMSO-d6)δ9.53(s,1H),9.16(s br,1H),7.76(d,J=9.0Hz,1H),7.72(d,J=1.5Hz,1H),7.42(dd,J=9.0,1.8Hz,1H),6.68(d,J=8.6Hz,1H),6.41(dd,J=8.6,2.8Hz,1H),6.06(d ,J=2.8Hz,1H),5.94(d,J=6.1Hz,1H),2.47(dd,J=11.8,6.1Hz,1H),2.21-2.13(m,1H),0.96(td,J=8.1,4.7Hz,1H),0.85(d,J=3.6Hz,1H)ppm. 13 C NMR(101MHz,DMSO-d6)δ175.04,149.90,147.63,141.33,136.41,130.93,127.46,125 .80,121.62,116.27,114.76,114.69,113.87,107.99,56.37,21.60,18.84,9.35ppm.

[0138] Synthesis of compound 50: Compound 46 was demethylated using the same method as that used to synthesize compound 7 to obtain target compound 50. 1HNMR(400MHz,DMSO-d6)δ9.58(s,1H),9.30(s br,1H),7.81-7.68(m,2H),7.47(dd,J=8.9,1.4Hz,1H),6.88(d,J=8.4Hz,2H),6.59(d,J=8.5Hz,2 H), 5.87 (d, J = 6.4Hz, 1H), 2.32 (t, J = 6.6Hz, 1H), 2.04 (d, J = 6.6Hz, 1H), 1.07 (d, J = 18.1Hz, 6H) ppm. 13 C NMR(101MHz,DMSO-d6)δ173.08,156.39,141.49,136.61,130.90,128.64,127.90,12 7.67,122.10,115.27,114.73,108.45,60.95,32.71,30.91,27.20,23.79,17.48ppm.

[0139] Synthesis of compound 51: Compound 47 was demethylated using the same method as that used to synthesize compound 7 to obtain target compound 51. 1 HNMR(400MHz, DMSO-d6)δ9.57(s,1H),7.80(d,J=8.9Hz,2H),7.50(dd,J=8.9,1.9Hz,1H),6.98(t,J=7.8Hz,1H),6.60-6.53( m,1H),6.50(d,J=7.8Hz,2H),5.92(d,J=6.6Hz,1H),2.35(t,J=6.7Hz,1H),2.05(d,J=6.7Hz,1H),1.08(d,J=16.4Hz,6H)ppm. 13 C NMR(101MHz,DMSO-d6)δ173.10,157.38,141.52,139.58,136.72,130.92,129.41,127.67 ,121.89,118.17,114.59,114.08,108.20,61.02,32.68,30.74,27.17,23.92,17.48ppm.

[0140] Synthesis of compound 61: Compound 57 was demethylated using the same method as that used to synthesize compound 7 to obtain target compound 61. 1HNMR (400MHz, DMSO-d6) δ9.69(s,1H),9.35(s,1H),9.14(s,1H),7.72(d,J=8.9Hz,1H),7.67(s,1H),7.37(d,J=8.9Hz,1H),6.43(d,J= 8.4Hz,1H),6.30(s,1H),5.91(d,J=8.3Hz,1H),5.87(d,J=5.9Hz,1H),2.45-2.36(m,1H),2.12(t,J=7.0Hz,1H),0.98-0.79(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.82,156.48,141.33,136.87,136.29,130.79,127.42,127.1 6,122.19,117.65,114.53,112.98,108.72,58.09,49.05,21.63,19.36,18.59,8.99ppm.

[0141] Synthesis of compound 62: Compound 23 was demethylated using the same method as that used to synthesize compound 7 to obtain the target compound 62. 1 HNMR(400MHz,DMSO-d6)δ9.53(s,1H),9.16(s br,1H),7.74-7.70(m,2H),7.42(dd,J=9.0,1.7Hz,1H),6.59(d,J=2.2Hz,1H),6.54(d,J=8.4Hz,1H),6.30(dd,J= 8.4, 2.3Hz, 1H), 5.92 (d, J = 6.0Hz, 1H), 2.52-2.45 (m, 1H), 2.45 (s, 3H), 2.22-2.14 (m, 1H), 0.93-0.88 (m, 2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.82,156.48,141.33,136.87,136.29,130.79,127.42,127.16, 122.19,117.65,114.53,112.98,108.72,58.09,49.05,21.63,19.36,18.59,8.99ppm.HRMS m / z:calcd for C 19 H 17 N3O2[M+H] + 320.1394, found 320.1394.

[0142] Example 3: Synthesis of compounds 33-39

[0143] Synthesis of Compound 34

[0144]

[0145] Compound 26 (100 mg, 0.3 mmol) was weighed into a reaction flask, 2 mL of dry dichloromethane solution was added, followed by triethylamine (66 mg, 0.7 mmol) and DMAP (8 mg, 0.1 mmol). The mixture was stirred at room temperature, and Boc anhydride (79 mg, 0.4 mmol) was added dropwise. After 15 minutes, the reaction was monitored by TLC to be basically complete. The mixture was then evaporated to dryness and subjected to column chromatography (70 mL of 20% PE / EA, 100 mL of 50% PE / EA, and 200 mL of 100% PE / EA) to give intermediate 26a (37 mg, 30% yield, white solid).

[0146] Intermediate 26a (37 mg, 0.1 mmol) was dissolved in 1 mL of dry DMF, and compound (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate (27 mg, 0.1 mmol) and cesium carbonate (45 mg, 0.1 mmol) were added. The mixture was stirred at 100 °C. After 2 hours, the reaction was monitored by TLC until it was complete. The mixture was extracted with EA (15 mL × 3), washed with saturated brine (20 mL × 3), and evaporated to dryness to obtain intermediate 26b.

[0147] Intermediate 26b (39 mg, pale yellow oil) was dissolved in 1 mL of dichloromethane, and 0.25 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature, and after 1 hour, the reaction was monitored by TLC to be complete. The pH was adjusted to neutral with saturated sodium bicarbonate, extracted with EA (15 mL × 3), and evaporated to dryness. The mixture was then subjected to column chromatography (2% DCM / MeOH 100 mL, 3% DCM / MeOH 100 mL, 5% DCM / MeOH 100 mL) to extract compound 34 (16 mg, white solid). 1H NMR(400MHz,DMSO-d6)δ12.34(s br,1H),8.13(d,J=2.7Hz,1H),7.43(d,J=1.7Hz,1H),7.41(d,J=8.7Hz,1H),7.28-7. 16(m,1H),7.12(d,J=8.7Hz,2H),6.80(dd,J=46.5,8.2Hz,2H),5.72(d,J=6.0Hz,1H) ,4.88(dd,J=6.1,4.7Hz,1H),3.84-3.66(m,4H),2.33(td,J=10.6,6.2Hz,1H),2.21- 2.08(m,2H),1.90-1.79(m,1H),0.95(dt,J=11.8,3.9Hz,1H),0.92-0.85(m,1H)ppm.

