Programmed cell necrosis inhibitor as well as preparation method and application thereof

Abstract

The invention provides a programmed cell necrosis inhibitor as well as a preparation method and application thereof. Specifically, the invention provides a compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, and the compound is as shown in a formula I in the specification. The invention also provides a preparation method of the compound and a pharmaceutical composition containing the compound or application of the compound in treatment or prevention of programmed necrosis of cells and / or human receptor interacting protein 1 kinase (RIPK1) related diseases or symptoms.

Description

A class of cell programmed necrosis inhibitors and their preparation method and use Technical Field

[0001] The present invention belongs to the field of small molecule compounds, and specifically relates to a class of programmed cell necrosis inhibitors and preparation methods and uses thereof. Background Art

[0002] During development and aging, the human body is constantly undergoing a dynamic regulation of cell proliferation and death. Active cell death is essential for physiological activities such as normal development, resistance to pathogenic microbial invasion, and maintenance of internal homeostasis. Its dysregulation often leads to a variety of diseases, including developmental malformations, immune system disorders, neurodegenerative diseases, and cancer, and even individual death. Therefore, intervening in programmed cell death is of great significance for disease treatment research. Apoptosis was the first mechanism of programmed cell death to be elucidated, and in recent years, programmed cell death (necroptosis) has become a new hot topic in the field of cell death. Numerous studies have reported that programmed cell death, a key pathological feature, is present in a variety of degenerative diseases (e.g., Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and retinal degenerative diseases), ischemia-reperfusion injury (e.g., cerebral infarction, myocardial infarction), and pathogen infection.

[0003] On the other hand, the activation of programmed cell necrosis pathways is often accompanied by the occurrence of inflammation. Persistent inflammation may cause irreversible damage to human tissues or organs, and also promote the progression of a variety of diseases such as cardiovascular disease, diabetes, cancer, non-alcoholic fatty liver disease, degenerative diseases or metabolic syndrome, and is described as the root of all diseases. Various chronic inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis or hepatitis, not only seriously affect the health and quality of life of patients, but may also trigger fatal myocardial infarction or cancer; and acute inflammatory storms caused by infection, such as sepsis or severe pneumonia caused by new coronavirus infection, may directly endanger life; tumor immunotherapy using CAR-T cells or PD-1 / PD-L1 antibodies often has varying degrees of acute inflammatory side effects, seriously affecting the quality of life or life safety of patients. Furthermore, programmed necrosis and inflammation also play a role in regulating the tumor microenvironment: lung cancer cells can induce programmed necrosis in specific cells within the vascular wall, enabling them to pass through the circulatory system and metastasize. Overexpression of the main component of the necrosome in pancreatic cancer can induce expression of the chemokine CXCL1, thereby suppressing the body's immune response. Therefore, inhibiting programmed necrosis is recognized to be beneficial in the treatment and alleviation of various diseases.

[0004] Studies have shown that tumor necrosis factor α (TNF-α) is one of the main pathways that stimulates programmed necrosis and inflammation in cells in the body, and its downstream signaling pathway is also the necrosis signaling pathway with the most clear mechanism. In this pathway, RIPK1 plays a key regulatory role: by forming signaling complex I (Complex I) with the TNFα receptor protein TNFR1 and other regulatory factors (TRADD, TRAF2, cIAP1 / 2, etc.), it activates the IKK complex and the NF-κB inflammatory pathway; after kinase activity is activated, it enters the cytoplasm and forms Complex IIa with apoptotic factors (FADD, Caspase-3, etc.) to mediate the occurrence of cell apoptosis; or it activates RIPK3 and polymerizes with it to form the necrosome Complex IIb, ultimately inducing the occurrence of programmed cell necrosis (necroptosis). During the process of programmed necrosis, the cell membrane structure is destroyed and a large number of inflammatory factors are released, thereby inducing a chain reaction of inflammation and cell death. Studies have shown that genetic mutations in the RIPK1 gene (D324V, D324H) cause abnormal accumulation and activation of RIPK1 protein, leading to the occurrence of autoimmune diseases; during the aging process, mutational inactivation of upstream inhibitory regulatory factors (such as OPTN, TBK1, TAK1, A20, CYLD, etc.) can also lead to RIPK1 activation, thereby aggravating degenerative diseases and inflammatory conditions; in a variety of fungal or viral infections and organ ischemia-reperfusion injuries, RIPK1 is also abnormally activated, thereby inducing the occurrence of inflammatory cell death. In the treatment of central nervous system diseases, antibody drugs have the disadvantages of being difficult to penetrate the blood-brain barrier and immunogenicity, while many existing targeted small molecule drugs may affect the normal function of neuronal cells; at the same time, the inhibition of certain key immune pathways will inevitably affect the normal immune function of the human body, thereby bringing the risk of serious infection. Therefore, RIPK1 kinase is recognized as a potential therapeutic target for a variety of degenerative or inflammatory diseases.

[0005] In preclinical studies, the first-in-class RIPK1 inhibitor Necrostatin-1 (Nec-1) and its analogs have demonstrated clear therapeutic effects on a variety of degenerative diseases, inflammation, cancer and other diseases. For example, it has a relieving effect on AD, ALS, MS, Parkinson's disease (PD), Huntington's disease (PD), inflammatory bowel disease, age-related macular degeneration, etc.; it has a protective effect on psoriasis, retinitis pigmentosa, inflammatory bowel disease, autoimmune diseases, bombesin-induced acute pancreatitis and sepsis / systemic inflammatory response syndrome (SIRS); it can effectively alleviate ischemic brain injury, ischemic myocardial injury, retinal ischemia / reperfusion injury, retinal detachment-induced photoreceptor cell necrosis, glaucoma, renal ischemia-reperfusion injury, cisplatin-induced renal injury and traumatic brain injury; it can at least partially alleviate other diseases associated with RIPK1-dependent apoptosis, necrosis or cytokine production, including blood and solid organ malignancies, bacterial infections and viral infections (including tuberculosis, influenza, etc.) and lysosomal storage diseases (especially Gaucher disease). Currently, multiple RIPK1 inhibitors are also in clinical trials for the treatment of various autodegenerative or immune diseases. For example, Sanofi's SAR443820 is in Phase II clinical trials for ALS and MS, and its SAR443122 is in Phase II clinical trials for lupus erythematosus and ulcerative bowel disease.

[0006] However, existing RIPK1 inhibitors all have varying degrees of deficiencies. For one thing, chronic diseases associated with programmed cell death, particularly degenerative diseases of the central nervous system, place high demands on drug safety. For example, Sanofi's SAR443060, originally in Phase I clinical trials, was found to have chronic toxic side effects in primates even after reaching the Phase I endpoint, forcing it to be replaced with SAR443820 for clinical trials. Furthermore, most RIPK1 inhibitors in clinical trials are analogs of GSK2982772, and their shared structural framework limits the scope for optimizing drugability. Such inhibitors often fail to effectively inhibit RIPK1 in non-primates, which limits their validation in preclinical disease models and hinders the selection of clinical indications. Finally, RIPK1 inhibitors that are both highly active and brain-penetrating are very limited, and their long-term safety also requires further verification. Therefore, small-molecule RIPK1 kinase inhibitors with a different chemical structure than GSK2982772, combined with high activity, high specificity, and high blood-brain barrier penetration, remain both a challenge and a hot topic in the development of new clinical drugs for necroptosis-related diseases. In summary, there is an urgent need for new RIPK1 inhibitors and / or necroptosis inhibitors with novel chemical structures and enhanced pharmacokinetic and pharmacodynamic properties as candidate drugs for the prevention and treatment of diseases involving cell death and / or inflammation.

[0007] Summary of the Invention

[0008] The purpose of the present invention is to provide a class of necroptosis inhibitors as candidate drugs for preventing and treating diseases or disorders associated with necroptosis and / or human receptor interacting protein 1 kinase (RIPK1).

[0009] The first aspect of the present invention provides a compound as shown in the following formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0010] Where:

[0011] X1 is selected from the group consisting of CH, N, or a chemical bond;

[0012] X2, X3, X4 and X5 are each independently selected from the group consisting of CH, N;

[0013] provided that the ring formed by X1, X2, X3, X4 and X5 is an aromatic ring;

[0014] M is selected from the group consisting of O, S, NR3, CHR3, or C(R3)2;

[0015] W and U are each independently selected from the group consisting of O, S, NR4, CHR4 or C(R4)2;

[0016] Ring A and Ring B are each independently selected from the group consisting of a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group;

[0017] R1 and R2 are each independently selected from the group consisting of none, H, substituted or unsubstituted C1-C6 alkyl, halogen;

[0018] When M is NR3, CHR3 or C(R3)2, R2 and R3 may form a substituted or unsubstituted 5-7 membered ring together with the C atom or N atom to which they are connected, and -CC(O)-;

[0019] R3 and R4 are selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, halogen;

[0020] R6 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkyne, or -CH≡CR5; wherein R5 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl;

[0021] R7 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkyne, or -CH≡CR8; wherein R8 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl;

[0022] Wherein, the substitution refers to that the hydrogen atoms on the group are replaced by one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 hydroxyalkyl, methylsulfone, -S(=O)2NH2, oxo (=O), -CN, hydroxyl, -NH2, carboxyl, C2-C6 amide (-C(=O)-N(R c) 2 or -NH-C(=O)(Rc), Rc is H or C1-C5 alkyl), C1-C6 alkyl-(C2-C6 amide), C1-C6 amine, deuterated C1-C6 amine, -NHRd (Rd is C3-C8 cycloalkyl, 4-7 membered heterocyclyl or heterocyclyl substituted by C1-C6 alkyl), C6-C10 aryl, 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, 4-7 membered heterocyclyl substituted by 1 or 2 Re (Re is halogen, C1-C6 alkyl, C1-C6 amine, -CN, C1-C6 alkoxy or 4-7 membered heterocyclyl).

[0023] In another preferred embodiment, the formula I has the structure shown in the following formula II:

[0024] M, W, U, A, B, R1, R6, and R7 are as defined above.

[0025] In another preferred embodiment, the A ring and the B ring are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaryl;

[0026] Substitution is as defined above.

[0027] In another preferred embodiment, the A ring and the B ring are each independently selected from the following group:

[0028] In another preferred embodiment, the A ring is an unsubstituted phenyl group.

[0029] In another preferred embodiment, the B ring is an unsubstituted phenyl group.

[0030] In another preferred embodiment, the M is NR3, and / or

[0031] W is CHR4;

[0032] R6 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl;

[0033] R7 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkyne, or -CH≡CR8; wherein R8 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl;

[0034] R3, R4 and substitution are as defined above.

[0035] In another preferred embodiment, R7 is selected from the following group: H, halogen, CN, -CH≡CR8; wherein, R8 is selected from the following group: substituted or unsubstituted 5-12 membered nitrogen-containing heteroaryl, substituted or unsubstituted 4-8 membered nitrogen-containing heterocyclic group.

[0036] In another preferred embodiment, the formula I has a structure shown in the following formula III:

[0037] M, W, U, A, B, X5, R1, R2, R3, R6, and R8 are defined as above.

[0038] In another preferred embodiment, the formula I has the structure shown in the following formula II:

[0039] M, W, U, A, B, R1, R6, and R8 are as defined above.

[0040] In another preferred embodiment, the compound shown in Formula I is selected from the following table:

[0041] The second aspect of the present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable carrier.

[0042] In the fourth aspect of the present invention, provided is a use of the compound according to the first aspect or the pharmaceutical composition according to the third aspect in the preparation of a medicament for treating or preventing diseases or conditions associated with programmed cell death and / or human receptor interacting protein 1 kinase (RIPK1).

[0043] In another preferred embodiment, the compound or pharmaceutical composition treats or prevents the disease or condition by inhibiting human receptor interacting protein 1 kinase (RIPK1).

[0044] In another preferred embodiment, the human receptor interacting protein 1 kinase (RIPK1) includes RIPK1 in an inactive (or unactivated) state and RIPK1 in an activated state.

[0045] In another preferred embodiment, the compound or pharmaceutical composition can also treat or prevent (especially treat) the disease or condition by inhibiting the activated human receptor interacting protein 1 kinase (RIPK1).

[0046] In another preferred embodiment, the inhibition of human receptor interacting protein 1 kinase (RIPK1) includes one or more of the following: inhibiting the activity of RIPK1, or inhibiting the phosphorylation of RIPK1.

[0047] In another preferred embodiment, the compound or pharmaceutical composition treats or prevents the disease or condition by inhibiting the programmed necrosis signaling pathway.

[0048] In another preferred embodiment, the inhibition of programmed necrosis pathway includes one or more of the following: inhibiting the activity of RIPK1, inhibiting the phosphorylation of RIPK1, or inhibiting the phosphorylation of MLKL.

[0049] In another preferred embodiment, the disease or condition is selected from one or more of the following groups: degenerative diseases, inflammation, ischemia-reperfusion injury, pathogen infection, Parkinson's disease (PD), age-related macular degeneration, autoimmune diseases, retinal detachment-induced photoreceptor cell necrosis, glaucoma, cisplatin-induced renal injury and traumatic brain injury, atherosclerosis caused by hyperlipidemia, other diseases related to RIPK1-dependent apoptosis, necrosis or cytokine production, bacterial infection, viral infection and lysosomal storage disease.

[0050] In another preferred embodiment, the degenerative diseases include: Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and retinal degenerative diseases.

