Polysubstituted aromatic amine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention provides a polysubstituted aromatic amine compound (as shown in a general formula I) as well as a preparation method, a pharmaceutical composition and application thereof, and particularly provides a compound with a structure as shown in the general formula I as well as an optical isomer, a medicinal salt or a mixture of the compound and the optical isomer. The compound has good IRAK4 inhibitory activity, so that the compound can be used for treating, preventing and relieving IRAK4 target related diseases, especially for treating autoimmune diseases such as arthritis, inflammatory bowel disease and the like, malignant tumors such as leukemia and the like or other related diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry and pharmacotherapy, in particular to a class of compounds containing general formula I as interleukin-1 receptor associated kinase 4 (IRAK-4) inhibitors, the preparation method thereof, pharmaceutical compositions containing such compounds and can be used for treating, preventing and relieving diseases related to IRAK-4 target, especially for treating rheumatoid arthritis, inflammatory bowel disease and other autoimmune diseases, colorectal cancer, acute myeloid leukemia and lymphoblastic cancer and other malignancies or other related diseases. BACKGROUND

[0002] Interleukin-1 receptor associated kinase 4 (IRAK-4) as a serine-threonine kinase is a key signaling node of the IL-1R family and TLR signaling pathways. Studies have found that IRAK-4 mediated inflammatory pathways can cause inflammation of the joints, intestines, liver and nervous system and other autoimmune diseases in the human body, and also the drug resistance of some cancer cells.

[0003] IRAK-4 belongs to the IRAK kinase family consisting of IRAK-1, IRAK-2, IRAK-M and IRAK-4, and is a protein kinase with a full length of 460 amino acids. The structure of IRAK family members usually includes an N-terminal death domain (DD), a conserved central kinase domain, a proline / serine / threonine-rich domain (ProST domain) and a C-terminal domain (except IRAK-4). IRAK-4 small molecule inhibitors bind to the ATP binding site, mainly interact in the hinge region between the β5 fold and the αD helix, bind to the main chain through hydrogen bonding with amino acid residues Met265 and Val263, the aromatic ring of the small molecule interacts with the gatekeeper residue Tyr262 in the form of π-π stacking, and other groups of the small molecule occupy the ATP ribose pocket and can form hydrogen bonds with P loop residues.

[0004] The cytoplasmic portion of TLRs is highly similar to IL-1R and is called the Toll / interleukin-1 receptor (TIR) domain. Upon activation of the extracellular portion of IL-1R and TLRs by binding to their cognate ligands, their TIR domains recruit the adaptor protein MyD88, which in turn recruits and activates IRAK-4 through its DD domain, accompanied by the activation and clustering of IRAK-1 and IRAK-2, and finally the recruitment of TRAF6, forming a complex called myddosome. Upon recruitment and activation of TRAF6, the signaling of mitogen activated protein (MAP) kinases p38, c-Jun N terminal kinase (JNK), and inhibitor of nuclear factor kappa-B kinase (IKKα / β) is further activated through transforming growth factor-activated kinase 1 (TAK1). This ultimately leads to the activation of nuclear factor kappa-B (NF-κΒ) and the production of activator protein-1 (AP-1), interferon regulatory factor 3 (IRF3), interferon regulatory factor 5 (IRF5), and other proinflammatory cytokines. Therefore, as the core of MyD88-dependent signaling, selective inhibition of IRAK-4 can simultaneously regulate TLR / IL-1R signaling and can be used for the treatment of various IRAK4-high-expressing inflammatory diseases and cancers.

[0005] Increasing evidence shows that over-activation of IRAK4-mediated TLR / IL-1R signaling pathway is closely related to the occurrence and development of various inflammatory diseases. Clinical studies have found that individuals lacking IRAK-4 are more susceptible to bacterial infections. TLR agonists (except TLR3) do not produce immune stimulation in peripheral blood mononuclear cells and lymphocytes derived from patients with low IRAK-4 expression, and IL-1β stimulation does not produce a response in the patient's fibroblasts. In various inflammatory disease models such as systemic lupus erythematosus, rheumatoid arthritis, neuroinflammatory diseases such as cerebral ischemia, necrotizing enterocolitis, and ethanol-induced liver injury inflammation, selective inhibition of IRAK-4 shows good anti-inflammatory effects, which strongly proves its wide clinical application prospect in inflammatory diseases. The imbalance of innate immune signaling components is increasingly recognized as an important mediator of cancer occurrence and development. Based on the central role of IRAK4 in immune regulation, its over-activation promotes tumor occurrence and progression by activating downstream JAK-STAT and NF-κB signaling pathways, and on the other hand, it promotes the highly inflammatory tumor microenvironment, leading to T cell exhaustion, resulting in tumor immune escape and resistance to existing therapies. In various tumor models such as chronic lymphocytic leukemia, colorectal cancer, and pancreatic ductal adenocarcinoma, selective inhibition of IRAK4 shows strong anti-tumor effects.

[0006] Currently, more than 30 small molecule IRAK4 inhibitors have entered clinical research, most of which are in the early stage of clinical trials, and the indications are concentrated in autoimmune diseases (hidradenitis suppurativa, atopic dermatitis, chronic kidney disease, etc.) and tumors. For example, PF-06650833, BAY-1830839, BAY-1834845, R-835, and CA-4948, etc. Among them, PF-06650833 developed by Pfizer is the first IRAK-4 small molecule inhibitor to enter clinical research worldwide, and is currently undergoing phase II clinical trial research for the treatment of rheumatoid arthritis and hidradenitis suppurativa.

[0007] In summary, given the important role of IRAK-4 over-activation in the occurrence and development of various autoimmune diseases and malignant tumors, IRAK-4 small molecule inhibitors have become the most promising research direction in the field of drug development for autoimmune diseases and tumors. However, most of the current drugs are concentrated in the I / II phase of clinical research to evaluate the safety and effectiveness of the compounds, and few drugs can enter the later stage of clinical trials, and how to balance in vivo activity and safety is a difficulty in the development of IRAK-4 targeted drugs. Therefore, there is still a lot of room for improvement in the field of IRAK-4 small molecule inhibitor research, which is worth further study. SUMMARY

[0008] The present application aims to provide a class of polysubstituted aromatic amine compounds (as shown in general formula I) and their preparation methods, pharmaceutical compositions and uses.

[0009] In the first aspect of the present application, a compound as shown in general formula I, and its optical isomer, pharmaceutically acceptable salt or mixture thereof is provided:

[0010]

[0011] wherein:

[0012] R 4 is selected from the group consisting of: R 4 is H; or said R 4 and R 4 together with the carbon atom to which they are attached form a 4-7 membered carbocyclic ring, or a 4-7 membered heterocyclic ring, which can be saturated or partially unsaturated;

[0013] ring, ring, ring and each ring is independently selected from the group consisting of substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclyl, or substituted or unsubstituted 9-20 membered aromatic fused ring;

[0014] Q is a bond or C1-C4 straight chain or branched alkyl;

[0015] R 1 , R 3 each independently is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted C1-C 10 straight chain or branched alkyl, substituted or unsubstituted C1-C 10 straight chain or branched alkoxy, C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 membered carbocyclyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heterocyclyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C0-C6 alkylamino (C0 alkylamino is NH2), substituted or unsubstituted C1-C6 amido, substituted or unsubstituted C1-C6 alkyl-sulfonyl or substituted or unsubstituted C1-C6 alkyl-sulfinyl, -(C=O)NR a R b ; wherein Ra , R b each independently selected from the group consisting of H, C1-C4 alkyl, C3-C4 carbocyclyl, -C1-C4 alkylene-NR c R d ; R c , R d each independently selected from the group consisting of H, C1-C4 alkyl;

[0016] R 2 selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted C0-C6 alkyl-hydroxyl (C0 hydroxyl is OH), C0-C6 amino (C0 amino is NH2), -(C=O)OR a , -(C=O)NR a R b ; wherein R a , R b each independently selected from the group consisting of H, C1-C4 alkyl;

[0017] L is, independently at each occurrence, absent (i.e., ring A is directly connected to ring B), or C1-C6 methylene or C1-C6 methine (where valence allows);

[0018] is a double bond or a single bond;

[0019] X is CR 5 or N; R 5 selected from the group consisting of H, deuterium, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted C1-C4 straight or branched alkyl;

[0020] Unless otherwise specified, each of the heteroaromatic, heterofused ring, or heterocyclyl groups independently contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0021] substituted means that a hydrogen atom on the group is replaced with one to three substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclyl, C6-C 10 aryl, 3-12 membered saturated or partially unsaturated heterocyclyl, and 5-12 membered heteroaryl;

[0022] halogen is F, Cl, Br, or I.

[0023] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0024]

[0025] In another preferred embodiment, the R 4 for And R 2 It is hydroxymethyl.

