Rhoa inhibitor compound, pharmaceutical composition and use thereof

Abstract

Provided in the present invention are an RhoA inhibitor compound, a pharmaceutical composition and the use thereof. Specifically provided are a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer or isotopically labeled compound thereof, and the use thereof as an RhoA inhibitor.

Description

A RhoA inhibitor compound, a pharmaceutical composition and its application Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a novel covalent inhibitor compound of RhoA wild-type or pathogenic mutants, pharmaceutical compositions and their applications. Background Technology

[0002] RAS superfamily proteins catalyze the hydrolysis of GTP and regulate their activation and inhibition within the cell by switching between GTP / GDP binding states, acting as molecular switches in the cell. Based on structural and functional similarity, RAS superfamily proteins can be divided into five subfamilies: RAS, Rho, Rab, Arf, and Ran, containing more than 170 members.

[0003] RAS protein is the best-understood small G protein to date. KRAS gene mutations account for over 80% of all RAS gene mutations, with mutations concentrated in key locations such as the p-loop and switch. In pancreatic ductal carcinoma, KRAS is the predominant mutation. G12D Mutations, and the main mutation type in non-small cell lung cancer is KRAS. G12C Currently, it is generally believed that mutations at the G12, G13, and Q61 sites of the RAS protein disrupt both the endogenous substrate hydrolysis activity of the RAS protein and the substrate hydrolysis activity of the RAS protein catalyzed by GAP proteins, placing the RAS protein in a GTP-binding activated state. However, the extremely strong affinity of small G proteins for the substrate GTP / GDP, and the fact that they have no other binding pockets besides the substrate pocket, pose significant challenges to the design of small molecules targeting small G proteins, severely limiting their development. Small molecule inhibitors such as sotarasib and adagrasib are considered first-generation targets for KRAS. G12C While covalent small molecule drugs bring hope to patients, they have also sparked debate regarding the targeting of KRAS. G12D The development of next-generation small molecules and other mutants.

[0004] Rho proteins are the second largest members of the RAS superfamily and regulate downstream signaling pathways, influencing cell morphology, cytoskeleton formation, cell cycle, and cell migration. RhoA, upon GTP activation, binds to and activates the downstream serine / threonine kinase ROCK. Activated ROCK phosphorylates myosin light chain phosphatase, promoting actin-myosin cross-linking to facilitate kinase contraction. It also activates filament-cleaving proteins and enhances actin filament stability, thereby affecting cytoskeleton formation, focal adhesion assembly, and cell migration. Furthermore, Rho protein expression can promote cell cycle progression from G1 to S phase; this function may be related to the regulation of cell cycle-related proteins.

[0005] RhoA mutations have been found in various cancers, and compared to RAS protein, RhoA has a greater variety of pathogenic mutations, with significant differences in activity characteristics among different mutants. In angioimmunoblastic T-cell lymphoma, the most common RhoA mutants detected are G17V mutations. G17V The mutants lose their GDP / GTP binding ability, leading to RhoA function suppression. This impaired RhoA function, combined with TET2 deficiency, is a major cause of AITL-specific pathogenesis. Approximately 20% of RhoA mutations are found in diffuse gastric cancer, with Y42C being a hotspot mutation. Y42C mutations weaken RhoA's ability to hydrolyze GTP and are considered a functionally gaining mutation. About 15% of mutations are also found in adult T-cell lymphomas, distributed near the GDP binding pocket. These mutations include C16 mutations (C16R, C16F, C16G, C16L), G17 mutations (G17V, G17E, G17R), K118 mutations (K118Q, K118E), and A161 mutations (A161P, A161V, A161E), with C16R mutations having the highest frequency. The G17V and A161E mutants cannot bind to the substrate GDP / GTP, while mutants such as C16R, C16F, K118E, A161P, and A161V exhibit decreased affinity for GTP / GDP and an accelerated rate of endogenous substrate exchange, thus being termed "fast-circulating mutants." Furthermore, RhoA mutations also exist in head and neck squamous cell carcinoma, with the mutation site concentrated at glutamate 40, and the mutation type being E40Q. Due to the high correlation between RhoA protein mutations and various cancers, RhoA has become an important drug target.

[0006] RhoA, which also belongs to the small G protein family, is also a recognized "difficult target protein." However, the lack of in-depth research on the structure, function, and regulatory mechanism of RhoA has limited the development of inhibitors targeting the RhoA pathway.