[0148] Synthesis of compound 33: Compound 33 was synthesized using compound 12 as the starting material, following the same method as compound 34. 1 H NMR(400MHz,DMSO-d6)δ12.37(s br,1H),8.14(s,1H),7.46(dd,J=3.2,2.0Hz,1H),7.43(d,J=8.6Hz,1H),7.12(dt,J =7.8,2.3Hz,2H),6.79(t,J=6.9Hz,1H),6.69(dd,J=13.5,11.1Hz,2H),5.76(d,J=5 .5Hz,1H),4.90(dt,J=6.0,4.3Hz,1H),3.89-3.58(m,4H),2.40-2.34(m,1H),2.19- 2.00(m,2H),1.92-1.62(m,1H),0.99(dd,J=7.4,3.5Hz,1H),0.91-0.84(m,1H)ppm.

[0149] Synthesis of Compound 35: Compound 35 was synthesized by replacing (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate with cyclopentylmethyl bromide, following the same method used to synthesize Compound 34. 11H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.15 - 7.05 (m, 3H), 6.74 (d, J = 8.7 Hz, 2H), 5.72 (d, J = 6.0 Hz, 1H), 3.70 (d, J = 7.0 Hz, 2H), 2.38 - 2.28 (m, 1H), 2.20 (dt, J = 14.8, 7.4 Hz, 1H), 2.11 (ddd, J = 8.9, 6.1, 3.1 Hz, 1H), 1.69 (qd, J = 7.3, 5.2 Hz, 2H), 1.50 (ddt, J = 12.0, 8.3, 5.6 Hz, 4H), 1.28 - 1.20 (m, 2H), 0.97 (dd, J = 7.6, 4.1 Hz, 1H), 0.87 (tt, J = 12.5, 6.3 Hz, 1H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 174.47, 158.37, 142.85, 132.53, 131.62, 128.32, 119.19, 115.15, 114.62, 111.15, 71.87, 61.57, 38.94, 29.40, 25.36, 21.65, 20.11, 8.93 ppm.

[0150] Compound 36: 1 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s br, 1H), 8.14 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.13 - 7.07 (m, 3H), 6.80 (d, J = 8.7 Hz, 2H), 5.72 (d, J = 6.0 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.78 (dt, J = 11.2, 4.2 Hz, 2H), 3.40 (ddt, J = 11.9, 9.6, 2.5 Hz, 2H), 2.37 - 2.27 (m, 1H), 2.11 (ddd, J = 9.0, 6.1, 3.1 Hz, 1H), 1.92 - 1.81 (m, 2H), 1.55 - 1.43 (m, 2H), 0.95 (dt, J = 11.2, 5.6 Hz, 1H), 0.87 (ddd, J = 16.2, 10.4, 5.9 Hz, 1H) ppm.

[0151] Compound 37: 1H NMR(400MHz, DMSO-d6)δ8.16(s,1H),7.45(d,J=1.6Hz,1H),7.42(d,J=8.6Hz,1H),7.29-7 .19(m,1H),7.13(d,J=8.7Hz,2H),6.85(dd,J=8.5,4.5Hz,2H),5.74(t,J=5.5Hz,1H),4.7 1-4.62(m,1H),2.44-2.32(m,3H),2.32-2.22(m,2H),2.12(ddd,J=12.5,6.4,3.3Hz,1H), 2.01(dt,J=17.2,8.7Hz,2H),1.96-1.81(m,2H),1.01-0.93(m,1H),0.93-0.84(m,1H)ppm.

[0152] Compound 38: 1 H NMR(400MHz,DMSO-d6)δ12.50(s br,1H),8.18(s,1H),7.44(d,J=1.9Hz,1H),7.42(d,J=8.7Hz,1H),7.30-7.18(m, 1H),7.16-7.09(m,2H),6.61(t,J=8.3Hz,2H),5.74(t,J=5.1Hz,1H),5.16(ddd,J =20.0,10.0,5.9Hz,1H),4.84(dt,J=11.3,6.7Hz,2H),4.51-4.43(m,2H),2.37-2 .29(m,1H),2.15-2.08(m,1H),0.95(dd,J=7.4,4.1Hz,1H),0.91-0.86(m,1H)ppm.

[0153] Example 4: Synthesis of compounds 51-56

[0154]

[0155] Synthesis of compound 52: 3-oxabicyclo[3.1.0]hexane-2,4-dione (50 mg, 0.45 mmol) was dissolved in anhydrous tetrahydrofuran, followed by the addition of triethylamine (68 mg, 0.67 mmol), and then the slow addition of 6-aminobenzimidazole (60 mg, 0.45 mmol). The mixture was refluxed at 70 °C with stirring. After 4 hours, the reaction was confirmed to be complete by TLC. The mixture was then cooled to room temperature, and EDCI (128 mg, 0.67 mmol) and HOBt (90 mg, 0.67 mmol) were added. After 2 hours, the reaction was confirmed to be complete by TLC. The tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate and purified by column chromatography (DCM:MeOH = 100:1 → 50:1) to give intermediate a1.

[0156] Intermediate a1 (50 mg, 0.22 mmol) was dissolved in dry tetrahydrofuran and pre-cooled at -78 °C under argon protection. 4-Methylphenyl magnesium bromide (2.2 mL, 2.2 mmol) was slowly added dropwise. After stirring for half an hour, the temperature was slowly raised to room temperature. After 10 hours, the reaction was monitored by TLC to ensure it was complete. After quenching with 10 drops of 10% ammonium chloride solution, the tetrahydrofuran was evaporated to dryness. The mixture was extracted with ethyl acetate and then subjected to column chromatography (DCM:MeOH = 50:1-20:1) to give compound 52 (white solid). 1 H NMR (400MHz, DMSO-d6) δ12.28(sbr,1H),10.16(s,1H),8.09(s,1H),7.91(d,J=8.0Hz,2H),7.79(s,1H),7.43(d,J=8.0Hz,1H),7.29(d,J=8 .1Hz,2H),7.08(d,J=8.2Hz,1H),2.88(dd,J=16.4,7.8Hz,1H),2.31(d,J=16.6Hz,3H),1.64(dd,J=10.4,6.4Hz,1H),1.32-1.20(m,2H)ppm.

[0157] Compound 53: 1 H NMR(400MHz,DMSO-d6)δ12.29(s br,1H),10.22(s,1H),8.10(d,J=8.7Hz,3H),7.80(d,J=8.5Hz,3H),7.74-7.66(m,2H),7.44(dq,J=9.7,7.3Hz,4H),7.11(dd,J =8.6,1.5Hz,1H),2.96(dd,J=16.1,8.0Hz,1H),2.64-2.54(m,1H),1.68(td,J=6.4,4.1Hz,1H),1.33(td,J=8.0,3.9Hz,1H)ppm.