[0026] In another preferred embodiment, the compound has the structure shown in Formula II or Formula III:

[0027]

[0028] In another preferred embodiment, the described The ring is selected from the group consisting of: substituted or unsubstituted 5-8-membered heteroaryl groups, substituted or unsubstituted 5-8-membered heterocyclic groups, or substituted or unsubstituted 9-12-membered aromatic fused rings;

[0029] Preferably, the aforementioned The ring is selected from the following group:

[0030]

[0031] In another preferred embodiment, The ring is selected from the group consisting of 5-12-membered heterocyclic groups or 5-12-membered heteroaryl groups, preferably 5-7-membered heterocyclic groups or 5-7-membered heteroaryl groups; more preferably, the ring... The ring has a structure selected from the following group:

[0032]

[0033] X is as described above.

[0034] In another preferred embodiment, Each ring is independently selected from the group consisting of phenyl, 5-12-membered heteroaryl, preferably phenyl, 5-7-membered heteroaryl; more preferably, the rings are... The ring is selected from the following group:

[0035] In another preferred embodiment, Each ring is independently selected from the group consisting of phenyl, 5-12-membered heteroaryl, preferably phenyl, 5-7-membered heteroaryl; more preferably, the rings are... Ring from the lower group:

[0036] In another preferred embodiment, R 1 Each is independently selected from the following group: hydrogen, deuterium, halogen, cyano, nitro, amino, substituted or unsubstituted C1-C. 10 Straight-chain or branched alkyl groups, substituted or unsubstituted C1-C2 10Straight-chain or branched alkoxy groups, substituted or unsubstituted C1-C2 10 Straight-chain or branched alkyl groups, -(C=O)NR a R b ;

[0037] Where R a R b Each is independently selected from the following group: H, C1-C4 alkyl, C3-C4 carbocyclic, -C1-C4 alkylene-NR c R d ;

[0038] L is selected from the following group: not present, -CH2, =CH-;

[0039] R 2 Each group is independently selected from the following groups: H, carboxyl, hydroxymethyl, -(C=O)OR a -(C=O)NR a R b 、;

[0040] R 3 Each is independently selected from the following group: H, halogens;

[0041] Where R c R d Each is independently selected from the following group: H, C1-C4 alkyl;

[0042] In another preferred embodiment, the compound is selected from the group consisting of:

[0043] Table 1 Preferred Compounds

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] In a second aspect of the invention, a pharmaceutical composition is provided comprising (i) a compound as described in the first aspect of the invention, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof; and (ii) a pharmaceutically acceptable carrier.

[0062] The third aspect of the invention provides the use of the compounds as described in the first aspect of the invention, their optical isomers, pharmaceutically acceptable salts, or mixtures thereof, or pharmaceutical compositions as described in the second aspect of the invention, for the preparation of medicaments for treating, preventing, and alleviating diseases associated with the IRAK-4 target, wherein the diseases associated with the IRAK-4 target are selected from the group consisting of: autoimmune diseases, malignant tumors; preferably, the autoimmune diseases are selected from the group consisting of: rheumatoid arthritis, ulcerative colitis, Crohn's disease, hidradenitis suppurativa, atopic dermatitis, systemic lupus erythematosus, and neuroinflammatory diseases; and the malignant tumors are selected from the group consisting of: colorectal cancer, acute myeloid leukemia, lymphoblastic carcinoma, cervical cancer, ovarian cancer, and liver cancer.

[0063] In another preferred embodiment, the use also includes the preparation of IRAK-4 inhibitors.

[0064] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described 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 described in detail here. Attached Figure Description

[0065] none Detailed Implementation

[0066] Through long-term and in-depth research, the inventors have designed and prepared a class of multi-substituted aromatic amine compounds (structures shown in general formula I). ​​These compounds have good IRAK-4 inhibitory activity and can be used to treat, prevent, and alleviate diseases related to IRAK-4 protein kinase.

[0067] the term

[0068] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0069] As used in this article, the term "C1-C" 10 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0070] The term "C3-C" 10 "Cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group having 3 to 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "C3-C6 cycloalkyl" has a similar meaning.

[0071] The term "C3-C8 carbon ring" refers to a saturated or partially unsaturated cyclic hydrocarbon group with 3 to 8 carbon atoms, whose ring skeleton consists entirely of carbon atoms. The carbon ring may be saturated or partially unsaturated, but it does not possess aromaticity.

[0072] The term "5-12 membered heterocyclic group" refers to a saturated or partially unsaturated cyclic group having 5 to 12 carbon atoms, wherein one or more atoms in its skeleton are selected from the group consisting of N, O, and S, wherein the ring N atom can be oxidized to NO, and the ring S atom can be oxidized to SO or SO2, and the remaining ring atoms are carbon. The heterocyclic group may be saturated or partially unsaturated, but it does not possess aromaticity.

[0073] The term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, or similar groups. 1-3 Expressions such as "alkoxy" have similar definitions.

[0074] The term "C6-C" 10 "Aryl" refers to an aryl group having 6-10 carbon atoms, including monocyclic or polycyclic aryl groups, such as phenyl, naphthyl, or similar groups.

[0075] The term "5-12 heteroaryl" refers to a heteroaryl group having 5-12 ring atoms (with 1-8 heteroatoms selected from N, O or S on the skeleton), such as pyrrole, pyridyl, furanyl, or similar groups.

[0076] The term "10-20 membered aromatic fused ring" refers to aromatic hydrocarbons with 10-20 carbon atoms, which are formed by the fusion of two or more benzene rings through the sharing of two adjacent carbon atoms, such as naphthalene, anthracene, and phenanthrene.

[0077] The term "substitution" refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of 1 to 3 substituents selected from the group consisting of: halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic groups, C6-C6... 10 Aryl, 3-12 membered saturated or partially unsaturated heterocyclic groups and 5-12 membered heteroaryl groups.

[0078] Unless otherwise specified, all compounds appearing in this invention are intended to include all possible optical isomers, including but not limited to enantiomers, diastereomers, cis-trans isomers, and trans-blocked isomers, as well as mixtures thereof (such as racemates). In all compounds of this 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] As used herein, the term "compound of the invention" refers to a compound of Formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of compounds of Formula I.

[0080] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts 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, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0081] compound

[0082] This invention provides a compound as represented by general formula I, and all possible optical isomers, pharmaceutically acceptable salts, or mixtures thereof:

[0083]

[0084] The definitions of each group are the same as above.

[0085] In another preferred embodiment, in the compound, R 4 R 4 '、 ring, ring, ring, Ring, Q, R1 R 2 R 3 L Each of X and X represents a functional group corresponding to a specific compound described in Table 1.

[0086] In another preferred embodiment, the compound is preferably one of the compounds listed in Table 1.

[0087] Preparation of Compound I

[0088] The present invention also provides a method for preparing a compound represented by general formula I, the method being carried out according to the following scheme (example):

[0089] Route 1:

[0090]

[0091] in: ring, Ring and Each ring is independently selected from the following group: substituted or unsubstituted C6-C6 rings. 10 Aryl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted 5-12-membered heterocyclic group, or substituted or unsubstituted 9-20-membered aromatic fused ring;

[0092] R2 is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted C0-C6 alkyl-hydroxyl (C0 hydroxyl is OH), C0-C6 amino (C0 amino is NH2), -(C=O)OR a -(C=O)NR a R b ;where R a R b Each is independently selected from the following group: H, C1-C4 alkyl.

[0093] Step a: Dissolve compounds 1 and 2 in a solvent, then add cuprous iodide, L-proline, and anhydrous potassium carbonate or cesium carbonate sequentially. Under argon protection, heat the mixture to react. The solvent is DMSO or 1,4-dioxane, and the heating temperature range is 90–100 °C.

[0094] Step b: Compound 4, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane), palladium catalyst, and potassium acetate are dissolved in a solvent, and the reaction is carried out under argon protection and heated. The solvent is 1,4-dioxane or DMF, and the heating temperature range is 90–100 °C.

[0095] Step c: Dissolve compound 3, compound 5, palladium catalyst, and anhydrous potassium carbonate in a solvent, and heat under argon protection. The solvents are THF, 1,4-dioxane, and DME, and the heating temperature range is 90–100 °C.

[0096] Step d: Dissolve compound 6 and aldehydes with different aromatic heterocycles in a solvent, add a small amount of pyridine solution dropwise at room temperature, and heat and stir the reaction mixture. The solvent is methanol, ethanol, or isopropanol, and the temperature range is 80–90 °C.

[0097] Route 2:

[0098]

[0099] in: ring, Ring and Each ring is independently selected from the following group: substituted or unsubstituted C6-C6 rings. 10 Aryl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted 5-12-membered heterocyclic group, or substituted or unsubstituted 9-20-membered aromatic fused ring;

[0100] R2 is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted C0-C6 alkyl-hydroxyl (C0 hydroxyl is OH), C0-C6 amino (C0 amino is NH2), -(C=O)OR a -(C=O)NR a R b ;where R a R b Each is independently selected from the following group: H, C1-C4 alkyl.