[0007] Currently reported small molecule inhibitors mainly include: covalent inhibitors targeting cysteine ​​residues of RhoAC107, represented by DC-Rhoin (Adv. Sci., 2020, 7(14), 2000098.), and protein-protein interaction inhibitors targeting the RhoA-GEF interaction interface, represented by Rhosin (Chem. Biol., 2012, 19(6), 699.). However, research on these small molecule inhibitors is limited to wild-type or artificially mutated RhoA proteins. Currently, there are no reports on drug research targeting pathogenic mutants of RhoA. Therefore, developing novel small molecule inhibitors targeting clinically pathogenic mutants of RhoA is of great significance. Summary of the Invention

[0008] The purpose of this invention is to provide a novel RhoA inhibitor compound with excellent activity.

[0009] In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or isotopic compound thereof.

[0010] in:

[0011] R 1 and R 2 Independently selected from the group consisting of: H, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, NO2, -COOC1-C6 alkyl, -CON (C1-C6 alkyl). 0-2 ;

[0012] A is selected from substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted phenyl-5-6-membered heterocyclic phenyl; wherein the substitution means that one or more (e.g., 2, 3 or 4) H on the group are independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl;

[0013] L is selected from unsubstituted, substituted, or unsubstituted C1-C8 alkylene, substituted, or unsubstituted (C0-C4 alkylene)X1-(C0-C4 alkylene), wherein X1 is selected from the group consisting of -O-, -S-, -NH-, CO, -SO-, and -SO2-; wherein substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of halogen, -OH, -CN, C1-C4 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo- or unsubstituted C2-C6 alkenyl, halo- or unsubstituted C2-C6 alkynyl; and

[0014] B is selected from H, halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -N(C1-C6 alkyl). 0-2 -OC1-C6 alkylene N (C1-C6 alkyl) 0-2 The group may contain substituted or unsubstituted C1-C6 alkylene groups (COOC1-C6 alkyl), substituted or unsubstituted C3-C10 cycloalkyl groups, substituted or unsubstituted 3-10 heterocyclic groups, substituted or unsubstituted C6-C10 aryl groups, or substituted or unsubstituted 5-10 heteroaryl groups. The substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halosubstituted or unsubstituted C1-C6 alkyl, halosubstituted or unsubstituted C2-C6 alkenyl, halosubstituted or unsubstituted C2-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl, or -N(C1-C6 alkyl). 0-2 -OC1-C6 alkylene N (C1-C6 alkyl) 0-2 -C1-C4 alkylene (OC1-C4 alkyl), substituted or unsubstituted C1-C6 alkylene (COOC1-C6 alkyl), substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, -L1-substituted or unsubstituted C3-C6 cycloalkyl, -L1-substituted or unsubstituted 3-6 membered heterocyclic group, -L1-N (substituted or unsubstituted benzyl) 1-2 -L1-COO (substituted or unsubstituted benzyl) 1-2-L1-substituted or unsubstituted phenyl groups, -L1-substituted or unsubstituted 5-6-membered heteroaryl groups, or two substituents on the same or adjacent ring atoms on ring B, together with the ring atoms they are attached to, constitute a C3-C6 cycloalkyl or a 3-6-membered heterocyclic group; wherein the substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halosubstituted or unsubstituted C1-C6 alkyl, halosubstituted or unsubstituted C2-C6 alkenyl, halosubstituted or unsubstituted C2-C6 alkoxy, -COOC1-C6 alkyl, -C1-C4 alkylene OC1-C4 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -OC1-C6 alkylene N (C1-C6 alkyl). 0-2 ;

[0015] Each L1 is independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkylene-, substituted or unsubstituted C1-C6 alkylene NHCO-; wherein the substitution refers to one or more (e.g., 2, 3 or 4) H on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy.

[0016] In another preferred embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or isotope thereof,

[0017] in:

[0018] R 1 and R 2 Independently selected from the group consisting of: H, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, NO2, -COOC1-C6 alkyl;

[0019] A is selected from substituted or unsubstituted 5-10-membered heteroaryl groups and substituted or unsubstituted C6-C10 aryl groups; wherein the substitution means that one or more (e.g., 2, 3 or 4) H on the group are independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl;

[0020] L is selected from unsubstituted, substituted, or unsubstituted C1-C8 alkylene, substituted, or unsubstituted (C0-C4 alkylene)X1-(C0-C4 alkylene), wherein X1 is selected from the group consisting of -O-, -S-, -NH-, -SO-, and -SO2-; wherein substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of halogen, -OH, -CN, C1-C4 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and

[0021] B is selected from H, halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C6-C10 aryl, etc. Substituted or unsubstituted 5-10-membered heteroaryl groups; wherein the substitution refers to one or more (e.g., 2, 3 or 4) H atoms on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl.