[0158] Compound 54: 1H NMR(400MHz,DMSO-d6)δ12.28(s br,1H),10.14(s,1H),8.09(s,1H),8.03-7.95(m,2H),7.79(s,1H),7.42(d,J=8.6Hz,1H),7.09(d,J=8.3Hz,1H),7.00(d,J=8.9Hz, 2H), 3.80 (s, 3H), 2.86 (dd, J = 16.2, 8.1Hz, 1H), 2.46 (d, J = 8.2Hz, 1H), 1.63 (td, J = 6.4, 4.1Hz, 1H), 1.26 (td, J = 8.0, 3.8Hz, 1H) ppm.

[0159] Compound 55: 1 H NMR(400MHz,DMSO-d6)δ12.24(s br,1H),10.17(s,1H),8.17-8.01(m,3H),7.77(s,1H),7.43(d,J=8.6Hz,1H),7.34(q,J=9.0Hz,2H),7.09(d,J= 8.0Hz,1H),2.92(dd,J=16.1,8.1Hz,1H),2.58-2.52(m,1H),1.65(td,J=6.4,4.2Hz,1H),1.35-1.26(m,1H)ppm.

[0160] Example 5: Synthesis of compounds 67-72

[0161]

[0162] Compound 62 (500 mg, 1.6 mmol) was weighed into a reaction flask, 8 mL of dry dichloromethane solution was added, followed by triethylamine (378 mg, 3.7 mmol) and DMAP (61 mg, 0.5 mmol). The mixture was stirred at room temperature, and Boc anhydride (458 mg, 2.1 mmol) was added dropwise. After 15 minutes, the reaction was monitored by TLC to be basically complete. The mixture was then evaporated to dryness and subjected to column chromatography (DCM:MeOH = 150:1 → 100:1) to give intermediate 67a (324 mg, 50% yield, white solid).

[0163] Add raw material I (500 mg, 2.5 mmol) to 15 mL of dry dichloromethane solution, add triethylamine (503 mg, 5.0 mmol) and DMAP (61 mg, 0.5 mmol), stir at room temperature, add p-toluenesulfonyl chloride (672 mg, 3.3 mmol) in portions, react at room temperature, and after the reaction is complete as monitored by TLC, evaporate to dryness and then perform column chromatography (PE:EA = 5:1 → 1:2) to give intermediate II (799 mg, yield 91%, white solid).

[0164] Intermediate 67a (324 mg, 0.8 mmol) was dissolved in 5 mL of dry DMF, and compound tert-butyl 4-(tolyloxy)piperidine-1-carboxylate (284 mg, 0.8 mmol) and cesium carbonate (261 mg, 0.8 mmol) were added. The mixture was stirred at 100 °C. After 2 hours, the reaction was monitored by TLC until it was complete. The mixture was extracted with EA (50 mL × 3), washed with saturated brine (20 mL × 3), concentrated under reduced pressure, and then subjected to column chromatography (PE:EA = 5:1 → 1:2) to give intermediate 67b (141 mg, 30% yield, white solid).

[0165] Intermediate 67b (141 mg, white solid) was dissolved in 1 mL of dichloromethane, and 1 mL of 2N hydrochloric acid 1,4-dioxane solution was added. The mixture was stirred at room temperature. After 1 hour, the reaction was monitored by TLC until it was complete, and a white solid precipitated out. The mixture was filtered, the solid was collected, washed with water and DCM, and dried to give compound 67 (25 mg, 28% yield, white solid). 1 H NMR(400MHz,MeOD)δ9.30(s,1H),7.80(s,1H),7.70(s,1H),7.52(d,J=6.3Hz,1H),6.87(s,1H),6.69(s,1H),6.57(s,1H),6.03( s,1H),4.59(s,1H),3.65(s,1H),3.18(s,2H),2.57(s,3H),2.47(s,1H),2.26(s,1H),2.09(s,2H),1.94(s,2H),1.02(s,2H)ppm. 13 CNMR(101MHz,MeOD)δ176.29,155.77,140.25,137.20,136.37,130.67,128.83,127.40,122.35,118.20 ,114.02,112.89,108.49,68.14,66.78,58.87,40.68,27.07,27.01,21.34,18.27,18.10,8.49ppm.HRMS m / z:calcd for C 24 H26 N4O2[M+H] + 403.2129, found 403.2129.

[0166] Synthesis of compound 68: Compound 68 was synthesized using 1-acetylpiperidin-4-yl-4-methylbenzenesulfonate, following the same method used to synthesize compound 67. 1 H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.14(s,1H),7.46(s,2H),7.08(s,1H),6.77(s,1H),6. 70(d,J=8.4Hz,1H),6.52(d,J=8.2Hz,1H),5.91(d,J=5.8Hz,1H),4.44(s,1H),4.14(d,J=5.1H z,1H),3.84-3.72(m,1H),3.60(d,J=13.0Hz,1H),3.30-3.21(m,1H),3.12(d,J=12.1Hz,1H), 2.48(s,3H),2.14(s,1H),1.98(s,3H),1.82(s,2H),1.56-1.33(m,2H),0.91-0.80(m,2H)ppm.

[0167] Synthesis of compound 69: Compound 69 was synthesized using cyclopropylmethyl-4-methylbenzenesulfonic acid, following the same method used to synthesize compound 67. 1 H NMR (400MHz, CD3OD) δ9.19(s,1H),7.75(s,1H),7.69(d,J=9.0Hz,1H),7.51(dd,J=9.0 ,1.5Hz,1H),6.76(d,J=2.2Hz,1H),6.65(d,J=8.6Hz,1H),6.46(dd,J=8.5,2.3Hz,1H) ,6.01(d,J=6.0Hz,1H),3.69(dd,J=6.8,2.3Hz,2H),2.55(s,4H),2.31-2.21(m,1H),1 .19-1.11(m,1H),1.11-0.98(m,2H),0.56(q,J=4.9Hz,2H),0.27(d,J=5.0Hz,2H)ppm. 13C NMR (101MHz, CD3OD) δ175.66,157.52,139.39,136.00,135.53,130.33,127.01,126.35,121. 33,115.95,113.20,110.59,107.61,71.55,58.17,20.53,17.33,9.07,7.58,1.42.ppm.HRMS m / z:calcd for C 23 H 23 N3O2[M+H] + 374.1863, found 374.1861.