[0101] Step a: Dissolve compound 1 in a solvent, then slowly add sodium borohydride and react at room temperature. The solvent is DMF or methanol.

[0102] Route 3:

[0103]

[0104] Where R1 is defined above, and X is CR 5 Or N;R 5 Selected from the following group: H, deuterium, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, substituted or unsubstituted C1-C4 straight-chain or branched alkyl; L is independently: absent (i.e. ring A is directly connected to ring B), or C1-C6 methylene or C1-C6 methine (where valence allows). It can be a double bond or a single bond;

[0105] in: ring, Ring and Each ring is independently selected from the following group: substituted or unsubstituted C6-C6 rings. 10 Aryl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted 5-12-membered heterocyclic group, or substituted or unsubstituted 9-20-membered aromatic fused ring;

[0106] Step a: Dissolve compounds 1 and 2 in a solvent, then add cuprous iodide, L-proline, and anhydrous potassium carbonate or cesium carbonate sequentially. Under argon protection, heat the mixture to react. The solvent is DMSO or 1,4-dioxane, and the heating temperature range is 90–100 °C.

[0107] Step b: Compound 4, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane), palladium catalyst, and potassium acetate are dissolved in a solvent, and the reaction is carried out under argon protection and heated. The solvent is 1,4-dioxane or DMF, and the heating temperature range is 90–100 °C.

[0108] Step c: Dissolve compound 5, NBS, and potassium hydroxide in a solvent and react at room temperature. The solvent is DMF or acetonitrile.

[0109] Step d: Compounds 3 and 6 were dissolved in a solvent, and palladium catalyst and anhydrous potassium carbonate were added sequentially. The reaction was carried out under argon protection and heated. The solvents were THF, 1,4-dioxane, and DME, and the heating temperature range was 90–100 °C.

[0110] Step e: Compound 7 is dissolved in a solvent, and palladium catalyst, anhydrous potassium carbonate, and borate esters containing different aromatic heterocycles are added sequentially. The reaction is carried out under argon protection and heated. The solvents are THF, 1,4-dioxane, and DME, and the heating temperature range is 90–100 °C.

[0111] Pharmaceutical Compositions and Administration

[0112] Because the compounds of the present invention have excellent IRAK-4 protease inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for diseases related to IRAK-4 protein kinase.

[0113] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg / kg) of the compound of the present invention per dose, more preferably, 10-2000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0114] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0115] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0116] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0117] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0118] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0119] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0120] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0121] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0122] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0123] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0124] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 6–600 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0125] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0126] Preparation of intermediates

[0127] Intermediate 1: (R)-2-((5-bromopyridin-3-yl)amino)-2-phenylethyl-1-ol

[0128]

[0129] 3,5-Dibromopyridine (3.0 g, 12.66 mmol) and D-phenylglycine (2.78 g, 20.26 mmol) were dissolved in 30 mL of dry DMSO. Then, L-proline (0.292 g, 2.53 mmol), cuprous iodide (0.241 g, 1.27 mmol), and anhydrous potassium carbonate (3.50 g, 25.33 mmol) were added sequentially. The reaction was carried out at 100 °C for 12 h under argon protection. The reaction was monitored by TLC. After the reaction was complete, the solution was diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, v / v) to give 1.53 g of a pale yellow solid, with a yield of 41.2%.

[0130] Intermediate 2: (S)-2-((5-bromopyridin-3-yl)amino)-2-phenylethyl-1-ol

[0131]

[0132] Replace D-phenylglycine with L-phenylglycine; the remaining raw materials, reagents, and preparation methods are the same as for intermediate 1.

[0133] Intermediate 3: 2-((5-bromopyridin-3-yl)amino)-2-phenylethyl-1-ol

[0134]

[0135] Replace D-phenylglycine with DL-phenylglycine; the remaining raw materials, reagents, and preparation methods are the same as for intermediate 1.

[0136] Intermediate 4: (R)-2-((6-bromopyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0137]

[0138] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and use the same raw materials, reagents and preparation methods as intermediate 1.

[0139] Intermediate 5: (R)-2-((5-bromopyridin-3-yl)amino)-2-phenylacetic acid

[0140]

[0141] Replace D-phenylglycine with (R)-2-amino-2-phenylacetic acid, and use the same raw materials, reagents and preparation methods as intermediate 1.

[0142] Intermediate 6: (R)-2-((6-bromopyrazin-2-yl)amino)-2-phenylacetic acid

[0143]

[0144] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, replace D-phenylglycine with (R)-2-amino-2-phenylacetic acid, and the other required raw materials, reagents and preparation methods are the same as those for intermediate 1.

[0145] Intermediate 7: (R)-2-((6-bromopyrimidin-4-yl)amino)-2-phenylethyl-1-ol

[0146]

[0147] 4,6-Dibromopyrimidine (3.12 g, 13.12 mmol) and D-phenylglycine (1.50 g, 10.93 mmol) were dissolved in 30 mL of dry 1,4-dioxane solution. Then, sodium tert-butoxide (2.10 g, 21.87 mmol), tris(dibenzylacetone)dipalladium(0) (0.50 g, 0.55 mmol), and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.521 g, 1.09 mmol) were added sequentially. The reaction was carried out at 100 °C for 12 h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, v / v) to give 1.68 g of a pale yellow oil, with a yield of 51.2%.

[0148] Intermediate 8: 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)indololin-2-one

[0149]

[0150] 5-Bromoindololin-2-one (1 g, 4.72 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentane) (1.8 g, 7.07 mmol) were dissolved in 15 mL of dry 1,4-dioxane solution. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.382 g, 0.47 mmol) and potassium acetate (0.926 g, 9.43 mmol) were added sequentially. The reaction was carried out at 80 °C for 12 h under argon protection. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth, diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 2:1, v / v) to give 1.04 g of brown solid, yield 85.11%.

[0151] Intermediate 9: 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indazole

[0152]

[0153] Replace 5-bromoindololin-2-one with 5-bromo-1H-indazole, and use the same raw materials, reagents and preparation methods as intermediate 8.

[0154] Intermediate 10: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborborane-2-yl)-1H-pyrazolo[3,4-c]pyridine

[0155]

[0156] Replace 5-bromoindololin-2-one with 5-bromo-1H-pyrazolo[3,4-c]pyridine, and use the same raw materials, reagents and preparation methods as intermediate 8.

[0157] Example 1 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0158]

[0159] 1,1(R)-2-((5-bromopyridin-3-yl)amino)-2-phenylethyl-1-ol

[0160] 3,5-Dibromopyridine (3.0 g, 12.66 mmol) and D-phenylglycine (2.78 g, 20.26 mmol) were dissolved in 30 mL of dry dimethyl sulfoxide, followed by the addition of cuprous iodide (0.241 g, 1.27 mmol), L-proline (0.292 g, 2.53 mmol), and anhydrous potassium carbonate (3.50 g, 25.33 mmol). The reaction was carried out at 100 °C for 12 h under argon protection. After the reaction was completed, the reaction mixture was poured into 300 mL of water and extracted three times with ethyl acetate (150 mL * 3). The organic phase was collected, washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (PE:EA = 5:1, v / v) to give 1.53 g of a pale yellow solid, with a yield of 41.2%.

[0161] 1,2-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)indololin-2-one

[0162] 5-Bromoindololin-2-one (1 g, 4.72 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentane) (1.8 g, 7.07 mmol) were dissolved in 15 mL of dry 1,4-dioxane solution. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.382 g, 0.47 mmol) and potassium acetate (0.926 g, 9.43 mmol) were added sequentially. The reaction was carried out at 80 °C for 12 h under argon protection. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth, diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 2:1, v / v) to give 1.04 g of brown solid, yield 85.11%.

[0163] 1,3(R)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0164] (R)-2-((5-bromopyridin-3-yl)amino)-2-phenylethyl-1-ol (0.50 g, 1.71 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)indololin-2-one (0.530 g, 2.05 mmol) were dissolved in a DME:H₂O mixture of 5:1 (v / v). Tetra(triphenylphosphine)palladium (0.395 g, 0.341 mmol) and anhydrous potassium carbonate (0.471 g, 3.41 mmol) were then added sequentially. The reaction was carried out at 95 °C for 12 h under argon protection. The reaction was monitored by TLC. After the reaction was completed, the diatomaceous earth was filtered, the filtrate was diluted with water, extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 35:1, volume ratio) to obtain 0.375 g of pale yellow solid, with a yield of 63.66%.

[0165] 1,4(R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0166] (R)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indoline-2-one (0.25 g, 0.724 mmol) and 1H-pyrrole-2-carboxaldehyde (0.206 g, 2.17 mmol) were dissolved in 10 mL of methanol, and a small amount of pyridine was added. The mixture was then heated at 85 °C and stirred overnight. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 35:1, v / v) to give 0.12 g of a yellow solid, with a yield of 39.24%. 1 H NMR (500MHz, DMSO-d6) δ13.25(s,1H),10.91(s,1H),7.97(d,J=1.9Hz,1H),7.82(d,J=2.6 Hz,1H),7.76(d,J=8.6Hz,2H),7.37(d,J=7.4Hz,2H),7.31(d,J=2.4Hz,1H),7.28–7.20(m ,3H),7.16(t,J=7.3Hz,1H),7.01(s,1H),6.86(d,J=8.0Hz,1H),6.80–6.76(m,1H),6.35– 6.26(m,2H),4.95(t,J=5.6Hz,1H),4.51–4.44(m,1H),3.58(dd,2H).LRMS(ESI)m / z:[M+H] + 423.