[0022] In another preferred embodiment, R 1 and R 2 It has only one C1-C6 alkyl group selected from H or halogenated or unsubstituted.

[0023] In another preferred embodiment, R 1 For H, R 2 Independently selected from the group consisting of: CN, NO2, -COOC1-C6 alkyl.

[0024] In another preferred embodiment, R 1 For H, R 2 It is NO2.

[0025] In another preferred embodiment, L is a C1-C7 alkylene (preferably a C1-C4 alkylene), -NH2CH2-, -O-, or SO2, preferably CH2, -O-, or SO2.

[0026] In another preferred embodiment, A is selected from substituted or unsubstituted benzo5-6 heteroaryl groups containing one or two nitrogen atoms, or substituted or unsubstituted C6-C10 aryl groups.

[0027] In another preferred embodiment, A is selected from substituted or unsubstituted phenyl, naphthyl, indolyl, pyrrolopyridine.

[0028] In another preferred embodiment, A is selected from substituted or unsubstituted: phenyl, pyridyl, indolyl, biphenyl, imidazolyl, benzopyridyl and benzopyrazinyl, preferably A is substituted or unsubstituted indolyl.

[0029] In another preferred embodiment, B is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from O, N and S, a substituted or unsubstituted C5-C6 cycloalkyl group, or a substituted or unsubstituted 5-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from O, N and S.

[0030] In another preferred embodiment, B is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N heteroatoms.

[0031] In another preferred embodiment, B is selected from substituted or unsubstituted: phenyl, morpholino, furanyl, piperazinyl, piperidinyl, morpholino, cyclopentyl, tetrahydropyranyl, triazolyl (e.g.) ).

[0032] In another preferred embodiment, B is selected from substituted or unsubstituted:

[0033] In another preferred embodiment, A is selected from the group consisting of substituted or unsubstituted groups:

[0034] In another preferred embodiment, A is selected from the group consisting of substituted or unsubstituted groups:

[0035] In another preferred embodiment, A is either substituted or unsubstituted. L is connected to the N atom on the ring.

[0036] In another preferred embodiment, A is either substituted or unsubstituted. L is connected to the N atom on the ring.

[0037] In another preferred embodiment, B is a substituted or unsubstituted phenyl group.

[0038] In another preferred embodiment, L is a substituted or unsubstituted C1-C4 alkylene group, CO, O, or SO2; wherein substitution means that one or more (e.g., 2, 3, or 4) H groups are independently substituted by groups selected from the group consisting of: halogen, -OH, -CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, halo- or unsubstituted C2-C3 alkenyl, halo- or unsubstituted C2-C3 alkynyl.

[0039] In another preferred embodiment, L is a substituted or unsubstituted Cl alkylene group; wherein substitution means that one H on the group is replaced by a group selected from the group consisting of -OH, -CN, methyl, and ethynyl.

[0040] In another preferred embodiment, B is substituted with a group selected from the group consisting of: substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, -L1-substituted or unsubstituted C3-C6 cycloalkyl, -L1-substituted or unsubstituted 3-6 membered heterocyclic group, -L1-N (substituted or unsubstituted benzyl). 1-2 -L1-COO (substituted or unsubstituted benzyl) 1-2 -L1-substituted or unsubstituted phenyl, -L1-substituted or unsubstituted 5-6-membered heteroaryl; or two substituents on adjacent ring atoms on ring B, together with the ring atoms they are attached to, constitute a C5-C6 cycloalkyl or a 5-6-membered heterocyclic group; wherein the substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -C1-C4 alkylene OC1-C4 alkyl, -OC1-C6 alkylene N (C1-C6 alkyl). 0-2 ;

[0041] Each L1 is independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkylene-, substituted or unsubstituted C1-C6 alkylene NHCO-; wherein the substitution refers to one or more (e.g., 2, 3 or 4) H on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy.