[0168] Synthesis of compound 70: Compound 70 was synthesized using 3-fluoropropyl-4-methylbenzenesulfonate, following the same method used to synthesize compound 67. 1 H NMR(400MHz,DMSO-d6)δ12.35(d,J=10.3Hz,1H),8.13(s,1H),7.40(dd,J=2 9.6,13.9Hz,2H),7.17-7.01(m,3H),6.78(d,J=8.4Hz,2H),5.73(d,J=6.0H z,1H),4.54(dt,J=47.3,5.9Hz,2H),3.95(t,J=6.2Hz,2H),2.33(d,J=3.7H z,1H),2.12(d,J=4.4Hz,1H),2.09-1.95(m,2H),1.01-0.84(m,2H)ppm.HRMS m / z:calcd for C 21 H 20 FN3O2[M+H] + 366.1612, found 366.1612.

[0169] Synthesis of compound 71: Compound 71 was synthesized using 1-acetylpyrrolidone-3-yl-4-methylbenzenesulfonate, following the same method used to synthesize compound 67. 1H NMR (400MHz, DMSO-d6) δ8.16 (s, 1H), 7.55-7.39 (m, 2H), 7.11 (d, J = 8.4Hz, 1H) ,6.78-6.63(m,2H),6.48(t,J=8.9Hz,1H),5.91(d,J=5.3Hz,1H),4.89(d,J=2 8.8Hz,1H),4.13(s,1H),3.71(dd,J=7.5,3.8Hz,1H),2.48(s,4H),2.14(d,J= 5.7Hz,2H),2.03-1.99(m,1H),1.90(d,J=16.1Hz,3H),0.94-0.75(m,2H)ppm.

[0170] Synthesis of compound 72: Compound 72 was synthesized using 1-acetazolidinyl-3-yl-4-methylbenzenesulfonate, following the same method used to synthesize compound 67. 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.52-7.37(m,2H),7.11(d,J=8.5Hz,1H),6.72(d ,J=8.5Hz,1H),6.65(s,1H),6.43-6.33(m,1H),5.92(d,J=5.8Hz,1H),4.86(s,1H),4. 50-4.39(m,1H),4.23-4.13(m,1H),3.96(d,J=8.7Hz,1H),3.67(d,J=9.5Hz,1H),2.48 (s,4H),2.14(d,J=5.8Hz,1H),1.73(d,J=2.8Hz,3H),0.85(dd,J=10.8,6.1Hz,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ174.59,170.31,155.33,142.89,137.44,132.62,130.65,127.76,118.94,118. 89,117.11,116.96,111.79,111.58,65.27,58.19,57.49,54.91,54.86,21.70,19.31,18.11,8.95ppm.

[0171] Example 6: Synthesis of compounds 73-83,85

[0172]

[0173]

[0174] Thiophene-2-carboxylic acid b1 (500 mg, 3.91 mmol) was dissolved in 10 mL of dry dichloromethane. After pre-treatment at 0 °C for 10 min, 100 μL of N,N-dimethylformamide was added dropwise as a catalyst, followed by the slow addition of thionyl chloride (511 mg, 4.30 mmol). The mixture was then moved to room temperature and reacted for about 1 hour. The mixture was then concentrated under reduced pressure to obtain intermediate b2 for the next step.

[0175] The purchased raw material 4-hydroxypiperidine (300 mg, 2.97 mmol) was dissolved in 10 mL of dry dichloromethane. After pre-treatment at 0 °C for 10 min, triethylamine (751 mg, 7.43 mmol) and intermediate b2 (480 mg, 3.27 mmol) were added dropwise. The mixture was then transferred to room temperature and reacted overnight. After concentration under reduced pressure, column chromatography (PE:DCM = 20:1 → 1:2) was performed to give compound b3 (376 mg, yield 60%, colorless liquid).

[0176] Compound b3 (376 mg, 1.78 mmol) was dissolved in 15 mL of dry dichloromethane solution, and triethylamine (361 mg, 3.56 mmol) and DMAP (44 mg, 0.36 mmol) were added. The mixture was stirred at room temperature, and p-toluenesulfonyl chloride (441 mg, 2.31 mmol) was added in portions. The mixture was reacted at room temperature for 1 hour. After the reaction was monitored by TLC until it was complete, the mixture was evaporated to dryness and then subjected to column chromatography (PE:EA = 100:1 → 10:1) to give intermediate b4 (618 mg, 95% yield, white solid).

[0177] Intermediate 23e (1000 mg, 4.60 mmol) of compound 23 was dissolved in 10 mL of dry dichloromethane and pre-cooled at 0 °C. 6 mL of boron tribromide (1 M / L DCM) solution was slowly added dropwise, and the reaction was allowed to proceed to room temperature. After 1 hour, the reaction was monitored by TLC until complete. The reaction was quenched with 10 mL of methanol and concentrated under reduced pressure. The solution was extracted with water (100 mL) and EA (100 mL × 3) to give compound 73a (840 mg, 90% yield, purple-pink solid).

[0178] Compound 73a (540 mg, 2.66 mmol) was dissolved in 810 mL of dry N,N-dimethylformamide, and compound b3 (1942 mg, 5.32 mmol) and cesium carbonate (25942 mg, 7.98 mmol) were added. The mixture was reacted at 110 °C for 1–3 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was extracted with water and EA. The organic phase was backwashed with saturated sodium chloride aqueous solution, collected, concentrated under reduced pressure, and subjected to column chromatography (DCM:MeOH = 150:1 → 80:1) to give intermediate 73b (788 mg, 75% yield, white solid).

[0179] Intermediate 73b (746 mg, 2.48 mmol) was synthesized according to steps iv, v, and vi of compound 1, finally yielding compound 73 (125 mg, 18% yield, white solid). 1 H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.19(s,1H),7.78(d,J=4.9Hz,1H),7.52(s,1H),7.48(d,J=8.4Hz,1H),7 .43(d,J=3.5Hz,1H),7.20-7.11(m,2H),6.84(d,J=1.8Hz,1H),6.76(d,J=8.6Hz,1H),6.58(dd,J=8.5,1.9Hz,1 H),5.97(d,J=6.0Hz,1H),4.61-4.52(m,1H),3.97-3.86(m,2H),3.49(s,2H),3.23(d,J=5.0Hz,1H),2.55-2.47 (m,4H),2.19(dd,J=11.6,5.8Hz,1H),1.95(d,J=3.1Hz,2H),1.60(dd,J=8.3,4.0Hz,2H),0.98-0.85(m,2H)ppm. 13 CNMR(101MHz,DMSO-d6)δ174.54,162.71,155.98,142.89,137.74,137.13,129.94,129.74,129. 25,127.65,127.51,118.15,112.82,71.81,60.23,58.26,31.20,21.70,19.31,18.15,8.94ppm.