[0051] In another preferred embodiment, the inflammation includes one or more of the following: enteritis, rheumatoid arthritis, psoriasis, retinitis pigmentosa, inflammatory bowel disease, Tinton's disease (PD), inflammatory bowel disease, bombesin-induced acute pancreatitis, sepsis / systemic inflammatory response syndrome (SIRS).

[0052] In another preferred embodiment, the ischemia-reperfusion injury includes one or more of the following: cerebral infarction, myocardial infarction, ischemic brain injury, ischemic myocardial injury, retinal ischemia / reperfusion injury, and renal ischemia-reperfusion injury.

[0053] In another preferred embodiment, the other diseases associated with RIPK1-dependent apoptosis, necrosis or cytokine production include one or more of the following: hematological and solid organ malignancies.

[0054] In another preferred embodiment, the viral infection includes one or more of the following diseases or conditions: tuberculosis, influenza, coronavirus infection and pneumonia caused therefrom.

[0055] In another preferred embodiment, the lysosomal storage disease includes Gaucher disease.

[0056] In the fourth aspect of the present invention, a method for treating or preventing diseases or conditions associated with programmed cell death and / or human receptor interacting protein 1 kinase (RIPK1) is provided, the method comprising: administering a therapeutically effective amount of the compound as described in the first aspect or the pharmaceutical composition as described in the second aspect to a subject in need.

[0057] In a fifth aspect of the present invention, a method for inhibiting programmed cell necrosis is provided, comprising the steps of culturing cells in the presence of the compound according to the first aspect, thereby inhibiting programmed cell necrosis.

[0058] In another preferred embodiment, the method is non-therapeutic in vitro.

[0059] In a sixth aspect of the present invention, a method for inhibiting RIPK1 protein kinase activity is provided, comprising the step of contacting RIPK1 protein kinase with the compound according to the first aspect, thereby inhibiting RIPK1 protein kinase activity.

[0060] In another preferred embodiment, the method is non-therapeutic in vitro.

[0061] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] FIG1 shows the effect of the representative compound QY-18-26 on RIPK1 kinase activity.

[0063] Figure 2 shows the pharmacokinetic properties of the representative compound QY-18-26.

[0064] FIG3 shows the brain penetration properties of the representative compound QY-18-26.

[0065] FIG4 shows the effect of the representative compound QY-18-26 on the systemic inflammatory response syndrome induced by TNFα. DETAILED DESCRIPTION

[0066] After long and in-depth research, the inventors unexpectedly discovered a class of novel structural necroptosis inhibitors. The necroptosis inhibitors have excellent RIPK1 inhibitory activity. Therefore, they can be used to prepare pharmaceutical compositions for preventing and / or treating diseases involving cell death, RIPK1 and / or inflammation. In particular, the preferred compounds provided by the present invention also have excellent inhibitory activity against activated RIPK1. Therefore, compared with existing RIPK1 inhibitors that only inhibit inactivated RIPK1, the compounds provided by the present invention have faster improvement or treatment of diseases or conditions (such as inflammation) involving cell death and / or RIPK1 inflammation. Based on the above findings, the inventors completed the present invention.

[0067] the term

[0068] Unless expressly stated otherwise, the terms used according to the present invention and herein have the following meanings:

[0069] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms. For example, a C1-C6 alkyl group refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like, or similar groups.

[0070] The term "cycloalkyl" refers to a cyclic alkyl group having the specified number of carbon atoms. For example, "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 1 to 8 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0071] The term "alkoxy" refers to an alkyl group as defined above, which is attached to the remainder of the molecule through an oxygen atom. For example, C1-C6 alkoxy refers to C1-C6 alkyl-O-.

[0072] The term "halogen" refers to F, Cl, Br and I.

[0073] The term "haloalkyl" refers to an alkyl group (alkyl is as defined above) substituted with a halogen.

[0074] The term "aryl" refers to a polyunsaturated (usually aromatic) hydrocarbon group having a specified number of ring atoms, which can be a single ring or multiple rings (such as a bicyclic ring) fused together or linked covalently. Examples of aryl include, but are not limited to, phenyl and naphthyl.

[0075] The term "heteroaryl" refers to an aryl group (or ring) having the specified number of ring atoms and containing 1 to 5 (e.g., 1, 2, 3, 4, or 5) heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized; for example, a 5-10 membered heteroaryl group (or ring) refers to a heteroaryl group (or ring) containing 5, 6, 7, 8, 9, or 10 ring atoms. As used herein, a nitrogen-containing heteroaryl group means that at least one of the heteroatoms contained is a nitrogen heteroatom. The heteroaryl group can be attached to the rest of the molecule through a heteroatom. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, and thienyl.

[0076] The term "pharmaceutically acceptable" refers to a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic response), ie, at a reasonable benefit / risk ratio.

[0077] The term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or preventive effect. The precise effective amount for a given subject depends on the subject's size and health, the nature and extent of the condition, and the therapeutic agent and / or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and is within the judgment of the clinician.

[0078] Unless otherwise specified, all compounds mentioned in the present invention are intended to include all possible optical isomers, such as single chiral compounds or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0079] The term "compound of the present invention" refers to a compound of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula I.

[0080] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0081] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0082] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0083] Synthesis Example 1

[0084] Method 1:

[0085] Synthesis of compound QY-12-88:

[0086] Methyl 1-methyl-1H-1,2,3-triazole-4-carboxylate (QY-12-88): In a 100-mL round-bottom flask, dissolve methyl 1,2,3-triazole-4-carboxylate (1.27 g, 10.0 mmol) in 20 mL of N,N-dimethylformamide. Add potassium carbonate (0.83 g, 6.0 mmol) at room temperature. Add iodomethane (1.50 g, 10.5 mmol) dropwise to the reaction mixture in an ice bath. Stir for 1 hour, then gradually return to room temperature and continue stirring for 16 hours. Stop the reaction when substrate consumption is complete, as monitored by LC-MS. After removing the organic solvent by rotary evaporation, the reaction solution was diluted with dichloromethane and transferred to a separatory funnel. The mixture was washed with distilled water (10 mL x 3) and extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed with saturated sodium chloride (10 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove dichloromethane. The mixture was then separated and purified by silica gel column chromatography (PE:EA = 10-90%) to obtain 305 mg of a white powdery solid in a 22% yield. ESI-MS m / z 142.1 (M+H) + .

[0087] Synthesis of compound QY-12-95:

[0088] Methyl 5-benzyl-1-methyl-1H-1,2,3-triazole-4-carboxylate (QY-12-95): To a 15 mL pressure bottle, add 5 mL of toluene and QY-12-88 (305 mg, 2.16 mmol). Stir thoroughly, then add palladium acetate (24 mg, 0.11 mmol), triphenylphosphine (113 mg, 0.43 mmol), potassium carbonate (746 mg, 5.40 mmol), and pivalic acid (66 mg, 0.65 mmol). Benzyl chloride (274 mg, 2.16 mmol) is added dropwise. Heat to 100°C under nitrogen and react overnight. Once the starting materials are consumed, remove the toluene by rotary evaporation. Dilute the reaction solution with ethyl acetate, filter with celite, and remove the organic solvent by rotary evaporation. Purify the solution by silica gel column chromatography (PE:EA = 0-80%) to afford 173 mg of a light yellow, transparent oily liquid in a 35% yield. ESI-MS m / z 232.1 (M+H) + .

[0089] Synthesis of compound QY-13-15:

[0090] 5-Benzyl-1-methyl-1H-1,2,3-triazole-4-carboxylic acid (QY-13-15): QY-12-95 (173 mg, 0.75 mmol) was dissolved in 3 mL of tetrahydrofuran and transferred to an 8 mL pressure bottle. Lithium hydroxide monohydrate (63 mg, 1.50 mmol) was dissolved in 0.8 mL of distilled water and added dropwise to the reaction solution at room temperature. The reaction progress was monitored in real time by LC-MS. After 8 h, the starting material was consumed. All solvents in the reaction system were removed by rotary evaporation. The crude product was directly used for subsequent synthesis without purification. ESI-MS m / z 218.0 (M+H) + .

[0091] Synthesis of compound QY-13-17:

[0092] (S)-5-Benzyl-N-(1-(4-iodophenyl)ethyl)-1-methyl-1H-1,2,3-triazole-4-carboxamide (QY-13-17): QY-13-15 (0.75 mmol) was dissolved in 5 mL of N,N-dimethylformamide in a 15 mL pressure bottle. HATU (341 mg, 0.90 mmol) and 4-iodobenzylamine (174 mg, 0.75 mmol) were added. N,N-diisopropylethylamine (289 mg, 2.24 mmol) was added dropwise at room temperature and the mixture was stirred continuously at room temperature. LC-MS real-time monitoring. After the reaction was complete, 15 mL of dichloromethane was added to dilute the reaction solution, which was then transferred to a separatory funnel and washed with 10 mL of distilled water. The solution was extracted with dichloromethane (10 mL x 3). The organic phases were combined and washed with saturated sodium chloride (10 mL x 2). The organic phase obtained after post-treatment was dried over anhydrous sodium sulfate, filtered, and spin-dried to remove dichloromethane. The product was then separated and purified by silica gel column chromatography (PE:EA = 0-100%) to obtain 153 mg of a white foamy solid in a 47% yield. ESI-MS m / z 447.0 (M+H) + .

[0093] Synthesis of compound QY-18-26:

[0094] (S)-5-Benzyl-1-methyl-N-(1-(4-(pyridin-2-ylethynyl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide (QY-18-26): In an 8 mL pressure bottle, 1 mL of tetrahydrofuran and QY-13-15 (32 mg, 0.072 mmol) were added in sequence. After stirring and dissolving evenly, 2-ethynylpyridine (11 mg, 0.11 mmol), cuprous iodide (2.7 mg, 0.014 mmol), N,N-diisopropylethylamine (37 mg, 0.288 mmol), and bis(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol) were added. The reaction was stirred at room temperature under nitrogen protection. After the reactants were consumed, the mixture was filtered through celite and the organic solvent was removed by rotary evaporation. The product was then purified by silica gel column chromatography (PE:EA = 10–80%) to obtain 10 mg of a yellow-brown oily liquid with a yield of 33%. ESI-MS m / z 422.2 (M+H) + .

[0095] Method 2:

[0096] Synthesis of compound QY-16-97:

[0097] Ethyl 3-(tert-Butoxymethyl)-1H-pyrazole-4-carboxylate (QY-16-97): Ethyl 4-(tert-Butoxy)-3-oxobutanoate (2.98 g, 14.7 mmol) and dimethoxy-N,N-dimethylmethanamine (2.45 g, 20.6 mmol) were uniformly dissolved in 25 mL of toluene, heated to 65 ° C and stirred for overnight, and then the organic solvent was directly removed by rotary evaporation; 9 mL of glacial acetic acid was added to dissolve the reaction system, and hydrazine hydrate (1.03 g, 20.6 mmol) was slowly added dropwise to the reaction solution while stirring at room temperature, and the reaction was stirred at room temperature overnight. The reaction system was diluted with 250 mL of ethyl acetate and transferred to a separatory funnel. The product was washed with saturated sodium bicarbonate solution (50 mL x 2), distilled water (10 mL x 2), and saturated sodium chloride (10 mL x 2). The product was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by rotary evaporation. The product was then purified by silica gel column chromatography (PE:EA = 0-60%) to obtain 1.76 g of an orange-yellow oily liquid in a 53% yield. ESI-MS m / z 227.1 (M+H) + .

[0098] Synthesis of compound QY-16-98:

[0099] Ethyl 3-(tert-Butoxymethyl)-1-methyl-1H-pyrazole-4-carboxylate (QY-16-98): In a 100 mL round-bottom flask, QY-16-97 (1.76 g, 7.8 mmol) was dissolved in 35 mL of acetonitrile. Cesium carbonate (6.34 g, 19.5 mmol) was added at room temperature. Methyl iodide (1.32 g, 9.3 mmol) was added dropwise to the reaction mixture under ice-cooling. The mixture was gradually returned to room temperature and stirred for 10 h. The reaction was stopped after substrate consumption was monitored by LC-MS. The organic solvent was removed by rotary evaporation, and the reaction mixture was diluted with ethyl acetate and transferred to a separatory funnel. The mixture was washed with distilled water (10 mL x 2) and saturated sodium chloride (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the dichloromethane was removed by rotary evaporation. The mixture was purified by silica gel column chromatography (PE:EA = 0–80%) to obtain 624 mg of a light yellow, transparent oil in a 33% yield. ESI-MS m / z 241.2 (M+H) + .

[0100] Synthesis of compound QY-17-11:

[0101] Ethyl 5-benzyl-3-(tert-butoxymethyl)-1-methyl-1H-pyrazole-4-carboxylate (QY-17-11): To a 30 mL pressure bottle, add 10 mL of toluene and QY-16-98 (603 mg, 2.51 mmol). Stir thoroughly, then add palladium acetate (56 mg, 0.25 mmol), triphenylphosphine (262 mg, 1.0 mmol), potassium carbonate (1214 mg, 8.79 mmol), and pivalic acid (77 mg, 0.75 mmol). Benzyl chloride (413 mg, 3.26 mmol) is added dropwise. Heat to 110°C under nitrogen and react overnight. Once the starting materials are consumed, remove the toluene by rotary evaporation. The reaction mixture is diluted with ethyl acetate, filtered through celite, and the organic solvent is removed by rotary evaporation. Purification by silica gel column chromatography (PE:EA = 0–50%) affords 108 mg of a light yellow, transparent oily liquid in a 13% yield. ESI-MS m / z 331.1 (M+H) + .