[0167] Example 2 (Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0168] Replace D-phenylglycine with DL-phenylglycine; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 423.

[0169] Example 3 (S,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0170] Replace D-phenylglycine with L-phenylglycine; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 423.

[0171] Example 4 (R,Z / E)-3-(furan-2-ylmethylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0172] Replace 1H-pyrrole-2-carboxaldehyde with 2-furancarboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 424.

[0173] Example 5 (Z / E)-3-(furan-2-ylmethylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0174] Replace D-phenylglycine with DL-phenylglycine, and 1H-pyrrole-2-carboxaldehyde with 2-furancarboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 424.

[0175] Example 6 (S,Z / E)-3-(furan-2-ylmethylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0176] Replace D-phenylglycine with L-phenylglycine, and 1H-pyrrole-2-carboxaldehyde with 2-furancarboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 424.

[0177] Example 7 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(thiophen-2-ylmethylene)indoline-2-one

[0178] Replace 1H-pyrrole-2-carboxaldehyde with thiophene-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 440.

[0179] Example 8 (Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(thiophen-2-ylmethylene)indoline-2-one

[0180] Replace D-phenylglycine with DL-phenylglycine, and 1H-pyrrole-2-carboxaldehyde with thiophene-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 440.

[0181] Example 9 (S,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(thiophen-2-ylmethylene)indoline-2-one

[0182] Replace D-phenylglycine with L-phenylglycine, and 1H-pyrrole-2-carboxaldehyde with thiophene-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 440.

[0183] Example 10 (R,Z / E)-3-((1H-imidazol-4-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0184] Replace 1H-pyrrole-2-carboxaldehyde with 1H-indazole-4-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 424.

[0185] Example 11 (Z / E)-3-((1H-imidazol-4-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0186] Replace D-phenylglycine with DL-phenylglycine, and 1H-pyrrole-2-carboxaldehyde with 1H-indazole-4-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 424.

[0187] Example 12 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(oxazol-5-ylmethylene)indoline-2-one

[0188] Replace 1H-pyrrole-2-carboxaldehyde with oxazol-5-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 425.

[0189] Example 13 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(thiazolyl-5-ylmethylene)indoline-2-one

[0190] Replace 1H-pyrrole-2-carboxaldehyde with thiazole-5-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 441.

[0191] Example 14 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(oxazol-2-ylmethylene)indoline-2-one

[0192] Replace 1H-pyrrole-2-carboxaldehyde with oxazol-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 425.

[0193] Example 15 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(pyridin-2-ylmethylene)indoline-2-one

[0194] Replace 1H-pyrrole-2-carboxaldehyde with pyridine-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 435.

[0195] Example 16 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(pyridin-4-ylmethylene)indololin-2-one

[0196] Replace 1H-pyrrole-2-carboxaldehyde with pyridine-4-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 435.

[0197] Example 17 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(pyrimidin-5-ylmethylene)indoline-2-one

[0198] Replace 1H-pyrrole-2-carboxaldehyde with pyrimidine-5-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 436.

[0199] Example 18 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(pyrimidin-2-ylmethylene)indololin-2-one

[0200] Replace 1H-pyrrole-2-carboxaldehyde with pyrimidine-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 436.

[0201] Example 19 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-((5-methyl-1H-pyrrolo-2-yl)methylene)indoline-2-one

[0202] Replace 1H-pyrrolo-2-carboxaldehyde with 5-methyl-1H-pyrrolo-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 437.

[0203] Example 20 (R,Z / E)-3-((3,5-dimethyl-1H-pyrrolo-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0204] Replace 1H-pyrrole-2-carboxaldehyde with 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 451.

[0205] Example 21 (R,Z / E)-N-(2-(diethylamino)ethyl)-5-((5-(5-(((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-2-oxoindoline-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

[0206] Replace 1H-pyrrole-2-carboxaldehyde with N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 593.

[0207] Example 22 (R,Z / E)-N-cyclobutyl-5-((5-(5-(((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-2-oxoindoline-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

[0208] Replace 1H-pyrrole-2-carboxaldehyde with N-cyclobutyl-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 548.

[0209] Example 23 (R,Z / E)-3-((1H-indol-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0210] Replace 1H-pyrrole-2-carboxaldehyde with 1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 473.

[0211] Example 24 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-((1-methyl-1H-pyrrolo-2-yl)methylene)indoline-2-one

[0212] Replace 1H-pyrrolo-2-carboxaldehyde with 1-methyl-1H-pyrrolo-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 437.

[0213] Example 25 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-((5-methyl-1H-indol-2-yl)methylene)indololin-2-one

[0214] Replace 1H-pyrrole-2-carboxaldehyde with 5-methyl-1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 487.

[0215] Example 26 (R,Z / E)-2-((5-(5-(((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-2-oxoindoline-3-ylidene)methyl)-1H-indo-5-carboxynitrile

[0216] Replace 1H-pyrrole-2-carboxaldehyde with 2-formyl-1H-indole-5-carboxynitrile; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 498.

[0217] Example 27 (R,Z / E)-3-((6-chloro-1H-indol-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0218] Replace 1H-pyrrole-2-carboxaldehyde with 6-chloro-1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 507.

[0219] Example 28 (R,Z / E)-3-((5-chloro-1H-indol-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0220] Replace 1H-pyrrole-2-carboxaldehyde with 5-chloro-1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 507.

[0221] Example 29 (R,Z / E)-3-((5-fluoro-1H-indol-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0222] Replace 1H-pyrrole-2-carboxaldehyde with 5-fluoro-1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 491.

[0223] Example 30 (R,Z / E)-3-((5-bromo-1H-indol-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0224] Replace 1H-pyrrole-2-carboxaldehyde with 5-bromo-1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H]+ 551.

[0225] Example 31 (R,Z / E)-3-((6-bromo-1H-indol-2-yl)methylene)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0226] Replace 1H-pyrrole-2-carboxaldehyde with 6-bromo-1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 551.

[0227] Example 32 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(morpholinomethylene)indololin-2-one

[0228] Replace 1H-pyrrole-2-carboxaldehyde with 4-morpholine-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 443.

[0229] Example 33 (R,Z / E)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-3-(quinolin-2-ylmethylene)indololin-2-one

[0230] Replace 1H-pyrrole-2-carboxaldehyde with 2-quinolinecarboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 485.

[0231] Example 34 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0232] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and use the same raw materials, reagents and preparation methods as in Example 1. 1H NMR(500MHz,DMSO-d6)δ13.33(s,1H),11.05(s,1H),8.29(s,1H),8.17(s,1H),7.94(s,1H ),7.80(d,J=5.9Hz,2H),7.50(dd,J=15.4,7.2Hz,3H),7.40(s,1H),7.34(t,J=7.5Hz,2H), 7.23(t,J=7.4Hz,1H),6.94(d,J=8.1Hz,1H),6.90(d,J=1.8Hz,1H),6.41(d,J=2.9Hz,1H) ,5.08(q,J=6.5Hz,1H),5.00(t,J=5.5Hz,1H),3.73(t,J=5.9Hz,2H).LRMS(ESI)m / z:[M+H] + 424.

[0233] Example 35 (R,Z / E)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)-3-(thiophen-2-ylmethylene)indoline-2-one

[0234] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with thiophene-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 441.

[0235] Example 36 (R,Z / E)-3-(furan-2-ylmethylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indoline-2-one

[0236] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrolo-2-carboxaldehyde with furan-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 425.

[0237] Example 37 (R,Z / E)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)-3-(thiazo-5-ylmethylene)indoline-2-one

[0238] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrolo-2-carboxaldehyde with thiazole-5-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 442.

[0239] Example 38 (R,Z / E)-3-((1H-imidazol-4-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indoline-2-one

[0240] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrolo-2-carboxaldehyde with 1H-imidazol-4-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 425.

[0241] Example 39 (R,Z / E)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)-3-((5-methyl-1H-pyrrolo-2-yl)methylene)indoline-2-one

[0242] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrolo-2-carboxaldehyde with 5-methyl-1H-pyrrolo-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 438.

[0243] Example 40 (R,Z / E)-3-((3,5-dimethyl-1H-pyrrolo-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0244] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrolo-2-carboxaldehyde with 3,5-dimethyl-1H-pyrrolo-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 452.

[0245] Example 41 (R,Z / E)-N-(2-(diethylamino)ethyl)-5-((5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)-2-oxoindoline-3(methylene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

[0246] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrolo-2-carboxaldehyde with N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrolo-3-carboxamide. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H + 594.