[0180] Synthesis of compound 74: Compound 74 was synthesized by replacing thiophene-2-carboxylic acid with benzoic acid, following the same method as compound 73. 1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.13(s,1H),7.46(s,1H),7.43-7.35(m,6H),7.10(s,1H) ,6.77(d,J=2.2Hz,1H),6.69(d,J=8.5Hz,1H),6.52(dd,J=8.5,2.3Hz,1H),5.91(d,J=6.0Hz,1H ),4.55-4.43(m,1H),3.92(s,1H),3.46(dd,J=9.5,4.4Hz,2H),3.21(s,1H),2.47(s,3H),2.18- 2.08(m,1H),1.85(d,J=21.3Hz,2H),1.51(s,2H),1.05(d,J=7.0Hz,1H),0.88-0.77(m,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ174.57,169.46,156.01,142.91,137.12,136.63,132.60,129.91,129.86,128. 86,127.64,127.14,118.80,118.17,112.78,71.97,58.27,56.53,21.72,19.30,19.04,18.16,8.96ppm.

[0181] Synthesis of compound 75: Compound 75 was synthesized by replacing thiophene-2-carboxylic acid with cyclopropionic acid, following the same method as compound 73. 1 H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.19(s,1H),7.52(s,1H),7.48(d,J=8.4Hz,1H),7.17(s,1H ),6.83(d,J=2.0Hz,1H),6.75(d,J=8.6Hz,1H),6.58(dd,J=8.5,2.0Hz,1H),5.97(d,J=6.0Hz,1H) ,4.58-4.46(m,1H),3.91(d,J=27.0Hz,2H),3.49(s,1H),3.23(d,J=5.0Hz,1H),2.53(s,4H),2.24 -2.14(m,1H),2.05-1.81(m,3H),1.50(d,J=40.5Hz,2H),0.97-0.85(m,2H),0.76-0.72(m,4H)ppm. 13C NMR(101MHz,DMSO-d6)δ174.54,171.31,156.03,142.89,137.11,132.57,129.86,127.63,118.79 ,118.13,112.80,72.13,58.26,42.53,31.78,30.87,21.70,19.30,18.15,10.73,8.93,7.30ppm.

[0182] Synthesis of compound 76: Compound 76 was synthesized by replacing thiophene-2-carboxylic acid with p-methoxybenzoic acid, following the same method as compound 73. 1 H NMR(400MHz,DMSO-d6)δ12.45(s br,1H),8.20(s,1H),7.52(d,J=1.6Hz,1H),7.48(d,J=8.7Hz,1H),7.40(d,J=8.7Hz,2H),7.1 6(dd,J=8.7,1.6Hz,1H),7.01(d,J=8.8Hz,2H),6.83(d,J=2.3Hz,1H),6.75(d,J=8.6Hz,1H), 6.58(dd,J=8.6,2.4Hz,1H),5.96(d,J=6.0Hz,1H),4.60-4.50(m,1H),3.83(s,3H),3.39(s,4 H),2.53(s,4H),2.22-2.14(m,1H),1.91(s,2H),1.56(d,J=4.6Hz,2H),0.94-0.86(m,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ174.55,169.44,160.56,156.03,142.88,137.12,132.65,129.89,129.27,128. 52,127.63,118.85,118.15,114.07,112.81,72.07,58.26,55.69,55.39,21.70,19.30,18.16,8.95ppm.

[0183] Synthesis of compound 77: Compound 77 was synthesized by replacing thiophene-2-carboxylic acid with 3,4-dimethoxybenzoic acid, following the same method as compound 73. 1H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.52(d,J=1.5Hz,1H),7.49(d,J=8.7Hz,1H),7.17(dd,J=8.7,1.7 Hz,1H),7.06-6.97(m,3H),6.83(d,J=2.1Hz,1H),6.75(d,J=8.6Hz,1H),6.58(dd,J=8.6,2.2Hz,1H),5 .97(d,J=6.0Hz,1H),4.59-4.50(m,1H),3.83(s,3H),3.81(d,J=2.8Hz,3H),2.58-2.55(m,3H),2.50(d ,J=7.2Hz,1H),2.20(dt,J=8.5,3.8Hz,1H),1.92(s,2H),1.58(d,J=4.3Hz,2H),0.95-0.83(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.60,169.44,156.02,150.18,148.81,142.84,137.14,132.71,129.85,128.64,127.63,1 20.18,118.93,118.11,115.22,112.78,111.58,111.24,110.74,72.07,58.27,55.99,21.70,19.29,18.17,8.94ppm.

[0184] Synthesis of compound 78: Compound 78 was synthesized by replacing thiophene-2-carboxylic acid with 2-methoxybenzoic acid, following the same method as compound 73. 1H NMR (400MHz, DMSO-d6) δ8.10(d,J=2.3Hz,1H),7.39(d,J=1.3Hz,1H),7.35(d,J=8.7Hz,1H),7.32-7.25(m,1H),7.11-7.06( m,1H),7.06-7.02(m,1H),6.97(d,J=8.4Hz,1H),6.89(t,J=7.4Hz,1H),6.68(s,1H),6.61(d,J=8.5Hz,1H),6.43(d,J=7.6Hz ,1H),5.83(d,J=6.0Hz,1H),4.38(s,1H),3.87(d,J=6.1Hz,1H),3.68(s,3H),3.22(dd,J=36.8,6.1Hz,3H),2.98(dd,J=18.7 ,5.1Hz,1H),2.39(s,3H),2.05(dd,J=11.6,5.9Hz,1H),1.81(s,1H),1.69(s,1H),1.50-1.26(m,2H),0.82-0.72(m,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ174.56,166.80,156.02,155.33,142.83,137.11,132.70,130.66,129.86,128.01,127.89,127.62,126. 31,121.11,118.90,118.13,115.22,112.75,111.74,110.67,72.03,58.25,55.90,55.38,43.87,21.70,19.29,18.16,8.95ppm.

[0185] Synthesis of compound 79: Compound 79 was synthesized by replacing thiophene-2-carboxylic acid with 2-methylbenzoic acid, following the same method as compound 73. 1H NMR(400MHz, DMSO-d6)δ8.20(s,1H),7.52(d,J=0.9Hz,1H),7.47(d,J=8.6Hz,1H),7.35-7.23(m,3H), 7.22-7.13(m,2H),6.81(s,1H),6.74(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.2Hz,1H),5.95(d,J=6.0Hz, 1H), 4.51 (s, 1H), 4.02 (d, J = 30.8Hz, 2H), 3.20-3.03 (m, 2H), 2.54-2.46 (m, 4H), 2.24 (s, 3H), 2.21-2. 14(m,1H),1.96(s,1H),1.79(s,1H),1.58(dd,J=8.4,4.2Hz,1H),1.46(s,1H),0.95-0.84(m,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ174.56,168.91,155.99,142.86,137.12,136.98,134.02,132.64,130.60,129.93,128. 99,127.63,126.26,125.92,118.85,118.18,112.77,58.26,55.38,43.89,21.70,19.29,18.99,18.15,8.95ppm.