[0102] Synthesis of compound QY-17-54:

[0103] Ethyl 5-benzyl-3-(hydroxymethyl)-1-methyl-1H-pyrazole-4-carboxylate (QY-17-54): QY-17-11 (108 mg, 0.33 mmol) was directly dissolved in 2 mL of hydrogen chloride in dioxane. The reaction was stirred at room temperature for 4 hours until complete. The product was separated and purified by C18 reverse-phase chromatography (CH3CN:H2O = 10-90%) to give 60 mg of a light yellow, transparent oily liquid in a 66% yield. ESI-MS m / z 275.1 (M+H)+ .

[0104] Synthesis of compound QY-17-69:

[0105] 5-Benzyl-3-formyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (QY-17-69): QY-17-54 (86 mg, 0.31 mmol) was directly dissolved in 4 mL of dichloromethane. Manganese dioxide powder (136 mg, 1.57 mmol) was added and heated to reflux with stirring overnight. The reaction was monitored by LC-MS. The solid was removed by filtration and the dichloromethane was removed by rotary evaporation to obtain a light yellow oily liquid product, which was directly used for the next reaction without isolation and purification. ESI-MS m / z 273.1 (M+H) + .

[0106] Synthesis of compound QY-18-57:

[0107] (S)-5-Benzyl-3-(((1-(4-iodophenyl)ethyl)amino)methyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (QY-18-57): QY-17-69 (0.169 mmol) was mixed with 3 mL of 1,2-dichloroethane and stirred in a 15 mL pressure bottle. (S)-1-(4-iodophenyl)ethan-1-amine hydrochloride (62 mg, 0.22 mmol), glacial acetic acid (3 drops), and sodium triacetoxyborohydride (90 mg, 0.42 mmol) were added and stirred at room temperature overnight. The reaction was stopped upon completion as monitored by LC-MS. The organic solvent was removed by rotary evaporation, and the reaction mixture was dissolved in dimethyl sulfoxide and filtered. The mixture was separated and purified by C18 reverse phase chromatography (CH3CN:H2O=10-90%) to afford 73 mg of a colorless, transparent oily liquid in an 86% yield. ESI-MS m / z 504.1 (M+H) + .

[0108] Synthesis of compound QY-18-59:

[0109] (S)-5-Benzyl-3-(((1-(4-iodophenyl)ethyl)amino)methyl)-1-methyl-1H-pyrazole-4-carboxylic acid (QY-18-59): QY-18-57 (73 mg, 0.145 mmol) was dissolved in 2 mL of ethanol and 2 mL of tetrahydrofuran, and transferred to a 15 mL pressure bottle. Sodium hydroxide (58 mg, 1.45 mmol) was dissolved in 1.0 mL of distilled water and added dropwise to the reaction solution at room temperature. The mixture was heated to 40°C and stirred overnight. The reaction was stopped after LC-MS monitoring of the reaction completion. 2N hydrochloric acid was added to acidify the reaction system to weak acidity, and the mixture was filtered through a C18 Reverse phase chromatography (CH3CN:H2O=0-80%) was used to separate and purify the product to give 46 mg of a colorless, transparent oily liquid with a yield of 67%. ESI-MS m / z 476.0 (M+H) + .

[0110] Synthesis of compound QY-18-62:

[0111] (S)-3-benzyl-5-(1-(4-iodophenyl)ethyl)-2-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one(QY-18-62): QY-18-59 (46 mg, 0.097 mmol) was dissolved in 2.5 mL of N,N-dimethylformamide in a 15 mL pressure bottle. HATU (44 mg, 0.116 mmol) was added, and N,N-diisopropylethylamine (50 mg, 0.388 mmol) was added dropwise at room temperature. Stirring was continued at room temperature. LC-MS was used for real-time monitoring. After the reaction was completed, trifluoroacetic acid was added to the reaction solution to adjust it to weak acidity. After filtration, the mixture was filtered through a C 18 Reverse phase chromatography (CH3CN:H2O=10-80%) was used to separate and purify the product to give 27 mg of a colorless, transparent oily liquid with a yield of 61%. ESI-MS m / z 457.9 (M+H) + .

[0112] Synthesis of compound QY-18-63:

[0113] (S)-3-benzyl-2-methyl-5-(1-(4-(pyridin-2-ylethynyl)phenyl)ethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one(QY-18-63): In a 15 mL pressure bottle, 1 mL of tetrahydrofuran and QY-18-62 (46 mg, 0.097 mmol) were added in sequence. After stirring and dissolving evenly, 2-ethynylpyridine (9.1 mg, 0.089 mmol), cuprous iodide (2.2 mg, 0.012 mmol), N,N-diisopropylethylamine (50 mg, 0.388 mmol), and bis(triphenylphosphine)palladium dichloride (4.1 mg, 0.006 mmol) were added. The reaction was stirred at room temperature under nitrogen protection. After the reactants were consumed, the organic solvent was removed by filtration through celite and rotary evaporation. The product was then purified by silica gel column chromatography (PE:EA = 10–100%) to obtain 21 mg of a yellow-brown oily liquid with a yield of 82%. ESI-MS m / z 433.2 (M+H) +.

[0114] According to the above method, by replacing different synthetic substrates, the compounds shown in Table 1 were obtained:

[0115] Table 1

[0116] The NMR data of the compounds shown in Table 1 are as follows:

[0117] QY-17-24: 1 H NMR(400MHz,DMSO-d6)δ9.06(d,J=8.4Hz,1H),7.65(t,J=1.8Hz,1H),7.42(dt,J=7.9,1.8Hz,2H),7.32-7.25(m, 3H),7.24-7.15(m,3H),5.16(p,J=7.3Hz,1H),4.41(q,J=15.3Hz,2H),3.89(s,3H),1.49(d,J=7.1Hz,3H).ESI-MS m / z 399.0(M+H) + .

[0118] QY-17-25: 1 H NMR(400MHz,DMSO-d6)δ8.92(d,J=8.5Hz,1H),7.42(d,J=7.1Hz,2H),7.37-7.09(m,8H), 5.18(p,J=7.3Hz,1H),4.42(q,J=15.3Hz,2H),3.88(s,3H),1.50(d,J=7.1Hz,3H).ESI-MS m / z 321.1(M+H) + .

[0119] QY-18-15: 1H NMR(400MHz,DMSO-d6)δ8.96(d,J=8.3Hz,1H),7.73-7.61(m,2H),7.33-7.13(m,7H),5.12(p,J=7.3Hz,1H),4.40(q,J=15.3Hz,2H),3.88(s,3H),1.48(d,J=7.1Hz,3H).ESI-MS m / z 446.9(M+H) + .

[0120] QY-18-25: 1 H NMR(400MHz,DMSO-d6)δ9.02(d,J=8.4Hz,1H),8.75(d,J=2.1Hz,1H),8.59(dd,J=4.9,1.7Hz,1H),7.98(dt,J=8.0,2.0Hz,1H),7.56(d,J=8.0Hz,2H),7.52-7.44(m,3H),7.28(t,J=7.3Hz,2H),7.24-7.15(m,3H),5.21(q,J=7.4Hz,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z 422.2(M+H) + .

[0121] QY-18-26: 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.4Hz,1H),8.61(d,J=4.8Hz,1H),7.86(td,J=7.8,1.9Hz,1H),7.64(d,J=7.8Hz,1H),7.58(d,J=7.9Hz,2H),7.50(d,J=7.9Hz,2H),7.42(dd,J=7.6,4.9Hz,1H),7.28(t,J=7.3Hz,2H),7.24-7.15(m,3H),5.22(p,J=7.1Hz,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.52(d,J=7.0Hz,3H).ESI-MS m / z 422.2(M+H) + .

[0122] QY-18-27: 1H NMR(400MHz,DMSO-d6)δ9.04(d,J=8.3Hz,1H),8.69(s,2H),7.65(d,J=5.1Hz,2H),7.60(d,J=8.1Hz,2H),7.52(d,J=8.0Hz,2H),7.28(t,J=7.3Hz,2H),7.24-7.16(m,3H),5.22(p,J=7.2Hz,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z 422.2(M+H) + .

[0123] QY-18-28: 1 H NMR(400MHz,DMSO-d6)δ9.01(d,J=8.4Hz,1H),7.89(d,J=8.6Hz,4H),7.64(dd,J=8.4,1.8Hz,1H),7.48(pd,J=7.1,1.7Hz,2H),7.28-7.22(m,2H),7.22-7.14(m,3H),5.35(p,J=7.2Hz,1H),4.52-4.21(m,2H),3.88(s,3H),1.60(d,J=7.0Hz,3H).ESI-MS m / z 371.2(M+H) + .

[0124] QY-18-41: 1 H NMR(400MHz,DMSO-d6)δ9.12(d,J=8.2Hz,1H),7.80(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,2H),7.30-7.24(m,2H),7.24-7.12(m,3H),5.22(p,J=7.3Hz,1H),4.40(q,J=15.3Hz,2H),3.88(s,3H),1.51(d,J=7.1Hz,3H).ESI-MS m / z 346.1(M+H) + .

[0125] QY-18-42: 1H NMR(400MHz,DMSO-d6)δ8.95(d,J=8.4Hz,1H),7.40(d,J=8.0Hz,2H),7.34(d,J=7.9Hz,2H),7.27(d,J=7.2Hz,2H),7.20(dd,J=14.8,7.1Hz,3H),5.18(p,J=7.1Hz,1H),4.41(q,J=15.3Hz,2H),3.88(s,3H),1.49(d,J=7.0Hz,3H),1.45(s,6H).ESI-MS m / z 403.2(M+H) + .

[0126] QY-18-43: 1 H NMR(400MHz,DMSO-d6)δ8.97(d,J=8.3Hz,1H),8.05(s,1H),7.67(s,1H),7.43(s,4H),7.28(t,J=7.3Hz,2H),7.24-7.16(m,3H),5.19(p,J=7.2Hz,1H),4.42(q,J=15.3Hz,2H),3.88(s,3H),3.85(s,3H),1.50(d,J=7.0Hz,3H).ESI-MS m / z 425.2(M+H) + .

[0127] QY-18-44: 1 H NMR(400MHz,DMSO-d6)δ8.95(d,J=8.4Hz,1H),7.37(q,J=8.4Hz,4H),7.28(dd,J=7.9,6.3Hz,2H),7.24-7.13(m,3H),5.17(p,J=6.9Hz,1H),4.41(q,J=15.3Hz,2H),3.88(s,3H),3.83-3.76(m,2H),3.48-3.40(m,2H),2.87(tt,J=9.0,4.1Hz,1H),1.90-1.76(m,2H),1.64-1.54(m,2H),1.49(d,J=7.0Hz,3H).ESI-MS m / z 429.2(M+H) + .

[0128] QY-18-47: 1H NMR(400MHz,DMSO-d6)δ8.93(d,J=8.6Hz,1H),7.36(d,J=8.0Hz,2H),7.33-7.24(m,4H),7.24-7.15(m,3H),5.16(p,J=7.4Hz,1H),4.41(q,J=15.3Hz,2H),3.88(s,3H),1.57-1.50(m,1H),1.49(s,3H),0.92-0.82(m,2H),0.75-0.66(m,2H).ESI-MS m / z 385.1(M+H) + .

[0129] QY-18-49: 1 H NMR(400MHz,DMSO-d6)δ8.98(d,J=8.4Hz,1H),7.54-7.37(m,4H),7.31-7.24(m,2H),7.24-7.14(m,3H),5.18(p,J=7.2Hz,1H),4.41(q,J=15.3Hz,2H),4.12(s,1H),3.88(s,3H),1.49(d,J=7.1Hz,3H).ESI-MS m / z 345.2(M+H) + .

[0130] QY-18-63: 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=4.8Hz,1H),7.86(td,J=7.7,1.8Hz,1H),7.65(d,J=7.8Hz,1H),7.60(d,J=8.0Hz,2H),7.42(dd,J=7.6,5.0Hz,1H),7.38(d,J=8.0Hz,2H),7.32(d,J=5.8Hz,4H),7.23(dt,J=5.8,2.8Hz,1H),5.46(q,J=7.2Hz,1H),4.40(d,J=16.3Hz,1H),4.19(s,2H),4.00(d,J=16.3Hz,1H),3.78(s,3H),1.61(d,J=7.2Hz,3H).ESI-MSm / z 433.2(M+H) + .

[0131] QY-18-77: 1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),9.01(d,J=8.4Hz,1H),8.95(s,1H),7.49(q,J=8.2Hz,4H),7.28(t,J=7.3Hz,2H),7.24-7.14(m,3H),5.21(p,J=7.3Hz,1H),4.42(q,J=15.4Hz,2H),3.89(s,3H),1.51(d,J=7.1Hz,4H).ESI-MS m / z 412.1(M+H) + .

[0132] QY-18-102: 1 H NMR(400MHz,DMSO-d6)δ8.62(d,J=4.8Hz,1H),7.87(td,J=7.7,1.8Hz,1H),7.64(dd,J=17.6,7.9Hz,3H),7.43(d,J=7.9Hz,3H),7.36-7.26(m,4H),7.25-7.18(m,1H),5.97(q,J=7.1Hz,1H),4.39(d,J=4.9Hz,2H),3.64(s,3H),3.50-3.42(m,1H),3.12-3.04(m,1H),2.80-2.62(m,2H),1.54(d,J=7.1Hz,3H).ESI-MS m / z 447.2(M+H) + .