[0042] In another preferred embodiment, B is substituted by a group selected from the group consisting of: substituted or unsubstituted C1-C6 alkylene (COOC1-C6 alkyl), substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 heteroaryl, -L1-substituted or unsubstituted phenyl, -L1-substituted or unsubstituted 5-6 heteroaryl; or two substituents on adjacent ring atoms of ring B together with the ring atoms they are attached to form a C5-C6 cycloalkyl or a 5-6 heterocyclic group; wherein the substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -C1-C4 alkylene (OC1-C4 alkyl), -OC1-C6 alkylene (N(C1-C6 alkyl)) 0-2 ;

[0043] Each L1 is independently selected from the group consisting of substituted or unsubstituted C1-C6 alkylene groups; wherein the substitution refers to one or more (e.g., 2, 3 or 4) H groups being independently substituted by groups selected from the group consisting of halogens, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl groups, halogenated or unsubstituted C2-C6 alkenyl groups, halogenated or unsubstituted C2-C6 alkynyl groups, and halogenated or unsubstituted C1-C6 alkoxy groups.

[0044] In another preferred embodiment, each L1 is independently selected from the group consisting of substituted or unsubstituted C1-C6 alkylene groups, wherein the substitution refers to the independent substitution of one H atom on the group by a group selected from the group consisting of OH, COOH; preferably -CH(COOH)-C1-C5 alkylene groups. In another preferred embodiment, R 1 For H, R 2 It is NO2;

[0045] A is a substituted or unsubstituted indole group; wherein the substitution means that one or more (e.g., 2, 3 or 4) H on the group are independently substituted by a group selected from the group consisting of halogen, halogenated or unsubstituted C1-C6 alkyl.

[0046] L can be CH2, CH2CH2, CH2CHOH, or SO2;

[0047] B is a substituted or unsubstituted phenyl group; the substitution refers to one or more (e.g., 2, 3 or 4) H atoms on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl.

[0048] In another preferred embodiment, B is a substituted phenyl group; the substitution refers to the independent substitution of one, two or three H atoms on the group by a group selected from the group consisting of halogens, OH, COOH, halogenated or unsubstituted C1-C6 alkyl groups and -COOC1-C6 alkyl groups.

[0049] In another preferred embodiment, L is SO2.

[0050] In another preferred embodiment, R 1 For H, R 2 It is NO2;

[0051] A is a substituted or unsubstituted phenyl group;

[0052] L represents none, O, or S;

[0053] B is a substituted or unsubstituted 5-6 membered heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group; the substitution refers to one or more (e.g., 2, 3, or 4) H groups being independently substituted by groups selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl.

[0054] In another preferred embodiment, the heterocyclic group and the heteroaryl group independently have 1, 2 or 3 heteroatoms selected from O, N and S, and preferably independently have 1, 2 or 3 N heteroatoms.

[0055] In another preferred embodiment, A is a naphthyl or a benzo[6] 6-membered heteroaryl containing one or two nitrogen heteroatoms.

[0056] In another preferred embodiment, L is absent and B is H, halogen, or C1-C3 alkyl.

[0057] In another preferred embodiment, R1, R2, A, L, and B are independently and optionally the groups corresponding to any specific compound of the present invention.

[0058] In another preferred embodiment, the compound is selected from the group consisting of:

[0059] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, a pharmaceutically acceptable salt, stereoisomer, or isotopic compound thereof; and a pharmaceutically acceptable excipient.

[0060] In another preferred embodiment, the excipients include at least one of solvents, excipients, diluents, binders, disintegrants, dispersants, flavoring agents, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, flow aids, or lubricants.

[0061] In a second aspect, the present invention provides pharmaceutically acceptable salts, stereoisomers, or isotopic compounds of the compounds described in the first aspect; and the use of the pharmaceutical compositions described in the second aspect in the preparation of medicaments for the prevention and / or treatment of RhoA-mediated diseases or conditions.

[0062] In another preferred embodiment, the RhoA is selected from wild-type RhoA and pathogenic mutants of RhoA (such as RhoA...). A161P and RhoA Y42C ).

[0063] In another preferred embodiment, the RhoA-mediated diseases or conditions are selected from hematologic malignancies, gastric cancer, adult blastoma, diffuse large B-cell lymphoma, colon cancer, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma; cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, and chronic lung diseases.

[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] Figure 1 shows the effects of compounds cpd37 / 38 / 43 / 44 on RhoA. A161P IC50 of inhibitory activity of protein substrate exchange 50 Fitted curve.