[0186] Synthesis of compound 80: Compound 80 was synthesized by replacing thiophene-2-carboxylic acid with 4-methoxybenzoic acid, following the same method as compound 73. 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.46(d,J=1.7Hz,1H),7.43(d,J=8.7Hz,1H),7.25(dd,J=19.5 ,8.0Hz,4H),7.11(dd,J=8.7,1.7Hz,1H),6.77(d,J=2.3Hz,1H),6.69(d,J=8.6Hz,1H),6.52(dd,J= 8.6,2.4Hz,1H),5.91(d,J=6.0Hz,1H),4.48(dd,J=7.6,3.9Hz,1H),3.90(s,2H),2.47(s,3H),2.45 (d,J=7.1Hz,1H),2.32(s,3H),2.17-2.08(m,1H),1.85(s,2H),1.51(s,2H),0.90-0.79(m,2H)ppm. 13C NMR(101MHz,DMSO-d6)δ174.60,169.63,156.02,142.84,139.53,137.12,133.65,132.70,129.87,129.32,1 27.63,127.28,118.90,118.15,115.26,112.79,110.74,72.01,58.27,21.71,21.35,19.29,18.17,8.95ppm.

[0187] Synthesis of compound 81: Compound 81 was synthesized by replacing thiophene-2-carboxylic acid with 1-methylpyrazole-4-carboxylic acid, following the same method as compound 73. 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),8.07(s,1H),7.68(s,1H),7.53(d,J=1.7Hz,1H),7.49(dd,J =8.6,3.2Hz,1H),7.17(dd,J=8.7,1.9Hz,1H),6.84(d,J=2.4Hz,1H),6.76(d,J=8.6Hz,1H),6.58( dd,J=8.6,2.4Hz,1H),5.97(d,J=5.9Hz,1H),4.59-4.50(m,1H),3.88(s,3H),2.53(s,3H),2.51( s,1H),2.22-2.15(m,1H),1.99-1.87(m,2H),1.56(dt,J=12.4,8.6Hz,2H),0.96-0.86(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.57,162.96,156.00,142.84,139.54,137.13,132.71,129.87,1 27.64,118.92,118.15,116.84,112.85,72.01,58.26,49.07,21.70,19.30,18.17,8.94ppm.

[0188] Synthesis of compound 82: Compound 82 was synthesized by replacing thiophene-2-carboxylic acid with tetrahydropyran-4-carboxylic acid, following the same method as compound 73. 1H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.51(dd,J=15.5,5.1Hz,2H),7.17(dd,J=8.7,1.8Hz,1H),6.82(d,J=1 .9Hz,1H),6.75(d,J=8.6Hz,1H),6.56(dd,J=8.6,2.3Hz,1H),5.96(d,J=6.0Hz,1H),4.54-4.43(m,1H),3.8 7(d,J=10.0Hz,3H),3.76(d,J=12.8Hz,2H),3.40(td,J=11.4,2.0Hz,2H),3.20(s,1H),2.94-2.85(m,1H),2 .52(s,3H),2.50(d,J=7.2Hz,1H),2.24-2.14(m,1H),1.87(s,2H),1.68-1.37(m,6H),0.97-0.85(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.57,172.56,156.02,142.82,137.11,132.75,129.86,127.62,118.94,118 .18,115.21,112.82,110.69,72.08,66.74,58.26,42.31,36.70,29.40,21.70,19.29,18.17,8.94ppm.

[0189] Synthesis of compound 83: Compound 83 was synthesized by replacing thiophene-2-carboxylic acid with 3-tetrahydrofuran carboxylic acid, following the same method as compound 73. 1H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.48(d,J=1.7Hz,1H),7.44(d,J=8.7Hz,1H),7.12(dd,J=8.7,1.9Hz,1H) ,6.77(d,J=1.9Hz,1H),6.70(d,J=8.6Hz,1H),6.52(dd,J=8.6,2.4Hz,1H),5.91(d,J=6.0Hz,1H),4.50-4.41( m,1H),3.84(td,J=8.1,3.4Hz,3H),3.72-3.64(m,4H),3.32(dt,J=14.5,7.3Hz,2H),3.24-3.15(m,1H),2.48( s,3H),2.17-2.11(m,1H),2.02-1.94(m,2H),1.82(d,J=6.4Hz,2H),1.53-1.35(m,2H),0.92-0.79(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.57,171.19,156.00,142.83,137.12,132.73,129.85,127.63,118.92,118.14 ,115.23,112.84,110.69,71.95,70.25,68.09,58.26,55.38,42.44,30.17,21.70,19.29,18.17,8.94ppm.

[0190] Synthesis of compound 85: Compound 85 was synthesized by replacing thiophene-2-carboxylic acid with 3-thiophenecarboxylic acid, following the same method as compound 73. 1H NMR(400MHz,DMSO-d6)δ12.38(s br,1H),8.15(s,1H),7.75(d,J=2.6Hz,1H),7.58(dd,J=4.7,3.0Hz,1H),7.47(s,1H),7.43(d,J=8.7Hz,1H),7.1 8(d,J=5.0Hz,1H),7.11(d,J=8.7Hz,1H),6.77(d,J=2.0Hz,1H),6.70(d,J=8.6Hz,1H),6.51(dd,J=8.5,2.1Hz,1 H),5.91(d,J=6.0Hz,1H),4.53-4.43(m,1H),3.75(d,J=77.3Hz,2H),3.33(dd,J=8.3,3.8Hz,2H),2.47(s,3H),2 .44(d,J=6.6Hz,1H),2.16-2.08(m,1H),1.86(s,2H),1.52(ddd,J=16.7,8.2,4.2Hz,2H),0.90-0.78(m,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ174.56,170.83,165.02,156.00,142.87,137.12,136.93,132.63,129.91,127.70,127. 64,126.95,126.92,118.83,118.15,112.81,71.99,60.24,58.26,21.71,21.24,19.31,18.16,14.56,8.95ppm.

[0191] Synthesis of compound 86: Compound 86 was synthesized by replacing thiophene-2-carboxylic acid with 4-phenylbenzoic acid, following the same method as compound 73. 1 H NMR(400MHz,DMSO-d6)δ12.37(s br,1H),8.14(s,1H),7.70(t,J=8.5Hz,4H),7.50-7.45(m,5H),7.45-7.36(m,2H ),7.12(d,J=8.6Hz,1H),6.78(s,1H),6.70(d,J=8.5Hz,1H),6.52(d,J=7.0Hz,1H ),5.91(d,J=5.9Hz,1H),4.49(s,1H),3.37(s,4H),2.47(s,3H),2.45-2.40(m,1H ), 2.13(dd,J=11.7,5.7Hz,1H),1.87(s,2H),1.54(s,2H),0.90-0.79(m,2H)ppm.13 C NMR (101MHz, DMSO-d6) δ174.56,169.25,156.02,142.90,141.60,139.80,137.13,135.52,132.60,129.93,129.50,128. 34,127.98,127.65,127.25,127.11,118.81,118.19,112.80,72.00,58.27,56.52,21.72,19.31,19.05,18.16,8.96ppm.