[0133] QY-19-53: 1 H NMR(400MHz,DMSO-d6)δ8.98(d,J=8.4Hz,1H),7.43-7.34(m,4H),7.28(t,J=7.3Hz,2H),7.24-7.15(m,3H),5.17(p,J=7.3Hz,1H),4.53-4.29(m,2H),3.88(s,3H),3.45-3.39(m,2H),3.26-3.18(m,2H),3.15-3.09(m,1H),3.04-3.00(m,1H),2.29-2.19(m,1H),1.96-1.86(m,1H),1.49(d,J=7.1Hz,3H).ESI-MS m / z 414.2(M+H) + .

[0134] QY-19-54: 1H NMR(400MHz,DMSO-d6)δ9.00(d,J=8.4Hz,1H),8.77(s,1H),7.50-7.36(m,4H),7.28(dd,J=8.0,6.4Hz,2H),7.24-7.12(m,3H),5.18(p,J=7.1Hz,1H),4.41(q,J=15.3Hz,2H),4.15(t,J=8.8Hz,2H),4.01-3.90(m,3H),3.88(s,3H),1.49(d,J=7.0Hz,3H).ESI-MS m / z 400.2(M+H) + .

[0135] QY-19-55: 1 H NMR(400MHz,DMSO-d6)δ8.98(d,J=8.4Hz,1H),7.39(q,J=8.4Hz,4H),7.28(dd,J=8.0,6.4Hz,2H),7.24-7.13(m,3H),5.17(p,J =7.2Hz,1H),4.50-4.29(m,2H),3.88(s,3H),3.46-3.38(m,2H),3.20-3.00(m,3H),2.69(s,3H),2.42-2.32(m,1H),2.06-1.96(m,1H),1.49(d,J=7.0Hz,3H).ESI-MS m / z 428.2(M+H) + .

[0136] QY-19-56: 1 H NMR(400MHz,DMSO-d6)δ8.99(d,J=8.4Hz,1H),7.48-7.35(m,4H),7.28(t,J=7.3Hz,2H),7.24-7.13(m,3H),5.18(p,J=7.2Hz,1H),4.41(q,J=15.3Hz,2H),4.10-4.00(m,2H),3.88(s,3H),3.82-3.66(m,3H),2.64(s,3H),1.49(d,J=7.0Hz,3H).ESI-MS m / z 414.2(M+H) + .

[0137] QY-19-60: 1H NMR(400MHz,DMSO-d6)δ8.98(d,J=8.4Hz,1H),7.39(q,J=8.0Hz,4H),7.28(t,J=7.4Hz,2H),7.23-7.15(m,3H),5.18(p,J=7.2Hz,1H),4.41(q,J=15.3Hz,2H),4.10(t,J=6.6Hz,1H),3.88(s,3H),3.06-2.98(m,1H),2.92-2.84(m,1H),2.16-2.04(m,1H),1.90-1.67(m,3H),1.49(d,J=7.1Hz,3H).ESI-MS m / z 414.2(M+H) + .

[0138] QY-19-62: 1 H NMR(400MHz,DMSO-d6)δ8.98(d,J=8.4Hz,1H),7.45-7.34(m,4H),7.28(dd,J=8.1,6.6Hz,2H),7.24-7.13(m,3H),5.17(p,J=7.3Hz,1H),4.41(q,J=15.3Hz,2H),3.88(s,3H),3.39(s,1H),2.80(s,1H),2.41(s,0H),2.37(s,3H),2.13(q,J=7.3Hz,1H),1.81(ddt,J=24.7,18.6,8.0Hz,3H),1.49(d,J=7.1Hz,3H).ESI-MS m / z 428.2(M+H) + .

[0139] SYL-30-52: 1 H NMR(400MHz,DMSO-d6)δ9.08-8.98(m,1H),7.82(d,J=3.0Hz,1H),7.59(d,J=7.6Hz,1H),7.43(d,J=7.4Hz,1H),7.28(dt,J=7.2,3.5Hz,2H),7.24-7.10(m,4H),5.28-4.90(m,1H),4.56-4.27(m,2H),3.89(d,J=2.7Hz,3H),1.48(dd,J=6.8,2.8Hz,3H).ESI-MS m / z 447.1(M+H) + .

[0140] SYL-30-56: 1H NMR(400MHz,DMSO-d6)δ9.01(d,J=8.4Hz,1H),7.47(s,1H),7.40(d,J=7.7Hz,1H),7.35-7.13(m,7H),5.15(t,J=7.6Hz,1H),4.41(q,J=15.3Hz,2H),3.88(s,3H),1.49(d,J=7.0Hz,3H),1.45(s,6H).ESI-MS m / z 403.2(M+H) + .

[0141] SYL-30-58: 1 H NMR(400MHz,DMSO-d6)δ9.04(d,J=8.4Hz,1H),8.78(d,J=2.2Hz,1H),8.61(dd,J=4.9,1.7Hz,1H),8.02(dt,J=8.0,2.0Hz,1H),7.67(d,J=1.9Hz,1H),7.54-7.45(m,3H),7.41(t,J=7.6Hz,1H),7.30- 7.24(m,2H),7.22-7.13(m,3H),5.20(p,J=7.1Hz,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.53(d,J=7.1Hz,3H).ESI-MS m / z 422.2(M+H) + .

[0142] SYL-30-62: 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.4Hz,1H),7.66(s,1H),7.53(d,J=7.7Hz,1H),7.48(d,J=7.7Hz,1H),7.40(t,J=7.7Hz,1H),7.27(t,J=7.4Hz,2H),7.23-7.14(m,3H),5.18(p,J=7.3Hz,1H),4.51-4.32(m,2H),3.89(s,3H),1.51(d,J=7.0Hz,3H).ESI-MS m / z 345.1(M+H) + .

[0143] SYL-30-65: 1H NMR(400MHz,DMSO-d6)δ8.99(d,J=8.4Hz,1H),8.52(s,1H),8.39(s,1H),7.48(s,1H),7.42(d,J=7.6Hz,1H),7.35-7.24(m,4H),7.23-7.15(m,3H),5.15(p,J=7.2Hz,1H),4.50-4.26(m,2H),3.88(s,3H),3.29-3.21(m,2H),3.10-2.93(m,3H),2.08-1.98(m,2H),1.81-1.70(m,2H),1.49(d,J=7.0Hz,3H).ESI-MS m / z 428.2(M+H) + .

[0144] QY-20-1: 1 H NMR(400MHz,DMSO-d6)δ8.91(d,J=8.0Hz,1H),8.71-8.53(m,1H),7.87(td,J=7.8,1.9Hz,1H),7.66(d,J=7.8Hz,1H),7.61-7.52(m,3H),7.42(td,J=7.9,5.7Hz,3H),7.33-7.21(m,3H),7.10(dd,J=7.4,2.0Hz,2H),7.01(d,J=2.1Hz,1H),5.68(s,2H),5.14(p,J=7.2Hz,1H),1.46(d,J=7.1Hz,3H).ESI-MS m / z 407.1(M+H) + .

[0145] QY-20-2: 1 H NMR(400MHz,DMSO-d6)δ8.62(d,J=5.0Hz,1H),8.44(d,J=7.9Hz,1H),8.07(s,1H),7.88(td,J=7.7,2.0Hz,1H),7.66(d,J=7.8Hz,1H),7.59(dd,J=8.2,1.9Hz,2H),7.51-7.38(m,3H),7.29-7.23(m,2H),7.21-7.11(m,3H),5.17(p,J=7.1Hz,1H),4.46-4.35(m,2H),3.65(s,3H),1.47(d,J=7.0Hz,3H).ESI-MS m / z 421.2(M+H) + .

[0146] QY-20-5: 1H NMR(400MHz,DMSO-d6)δ8.89(d,J=7.9Hz,1H),8.70-8.56(m,1H),7.87(td,J=7.7,1.8Hz,1H),7.66(dd,J=6.1,4.3Hz,2H),7.56(d,J=7.9Hz,2H),7.48-7.35(m,3H),7.33-7.25(m,3H),7.09(dd,J=6.6,2.9Hz,2H),5.59-5.36(m,2H),5.12(p,J=7.2Hz,1H),1.42(d,J=7.0Hz,3H).ESI-MS m / z 425.2(M+H) + .

[0147] QY-20-18: 1 H NMR(400MHz,DMSO-d6)δ9.12(d,J=8.3Hz,1H),8.80(d,J=5.7Hz,1H),8.66-8.56(m,1H),7.88(td,J=7.8,1.8Hz,1H),7.66(d,J=7.9Hz,1H),7.57(d,J=8.0Hz,2H),7.54-7.41(m,5H),7.34(t,J=7.4Hz, 1H),7.29(d,J=7.9Hz,2H),7.17(d,J=5.7Hz,1H),5.12(p,J=7.2Hz,1H),1.48(d,J=7.0Hz,3H).ESI-MS m / z 420.1(M+H) + .

[0148] QY-20-53: 1 H NMR(400MHz,DMSO-d6)δ9.06(d,J=8.3Hz,1H),8.70-8.53(m,1H),7.86(td,J=7.7,1.8Hz,1H),7.65(d,J=7.8Hz,1H),7.58(d,J=8.2Hz,2H),7.50(d,J=8.1Hz,2H),7.42(ddd,J=7.6,4.9,1.3Hz,1H),7.29-7.21(m,2H),7.16-7.07(m,2H),5.22(p,J=7.3Hz,1H),4.40(q,J=15.3Hz,2H),3.90(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z 440.2(M+H) + .

[0149] QY-20-54: 1H NMR(400MHz,DMSO-d6)δ9.08(d,J=8.3Hz,1H),8.72-8.55(m,1H),7.87(td,J=7.8,1.9Hz,1H),7.66(d,J=7.8Hz,1H),7.58(d,J=8.1Hz,2H),7.50(d,J=8.1Hz,2H),7.46-7.40(m,1H),7.33(q,J=7.4Hz,1H),7.11-7.00(m,3H),5.22(p,J=7.2Hz,1H),4.50-4.37(m,2H),3.92(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z 440.2(M+H) + .

[0150] QY-20-55: 1 H NMR(400MHz,DMSO-d6)δ9.06(d,J=8.3Hz,1H),8.90(s,1H),7.96(d,J=1.4Hz,1H),7.60(d,J=8.1Hz,2H),7.52(d,J=8.1Hz,2H),7.28(dd,J=8.0,6.5Hz,2H),7.24-7.16(m,3H),5.21(p,J=7.2Hz,1H),4.51-4.33(m,2H),3.89(s,3H),3.86(s,3H),1.52(d,J=7.1Hz,3H).ESI-MSm / z 425.2(M+H) + .

[0151] IRCBC-002: 1 H NMR(400MHz,DMSO-d6)δ9.08(d,J=8.2Hz,1H),7.66(d,J=8.1Hz,2H),7.57(t,J=8.6Hz,3H),7.30(dd,J=8.0,6.5Hz,2H),7.26-7.16(m,3H),5.30-5.19(m,1H),4.57-4.29(m,2H),3.91(s,3H),3.85(s,3H),1.54(d,J=7.1Hz,3H).ESI-MS m / z=425.1(M+H)+.

[0152] IRCBC-003: 1H NMR(400MHz,DMSO-d6)δ9.01(d,J=8.3Hz,1H),7.54(d,J=8.2Hz,2H),7.50-7.44(m,3H),7.25(dd,J=8.1,6.6Hz,2H),7.21-7.12(m,3H),6.58(d,J=2.0Hz,1H),5.21-5.10(m,1H),4.45-4.32(m,2H),3.90(s,3H),3.86(s,3H),1.48(d,J=7.1Hz,3H).ESI-MS m / z=425.2(M+H)+.

[0153] IRCBC-004: 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.4Hz,1H),7.79(d,J=2.3Hz,1H),7.53-7.45(m,4H),7.30(dd,J=8.1,6.5Hz,2H),7.25-7.17(m,3H),6.52(d,J=2.3Hz,1H),5.29-5.16(m,1H),4.43(q,J=15.3Hz,2H),3.90(s,3H),3.88(s,3H),1.53(d,J=7.1Hz,3H).ESI-MS m / z=425.2(M+H)+.

[0154] IRCBC-006: 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.4Hz,1H),7.67-7.54(m,6H),7.48(s,3H),7.34-7.18(m,2H),5.22(t,J=7.6Hz,1H),4.50-4.36(m,2H),3.90(s,3H),1.53(d,J=7.1Hz,3H)..ESI-MS m / z=411.2(M+H)+.

[0155] IRCBC-007: 1 H NMR(400MHz,DMSO-d6)δ9.09(d,J=8.4Hz,1H),8.07-7.90(m,1H),7.59(dd,J=43.8,7.9Hz,4H),7.38-7.17(m,5H),5.23(d,J=9.4Hz,1H),4.44(q,J=15.2Hz,2H),3.91(s,3H),1.54(d,J=7.1Hz,3H).ESI-MS m / z=428.0(M+H)+.

[0156] IRCBC-005: 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.74(s,1H),7.56(s,1H),7.46(s,4H),7.30(t,J=7.3Hz,1H),7.26-7.18(m,3H),5.21(t,J=7.5Hz,1H),4.50-4.39(m,2H),3.90(s,3H),1.53(d,J=7.1Hz,3H).ESI-MS m / z=411.1(M+H)+.

[0157] IRCBC-010: 1 H NMR(400MHz,DMSO-d6)δ9.00(d,J=8.4Hz,1H),7.39(q,J=8.2Hz,6H),7.30(dd,J=8.1,6.6Hz,3H),7.26–7.17(m,4H),5.23–5.13(m,1H),4.43(q,J=15.3Hz,2H),3.98(t,J=7.6Hz,1H),3.90(s,4H),3.85(td,J=8.2,5.9Hz,1H),3.80–3.72(m,1H),3.59(dd,J=8.0,6.8Hz,1H),3.30–3.22(m,1H),2.31–2.22(m,1H),2.04–1.88(m,1H),1.50(d,J=7.1Hz,4H).ESI-MS m / z=414.9(M+H)+.