[0066] Figure 2 shows the effects of compound cpd77 / 83 / 84 / 85 / 93 / 98 / 100 / 109 / 110 / 111 on RhoA wild-type and RhoA Y42C IC50 of inhibitory activity of protein substrate exchange 50 Fitted curve. Detailed Implementation

[0067] Through extensive and in-depth research, including numerous screenings and tests, the inventors have developed a novel class of RhoA inhibitor compounds with superior activity. These compounds can be used as inhibitors to dynamically regulate RhoA protein and suppress wild-type RhoA or corresponding pathogenic mutant proteins such as RhoA2. A161P and RhoA Y42C The invention was completed based on the C42 site, which effectively treats diseases and conditions mediated by RhoA.

[0068] the term

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0070] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0071] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0072] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0073] When a substituent is described using a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- includes -OCH2-.

[0074] In this invention, the halogen is F, Cl, Br or I.

[0075] In this invention, the terms "C1-C8" refer to having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C0-C4" refers to having 0, 1, 2, 3, or 4 carbon atoms, and so on. "3-6 elements" refers to having 3, 4, 5, or 6 ring atoms, and so on.

[0076] In this invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety, and the alkyl group used herein, or as part of other groups, has 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), 1 to 4 carbon atoms (i.e., C1-C4 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Non-limitingly included are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0077] In this invention, the term "alkoxy" refers to an -O-(alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms (including 1 to 3 carbon atoms), and includes, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, and butoxy.

[0078] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one double bond. For example, the term "C2-C8 alkenyl" refers to a straight-chain or branched alkenyl moiety containing one or two double bonds having 2 to 8 carbon atoms (including 2 to 6 carbon atoms or 2 to 4 carbon atoms), and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl.

[0079] In this invention, the term "alkynyl" refers to a straight-chain or branched alkynyl group containing one triple bond. For example, the term "C2-C8 alkynyl" refers to a straight-chain or branched alkynyl group containing one or two triple bonds with 2 to 8 carbon atoms (including 2-6 carbon atoms or 2-4 carbon atoms). It includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentyynyl (2-methyl-3-butynyl, 2-pentynyl, 3-pentynyl) and hexynyl, etc.

[0080] Divalent groups such as "alkylene", "alkenylene", and "alkynylene" refer to divalent groups formed by the loss of one H atom from alkyl, alkenyl, or alkynyl groups. The alkyl, alkenyl, or alkynyl groups defined above in this article can be used for alkylene, alkenylene, and alkynylene, respectively.

[0081] In this invention, the term "cycloalkyl" refers to a saturated monocyclic, bridged, or spirocyclic cyclic hydrocarbon moiety, such as the term "C3-C". 10"Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms (including 3-8 carbon atoms or 5-6 carbon atoms) on a ring, whether monocyclic, bridged, or spirocyclic, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. The term "bridged cycloalkyl" includes, without limitation, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, and bicyclo[3,2,2]octyl.

[0082] In this invention, the term "aryl" refers to a hydrocarbon moiety comprising one or more aromatic rings. For example, the term "C6-C..." 10 "Aryl" refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl.

[0083] In this invention, the term "heterocyclic group" or "heterocyclic alkyl group" refers to a saturated or unsaturated, non-aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., independently selected from N, O, or S). For example, the term "3-10 membered heterocyclic group" refers to a monocyclic, bridged, or spirocyclic heterocyclic group having 3 to 10 ring atoms (including 3-8 ring atoms or 5-6 ring atoms) on the ring, such as tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothiophenyl, or morpholinyl.

[0084] In this invention, the term "heteroaryl" refers to an aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., independently selected from N, O, or S). For example, the term "5-10-membered heteroaryl" refers to a heteroaryl group having 5 to 10 ring atoms (including 5-6 ring atoms) on the ring, such as furanyl, pyrroleyl, thiopheneyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, indolyl, pyrimidinyl, and pyranyl.

[0085] The term "multiple" can refer to 2, 3, 4, 5, or 6.

[0086] Unless otherwise specified, the substitution referred to herein means that one or more H atoms on a group are independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl.

[0087] compound

[0088] This invention provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, or isotopic compound thereof:

[0089] Among them, R 1 ,R 2 A, L, and B are defined as above.