[0192] Synthesis of compound 87: Compound 87 was synthesized by replacing thiophene-2-carboxylic acid with 4-propoxybenzoic acid, following the same method as compound 73. 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.48(s,1H),7.43(d,J=8.6Hz,1H),7.33(d,J=8.5Hz,2H),7.12(d,J=8.7Hz ,1H),6.94(d,J=8.5Hz,2H),6.77(s,1H),6.70(d,J=8.5Hz,1H),6.50(dd,J=8.4,1.6Hz,1H),5.91(d,J=5.9Hz,1H ),4.46(s,1H),3.93(t,J=6.5Hz,2H),3.85-3.57(m,2H),3.28(s,2H),2.47(s,3H),2.43(d,J=6.4Hz,1H),2.13(d d,J=11.7,5.7Hz,1H),1.84(s,2H),1.76-1.67(m,2H),1.50(s,2H),0.96(t,J=7.4Hz,3H),0.89-0.81(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.50,169.41,159.98,155.96,142.82,137.06,132.59,129.83,129.25,128.28, 127.58,118.78,118.10,114.45,112.72,72.00,69.44,58.22,22.39,21.68,19.26,18.12,10.80,8.91ppm.

[0193] Synthesis of Compound 88: Compound 88 was synthesized by replacing thiophene-2-carboxylic acid with 4-propoxybenzoic acid and replacing 4-(3-methoxy-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-one with 4-(3-methoxy-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-one with 4-(3-methoxy-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-one, following the same method as that used for Compound 73. 1 HNMR (400MHz, DMSO-d6) δ12.36(s,1H),8.14(s,1H),7.48(s,1H),7.43(d,J=8.1Hz,1H),7.38(d,J=8.5Hz,2H),7.14 (s,1H),6.96(d,J=8.5Hz,2H),6.85(t,J=7.9Hz,1H),6.79(d,J=8.1Hz,1H),6.41(d,J=7.5Hz,1H),6.01(d,J=6.0Hz ,1H),4.56(s,1H),3.95(t,J=6.5Hz,2H),3.73(s,2H),2.45(dd,J=11.1,5.5Hz,1H),2.37(s,3H),2.14(t,J=8.6Hz, 1H),1.92(s,2H),1.74(dt,J=14.0,7.0Hz,2H),1.66(s,2H),0.97(t,J=7.4Hz,3H),0.85(dd,J=9.7,4.4Hz,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ174.57,169.56,160.08,155.22,142.90,139.25,129.36,128.37,126.25,124 .61,119.03,114.53,112.01,72.32,69.52,58.87,31.17,22.45,21.70,17.97,11.16,10.85,8.98ppm.

[0194]

[0195] Synthesis of compound 89: 3,4-dimethoxyaniline (89a, 1.0 g, 6.54 mmol) and sodium bicarbonate (1.1 g, 13.08 mmol) were dissolved in 20 mL of ethyl acetate. After argon protection, the mixture was pre-cooled at 0 °C for 10 minutes and then slowly added dropwise with 2,2,2-trichloroethyl chloroformate (89b, 1.4 g, 6.54 mmol). After the addition was complete, the mixture was moved to room temperature and reacted for about 3 hours. After the reaction was monitored by thin-layer chromatography (TLC) to ensure complete reaction, the organic solvent was removed by concentration under reduced pressure. Intermediate 89c (1.9 g, 90% yield, brown solid) was obtained without purification.

[0196] Compound 89 was synthesized by replacing the obtained intermediate 2,2,2-trichloroethyl(3,4-dimethoxyphenyl)carbamate (89c) with thiophene-2-formyl chloride, following the same method used to synthesize compound 73. 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),8.37(s,1H),8.13(s,1H),7.46(s,2H),7.15(d,J=2.3Hz,1H),6. 96(dd,J=8.7,2.2Hz,1H),6.83-6.75(m,2H),6.70(s,1H),6.53(d,J=8.4Hz,1H),5.91(d,J=5.9Hz,1H), 4.47-4.38(m,1H),4.13(d,J=4.4Hz,1H),3.75(d,J=14.4Hz,4H),3.69(s,3H),3.68(s,3H),2.48(s,3H ),2.46-2.42(m,1H),2.13(s,1H),1.88(d,J=18.6Hz,2H),1.46(d,J=9.4Hz,2H),0.89-0.79(m,2H)ppm.

[0197] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0198] Experimental Example 1: Inhibitory activity of the compound of the present invention against sQC / gQC enzymes

[0199] (1) Experimental reagents and materials

[0200] In the prokaryotic system, the pET32a vector was used to express recombinant human sQC (33-361aa) and human gQC (53-382aa) proteins (method: Protein Expr Purif. 2005 43(1):65-72); the pET28 vector was used to express recombinant Bacillus amyloliquefaciens PGP-I (1-215aa) protein (method: J Biomol Struct Dyn. 2011 29(2):267-82); fluorescent substrate H-Gln-AMC (Nanjing Leon Biotechnology Co., Ltd.); fluorescent substrate pGA (synthesized in this study), and all synthesized target compounds.

[0201] (2) Experimental methods

[0202] For detailed operating procedures, please refer to J.Med.Chem.2024 67(11):8730-8756; The activity test of sQC / gQC protein was performed in a black 96-well plate. 10 μL of different concentrations of the compound, 30 μL of buffer (25 mM Tris-HCl, 150 mM NaCl, 10% glycerol, pH 8.0), and 10 μL of sQC / gQC enzyme (final concentration 30 nM) were added to each well of the plate. After incubation at room temperature for 20 minutes, 10 μL of PGP-1 enzyme (final concentration 100 nM) and 10 μL of fluorescent substrate H-Gln-AMC (final concentration 3 μM) were added. The fluorescence (λ) of the system within 10 minutes was immediately detected. ex =380nm, λ em =460nm) change value.

[0203] In addition, to rule out false positives that the compound might inhibit the final fluorescence result of PGP-1, an activity assay of PGP-1 was performed. The entire reaction system was 60 μL. 0.6 μL of the compound (final concentration 100 μM), 39.4 μL of buffer (25 mM Tris-HCl, 150 mM NaCl, 10% glycerol, pH 8.0), 10 μL of PGP-1 (final concentration 0.05 μM), and 10 μL of substrate pGA (final concentration 1 μM) were added sequentially to the test wells. The fluorescence (λ) of the system was detected immediately after the substrate addition within 10 min. ex =380nm, λ em =460nm) change value.

[0204] Each experiment was performed in three independent replicates, with the reaction wells without the compound serving as a blank control group. The dose-response relationship obtained was fitted using GraphPad to the corresponding half-maximal inhibitory concentration (IC50).