[0158] IRCBC-016: 1 H NMR(400MHz,DMSO-d6))δ9.09(d,J=8.4Hz,1H),8.64-8.60(m,1H),7.86(td,J=7.7,1.8Hz,1H),7.65(dt,J=7.9,1.1Hz,1H),7.62-7.57(m,2H),7.54-7.49(m,2H),7.43(ddd,J=7.6,4.9,1.2Hz,1H),7.38-7.28(m,3H),7.17(dt,J=6.9,1.8Hz,1H),5.24(p,J=7.1Hz,1H),4.51-4.39(m,2H),3.94(s,3H),1.54(d,J=7.1Hz,3H).ESI-MS m / z=456.0(M+H)+.

[0159] IRCBC-008: 1H NMR(400MHz,Chloroform-d)δ7.68(d,J=0.8Hz,1H),7.61-7.57(m,2H),7.54(d,J=7.9Hz,1H),7.45-7.39(m,2H),7.27(dd,J=8.0,6.3Hz,2H),7.22(dd,J=6.7,1.2Hz,2H),7.15(dd,J=6.8,1.9Hz,2H),5.31(p,J=7.1Hz,1H),4.56(d,J=15.7Hz,1H),4.39(d,J=15.6Hz,1H),3.84(s,3H),1.61(d,J=7.0Hz,3H).ESI-MS m / z=412.0(M+H)+.

[0160] IRCBC-032: 1 H NMR(400MHz,DMSO-d6)δ9.07(d,J=8.3Hz,1H),8.64–8.56(m,1H),7.85(td,J=7.7,1.8Hz,1H),7.63(d,J=7.8Hz,1H),7.57(d,J=8.2Hz,2H),7.49(d,J=8.1Hz,2H),7.45-7.37(m,1H),7.10(tt,J=9.4,2.4Hz,1H),6.96(h,J=4.6Hz,2H),5.22(t,J=7.5Hz,1H),4.54–4.34(m,2H),3.94(s,3H),1.52(d,J=7.1Hz,3H)..ESI-MS m / z=457.9(M+H)+.

[0161] IRCBC-036: 1 H NMR(400MHz,Deuterium Oxide)δ7.52(d,J=8.1Hz,1H),7.41(d,J=8.3Hz,2H),7.34(d,J=8.0Hz,2H),7.28-7.25(m,2H),7.24-7.19(m,1H),7.17-7.12(m,2H),5.29(p,J=7.2Hz,1H),4.55(d,J=15.6Hz,1H),4.40(d,J=15.6Hz,1H),3.83(s,3H),3.42(s,3H),1.59(d,J=7.0Hz,3H),1.54(s,6H).ESI-MS m / z=417.2(M+H)+.

[0162] IRCBC-154: 1H NMR(400MHz,Chloroform-d)δ8.46(d,J=3.0Hz,1H),7.70-7.63(m,2H),7.59(d,J=8.1Hz,1H),7.45(d,J=7.9Hz,2H),7.37-7.28(m,4H),7.22-7.15(m,2H),5.34(q,J=7.3Hz,1H),4.60(d,J=15.6Hz,1H),4.43(d,J=15.7Hz,1H),3.96-3.90(m,4H),3.88(d,J=1.5Hz,3H),3.32(dd,J=5.9,3.9Hz,4H),1.65(d,J=7.0Hz,3H).ESI-MS m / z=531.9(M+H)+.

[0163] IRCBC-159: 1 H NMR(400MHz,Chloroform-d)δ8.29(d,J=2.9Hz,1H),7.61-7.51(m,3H),7.39(dd,J=8.5,7.1Hz,3H),7.33-7.19(m,5H),7.18-7.08(m,3H),5.34(d,J=6.8Hz,1H),4.56(d,J=15.6Hz,1H),4.41(d,J=15.6Hz,1H),3.84(s,3H),3.35-3.28(m,4H),2.72(dd,J=6.2,3.9Hz,4H),1.61(d,J=7.0Hz,3H),1.11(d,J=6.5Hz,6H).ESI-MS m / z=548.4(M+H)+.

[0164] IRCBC-051: 1 H NMR(400MHz,DMSO-d6)δ9.05-9.01(m,2H),8.37(dd,J=8.2,2.2Hz,1H),7.84(dd,J=8.2,0.8Hz,1H),7.63(d,J=8.3Hz,2H),7.53(d,J=8.3Hz,2H),7.28(t,J=7.2Hz,2H),7.23-7.16(m,3H),5.26-5.19(m,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.52(d,J=7.1Hz,3H).ESI-MSm / z=447.2(M+H)+.

[0165] IRCBC-059: 1H NMR(400MHz,DMSO-d6)δ9.18(t,J=6.2Hz,1H),8.63-8.60(m,1H),7.87(td,J=7.7,1.8Hz,1H),7.66(d,J=7.8Hz,1H),7.50-7.39(m,4H),7.30(t,J=7.2Hz,2H),7.22(dd,J=8.6,7.0Hz,3H),4.55(d,J=6.1Hz,2H),4.46(s,2H),3.90(s,3H).ESI-MS m / z=426.1(M+H)+.

[0166] IRCBC-067: 1 H NMR(400MHz,DMSO-d6)δ9.02(d,J=8.4Hz,1H),8.60(ddd,J=4.9,1.8,0.9Hz,1H),7.85(td,J=7.7,1.8Hz,1H),7.63(dt,J=7.9,1.1Hz,1H),7.59-7.53(m,2H),7.51-7.45(m,2H),7.41(ddd,J=7.7,4.9,1.2Hz,1H),7.29(tdd,J=7.6,5.4,1.8Hz,1H),7.19(ddd,J=9.8,8.3,1.3Hz,1H),7.09(td,J=7.5,1.3Hz,1H),7.00(td,J=7.7,1.8Hz,1H),5.28-5.09(m,1H),4.57-4.36(m,2H),3.90(s,3H),1.50(d,J=7.1Hz,3H).ESI-MS m / z=440.1(M+H)+.

[0167] IRCBC-033: 1 H NMR(400MHz,DMSO-d6))δ8.62(d,J=4.5Hz,1H),8.52(d,J=7.9Hz,1H),8.10(s,1H),7.86(dt,J=7.7,3.9Hz,1H),7.65(d,J=7.8Hz,1H),7.59(d,J=8.1Hz,2H),7.50-7.40(m,3H),7.07(d,J=9.4Hz,1H),6.92(d,J=6.7Hz,2H),5.19(t,J=7.3Hz,1H),4.44(d,J=8.4Hz,2H),3.71(s,3H),1.49(d,J=7.0Hz,3H).ESI-MS m / z=456.9(M+H)+.

[0168] IRCBC-041: 1 H NMR(400MHz,CDCl3)δ7.69-7.37(m,7H),7.20(s,2H),5.34(s,1H),4.60(d,J=16.3Hz,1H),4.45(d,J=15.4Hz,1H),3.87(s,4H),1.64(d,J=6.4Hz,3H),1.29(s,2H),1.24-0.87(m,4H).ESI-MS m / z=451.1(M+H)+.

[0169] IRCBC-043: 1 H NMR(400MHz,DMSO-d6)δ8.76(d,J=8.6Hz,1H),7.30(t,J=7.8Hz,4H),7.21(s,3H),6.92(d,J=8.7Hz,2H),5.17-5.08(m,1H),4.44(d,J=10.8Hz,2H),3.89(s,3H),3.73(s,2H),3.44(d,J=6.6Hz,4H),2.90(s,3H),1.48(d,J=7.0Hz,3H).ESI-MS m / z=432.9(M+H)+.

[0170] IRCBC-049: 1 H NMR(400MHz,DMSO-d6)δ9.06(d,J=8.4Hz,1H),8.63(d,J=2.8Hz,1H),7.86-7.73(m,2H),7.59(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H),7.29(d,J=7.4Hz,2H),7.21(t,J=6.5Hz,3H),5.27-5.19(m,1H),4.43(q,J=15.4Hz,2H),3.90(s,3H),1.53(d,J=7.1Hz,3H).ESI-MSm / z=440.0(M+H)+.

[0171] IRCBC-050: 1H NMR(400MHz,DMSO-d6)δ9.05(d,J=8.3Hz,1H),8.67(d,J=2.4Hz,1H),8.01(dd,J=8.3,2.4Hz,1H),7.71(s,1H),7.60(d,J=8.1Hz,2H),7.52(d,J=8.2Hz,2H),7.29(d,J=7.5Hz,2H),7.20(d,J=7.1Hz,3H),5.27-5.19(m,1H),4.44(q,J=15.3Hz,2H),3.90(s,3H),1.54(d,J=7.0Hz,3H).ESI-MS m / z=456.1(M+H)+.

[0172] IRCBC-054: 1 H NMR(400MHz,DMSO-d6)δ9.08(d,J=8.4Hz,1H),8.73(s,1H),8.51(d,J=4.8Hz,1H),7.71-7.66(m,1H),7.63(d,J=8.3Hz,2H),7.54(d,J=8.3Hz,2H),7.30(t,J=7.2Hz,2H),7.22(dd,J=13.6,7.1Hz,3H),5.29-5.19(m,1H),4.44(q,J=15.2Hz,2H),3.91(s,3H),1.54(d,J=7.1Hz,3H).ESI-MS m / z=440.1(M+H)+.

[0173] IRCBC-096: 1 H NMR(400MHz,CDCl3)δ9.03(d,J=8.3Hz,1H),8.99(s,1H),8.27(dd,J=8.4,2.2Hz,1H),7.86(d,J=8.2Hz,1H),7.63(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.27(d,J=7.5Hz,2H),7.19(dd,J=7.3,6.0Hz,3H),5.26-5.18(m,1H),4.41(d,J=14.5Hz,2H),3.88(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=490.1(M+H)+.

[0174] IRCBC-097:1H NMR(400MHz,Chloroform-d)δ8.18(s,2H),7.62(d,J=8.0Hz,2H),7.55(d,J=8.1Hz,1H),7.39(d,J=8.0Hz,2H),7.28(s,2H),7.22(s,1H),7.16(d,J=7.4Hz,2H),5.39–5.25(m,1H),4.57(d,J=15.6Hz,1H),4.41(d,J=15.6Hz,1H),3.84(s,3H),3.06(s,6H),1.61(d,J=6.9Hz,3H).ESI-MS m / z=466.2(M+H)+

[0175] IRCBC-093: 1 H NMR(400MHz,DMSO-d6)δ9.05(d,J=8.3Hz,1H),8.77(s,1H),8.57(d,J=5.0Hz,1H),7.67(d,J=5.0Hz,1H),7.61(d,J=8.2Hz,2H),7.53(d,J=8.2Hz,2H),7.28(t,J=7.2Hz,2H),7.23-7.16(m,3H),5.27-5.18(m,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=456.2(M+H)+.

[0176] IRCBC-095: 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.3Hz,1H),8.59(s,2H),7.60(d,J=8.3Hz,2H),7.50(d,J=8.3Hz,2H),7.32-7.25(m,2H),7.24-7.15(m,3H),5.22(p,J=7.2Hz,1H),4.42(q,J=15.3Hz,2H),3.96(s,3H),3.89(s,3H),1.53(d,J=7.1Hz,3H).ESI-MS m / z=453.0(M+H)+.

[0177] IRCBC-094: 1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),9.04(d,J=8.3Hz,1H),8.88(d,J=5.2Hz,1H),7.78(d,J=5.2Hz,1H),7.63(d,J=8.2Hz,2H),7.56(d,J=8.3Hz,2H),7.27(d,J=7.5Hz,2H),7.20(dd,J=14.1,7.1Hz,3H),5.27-5.18(m,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.53(d,J=7.1Hz,3H).ESI-MS m / z=893.6(2M+H)+.

[0178] IRCBC-056: 1 H NMR(400MHz,DMSO-d6)δ9.29(t,J=6.2Hz,1H),8.63(dd,J=11.8,2.9Hz,2H),7.89(td,J=7.7,1.7Hz,1H),7.81(dd,J=8.0,2.1Hz,1H),7.70(t,J=6.9Hz,2H),7.46(ddd,J=7.6,4.9,1.0Hz,1H),7.30(t,J=7.2Hz,2H),7.22(t,J=7.7Hz,3H),4.53(d,J=6.2Hz,2H),4.46(s,2H),3.90(s,3H).ESI-MS m / z=408.9(M+H)+.

[0179] IRCBC-101: 1 H NMR(400MHz,DMSO-d6)δ9.02(d,J=8.4Hz,1H),8.10(d,J=5.0Hz,1H),7.56(d,J=8.3Hz,2H),7.49(d,J=8.3Hz,2H),7.29(t,J=7.2Hz,2H),7.21(dd,J=13.6,7.1Hz,3H),6.73(s,1H),6.66(dd,J=5.1,1.1Hz,1H),5.27-5.17(m,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),3.04(s,6H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=465.2(M+H)+.