[0090] In another preferred embodiment, R 1 ,R 2 A, L, and B are optionally and independently selected from the corresponding groups in the compounds of the embodiments of the present invention.

[0091] The pharmaceutically acceptable salts described in this invention can be salts formed by anion and a positively charged group on a compound of Formula I. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, or maleate. Similarly, salts can be formed by cations and negatively charged groups on a compound of Formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium ions.

[0092] "Pharmaceutically acceptable salts" refer to salts formed by compounds of Formula I with acids selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid; or sodium, potassium, calcium, aluminum, or ammonium salts formed by compounds of Formula I with inorganic bases; or methylamine, ethylamine, or ethanolamine salts formed by compounds of general Formula I with organic bases.

[0093] This invention is also intended to include crystal forms of the compounds of this invention, such as hydrates, solvates, etc.

[0094] This invention is also intended to include esters, prodrugs, or metabolites of the compounds of this invention.

[0095] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0096] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0097] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0098] Pharmaceutical Composition

[0099] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective range, and pharmaceutically acceptable excipients.

[0100] The "active ingredient" mentioned in this invention refers to the compound of formula I described in this invention, and its pharmaceutically acceptable salt, stereoisomer, or isotope compound.

[0101] The "active ingredient" and pharmaceutical composition described in this invention are used to prepare remedies for treating RhoA-mediated diseases or conditions. The "active ingredient" and pharmaceutical composition described in this invention can be used as RhoA inhibitors, thereby enabling the treatment of diseases associated with RhoA abnormalities.

[0102] The RhoA includes wild-type RhoA and pathogenic mutants of RhoA (such as RhoA...). A161P and RhoA Y42C ).

[0103] The diseases or conditions mediated by RhoA are selected from hematologic malignancies, gastric cancer, adult blastoma, diffuse large B-cell lymphoma, colon cancer, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma; cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, and chronic lung diseases.

[0104] "Safe and effective dose" refers to an amount of active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg of active ingredient per dose. Preferably, "one dose" refers to one tablet.

[0105] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0106] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0107] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, 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 thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0108] In addition to the active ingredient, 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.

[0109] 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.

[0110] The compounds of this invention can be administered alone or in combination with other therapeutic agents (such as antitumor drugs).

[0111] 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 20–500 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 skills of a skilled physician.

[0112] The main advantages of this invention include:

[0113] 1. This invention provides a class of compounds with novel structures and excellent RhoA inhibitory activity, which can be used to prepare drugs for the prevention and / or treatment of RhoA-mediated diseases or conditions.

[0114] 2. The compounds of the present invention have excellent pharmacokinetic and pharmacodynamic properties, high bioavailability, and very good drug-like properties.

[0115] 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.

[0116] Example 1:

[0117] S1: Indole-4-carboxaldehyde (200 mg, 1.38 mmol, 1.0 equivalent) was dissolved in DMF (3 mL). NaH (138 mg, 3.44 mmol, 2.5 equivalent, 60% in mineral oil) was added in portions under an ice-water bath. The mixture was stirred for 0.5 h under an ice-water bath, followed by the addition of iodomethane (94 μL, 1.52 mmol, 1.1 equivalent). The mixture was then brought to room temperature and stirred for another 3 h. The mixture was quenched in ice water, extracted with water and ethyl acetate, and the organic phases were combined and washed twice with water and once with saturated brine. The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by a Flash column chromatography (ethyl acetate / petroleum ether) to obtain 105 mg of a pale yellow oil, int-1, in yield 47.9%. 1 HNMR (500MHz, Chloroform-d) δ10.25(s,1H),7.64(d,J=7.3Hz,1H),7.61(d,J=8.1Hz,1H),7.38–7.34(m,1H),7.28–7.26(m,2H),3.87(s,3H). MS(ESI)m / z:159.97[M+H] + .

[0118] S2: Int-1 (100 mg, 0.63 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (19 mg, 0.25 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 4 h. The mixture was quenched with water, extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative liquid chromatography (C18, water / ACN) to give 60 mg of pale yellow solid cpd-1, yield 47.2%. 1 H NMR(500MHz,Chloroform-d)δ8.39(d,J=13.7Hz,1H),7.81(d,J=13.7Hz,1H),7.49(d,J=8.2Hz,1H), 7.39 (d, J = 7.4Hz, 1H), 7.29 (d, J = 7.8Hz, 1H), 7.26–7.25 (m, 1H), 6.70 (d, J = 3.2Hz, 1H), 3.87 (s, 3H). MS(ESI)m / z:203.1[M+H] + .