[0247] Example 42 (R,Z / E)-3-((1H-indol-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0248] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with 1H-indole-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 474.

[0249] Example 43 (R,Z / E)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)-3-((5-methyl-1H-indol-2-yl)methylene)indololin-2-one

[0250] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with 5-methyl-1H-indole-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H]+: 488.

[0251] Example 44 (R,Z / E)-3-((5-chloro-1H-indol-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0252] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with 5-chloro-1H-indole-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 509.

[0253] Example 45 (R,Z / E)-3-((6-chloro-1H-indol-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0254] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with 6-chloro-1H-indole-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 509.

[0255] Example 46 (R,Z / E)-3-((5-fluoro-1H-indol-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0256] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with 5-fluoro-1H-indole-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 492.

[0257] Example 47 (R,Z / E)-3-((5-bromo-1H-indol-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0258] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with 5-bromo-1H-indole-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 553.

[0259] Example 48 (R,Z / E)-3-((6-bromo-1H-indol-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0260] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrole-2-carboxaldehyde with 6-bromo-1H-indole-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 553.

[0261] Example 49 3-((1H-pyrrolo-2-yl)methyl)-5-(5-(((R)-2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0262]

[0263] (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-(((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one (0.217 g, 0.514 mmol) was dissolved in methanol:DMF = 2:1 (v / v), and then sodium borohydride (0.189 g, 5.14 mmol) was slowly added at 0 °C. The reaction was then stirred at room temperature for 3 h. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, then concentrated under reduced pressure, diluted with water, extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 35:1, v / v) to give 0.138 g of yellow solid, yield 63.29%. 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.90–7.74(m,2H),7.41(ddt,J=8.1,3.3,1. 4Hz,2H),7.36–7.16(m,4H),6.97–6.80(m,2H),6.75–6.56(m,3H),5.92(dq,J=11. 7,2.7Hz,1H),5.70(s,1H),5.20(t,J=5.9Hz,1H),4.47(t,J=6.0Hz,1H),3.77(dd, J=9.6,4.9Hz,1H),3.71–3.57(m,2H),3.17(d,J=4.4Hz,2H).LRMS(ESI)m / z:[M+H] + 425.

[0264] Example 50 3-(furan-2-ylmethyl)-5-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)indololin-2-one

[0265] Replace 1H-pyrrole-2-carboxaldehyde with furan-2-carboxaldehyde, and use the same raw materials, reagents and preparation methods as in Example 49. 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),7.87(dd,J=6.5,2.6Hz,1H),7.84(t,J=2.1Hz,1H),7.51(dd,J=5.2,1.8Hz, 1H),7.41(d,J=7.2Hz,2H),7.36–7.26(m,3H),7.22(td,J=7.2,1.3Hz,1H),7.05–6.80(m,3H),6.46–6.37(m,1H), 6.33(td,J=3.3,1.9Hz,1H),6.02(d,J=3.2Hz,1H),5.02(td,J=5.7,2.7Hz,1H),4.49(q,J=6.4Hz,1H),3.79(t,J= 6.5Hz,1H),3.65(h,J=5.6Hz,2H),3.18(d,J=5.0Hz,1H),3.02(dd,J=15.2,8.1,4.3Hz,1H).LRMS(ESI)m / z:[M+H] + 426.

[0266] Example 51 (R,Z / E)-2-((5-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyridin-3-yl)amino)-2-phenylacetamide

[0267] 1,1(R)-2-((5-(2-oxoindololin-5-yl)pyridin-3-yl)amino)-2-phenylacetic acid

[0268] Replace D-phenylglycine with (R)-2-amino-2-phenylacetic acid, and use the same raw materials, reagents and preparation methods as in Example 1.

[0269] 1,2(R)-2-((5-(2-oxoindoline-5-yl)pyridin-3-yl)amino)-2-phenylacetamide

[0270] (R)-2-((5-(2-oxoindololin-5-yl)pyridin-3-yl)amino)-2-phenylacetic acid (0.72 g, 2.0 mmol) was dissolved in 10 mL of DMF. Then, a 0.4 M solution of 1,4-dioxane containing ammonia and 1.12 mL of triethylamine were added at room temperature. After stirring for half an hour at room temperature, HATU (1.52 g, 4.01 mmol) was slowly added. The mixture was then stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 35:1, v / v) to give 0.35 g of a pale yellow oil, with a yield of 48.74%.

[0271] 1,3(R,Z / E)-2-((5-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyridin-3-yl)amino)-2-phenylacetamide

[0272] (R)-2-((5-(2-oxoindololin-5-yl)pyridin-3-yl)amino)-2-phenylacetamide (0.168 g, 0.469 mmol) and 1H-pyrrole-2-carboxaldehyde (0.134 g, 1.41 mmol) were dissolved in 10 mL of methanol, and a small amount of pyridine was added. The mixture was then heated at 85 °C and stirred overnight. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 35:1, v / v) to give 0.085 g of a yellow solid, with a yield of 41.64%. LRMS(ESI) m / z: [M+H]+: 436.

[0273] Example 52 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrimidin-4-yl)indololin-2-one

[0274] Replace 3,5-dibromopyridine with 4,6-dibromopyrimidine; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H]+ 424.

[0275] Example 53 (R,Z / E)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrimidin-4-yl)-3-(thiophen-2-ylmethylene)indoline-2-one

[0276] Replace 3,5-dibromopyridine with 4,6-dibromopyrimidine, and 1H-pyrrolo-2-carboxaldehyde with thiophene-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 441.

[0277] Example 54 (R,Z / E)-3-(furan-2-ylmethylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrimidin-4-yl)indololin-2-one

[0278] Replace 3,5-dibromopyridine with 4,6-dibromopyrimidine, and 1H-pyrrolo-2-carboxaldehyde with furan-2-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 425.

[0279] Example 55 (R,Z / E)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrimidin-4-yl)-3-(thiazolyl-5-ylmethylene)indololin-2-one

[0280] Replace 3,5-dibromopyridine with 4,6-dibromopyrimidine, and 1H-pyrrolo-2-carboxaldehyde with thiazole-5-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 442.

[0281] Example 56 (R,Z / E)-3-((1H-imidazol-4-yl)methylene)-5-(6-((2-hydroxy-1-phenylethyl)amino)pyrimidin-4-yl)indololin-2-one

[0282] Replace 3,5-dibromopyridine with 4,6-dibromopyrimidine, and 1H-pyrrolo-2-carboxaldehyde with 1H-imidazol-4-carboxaldehyde. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 425.

[0283] Example 57(R)-2-((5-(3-(1H-pyrrolo-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0284]

[0285] 1,1(R)-2-((5-bromopyridin-3-yl)amino)-2-phenylethyl-1-ol

[0286] 3,5-Dibromopyridine (3.0 g, 12.66 mmol) and D-phenylglycine (2.78 g, 20.26 mmol) were dissolved in 30 mL of dry DMSO. Then, L-proline (0.292 g, 2.53 mmol), cuprous iodide (0.241 g, 1.27 mmol), and anhydrous potassium carbonate (3.50 g, 25.33 mmol) were added sequentially. The reaction was carried out at 100 °C for 12 h under argon protection. The reaction was monitored by TLC. After the reaction was complete, the solution was diluted with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, v / v) to give 1.53 g of a pale yellow solid, with a yield of 41.2%.

[0287] 1,2,5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indazole

[0288] 5-Bromo-1H-indazole (1.0 g, 5.08 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentane) (1.93 g, 7.61 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (0.375 g, 0.51 mmol), and potassium acetate (0.834 g, 10.15 mmol) were dissolved in 15 mL of ultradry 1,4-dioxane solution. After removing the air and replacing it with argon for protection, the solution was heated at 80 °C and stirred overnight. The reaction was monitored by TLC. After the reaction was completed, the diatomaceous earth was filtered, the filtrate was diluted with water, extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 8:1, volume ratio) to obtain 0.98 g of pale yellow solid, with a yield of 79.10%.

[0289] 1.3 3-Bromo-5-(4,4,5,5-Tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indazole

[0290] 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indazole (1.0 g, 4.10 mmol) was dissolved in 10 mL of DMF solution, followed by the addition of NBS (1.09 g, 6.41 mmol) and potassium hydroxide (0.46 g, 8.19 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth, the filtrate was diluted with water, extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, v / v) to give 0.49 g of a pale yellow oil, with a yield of 38.71%.

[0291] 1,4(R)-2-((5-(3-bromo-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0292] (R)-2-((5-bromopyridin-3-yl)amino)-2-phenylethyl-1-ol (1.15 g, 3.92 mmol), 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indazole (1.52 g, 4.71 mmol), tetra(triphenylphosphine)palladium (0.907 g, 0.785 mmol), and anhydrous potassium carbonate (1.09 g, 7.85 mmol) were dissolved in a DME:H₂O mixture of 5:1 (v / v). The mixture was then evacuated, replaced with argon for protection, and heated at 95 °C with stirring overnight. The reaction was monitored by TLC. After the reaction was completed, the diatomaceous earth was filtered, the filtrate was diluted with water, extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 35:1, volume ratio) to obtain 0.41 g of a pale yellow oil, with a yield of 25.54%.