[0180] IRCBC-046: 1H NMR(400MHz,DMSO-d6)δ9.05(d,J=8.3Hz,1H),8.84(d,J=4.9Hz,2H),7.63(d,J=8.3Hz,2H),7.52(dd,J=8.6,3.6Hz,3H),7.29(dd,J=9.9,4.5Hz,2H),7.24-7.16(m,3H),5.22(p,J=7.1Hz,1H),4.42(dd,J=31.0,15.3Hz,2H),3.89(s,3H),1.53(d,J=7.1Hz,3H).ESI-MSm / z=423.1(M+H)+.

[0181] IRCBC-048: 1 H NMR(400MHz,DMSO-d6)δ9.04(d,J=8.3Hz,1H),8.87(d,J=1.5Hz,1H),8.69(dd,J=2.5,1.6Hz,1H),8.64(d,J=2.5Hz,1H),7.63(d,J=8.3Hz,2H),7.52(d,J=8.2Hz,2H),7.27(d,J=7.5Hz,2H),7.20(dd,J=7.3,6.0Hz,3H),5.27-5.18(m,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.53(d,J=7.1Hz,3H).ESI-MS m / z=423.0(M+H)+.

[0182] IRCBC-052: 1 H NMR(400MHz,DMSO-d6)δ9.00(d,J=8.3Hz,1H),8.31(d,J=2.9Hz,1H),7.60(d,J=8.7Hz,1H),7.54(d,J=8.2Hz,2H),7.50-7.40(m,3H),7.31-7.15(m,6H),5.25-5.17(m,1H),4.42(q,J=15.4Hz,2H),3.88(d,J=6.9Hz,6H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=452.1(M+H)+.

[0183] IRCBC-064: 1H NMR(400MHz,DMSO-d6)δ9.00(d,J=8.3Hz,1H),8.31(d,J=2.9Hz,1H),7.60(d,J=8.7Hz,1H),7.54(d,J=8.2Hz,2H),7.50-7.40(m,3H),7.31-7.15(m,6H),5.25-5.17(m,1H),4.42(q,J=15.4Hz,2H),3.88(d,J=6.9Hz,6H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=422.1(M+H)+.

[0184] IRCBC-053: 1 H NMR(400MHz,DMSO-d6)δ8.98(d,J=8.4Hz,1H),8.10(d,J=3.0Hz,1H),7.47(q,J=8.4Hz,4H),7.40(d,J=8.8Hz,1H),7.28(t,J= 7.2Hz,2H),7.23-7.17(m,3H),7.06(dd,J=8.9,3.1Hz,1H),5.20(p,J=7.1Hz,1H),4.42(d,J=14.2Hz,2H),3.89(s,3H),2.99(s,6H),1.51(d,J=7.1Hz,3H).ESI-MS m / z=465.1(M+H)+.

[0185] IRCBC-058: 1 H NMR(400MHz,DMSO-d6))δ9.26(t,J=6.3Hz,1H),8.62(d,J=4.2Hz,1H),7.87(td,J=7.7,1.8Hz,1H),7.65(t,J=7.6Hz,2H),7.44(ddd,J=7.7,4.9,1.1Hz,1H),7.30(t,J=7.5Hz,3H),7.22(t,J=6.6Hz,4H),4.51(d,J=6.3Hz,2H),4.46(s,2H),3.90(s,3H).ESI-MS m / z=426.1(M+H)+.

[0186] IRCBC-071: 1H NMR(400MHz,DMSO-d6)δ9.07(d,J=8.3Hz,1H),8.65-8.58(m,1H),7.85(td,J=7.7,1.9Hz,1H),7.76(d,J=8.2Hz,2H),7.64(d,J=7.8Hz,1H),7.58(d,J=8.2Hz,2H),7.49(d,J=8.1Hz,2H),7.44-7.36(m,3H),5.20(q,J=7.4Hz,1H),4.52(q,J=15.7Hz,2H),3.92(s,3H),1.52(d,J=7.0Hz,3H).ESI-MS m / z=446.8(M+H)+.

[0187] IRCBC-072: 1 H NMR(400MHz,DMSO-d6)δ9.08(d,J=8.4Hz,1H),8.60(ddd,J=4.8,1.7,0.9Hz,1H),7.85(td,J=7.7,1.8Hz,1H),7.73-7.69(m,2H),7.65-7.62(m,1H),7.57(dd,J=7.5,5.6Hz,2H),7.54-7.47(m,4H),7.41(ddd,J=7.6,4.9,1.1Hz,1H),5.26-5.16(m,1H),4.47(dd,J=31.6,15.5Hz,2H),3.94(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=447.2(M+H)+.

[0188] IRCBC-057: 1 H NMR(400MHz,DMSO-d6)δ9.28(d,J=6.4Hz,1H),8.63(dd,J=11.8,3.0Hz,2H),7.89(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.0,2.2Hz,1H),7.70(t,J=7.1Hz,2H),7.47(ddd,J=7.6,4.8,1.1Hz,1H),7.33-7.28(m,2H),7.23(dd,J=8.7,7.0Hz,4H),4.54(d,J=6.2Hz,2H),4.46(s,2H),3.90(s,3H).ESI-MS m / z=409.2(M+H)+.

[0189] IRCBC-091: 1H NMR(400MHz,DMSO-d6)δ9.07(d,J=8.3Hz,1H),8.68(s,2H),7.63(d,J=8.3Hz,2H),7.55(d,J=8.3Hz,2H),7.29(t,J=7.2Hz,2H),7.24-7.17(m,3H),5.27-5.19(m,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),1.53(d,J=7.1Hz,3H).ESI-MS m / z=458.1(M+H)+.

[0190] IRCBC-099: 1 H NMR(400MHz,DMSO-d6)δ9.02(d,J=8.4Hz,1H),7.57-7.53(m,2H),7.52-7.45(m,3H),7.32-7.25(m,2H),7.24-7.17(m,3H),6.82(d,J=7.0Hz,1H),6.67(d,J=8.6Hz,1H),5.27-5.17(m,1H),4.43(dd,J= 30.4,15.3Hz,2H),3.89(s,3H),3.03(s,6H),1.52(d,J=7.1Hz,3H).ESI-MSm / z=465.3(M+H)+.

[0191] IRCBC-100: 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.4Hz,1H),8.38(d,J=4.9Hz,1H),7.61(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,2H),7.28(t,J=7.2Hz,2H),7.24-7.17(m,3H),5.27-5.18(m,1H),4.42(q,J=15.3Hz,2H),3.89(s,3H),3.12(s,6H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=466.2(M+H)+.

[0192] IRCBC-102: 1H NMR(400MHz,DMSO-d6)δ8.99(d,J=8.4Hz,1H),7.95(d,J=2.6Hz,1H),7.50-7.43(m,4H),7.35(d,J=8.5Hz,1H),7.29(t,J=7.2Hz,2H),7.24-7.17(m,3H),6.86(dd,J=8.6,2.9Hz,1H),6.37(q,J=5.0Hz,1H),5.25-5.16(m,1H),4.43(q,J=15.3Hz,2H),3.89(s,3H),2.74(d,J=5.0Hz,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=450.22(M+H)+.

[0193] IRCBC-105: 1 H NMR(400MHz,DMSO-d6)δ9.00(d,J=8.4Hz,1H),8.32(d,J=2.8Hz,1H),7.54-7.44(m,5H),7.28(d,J=7.5Hz,3H),7.24-7.16(m,3H),5.21(p,J=7.2Hz,1H),4.43(d,J=14.2Hz,2H),3.89(s,3H),3.78-3.72(m,4H),3.28-3.24(m,4H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=506.24(M+H)+.

[0194] IRCBC-106: 1 H NMR(400MHz,DMSO-d6)δ9.00(d,J=8.4Hz,1H),7.48(q,J=8.4Hz,4H),7.28(d,J=7.5Hz,2H),7.20(t,J=6.8Hz,3H),7.14(s,1H),5.25-5.16(m,1H),4.42(d,J=15.0Hz,2H),3.89(s,3H),3.05(s,6H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=470.19(M+H)+.

[0195] IRCBC-119: 1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ9.00(d,J=8.4Hz,1H),8.53(s,2H),7.47(d,J=4.3Hz,4H),7.28(d,J=7.5Hz,2H),7.24-7.17(m,3H),5.21(p,J=7.1Hz,1H),4.43(q,J=15.3Hz,2H),3.89(s,3H),3.17(s,6H),1.51(d,J=7.1Hz,3H).ESI-MS m / z=465.23(M+H)+.

[0196] IRCBC-098: 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.3Hz,1H),8.29(d,J=1.4Hz,1H),8.19(d,J=1.5Hz,1H),7.56-7.45(m,4H),7.34-7.18(m,5H),5.23(t,J=7.5Hz,1H),4.49-4.36(m,2H),3.91(s,3H),3.14(s,6H),1.54(d,J=7.0Hz,3H).ESI-MS m / z=466.1(M+H)+.

[0197] IRCBC-120: 1 H NMR(400MHz,Chloroform-d)δ8.66(d,J=2.5Hz,1H),7.74(dd,J=8.2,2.4Hz,1H),7.49(d,J=8.1Hz,3H),7.42(d,J=8.2Hz,1H),7.33(d,J=8.1Hz,2H),7.25-7.16(m,3H),7.16-7.09(m,2H),7.07(s,1H),5.25(p,J=7.1Hz,1H),4.49(m,1H),4.33(m,1H),3.77(s,3H),1.55(s,9H).ESI-MS m / z=480.3(M+H)+.

[0198] IRCBC-121: 1H NMR(400MHz,Chloroform-d)δ8.71(dd,J=4.9,1.8Hz,1H),7.90(dd,J=7.9,1.8Hz,1H),7.64-7.57(m,2H),7.49(d,J=7.9Hz,1H),7.37(d,J=8.2Hz,2H),7.26-7.05(m,6H),5.25(p,J=7.1Hz,1H),4.49(m,1H),4.32(m,1H),3.77(s,3H),1.55(d,J=7.0Hz,3H).ESI-MS m / z=447.2(M+H)+.

[0199] IRCBC-122: 1 H NMR(400MHz,Chloroform-d)δ8.36(dd,J=3.9,2.2Hz,1H),7.54(d,J=8.1Hz,2H),7.49(d,J=8.0Hz,1H),7.41-7.35(m,2H),7.20(dt,J=7.4,3.7Hz,3H),7.17-7.12(m,1H),7.11-7.04(m,2H),5.25(p,J=7.1Hz,1H),4.49(d,J=15.7Hz,1H),4.33(d,J=15.7Hz,1H),3.77(s,3H),1.55(d,J=6.9Hz,3H).ESI-MS m / z=440.2(M+H)+.

[0200] IRCBC-125: 1 H NMR(400MHz,Chloroform-d)δ8.15(d,J=6.1Hz,1H),7.54-7.49(m,2H),7.46(d,J=8.2Hz,1H),7.35-7.28(m,2H),7.21(d,J=1.7Hz,3H),7.17-7.13(m,1H),7.09(dd,J=7.0,1.8Hz,2H),6.71(d,J=2.7Hz,1H),6.38(dd,J=6.1,2.7Hz,1H),5.25(p,J=7.1Hz,1H),4.49(m,1H),4.34(m,1H),3.77(s,3H),2.96(s,5H),1.54(d,J=7.0Hz,3H).ESI-MSm / z=465.3(M+H)+.

[0201] IRCBC-103: 1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.57(d,J=8.0Hz,2H),7.39(t,J=8.4Hz,2H),7.31(d,J=6.0Hz,4H),7.26(d,J=6.9Hz,1H),7.19(d,J=7.4Hz,2H),6.69(dd,J=8.3,2.7Hz,1H),5.35(p,J=7.0Hz,1H),4.60(m,1H),4.44(m,1H),4.02(t,J=7.3Hz,4H),3.87(s,3H),2.49(p,J=7.3Hz,2H),1.65(d,J=7.0Hz,3H).ESI-MS m / z=477.2(M+H)+.

[0202] IRCBC-104: 1 H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.57(d,J=8.0Hz,3H),7.39(d,J=8.2Hz,2H),7.30(d,J=5.9Hz,4H),7.19(d,J=7.4Hz,2H),6.78(d,J=8.6Hz,1H),5.38-5.30(m,1H),4.59(m,1H),4.44(m 1H), 3.86(s,3H),3.37(d,J=4.7Hz,3H),2.08(d,J=7.1Hz,3H),1.64(d,J=6.9Hz,3H),0.90(d,J=6.9Hz,2H).ESI-MS m / z=491.1(M+H)+.

[0203] IRCBC-145: 1 H NMR(400MHz,Chloroform-d)δ8.26(s,1H),7.91(s,1H),7.58(t,J=8.6Hz,3H),7.41(d,J=7.9Hz,2H),7.30(q,J=9.2,8.1Hz,3H),7.19(d,J=7.5Hz,2H),5.34(p,J=7.3Hz,1H),4.98(s,1H),4.59(m,1H),4.44(m,1H),3.87(s,3H),3.04(d,J=4.9Hz,3H),1.64(d,J=6.9Hz,3H).ESI-MS m / z=452.3(M+H)+.

[0204] IRCBC-123: 1H NMR(400MHz,Chloroform-d)δ8.25(s,1H),7.67-7.61(m,2H),7.57(d,J=8.1Hz,1H),7.42(d,J=7.9Hz,2H),7.32-7.29(m,2H),7.25(d,J=4.6Hz,3H),7.19(d,J=7.4Hz,2H),5.35(p,J=7.0Hz,1H),4.59(m,1H),4.44(m,1H),3.96(d,J=1.3Hz,3H),3.87(d,J=1.4Hz,3H),1.64(d,J=6.9Hz,3H).ESI-MS m / z=903.8(2M+H)+.