[0119] Example 2

[0120] S1: The preparation method is the same as in Example 1S1. Indole-4-carboxaldehyde and bromoethane were used to separate and purify 203 mg of light yellow oily substance int-2, with a yield of 85.1%. 1 H NMR (500MHz, Chloroform-d) δ10.25 (s, 1H), 7.65–7.62 (m, 2H), 7.37–7.33 (m, 2H), 7.29 (d, J = 3.0Hz, 1H), 4.25 (q, J = 7.3Hz, 2H), 1.50 (t, J = 7.3Hz, 3H).

[0121] S2: The preparation method is the same as in Example 1S2. Using int-2, 62 mg of brownish-yellow solid cpd-2 was obtained by separation and purification, with a yield of 24.8%. 1 H NMR(500MHz,Chloroform-d)δ8.39(d,J=13.6Hz,1H),7.81(d,J=13.6Hz,1H),7.52(d,J=8.2Hz,1H),7.38(d,J=7.3H z,1H),7.32(d,J=3.2Hz,1H),7.29–7.24(m,1H),6.71(d,J=3.2Hz,1H),4.24(q,J=7.3Hz,2H),1.50(t,J=7.3Hz,3H). MS(ESI)m / z:217.1[M+H] + .

[0122] Example 3

[0123] S1: The preparation method is the same as in Example 1S1. Indole-4-carboxaldehyde and tert-butyl 4-bromobutyrate were used to separate and purify 262 mg of orange solid int-3, with a yield of 66.2%. 1 H NMR(500MHz,Chloroform-d)δ10.25(s,1H),7.67–7.61(m,2H),7.34(t,J=7.7Hz,1H),7.3 1–7.28(m,2H),4.26(t,J=6.8Hz,2H),2.21–2.17(m,2H),2.15–2.08(m,2H),1.44(s,9H). MS(ESI)m / z:232.01[M–55].

[0124] S2: The preparation method is the same as in Example 1S2. Using int-3, 177 mg of reddish-brown oily substance cpd-3 was obtained by separation and purification, with a yield of 58.8%. 1H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.7Hz,1H),7.80(d,J=13.6Hz,1H),7.53(d,J=8.1Hz,1H),7.38(d,J=7.4Hz,1 H),7.31–7.24(m,2H),6.71(d,J=3.2Hz,1H),4.25(t,J=7.1Hz,2H),2.24–2.18(m,2H),2.16–2.09(m,3H),1.45(s,9H). MS(ESI)m / z:331.1[M+H] + .

[0125] Example 4

[0126] S1: Indole-4-carboxaldehyde (200 mg, 1.38 mmol, 1.0 equivalent) was dissolved in DMF (3 mL). NaH (138 mg, 3.44 mmol, 2.5 equivalent, 60% in mineral oil) was added in portions under an ice-water bath, and stirring was continued for 0.5 h under an ice-water bath. Then, 4-(3-bromopropyl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.81 mmol, 0.59 equivalent) was added, and the mixture was brought back to room temperature and stirred for another 3 h. The mixture was quenched in ice water, extracted with water and ethyl acetate, and the organic phases were combined and washed twice with water and once with saturated brine. The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 238 mg of a light brown oil, int-4, in yield 82.7%. 1 H NMR(500MHz,Chloroform-d)δ10.24(s,1H),7.67(d,J=8.2Hz,1H),7.62(d,J=7.2Hz,1H),7.35–7.31(m,2H),7.28(d,J=3.1Hz ,1H),4.29(t,J=6.6Hz,2H),3.44(t,J=5.0Hz,4H),2.36–2.27(m,4H),2.23(t,J=6.7Hz,2H),2.03–1.97(m,2H),1.46(s,9H). MS(ESI)m / z:372.2[M+H] + .

[0127] S2: The preparation method is the same as in Example 1S2. Using int-4, 104 mg of dark brownish-yellow solid cpd-4a was obtained by separation and purification, with a yield of 39.2%. 1H NMR(500MHz,Chloroform-d)δ8.37(d,J=13.6Hz,1H),7.80(d,J=13.6Hz,1H),7.53(d,J=8.2Hz,1H),7.38(d,J=7.4Hz,1H),7.30(d,J=3.2Hz,1H),7.28–7.2 5(m,1H),6.72(d,J=3.2Hz,1H),4.29(t,J=6.7Hz,2H),3.53(t,J=5.2Hz,4H), 2.58(t,J=5.1Hz,4H), 2.50(t,J=7.3Hz,2H), 2.18–2.11(m,2H), 1.45(s,9H). MS(ESI) m / z: 415.2 [M+H] + .