[0293] 1,5(R)-2-((5-(3-(1H-pyrrolo-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0294] (R)-2-((5-(3-bromo-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol (0.4 g, 0.977 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole (0.226 g, 1.17 mmol), tetra(triphenylphosphine)palladium (0.226 g, 0.195 mmol), and anhydrous potassium carbonate (0.272 g, 1.95 mmol) were dissolved in a mixed solution of DME:H₂O = 5:1 (v / v). The solution was then evacuated, replaced with argon for protection, and heated at 95 °C with stirring overnight. The reaction was monitored by TLC. After the reaction was complete, the diatomaceous earth was filtered, the filtrate was diluted with water, extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 35:1, v / v) to obtain 0.108 g of a pale yellow oil, with a yield of 27.94%. LRMS(ESI) m / z: [M+H] + 396.

[0295] Example 58(R)-2-((5-(3-(furan-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0296] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane, and the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H + 397.

[0297] Example 59(R)-2-((5-(3-(1H-indol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0298] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 446.

[0299] Example 60(R)-2-((5-(3-(1H-indol-7-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0300] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 446.

[0301] Example 61(R)-2-((5-(3-(furan-2-ylmethyl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0302] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 411.

[0303] Example 62(R)-2-((5-(3-(thiophen-2-ylmethyl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0304] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 4,4,5,5-tetramethyl-2-(thiophene-2-ylmethyl)-1,3,2-dioxoboronane; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 427.

[0305] Example 63(R)-2-((6-(3-(furan-2-ylmethyl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0306] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 412.

[0307] Example 64 (R)-2-phenyl-2-((6-(3-(thiophen-2-ylmethyl)-1H-indazol-5-yl)pyrazin-2-yl)amino)1-ethanol

[0308] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 4,4,5,5-tetramethyl-2-(thiophene-2-ylmethyl)-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 428.

[0309] Example 65(R)-2-((6-(3-(1H-pyrrolo-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0310] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 397.

[0311] Example 66(R)-2-((6-(3-(furan-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0312] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 398.

[0313] Example 67(R)-2-((6-(3-(1H-indol-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0314] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 447.

[0315] Example 68(R)-2-((6-(3-(1H-indol-7-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0316] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 447.

[0317] Example 69 (R)-2-phenyl-2-((5-(3-(thiophen-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)1-ethanol

[0318] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 4,4,5,5-tetramethyl-2-(thiophenon-2-yl)-1,3,2-dioxoboronane; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 413.

[0319] Example 70(R)-2-phenyl-2-((6-(3-(thiophen-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)1-ethanol

[0320] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 4,4,5,5-tetramethyl-2-(thiophenon-2-yl)-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 414.

[0321] Example 71 3-((1H-pyrrolo-2-yl)methyl)-5-(6-(((R)-2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indololin-2-one

[0322] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine; the remaining raw materials, reagents, and preparation methods are the same as in Example 49. LRMS(ESI) m / z: [M+H] + 426.

[0323] Example 72 3-(furan-2-ylmethyl)-5-(6-(((R)-2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)indoline-2-one

[0324] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 1H-pyrrolo-2-carboxaldehyde with furan-2-carboxaldehyde; the remaining raw materials, reagents, and preparation methods are the same as in Example 49. LRMS(ESI) m / z: [M+H] + 427.

[0325] Example 73 (R,Z / E)-2-((6-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyrazin-2-yl)amino)-2-phenylacetamide

[0326] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine; the remaining raw materials, reagents, and preparation methods are the same as in Example 51. LRMS(ESI) m / z: [M+H] + 437.

[0327] Example 74 (R,Z / E)-2-((6-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyrazin-2-yl)amino)-2-phenylacetic acid

[0328] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine; the remaining raw materials, reagents, and preparation methods are the same as in Example 51. LRMS(ESI) m / z: [M+H] + 438.

[0329] Example 75 (R,Z / E)-2-((5-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyridin-3-yl)amino)-2-phenylacetic acid

[0330] The required raw materials, reagents, and preparation methods are the same as in Example 51. LRMS(ESI) m / z: [M+H] + 437.

[0331] Example 76 (R,Z / E)-2-((5-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyridin-3-yl)amino)-2-phenylacetic acid methyl ester

[0332] (R)-2-amino-2-phenylacetic acid was replaced with methyl (R)-2-amino-2-phenylacetic acid; the remaining raw materials, reagents, and preparation methods were the same as in Example 51. LRMS(ESI) m / z: [M+H] + 451.

[0333] Example 77 (R,Z / E)-2-((6-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyrazin-2-yl)amino)-2-phenylacetic acid methyl ester

[0334] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and (R)-2-amino-2-phenylacetic acid with methyl (R)-2-amino-2-phenylacetic acid. The remaining raw materials, reagents, and preparation methods are the same as in Example 51. LRMS(ESI) m / z: [M+H] + 452.

[0335] Example 78 (R,Z / E)-2-((6-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyrazin-2-yl)amino)butyric acid

[0336] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and (R)-2-amino-2-phenylacetic acid with (R)-2-aminobutyric acid. The remaining raw materials, reagents, and preparation methods are the same as in Example 51. LRMS(ESI) m / z: [M+H] + 390.

[0337] Example 79 (R,Z / E)-2-((5-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyridin-3-yl)amino)butyric acid

[0338] Replace (R)-2-amino-2-phenylacetic acid with (R)-2-aminobutyric acid; the remaining raw materials, reagents, and preparation methods are the same as in Example 51. LRMS(ESI) m / z: [M+H + 389.

[0339] Example 80 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((1-hydroxybut-2-yl)amino)pyridin-3-yl)indololin-2-one

[0340] Replace D-phenylglycine with (R)-2-aminobut-1-ol; the remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 375.

[0341] Example 81 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(6-((1-hydroxybut-2-yl)amino)pyrazin-2-yl)indoline-2-one

[0342] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and D-phenylglycine with (R)-2-aminobut-1-ol. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 376.

[0343] Example 82 (Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(6-((1-(hydroxymethyl)cyclopentyl)amino)pyrazin-2-yl)indoline-2-one

[0344] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and D-phenylglycine with (1-aminocyclopentyl)methanol. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 402.

[0345] Example 83 (Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((1-(hydroxymethyl)cyclopentyl)amino)pyridin-3-yl)indololin-2-one

[0346] D-phenylglycine was replaced with (1-aminocyclopentyl)methanol; the remaining raw materials, reagents, and preparation methods were the same as in Example 1. LRMS(ESI) m / z: [M+H] + 401.

[0347] Example 84(R)-2-((6-(3-(furan-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0348] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 399.

[0349] Example 85(R)-2-((6-(3-(1H-pyrrolo-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0350] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 398.

[0351] Example 86(R)-2-((5-(3-(1H-pyrrolo-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0352] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z:[M+H] + 397.

[0353] Example 87 (R)-2-((5-(3-(furan-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0354] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z:[M+H] + 398.

[0355] Example 88(R)-2-((5-(3-(1H-pyrrolo-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-(3-fluorophenyl)ethyl-1-ol

[0356] D-phenylglycine was replaced with (R)-2-amino-2-(3-fluorophenyl)ethyl-1-ol; the remaining raw materials, reagents, and preparation methods were the same as in Example 57. LRMS(ESI) m / z: [M+H] + 414.

[0357] Example 89(R)-2-((5-(3-(1H-pyrrolo-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-(4-fluorophenyl)ethyl-1-ol

[0358] D-phenylglycine was replaced with (R)-2-amino-2-(4-fluorophenyl)ethyl-1-ol; the remaining raw materials, reagents, and preparation methods were the same as in Example 57. LRMS(ESI) m / z: [M+H] + 414.

[0359] Example 90(R)-2-(4-fluorophenyl)-2-((5-(3-(furan-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)ethyl-1-ol

[0360] D-phenylglycine was replaced with (R)-2-amino-2-(4-fluorophenyl)ethyl-1-ol, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole was replaced with 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods were the same as in Example 57. LRMS(ESI) m / z: [M+H] + 415.

[0361] Example 91(R)-2-(3-fluorophenyl)-2-((6-(3-(furan-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)ethyl-1-ol

[0362] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, D-phenylglycine with (R)-2-amino-2-(3-fluorophenyl)ethyl-1-ol, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 416.

[0363] Example 92(R)-2-((6-(3-(1H-pyrrolo-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrazin-2-yl)amino)-2-(4-fluorophenyl)1-ethanol

[0364] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, 3,5-dibromopyridine with 2,6-dibromopyrazine, and D-phenylglycine with (R)-2-amino-2-(4-fluorophenyl)ethyl-1-ol. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 416.