[0205] IRCBC-129: 1 H NMR(400MHz,Chloroform-d)δ9.24(s,1H),8.30(s,1H),7.66(d,J=7.8Hz,3H),7.48(d,J=7.8Hz,2H),7.32(d,J=8.1Hz,3H),7.26(d,J=6.9Hz,1H),7.18(d,J=7.2Hz,2H),5.38(t,J=7.2Hz,1H),4.62(m,1H),4.43(m,1H),3.89(s,3H),1.66(d,J=7.0Hz,3H).ESI-MS m / z=463.1(M+H)+.

[0206] IRCBC-131: 1 H NMR(400MHz,Chloroform-d)δ8.40(dd,J=4.4,1.6Hz,1H),7.97(s,1H),7.92(dd,J=9.2,1.7Hz,1H),7.57–7.51(m,2H),7.49(d,J=8.1Hz,1H),7.39–7.32(m,2H),7.24–7.18(m,3H),7.18–7.13(m,1H),7.13–7.07(m,2H),7.04(dd,J=9.2,4.4Hz,1H),5.31–5.20(m,1H),4.49(d,J=15.6Hz,1H),4.34(d,J=15.6Hz,1H),3.77(s,3H),1.55(d,J=6.9Hz,3H).ESI-MS m / z=462.2(M+H)+

[0207] IRCBC-134: 1H NMR(400MHz,Chloroform-d)δ8.32(s,1H),7.61–7.55(m,3H),7.42(t,J=8.2Hz,3H),7.32(d,J=7.2Hz,1H),7.26(d,J=6.8Hz,1H),7.19(d,J=7.5Hz,2H),7.15(dd,J=8.9,2.9Hz,1H),5.35(q,J=7.0Hz,1H),4.60(d,J=15.6Hz,1H),4.44(d,J=15.7Hz,1H),3.87(d,J=1.3Hz,3H),3.35(t,J=5.1Hz,4H),2.67(t,J=5.2Hz,4H),2.53(q,J=7.2Hz,2H),1.64(d,J=6.9Hz,3H),1.20–1.16(m,3H).ESI-MS m / z=534.6(M+H)+

[0208] IRCBC-146: 1 H NMR(400MHz,Chloroform-d)δ8.00(d,J=2.9Hz,1H),7.56(d,J=8.1Hz,3H),7.42-7.26(m,5H),7.26-7.21(m,1H),7.21-7.15(m,2H),6.82(dd,J=8.6,2.9Hz,1H),5.33(p,J=7.1Hz,1H),4.58(m,1H),4.43(m,1H),3.86(s,3H),3.76(s,1H),3.68(s,1H),1.63(d,J=7.0Hz,3H),1.26(d,J=6.2Hz,6H).ESI-MS m / z=479.2(M+H)+.

[0209] IRCBC-124: 1H NMR(400MHz,Chloroform-d)δ8.20(dd,J=4.5,1.5Hz,1H),7.65-7.60(m,2H),7.58(d,J=9.4Hz,2H),7.43(d,J=8.0Hz,2H),7.33-7.31(m,1H),7.28-7.23(m,2H),7.20(td,J=4.8,3.0Hz,3H),5.38(d,J=7.2Hz,1H),4.61(d,J=9.9Hz,1H),4.44(d,J=4.6Hz,1H),3.88(d,J=3.9Hz,3H),3.06(s,4H),1.71(d,J=7.0Hz,2H),1.65(d,J=7.0Hz,3H).ESI-MSm / z=465.2(M+H)+.

[0210] IRCBC-149: 1 H NMR(400MHz,Chloroform-d)δ8.47(s,1H),8.19(d,J=8.7Hz,1H),7.87(s,1H),7.63(d,J=7.9Hz,1H),7.55(d,J=7.9Hz,2H),7.49(d,J=8.6Hz,1H),7.40(d,J=8.0Hz,2H),7.30-7.21(m,3H),7.17(d,J=7.4Hz,2H),5.31(p,J=7.1Hz,1H),4.59(m,1H),4.43(m,1H),3.88(s,3H),2.24(s,3H),1.64(d,J=7.0Hz,3H).ESI-MS m / z=479.0(M+H)+.

[0211] IRCBC-150: 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.46(d,J=8.1Hz,3H),7.27(dd,J=8.0,5.7Hz,3H),7.23-7.04(m,6H),6.73(dd,J=8.5,2.8Hz,1H),5.23(p,J=7.1Hz,1H),4.47(m,1H),4.32(m,1H),3.75(d,J=2.0Hz,3H),1.52(d,J=7.0Hz,3H).ESI-MS m / z=454.2(M+H)+.

[0212] IRCBC-157: 1H NMR(400MHz,Chloroform-d)δ8.27(s,2H),7.55(d,J=8.0Hz,2H),7.46(d,J=8.1Hz,1H),7.32(d,J=8.0Hz,2H),7.24-7.05(m,5H),5.25(p,J=7.2Hz,1H),4.49(m,1H),4.33(m,1H),3.82(t,J=4.9Hz,4H),3.77(s,3H),3.21(dd,J=5.8,4.0Hz,4H),1.54(d,J=7.0Hz,3H).ESI-MSm / z=508.0(M+H)+.

[0213] IRCBC-158: 1 H NMR(400MHz,Chloroform-d)δ8.38(s,2H),7.70-7.63(m,2H),7.58(d,J=8.1Hz,1H),7.49-7.40(m,2H),7.32-7.25(m,3H),7.20(dd,J=6.8,1.7Hz,2H),5.35(p,J=7.1Hz,1H),4.60(m,1H),4.44(m,1H),3.88(s,3H),3.42-3.35(m,4H),2.70-2.63(m,4H),2.53(q,J=7.2Hz,2H),1.65(d,J=7.0Hz,3H),1.18(t,J=7.2Hz,3H).ESI-MS m / z=535.3(M+H)+.

[0214] IRCBC-259: 1 H NMR(400MHz,Chloroform-d)δ7.86(s,2H),7.57-7.50(m,2H),7.46(d,J=8.1Hz,1H),7.31(d,J=8.1Hz,2H),7.21(d,J=6.7Hz,2H),7.14(d,J=7.3Hz,1H),7.11-7.05(m,2H),5.24(p,J=7.1Hz,1H),4.49(m,1H),4.34(m,1H),4.03(t,J=7.3Hz,2H),3.77(d,J=4.2Hz,5H),3.34-3.23(m,1H),2.16(s,6H),1.54(d,J=7.0Hz,3H).ESI-MS m / z=521.5(M+H)+.

[0215] IRCBC-260: 1H NMR(400MHz,Chloroform-d)δ8.05(s,2H),7.68-7.62(m,2H),7.58(d,J=8.1Hz,1H),7.42(dd,J=8.8,6.9Hz,2H),7.32-7.24(m,3H),7.21-7.15(m,2H),5.35(p,J=7.1Hz,1H),4.59(m,1H),4.49-4.38(m,5H),3.87(s,3H),1.64(d,J=7.0Hz,3H).ESI-MS m / z=514.3(M+H)+.

[0216] IRCBC-153: 1 H NMR(400MHz,Chloroform-d)δ7.82(d,J=3.1Hz,1H),7.51-7.43(m,3H),7.37-7.27(m,3H),7.21-7.14(m,3H),7.08(d,J=7.3Hz,2H),6.69(dt,J=8.6,2.5Hz,1H),5.24(p,J=7.4Hz,1H),4.49(m,1H),4.34(m,1H),4.25(d,J=2.0Hz,4H),3.76(d,J=2.0Hz,3H),1.54(dd,J=7.0,2.0Hz,3H).ESI-MS m / z=513.2(M+H)+.

[0217] IRCBC-156: 1 H NMR(400MHz,Chloroform-d)δ7.87(d,J=2.8Hz,1H),7.65-7.53(m,3H),7.47-7.35(m,3H),7.35-7.15(m,5H),6.71(dd,J=8.5,2.9Hz,1H),5.34(p,J=6.9Hz,1H),4.59(m,1H),4.48-4.37(m,2H),4.25-4.17(m,2H),3.89-3.81(m,5H),3.38(s,3H),1.64(d,J=7.0Hz,3H).ESI-MSm / z=507.3(M+H)+.

[0218] IRCBC-161: 1H NMR(400MHz,DMSO-d6)δ8.99(d,J=8.4Hz,1H),8.10(s,2H),7.52(d,J=8.4Hz,2H),7.47(d,J=8.3Hz,2H),7.32-7.24(m,2H),7.24-7.15(m,3H),5.97(s,2H),5.20(p,J=7.2Hz,1H),4.46(m,1H),4.38(m,1H),3.88(s,3H),1.52(d,J=7.1Hz,3H).ESI-MS m / z=437.9(M+H)+.

[0219] IRCBC-152: 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=2.8Hz,1H),7.51-7.42(m,3H),7.33-7.24(m,3H),7.21-7.18(m,2H),7.17-7.14(m,1H),7.09(dd,J=6.9,1.8Hz,2H),6.60(dd,J=8.5,2.9Hz,1H),5.24(p,J=7.0Hz,1H),4.49(m,1H),4.34(m,1H),3.98(t,J=7.2Hz,2H),3.77(s,3H),3.70(dd,J=7.5,5.4Hz,2H),3.24(dd,J=6.8,5.4Hz,1H),2.16(s,6H),1.54(d,J=7.0Hz,3H).ESI-MS m / z=520.5(M+H)+.

[0220] IRCBC-155: 1 H NMR(400MHz,Chloroform-d)δ7.86(d,J=2.8Hz,1H),7.54(t,J=8.5Hz,3H),7.39(dd,J=8.4,6.7Hz,3H),7.28-7.21(m,3H),7.18-7.13(m,2H),6.72(dd,J=8.5,2.9Hz,1H),5.31(p,J=7.2Hz,1H),4.56(m,1H),4.41(m,1H),4.29(dd,J=8.5,7.3Hz,2H),4.20(dd,J=7.3,6.2Hz,2H),3.84(s,3H),3.67(tt,J=8.5,6.2Hz,1H),1.61(d,J=7.0Hz,3H).ESI-MSm / z=502.3(M+H)+.

[0221] IRCBC-160:1 H NMR(400MHz,Chloroform-d)δ8.14(s,2H),7.68-7.61(m,2H),7.58(d,J=8.1Hz,1H),7.47-7.39(m,2H),7.30(d,J=2.9Hz,2H),7.25(d,J=7.4Hz,1H),7.22-7.16(m,2H),5.35(p,J=7.1Hz,1H),4.60(m,1H),4.44(m,1H),4.07(d,J=5.4Hz,1H),3.88(s,3H),2.97(d,J=5.3Hz,3H),1.64(s,3H).ESI-MS m / z=452.3(M+H)+.

[0222] IRCBC-257: 1 H NMR(400MHz,Chloroform-d)δ8.08(s,1H),7.58-7.51(m,2H),7.47(d,J=8.1Hz,1H),7.33(d,J=7.8Hz,2H),7.25-7.11(m,3H),7.11-7.05(m,2H),6.93(t,J=2.3Hz,1H),5.24(t,J=7.3Hz,1H),4.49(m,1H),4.33(m,1H),4.18(s,1H),3.77(d,J=1.9Hz,3H),1.58-1.53(m,3H).ESI-MS m / z=479.3(M+H)+.

[0223] IRCBC-256: 1 H NMR(400MHz,Chloroform-d)δ8.12(d,J=3.8Hz,2H),7.63(dd,J=8.8,3.3Hz,2H),7.59(dd,J=8.0,3.8Hz,1H),7.41(d,J=7.9Hz,2H),7.35-7.23(m,3H),7.23-7.15(m,2H),5.34(t,J=7.3Hz,1H),4.59(m,1H),4.43(m,1H),4.18(s,1H),3.87(d,J=4.3Hz,3H),1.64(d,J=6.9Hz,3H).ESI-MS m / z=455.2(M+H)+.

[0224] IRCBC-258: 1H NMR(400MHz,Chloroform-d)δ8.14(d,J=2.9Hz,1H),7.61-7.51(m,2H),7.47(d,J=8.0Hz,1H),7.33(d,J=8.1Hz,2H),7.21(d,J=9.1Hz,2H),7.17-7.13(m,1H),7.14-7.03(m,3H),5.24(p,J=7.0Hz,1H),4.49(m,1H),4.33(m,1H),4.05(s,2H),3.77(s,3H),1.54(d,J=7.0Hz,3H).ESI-MS m / z=462.2(M+H)+.

[0225] IRCBC-261: 1 H NMR(400MHz,Chloroform-d)δ8.02(s,2H),7.66(d,J=8.1Hz,2H),7.58(d,J=8.1Hz,1H),7.43(d,J=8.1Hz,2H),7.32(d,J=7.3Hz,1H),7.26(d,J=6.9Hz,1H),7.19(d,J=7.4Hz,2H),5.39-5.31(m,1H), 4.60(m,1H),4.48-4.36(m,3H),4.32(t,J=6.8Hz,2H),3.88(s,3H),3.84-3.72(m,1H),1.65(d,J=7.0Hz,4H).ESI-MS m / z=503.4(M+H)+.

[0226] IRCBC-262: 1 H NMR(400MHz,Chloroform-d)δ7.94(s,2H),7.64(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,1H),7.42(d,J=8.2Hz,2H),7.32(d,J=6.8Hz,2H),7.25(t,J=7.3Hz,1H),7.22-7.16(m,2H),5.35(p,J=7.3Hz,1H),4.60(m,1H),4.44(m,1H),4.06(t,J=7.4Hz,2H),3.91-3.83(m,5H),3.70-3.60(m,1H),3.34(t,J=7.1Hz,4H),2.19(p,J=7.0Hz,2H),1.64(d,J=7.0Hz,3H).ESI-MS m / z=533.6(M+H)+.