[0205] (3) Experimental Results

[0206] The inhibitory activity of the compounds of this invention against sQC / gQC was tested using the above experimental methods. Specifically, the half-maximal inhibitory concentration (IC50) of the compounds against sQC / gQC was determined. 50 See Table 1.

[0207] Table 1. Inhibitory activity of the compounds of the present invention against human sQC and gQC

[0208]

[0209]

[0210]

[0211] Note: ++:IC50 >10μM; +++: 100 nM <IC 50 <10μM; ++++:IC 50 <100 nM

[0212] The above results indicate that the compounds of the present invention exhibit good inhibitory activity against both sQC and gQC, particularly compounds 23, 30, 60, 65, 69-83, and 85-89, which show high IC50 inhibition against at least one enzyme. 50 The value is less than 100 nM, indicating excellent inhibitory activity.

[0213] This invention provides a class of 3-benzimidazole-3-azabicyclohexane-2-one compounds and their preparation method for the preparation of sQC / gQC enzyme inhibitors. This invention provides new lead or candidate drugs for the development of small molecule inhibitors of sQC / gQC and new drugs for sQC / gQC-related diseases.

Claims

1. The compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof: in, R1 is selected from H or hydroxyl groups; R2 is selected from substituted or unsubstituted C6-C. 10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic alkyl groups, wherein the substituents are selected from halogens, hydroxyl groups, C1-C6 groups. 10 Alkyl, C6-C 10 Aryl, benzyl, C2-C 10 Ether group, -OR5, cyano group, amino group, 5-10 heteroaryl group, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C1-C 10 Haloalkyl, C1-C 10 Ester group, C1-C 10 Carboxyl group, C1-C 10 Acyl group, C1-C 10 amide group, C1-C 10 An amino group, or at least two substituents linked together, forms a C3-C group that is either substituted or unsubstituted with at least one R6 group. 10 Cycloalkyl, 5-10 membered heterocyclic alkyl groups substituted with at least one R6 or unsubstituted; R3 and R4 are independently selected from H, halogens, and C1-C, respectively. 10 alkyl; R5 is selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 Ether group, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic alkyl, substituted or unsubstituted C1-C 10 Ester group, substituted or unsubstituted C1-C 10 Carboxyl, substituted or unsubstituted C1-C 10 Acyl group, wherein the substituent is selected from halogen, benzyloxy group, C3-C group. 10 Cycloalkyl, -COR7, -COOR7, -CONHR7; R6 is selected from halogens, hydroxyl groups, and C1-C. 10 Alkyl, C6-C 10 Aryl, benzyl, C2-C 10 Ether group, -OR5, cyano group, amino group, 5-10 heteroaryl group, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C1-C 10 Haloalkyl, C1-C 10 Ester group, C1-C 10 Carboxyl group, C1-C 10 Acyl group, C1-C 10 amide group, C1-C 10 amino group; R7 is selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic alkyl groups, wherein the substituents are selected from C1-C2. 10 Alkyl, C1-C 10 Alkoxy, C6-C 10 Aryl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, characterized in that: R2 is selected from phenyl, 9-membered heteroaryl, and C6 cycloalkyl groups that are substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from F, Cl, hydroxyl, C1-C4 alkyl, phenyl, benzyl, C3 ether, -OR5, or at least two substituents are linked to form a 5-membered heterocycloalkyl group that is substituted or unsubstituted with 1-2 R6 groups. R6 is selected from F.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, characterized in that: R5 is selected from C1-C3 alkyl, trifluoromethyl, phenyl, C3 ether, C6 cycloalkyl, 4-6 heterocyclic alkyl, C3 ester, C2 carboxyl, and C2 acyl groups, which are substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from F, benzyloxy, C3-C5 cycloalkyl, -COR7, -COOR7, and -CONHR7; R7 is selected from C1-C3 alkyl, phenyl substituted with 1-2 substituents or unsubstituted, 5-membered heteroaryl substituted with 1-2 substituents or unsubstituted, C3 cycloalkyl, 5-6-membered heterocycloalkyl, wherein the substituent is selected from methyl, C1-C3 alkoxy, phenyl.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, characterized in that: R3 and R4 are independently selected from H, F, and methyl groups, respectively.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, characterized in that: The structural formula of the compound is shown in Formula II: in, R2 is selected from phenyl groups substituted with 1-2 substituents, or sulfur-containing 9-membered heteroaryl groups, wherein the substituents are selected from methyl groups, -OR5 groups; R5 is selected from C1-C3 alkyl groups substituted or unsubstituted with 1-2 substituents, trifluoromethyl groups, and 4-6 heterocyclic alkyl groups substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from F, C3 cycloalkyl, -COR7, and -CONHR7. R7 is selected from methyl, phenyl substituted with 1-2 substituents or unsubstituted, 5-membered heteroaryl substituted with 1-2 substituents or unsubstituted, C3 cycloalkyl, 5-6-membered heterocycloalkyl, wherein the substituent is selected from methyl, C1-C3 alkoxy, phenyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, characterized in that: The structural formula of the compound is selected from:

7. A method for preparing the compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, characterized in that, Includes the following steps: Step 1: Compound e is reacted with 4-fluoro-1,2-dinitrobenzene to obtain compound f; Step 2: Reduce compound f to obtain compound g; Step 3: React compound g with triethyl orthoformate to obtain the compound shown in Formula I; Wherein, R1, R2, R3, and R4 are as described in any one of claims 1-8; In step 1, the solvent for the reaction is selected from DMF; And / or, in step 1, the reaction is carried out in the presence of a base, which is selected from at least one of potassium tert-butoxide and sodium hydride; And / or, in step 1, the reaction temperature is 20-50℃; And / or, in step 2, the solvent for the reaction is selected from a mixture of ethanol and water; And / or, in step 2, the reaction is carried out under the action of a reducing agent, which is selected from iron; And / or, in step 2, the reaction is carried out under the action of an acid, which is selected from ammonium chloride; And / or, in step 2, the reaction temperature is 70-85℃; And / or, in step 3, the solvent for the reaction is selected from acetonitrile; And / or, in step 3, the reaction is carried out in the presence of a catalyst, which is selected from elemental iodine; And / or, in step 3, the reaction temperature is 20-30℃.

8. Use of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, in the preparation of a glutamine cyclase inhibitor.

9. The use according to claim 8, characterized in that: The glutamine cyclase inhibitor is a secretory glutamine cyclase inhibitor and / or a Golgi-resident glutamine cyclase inhibitor. And / or, the glutamine cyclase inhibitor is a drug used to treat at least one of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, tumors, synovitis, gout, acute / chronic enteritis, rheumatoid arthritis, or inflammatory diseases.

10. A pharmaceutical composition, characterized in that: It is a formulation made by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof as the active ingredient.

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