[0365] Example 93(R)-2-((5-(3-(1H-pyrrolo-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yl)amino)-2-(3-fluorophenyl)1-ethanol

[0366] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, and D-phenylglycine with (R)-2-amino-2-(3-fluorophenyl)ethyl-1-ol. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] +415.

[0367] Example 94(R)-2-(4-fluorophenyl)-2-((5-(3-(furan-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yl)amino)1-ethanol

[0368] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, D-phenylglycine with (R)-2-amino-2-(4-fluorophenyl)ethyl-1-ol, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronane. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 416.

[0369] Example 95(R)-2-((5-(3-(1H-imidazol-5-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0370] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-imidazol, with the remaining raw materials, reagents, and preparation methods the same as in Example 57. LRMS(ESI) m / z: [M+H] + 397.

[0371] Example 96(R)-2-((5-(3-(1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0372] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-imidazol. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z:[M+H] + 398.

[0373] Example 97(R)-2-((5-(3-(1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yl)amino)-2-(4-fluorophenyl)1-ethanol

[0374] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-imidazol, and D-phenylglycine with (R)-2-amino-2-(4-fluorophenyl)ethyl-1-ol. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 416.

[0375] Example 98(R)-2-((5-(3-(1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yl)amino)-2-(3-fluorophenyl)1-ethanol

[0376] Replace 5-bromo-1H-indazole with 5-bromo-1H-pyrazolo[3,4-c]pyridine, 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-imidazol, and D-phenylglycine with (R)-2-amino-2-(3-fluorophenyl)ethyl-1-ol. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 416.

[0377] Example 99 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(6-((1-(3-fluorophenyl)-2-hydroxyethyl)amino)pyrazin-2-yl)indoline-2-one

[0378] 3,5-Dibromopyridine was replaced with 2,6-dibromopyrazine, and D-phenylglycine was replaced with (R)-2-amino-2-(3-fluorophenyl)ethyl-1-ol. The remaining raw materials, reagents, and preparation methods were the same as in Example 1. LRMS(ESI) m / z: [M+H] + 442.

[0379] Example 100 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((1-(3-fluorophenyl)-2-hydroxyethyl)amino)pyridin-3-yl)indololin-2-one

[0380] D-phenylglycine was replaced with (R)-2-amino-2-(3-fluorophenyl)ethyl-1-ol; the remaining raw materials, reagents, and preparation methods were the same as in Example 1. LRMS(ESI) m / z: [M+H] + 441.

[0381] Example 101 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(5-((1-(4-fluorophenyl)-2-hydroxyethyl)amino)pyridin-3-yl)indololin-2-one

[0382] D-phenylglycine was replaced with (R)-2-amino-2-(4-fluorophenyl)ethyl-1-ol; the remaining raw materials, reagents, and preparation methods were the same as in Example 1. LRMS(ESI) m / z: [M+H] + 441.

[0383] Example 102 (R,Z / E)-3-((1H-pyrrolo-2-yl)methylene)-5-(6-((1-(4-fluorophenyl)-2-hydroxyethyl)amino)pyrazin-2-yl)indololin-2-one

[0384] 3,5-Dibromopyridine was replaced with 2,6-dibromopyrazine, and D-phenylglycine was replaced with (R)-2-amino-2-(4-fluorophenyl)ethyl-1-ol. The remaining raw materials, reagents, and preparation methods were the same as in Example 1. LRMS(ESI) m / z: [M+H] + 442.

[0385] Example 103(R,Z / E)-2-((6-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyrazin-2-yl)amino)-N-methyl-2-phenylacetamide

[0386] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and D-phenylglycine with (R)-2-amino-N-methyl-2-phenylacetamide. The remaining raw materials, reagents, and preparation methods are the same as in Example 1. LRMS(ESI) m / z: [M+H] + 451.

[0387] Example 104 (R,Z / E)-2-((5-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-5-yl)pyridin-3-yl)amino)-N-methyl-2-phenylacetamide

[0388] D-phenylglycine was replaced with (R)-2-amino-N-methyl-2-phenylacetamide; the remaining raw materials, reagents, and preparation methods were the same as in Example 1. LRMS(ESI) m / z: [M+H] + 450.

[0389] Example 105(R)-2-((5-(3-(5-fluoro-1H-indol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0390] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 464.

[0391] Example 106(R)-2-((5-(3-(5-bromo-1H-indol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0392] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 524.

[0393] Example 107(R)-2-((5-(3-(5-methyl-1H-indol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0394] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 460.

[0395] Example 108(R)-2-(5-(5-(((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-1H-indazole-3-yl)-1H-indole-5-carboxynitrile

[0396] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indol-5-carboxynitrile; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 471.

[0397] Example 109(R)-2-((5-(3-(5-chloro-1H-indol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0398] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 480.

[0399] Example 110(R)-2-((5-(3-(5-(trifluoromethyl)-1H-indol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)amino)-2-phenylethyl-1-ol

[0400] Replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-5-trifluoromethyl-1H-indole; the remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 514.

[0401] Example 111(R)-2-((6-(3-(5-methyl-1H-indol-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0402] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 461.

[0403] Example 112(R)-2-((6-(3-(5-(trifluoromethyl)-1H-indol-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0404] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-5-trifluoromethyl-1H-indole. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 515.

[0405] Example 113(R)-2-(5-(6-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)-1H-indazole-3-yl)-1H-indole-5-carboxynitrile

[0406] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indol-5-carboxynitrile. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 472.

[0407] Example 114(R)-2-((6-(3-(5-chloro-1H-indol-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0408] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] + 481.

[0409] Example 115(R)-2-((6-(3-(5-fluoro-1H-indol-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)amino)-2-phenylethyl-1-ol

[0410] Replace 3,5-dibromopyridine with 2,6-dibromopyrazine, and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrrole with 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indole. The remaining raw materials, reagents, and preparation methods are the same as in Example 57. LRMS(ESI) m / z: [M+H] +465.

[0411] Pharmacological activity test examples

[0412] Pharmacological Example 1: In vitro inhibitory activity test of the compound against IRAK4

[0413] IRAK4 activity assays used HTRF S1 as a substrate. IRAK4, with the participation of ATP, catalyzes phosphorylation modification of the biotin-labeled peptide substrate S1. An Eu-labeled S1-specific phosphorylation antibody reacts with the substrate via an antigen-antibody reaction. Simultaneously, the streptavidin-labeled receptor XL665 interacts specifically with biotin, allowing the Eu-labeled donor and the streptavidin-labeled receptor to approach each other spatially. Under 320 nm excitation, the Eu-labeled donor emits energy at a wavelength of 620 nm. When biomolecular interactions cause the fluorophores of the donor and receptor to approach each other, some energy resonantly transfers to the receptor XL665, exciting it and causing it to emit light at a wavelength of 665 nm. The 665 nm emission is solely generated by FRET induced by the donor. After phosphorylation of the S1 substrate by IRAK4, it is used in Envision... TM The excitation wavelength was set to 320 nm, and fluorescence values ​​were read at emission wavelengths of 620 nm and 665 nm. The initial reaction rate of IRAK4 was calculated by detecting the change in the fluorescence ratio at 665 nm and 620 nm per unit time.

[0414] Mix the compound, enzyme, and reaction buffer thoroughly, then add the substrate to a 384 reaction plate (ProxiPlate). TM The reaction was started in a PerkinElmer (-384Plus) and incubated at room temperature for one hour. Then, XL665 and antibody were added and incubated for another hour. Finally, the reaction was carried out using Envision. TM The ratio of fluorescence signals at 665 nm to 620 nm was detected. A blank control group without enzyme, a solvent control group with DMSO replacing the compound, and a positive control group were also included. The final reaction volume was 10 μL, and the specific reaction system consisted of: 2% DMSO, 1 ng / μL IRAK4, 1 μM S1, 100 μM ATP, 5 mM MgCl2, 1 mM DTT, and 1× kinase buffer. Nonlinear fitting was performed using Graphpad Prism 5 software.

[0415] Table 2: Inhibitory activity of representative compounds against IRAK4

[0416]

[0417]

[0418]

[0419] PF-06650833 * The positive control compound tested in the same batch as the compound:

[0420]

[0421] 116 * Here are the compounds in the prior art and the control compound:

[0422]

[0423] Experimental conclusions: Through molecular-level enzyme inhibitory activity screening, several of the above-mentioned compounds were found to have good inhibitory effects on IRAK4 protease. Fifteen compounds showed comparable activity to the positive control PF-06650833; the compound with the best activity was IC50. 50 It reached 2.4 nM.

[0424] For 116 * Molecular-level screening of the control compound for enzyme inhibitory activity revealed an activity of 488.25 ± 62.72 nM, significantly weaker than the inhibitory activity of the compound described in this application. This demonstrates the importance of the substitution fragment on the B ring in maintaining activity.