[0227] IRCBC-269:1 H NMR(400MHz,Chloroform-d)δ8.07(s,2H),7.61(d,J=8.2Hz,2H),7.54(s,1H),7.38(d,J=8.2Hz,2H),7.28(d,J=6.9Hz,1H),7.24-7.19(m,2H),7.17 -7.13(m,2H),5.34(d,J=5.0Hz,1H),4.56(m,1H),4.43(s,1H),3.84(s,3H ),3.75-3.70(m,2H),1.61(d,J=7.0Hz,3H),1.24(d,J=7.0Hz,6H).ESI-MS m / z=480.1(M+H)+.

[0228] IRCBC-271: 1 H NMR(400MHz,Chloroform-d)δ8.19(s,2H),7.58-7.51(m,2H),7.46(d,J=8.1Hz,1H),7.35-7.2 8(m,2H),7.20(s,3H),7.09(dd,J=6.9,1.9Hz,2H),5.25(p,J=7.2Hz,1H),4.49(m,1H),4.34(m 1H),4.29(s,1H),3.77(s,3H),2.45(pd,J=4.3,3.1Hz,1H),1.54(d,J=6.9Hz,3H),0.91-0.75(m,2H),0.56-0.48(m,2H).ESI-MS m / z=478.3(M+H)+.

[0229] IRCBC-276: 1 H NMR (400MHz, Chloroform-d) δ7.86 (s, 2H), 7.57-7.50 (m, 2H), 7.46 (d, J = 8.1Hz, 1H), 7.35-7.28 (m, 2H), 7.21-7.18 (m, 2H), 7.16-7.13 (m, 1H) ),7.10-7.06(m,2H),5.24(p,J=7.1Hz,1H),4.80(s,4H),4.49(m,1H),4.33(m,1H),4.13(s,4H),3.77(s,3H),1.54(d,J=7.0Hz,3H).ESI-MS m / z=520.3(M+H)+.

[0230] Biological Test Example 1: Inhibitory Activity Test of RIPK1 Inhibitors on Programmed Necrosis

[0231] The biological test scheme used was: the effect of the compound on TNF-induced FADD (Fas-associated death domain)-deficient Jurkat cells and L929 cells programmed necrosis.

[0232] In order to verify the inhibitory effect of the compounds of the present invention on programmed cell necrosis at the cellular level, cell types closely related to the RIP1 pathway, namely FADD-deficient Jurkat cells (a human peripheral blood leukemia T cell line) and L929 cells, were selected. Two different stimulation methods were used: tumor necrosis factor (TNFα) alone, or TNFα combined with mitochondrial-derived activator of cysteine ​​aspartate (SMAC) SM164. Cell viability was calculated by detecting chemiluminescence values, thereby obtaining the biological activity of the compounds in inhibiting programmed cell necrosis.

[0233] Methods: FADD-deficient Jurkat cells (human peripheral blood leukemia T cell line) were cultured in vitro. After growing to the logarithmic growth phase, the cells were collected and centrifuged at 1000 rpm for 5 min. The supernatant was discarded and the cell concentration was adjusted to 2.5×10 5 / mL, the cells were seeded into 384-well plates, 40μl per well. 5μL of SM164 (50nM) and compound diluted in cell culture medium were added to the corresponding wells. After pretreatment at 37°C for 1h, 5μL of TNFα (50ng / mL) diluted in cell culture medium was added to each well of the stimulation group, and 5μL of culture medium was added to the control group. After culturing in a cell culture incubator (37°C, 5% CO2) for 14h, 15μl of Cell Titer-Glo solution was added to each well, incubated at room temperature for 30min, and chemiluminescence was detected to measure the intracellular ATP level. The unstimulated DMSO control wells were taken as 100% cell viability. L929 cells: L929 cells (mouse fibroblasts) cultured in vitro were digested and diluted to 6.25×10 4 / ml, the cells were seeded into 384-well plates, 40μl per well. Place in a cell culture incubator (37°C, 5% CO2) and culture for 12h. Add 5μL of SM164 (500nM) and compound diluted with cell culture medium to the corresponding wells. After pretreatment at 37°C for 1h, 5μL of TNFα (500ng / mL) diluted with cell culture medium was added to each well of the stimulation group, and 5μL of culture medium was added to the control group. After culture in a cell culture incubator (37°C, 5% CO2) for 14h, 15μl of Cell Titer-Glo solution was added to each well, incubated at room temperature for 30min, and chemiluminescence was detected to measure the intracellular ATP level. The unstimulated DMSO control well was taken as 100% cell viability. Prism Graphpad statistical software was used to calculate the compound EC50 The results are shown in Table 2.

[0234] Table 2. Test results of the inhibitory activity of RIPK1 inhibitors on programmed cell necrosis

[0235] The experimental results in Table 2 show that, whether stimulated by TNFα alone or in combination with SM164, the preferred compounds of the present invention, such as QY-18-26, QY-18-27, QY-20-53 and QY-20-54, exhibited stronger necroptosis inhibitory activity than the clinical inhibitor SAR443122 on human FADD-deficient Jurkat cells; and on mouse L929 cells in which SAR443122 was almost inactivated, the preferred compounds of the present invention were still able to effectively inhibit the occurrence of necroptosis.

[0236] Biological test example 2: Testing the effect of the representative compound QY-18-26 on RIPK1 kinase activity.

[0237] The biological assay protocol employed was to test the effect of compound QY-18-26 on the kinase activity of the RIPK1(1-330) protein. The purified RIPK1(1-330) protein retained its intact kinase domain and maintained good kinase activity. SAR443122, a known clinical RIPK1 inhibitor, was used as a control.

[0238] Methods: RIPK1 (1-330) protein with a final concentration of 2 μM and ATP (1X kinase buffer) with a final concentration of 5 μL were added to a 384-well plate. At least 3 replicate wells were set up for each group. The plates were reacted at 37°C for 2 h. 5 μL ADP-Glo ​​reagent was added to stop the kinase reaction and remove residual ATP in the reaction system. The plates were allowed to stand at room temperature for 40 min. 10 μL Kinase Detection Reagent was added to convert ADP into ATP and introduce luciferase and luciferin for detecting ATP into the system. The plates were allowed to react at room temperature for 1 h. Luminescence was detected using the 7500 Fast Real-Time PCR System. The IC value of the compound inhibiting the kinase reaction was calculated using Prism Graphpad statistical software. 50 The experimental results are shown in Figure 1.

[0239] The experimental results showed that the representative compound QY-18-26 exhibited concentration-dependent effective inhibition of RIPK1 kinase, with an effective half-inhibitory concentration of 6.4 nM, which was better than the control SAR443122 (effective half-inhibitory concentration of 9.6 nM).

[0240] Biological Test Example 3: Pharmacokinetic Properties of Representative Compound QY-18-26

[0241] The biological test scheme used is: drug metabolism test of the compound in living mice.

[0242] To validate the pharmacokinetic properties of the compounds of this invention in vivo, representative compound QY-18-26 was tested in mice (n=3) using single oral gavage (PO, 10 mg / kg) or intravenous injection (IV, 1 mg / kg). The results are shown in Figure 2.

[0243] The results showed that after a single dose of QY-18-26, the concentration in mice rapidly reached a peak and showed a very high maximum blood concentration (C max ), exposure (AUC) and bioavailability (F). During the 24 hours after oral administration of 10 mg / kg, the blood drug concentration could be stably maintained above the effective inhibitory concentration (5 ng / mL) for most of the time.

[0244] Biological Test Example 4: Brain Penetration Properties of Representative Compound QY-18-26

[0245] The biological testing protocol used was: brain / blood drug concentration testing of the compound in living mice and rats.

[0246] To verify the brain penetration properties of the compounds of this invention in vivo, representative compound QY-18-26 was tested in mice (n=3) using single oral gavage (10 mg / kg) or intravenous injection (2 mg / kg) to determine brain and blood concentrations at different time points. Furthermore, single oral gavage (5 mg / kg) was used to determine brain and blood concentrations at different time points in rats (n=3). The results are shown in Figure 3.

[0247] After a single dose of QY-18-26, the concentration in the brain of mice and rats was approximately 40% of the concentration in plasma, and it maintained a stable brain-blood distribution at 4 hours. Its brain drug concentration was far above the effective inhibitory concentration (5ng / g), indicating that the compound has ideal brain penetrating properties.

[0248] Biological Test Example 5: Effect of Representative Compound QY-18-26 on Systemic Inflammatory Response Syndrome Induced by TNFα

[0249] Biological testing protocol employed: Systemic inflammatory response syndrome (SIRS), also known as inflammatory storm, refers to a systemic, nonspecific inflammatory response caused by infectious or non-infectious insults such as severe infection, multiple trauma, burns, ischemia-reperfusion, and acute pancreatitis. This condition results in the release of a large number of inflammatory factors, which in severe cases can lead to uncontrolled inflammatory responses, resulting in multiple organ failure and even death. Tail vein injection of tumor necrosis factor (TNF) induces SIRRS in mice, leading to hypothermia and death. The representative compound QY-18-26 was tested for its effect on TNFα-induced SIRRS, monitoring mice for changes in body temperature and mortality. A known RIPK1 inhibitor, Nec-1s, was used as a control; the clinical inhibitor SAR443122 has very poor inhibitory activity against murine RIPK1 and was therefore omitted.

[0250] Methods: Test compounds were dissolved in 0.5% carboxymethyl cellulose at the desired concentration one day in advance and sonicated overnight. Each mouse was gavaged with 200 μl of the solution. 20 minutes later, 10 mg of TNFα (dissolved in 125 μl of PBS) was injected via the tail vein. After injection, body temperature was monitored using an infrared thermometer. The effects of the compounds were calculated using Prism Graphpad software. The results are shown in Figure 4.

[0251] The experimental results showed that in the absence of inhibitors, all mice died within hours after being injected with TNFα; the compound QY-18-26 was able to effectively resist the hypothermia, inflammatory response and death caused by TNFα at a low dose (1 mg / kg).

Claims

1. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: The compound is shown in Formula I: Where: X1 is selected from the group consisting of CH, N or a chemical bond; X2, X3, X4 and X5 are each independently selected from the group consisting of CH, N; Provided that the ring formed by X1, X2, X3, X4 and X5 is an aromatic ring; M is selected from the group consisting of O, S, NR3, CHR3 or C(R3)2; W and U are each independently selected from the group consisting of O, S, NR4, CHR4 or C(R4)2; The A ring and the B ring are each independently selected from the following group: a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group; R1 and R2 are each independently selected from the group consisting of none, H, substituted or unsubstituted C1-C6 alkyl, halogen; When M is NR3, CHR3 or C(R3)2, R2 and R3 may form a substituted or unsubstituted 5-7 membered ring together with the C atom or N atom to which they are connected and -CC(O)-; R3 and R4 are selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, halogen; R6 is selected from the following group: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkyne, or -CH≡CR5; wherein R5 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl; R7 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkyne, or -CH≡CR8; wherein R8 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl; Wherein, the substitution refers to that the hydrogen atom on the group is replaced by one or more (for example, 2, 3, 4, etc.) substituents selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 hydroxyalkyl, methyl sulfone, -S(=O)2NH2, oxo(=O), -CN, hydroxyl, -NH2, carboxyl, C2-C6 amide (-C(=O)-N(Rc)2 or -NH-C(=O)(Rc), Rc is H or C1-C5 C1-C6 alkyl-(C2-C6 amide), C1-C6 amine, deuterated C1-C6 amine, -NHRd (Rd is C3-C8 cycloalkyl, 4-7 membered heterocyclyl or heterocyclyl substituted by C1-C6 alkyl), C6-C10 aryl, 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, 4-7 membered heterocyclyl substituted by 1 or 2 Re (Re is halogen, C1-C6 alkyl, C1-C6 amine, -CN, C1-C6 alkoxy or 4-7 membered heterocyclyl).

2. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: The compound is shown in Formula II: The definitions of M, W, U, A, B, R1, R6 and R7 are as described in claim 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: The A ring and the B ring are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaryl; Substitution is defined as in claim 1.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: The A ring and the B ring are each independently selected from the following group:

5. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: In the formula I, M is NR3, and / or W is CHR4; R6 is selected from the group consisting of H, halogen, CN, substituted or unsubstituted C1-C6 alkyl; R7 is selected from the following group: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkyne, or -CH≡CR8; wherein R8 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl; R3, R4 and substitution are as defined in claim 1.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: The compound is shown in formula III: The definitions of M, W, U, A, B, X5, R1, R2, R3, R6, and R8 are as described in claim 1.

7. The compound according to claim 1, characterized in that The compound is selected from the following table:

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises (a) a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable carrier.

9. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating or preventing a disease or condition associated with programmed cell death and / or human receptor interacting protein 1 kinase (RIPK1).

10. The use according to claim 9, characterized in that The disease or condition is selected from one or more of the following groups: degenerative diseases, inflammation, ischemia-reperfusion injury, pathogen infection, Parkinson's disease (PD), age-related macular degeneration, autoimmune diseases, retinal detachment-induced photoreceptor cell necrosis, glaucoma, cisplatin-induced renal injury and traumatic brain injury, atherosclerosis caused by hyperlipidemia, other diseases related to RIPK1-dependent apoptosis, necrosis or cytokine production, bacterial infection, viral infection and lysosomal storage disease.

Images