[0425] Pharmacological Example 2: Test of the inhibitory activity of the compound on LPS-induced THP-1 secretion of TNF-α

[0426] THP-1 cells 7.5 × 10 6 Cells were seeded in cell culture dishes (Corning, 430167) and induced to differentiate for 48 hours with PMA (MCE, HY-18739, final concentration 100 ng / mL). 1 × 10⁶ cells were then cultured after differentiation. 5 / wells were seeded into 96-well cell culture plates. After overnight adhesion, the compound and LPS (MCE, HY-D1056, final concentration 100 ng / mL) were added and incubated for 24 hours. TNF-α levels were detected using the hTNF-α ELISA kit (BD, 555212).

[0427] Table 3: Inhibitory activity of representative compounds against LPS-induced TNF-α secretion in THP-1 cells

[0428]

[0429]

[0430] PF-06650833 * A positive control compound tested in the same batch as the compound.

[0431] Experimental Conclusion: Through screening the inhibitory activity of compounds against LPS-induced TNF-α secretion in THP-1 cells, several of the aforementioned compounds were found to have excellent inhibitory effects on LPS-induced TNF-α secretion in THP-1 cells. In THP-1 cells, 15 compounds showed significantly better inhibitory activity against LPS-induced TNF-α secretion than the positive control PF-06650833, with the compound exhibiting the best activity (IC50). 50 It is 3.06 nM.

[0432] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of Formula I: ###0001### I and optical isomers, pharmaceutically acceptable salts, or mixtures thereof, wherein: Q is a bond or C1-C4 straight or branched alkyl; each L is independently absent (i.e., ring A is directly connected to ring B), or C1-C6 methylene or C1-C6 methine (where valence allows); each of the heteroaromatic, heterofused ring, or heterocyclyl groups independently contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen; and each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaromatic, heterofused ring, and heterocyclyl groups is optionally substituted with one or more substituents selected from the group consisting of: halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylthio, C1-C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 haloalkylamino, C1-C6 dialkylaminoalkyl, C1-C6 haloalkylaminoalkyl, C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, C1-C6 haloalkylaminocarbonyl, C1-C6 dialkylaminocarbonylalkyl, C1-C6 haloalkylaminocarbonylalkyl, C1-C6 alkylcarbonylamino, C1-C6 haloalkylcarbonylamino, C1-C6 alkylcarbonyloxy, C1-C6 haloalkylcarbonyloxy, C1-C6 alkylcarbonylaminoalkyl, C1-C6 haloalkylcarbonylaminoalkyl, C1-C6 alkylsulfonyloxy, C1-C6 haloalkylsulfonyloxy, C1-C6 alkylsulfonylamino, C1-C6 haloalkylsulfonylamino, C1-C6 alkylsulfonylalkyl, C1-C6 haloalkylsulfonylalkyl, C1-C6 alkylcarbonylalkyl, C1-C6 haloalkylcarbonylalkyl, C1-C6 alkylcarbonyloxyalkyl, C1-C6 haloalkylcarbonyloxyalkyl, C1-C6 alkylcarbonylaminoalkyl, C1-C6 haloalkylcarbonylaminoalkyl, C1-C6 alkylaminoalkyl, C1-C6 haloalkylaminoalkyl, C1-C6 dialkylaminoalkyl, C1-C6 haloalkylaminoalkyl, C1-C6 alkylsulfonylalkyl, C1-C6 haloalkylsulfonylalkyl, C1-C6 alkylsulfinylalkyl, C1-C6 haloalkylsulfinylalkyl, C1-C6 alkylsulfonylalkyl, C1-C6 haloalkylsulfonylalkyl, C1-C6 alkylaminoalkyl, C1-C6 haloalkylaminoalkyl, C1-C6 dialkylaminoalkyl, C1-C6 haloalkylaminoalkyl, C1-C6 alkylsulfonylalkyl, C1-C6 haloalkylsulfonylalkyl, C1-C6 alkylsulfinyl ​ R 4 is selected from the group consisting of: R 4 H; or said R 4 and R 4 together with the carbon atom to which they are attached form a 4-7 membered carbocyclic ring, or a 4-7 membered heterocyclic ring, which can be saturated or partially unsaturated; ring, ring, ring and each R is independently selected from the group consisting of substituted or unsubstituted C6-C20aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclyl, or substituted or unsubstituted 9-20 membered aromatic fused ring; 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclyl, or substituted or unsubstituted 9-20 membered aromatic fused ring; ​ R 1 R 3 Each group is independently selected from the following: hydrogen, deuterium, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted C1-C. 10 Straight-chain or branched alkyl groups, substituted or unsubstituted C1-C2 10 Straight-chain or branched alkoxy groups, C2-C6 straight-chain or branched alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted saturated or partially unsaturated C3-C6 alkynyl groups. 10 A basic carbonyl group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heterocyclic groups, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C0-C6 alkylamino (C0 alkylamino is NH2), substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 alkyl-sulfonyl or substituted or unsubstituted C1-C6 alkyl-sulfinyl, -(C=O)NR a R b ;where R a R b Each is independently selected from the following group: H, C1-C4 alkyl, C3-C4 carbocyclic, -C1-C4 alkylene-NR c R d ;R c R d Each is independently selected from the following group: H, C1-C4 alkyl; R 2 selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted Co-C6alkyl-hydroxy (Cohydroxy is OH), Co-C6amino (Coamino is NH2), -(C=0)OR a , -(C=0)NR a R b ; wherein R a , R b are each independently selected from the group consisting of H, C1-C4alkyl; ​ is a double or single bond; X is CR 5 or N; R 5 selected from the group consisting of H, deuterium, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted C1-C4 linear or branched alkyl; ​ said substituents are 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, mercapto, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, C1-C6haloalkoxy, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylsulfonyl, C3-C8saturated or partially unsaturated carbocyclyl, C6-C10aryl, 3-12 membered saturated or partially unsaturated heterocyclyl, and 5-12 membered heteroaryl; and 10 aryl, 3-12 membered saturated or partially unsaturated heterocyclyl, and 5-12 membered heteroaryl; ​ 2. The compound according to claim 1, and its optical isomers, pharmaceutically acceptable salts or their mixtures, characterized in that, ​ 3. The compound according to claim 1, and its optical isomers, pharmaceutically acceptable salts or their mixtures, characterized in that, The the ring is selected from the group consisting of substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered heterocyclyl, or substituted or unsubstituted 9-12 membered aromatic fused ring; Preferably, said the ring is selected from the group consisting of 4. The compound according to claim 1, and its optical isomers, pharmaceutically acceptable salts or their mixtures, characterized in that, The ring is selected from the group consisting of 5-12 membered heterocyclyl or 5-12 membered heteroaryl, preferably 5-7 membered heterocyclyl or 5-7 membered heteroaryl; more preferably, the The ring has a structure selected from the group consisting of: ​ 5. The compound according to claim 1, and its optical isomers, pharmaceutically acceptable salts or their mixtures, characterized in that, ###00002### 5 each ring is independently selected from the group consisting of phenyl, 5-12 membered heteroaryl, preferably phenyl, 5-7 membered heteroaryl; more preferably, the the ring is selected from the group consisting of:

6. The compound according to claim 1, and its optical isomers, pharmaceutically acceptable salts or their mixtures, characterized in that, each ring is independently selected from the group consisting of phenyl, 5-12 membered heteroaryl, preferably phenyl, 5-7 membered heteroaryl; more preferably, the each ring is independently selected from the group consisting of phenyl, 5-12 membered heteroaryl, preferably phenyl, 5-7 membered heteroaryl; more preferably, the 7. The compound of claim 1, and its optical isomers, pharmaceutically acceptable salts, or mixtures thereof, characterized in that, R 1 Each is independently selected from the following group: hydrogen, deuterium, halogen, cyano, nitro, amino, substituted or unsubstituted C1-C. 10 Straight-chain or branched alkyl groups, substituted or unsubstituted C1-C2 10 Straight-chain or branched alkoxy groups, substituted or unsubstituted C1-C2 10 Straight-chain or branched alkyl groups, -(C=O)NR a R b ; wherein R a , R b are each independently selected from the group consisting of H, C1-C4alkyl, C3-C4carbocyclyl, -C1-C4alkylene-NR c R d ; ​ R 2 each independently is selected from the group consisting of H, carboxyl, hydroxymethyl, -(C=0)OR a , -(C=0)NR a R b , ; R 3 each independently is selected from the group consisting of H, halogen; wherein R c , R d each independently is selected from the group consisting of H, C1-C4alkyl; 8. The compound according to claim 1, and its optical isomers, pharmaceutically acceptable salts or their mixtures, characterized in that, ###00011### ​ 9. A pharmaceutical composition, characterized by, ​ 10. The use of a compound according to claim 1, and its optical isomers, pharmaceutically acceptable salts or mixtures thereof or a pharmaceutical composition according to claim 9, wherein ​ 11. Use of a compound according to claim 1, and optical isomers, pharmaceutically acceptable salts thereof or mixtures thereof or a pharmaceutical composition according to claim 9, wherein ​

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