[0128] S3: Dissolve cpd-4a (20 mg, 0.05 mmol) in DCM (3 mL), add TFA (100 μL), and stir at room temperature for 1 h. Extract the mixture with water and DCM, dry to MgSO4, filter, and concentrate under reduced pressure to obtain the residue. Separate and purify the residue by preparative liquid chromatography (C18, water / ACN) to obtain 2.49 mg of brownish-yellow solid cpd-4b, yield 16.4%. 1 H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.7Hz,1H),7.80(d,J=13.7Hz,1H),7.4 6(d,J=8.2Hz,1H),7.38(d,J=7.4Hz,1H),7.28–7.26(m,1H),7.26–7.24(m,1H),6 .71(d,J=3.2Hz,1H),4.17(t,J=7.0Hz,2H),2.73(t,J=12.0Hz,4H),2.04–1.98(m ,1H),1.90–1.83(m,2H),1.80–1.75(m,2H),1.42–1.46(m,2H),1.33–1.31(m,2H). MS(ESI) m / z: 315.1 [M+H] + .

[0129] Example 5

[0130] S1: The preparation method is the same as in Example 1S1. Indole-4-carboxaldehyde and N-Boc-bromoethylamine were used to separate and purify 150 mg of light yellow oily substance int-5, with a yield of 37.8%. 1H NMR(500MHz,Chloroform-d)δ10.23(s,1H),7.67–7.63(m,2H),7.35(t,J=7.7Hz,1H),7. 32–7.27(m,2H),4.56(s,1H),4.35(t,J=6.1Hz,2H),3.49(q,J=6.1Hz,2H),1.43(s,9H). MS(ESI)m / z:311.1[M+Na] + .

[0131] S2: The preparation method is the same as in Example 1S2. Using int-5, 58 mg of yellow solid cpd-5 was obtained by separation and purification, with a yield of 33.6%. 1 H NMR(500MHz,Chloroform-d)δ8.37(d,J=13.6Hz,1H),7.79(d,J=13.6Hz,1H),7.54(d,J=8.2Hz,1H),7.38(d,J=7 .3Hz,1H),7.31–7.23(m,2H),6.78–6.69(m,1H),4.57(s,1H),4.40–4.28(m,2H),3.54–3.45(m,2H),1.43(s,9H). MS(ESI)m / z:276.1[M–55].

[0132] Examples 6-15

[0133] Examples 6-15 provide a series of small molecule compounds, prepared according to Example 1S2. Aldehydes (1.0 equivalent) were dissolved in CH3NO2 (3 mL), ammonium acetate (0.4 equivalent) was added, and the mixture was stirred at 100 °C for 4 h. The mixture was quenched with water, extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative liquid chromatography (C18 column, water / ACN) to obtain the final product, with yields ranging from 2.7% to 57.9%. Specific compound structures and characterization data are shown in Table 1 below.

[0134] Table 1. Compound structures and characterization data from Examples 6-15

[0135] Example 16

[0136] S1: The preparation method is the same as in Example 1S1. Indole-4-carboxaldehyde and 6-bromohexanoic acid were used to separate and purify 186 mg of brown oily substance int-16, with a yield of 52.1%. 1H NMR(500MHz,Chloroform-d)δ10.24(s,1H),7.64–7.59(m,2H),7.36–7.32(m,1H),7.30(d,J=3.1Hz,1H),7.28(d,J =3.1Hz,1H),4.19(t,J=7.1Hz,2H),2.33(t,J=7.3Hz,2H),1.91–1.84(m,2H),1.70–1.63(m,2H),1.40–1.33(m,2H). MS(ESI)m / z:258.1[MH] - .

[0137] S2: Int-16 (172 mg, 0.66 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (20 mg, 0.26 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 4 h. The mixture was quenched with water, extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 159 mg of deep yellow solid cpd-16, yield 79.3%. 1 H NMR (500MHz, DMSO-d6) δ11.98(s,1H),8.39(d,J=13.6Hz,1H),8.18(d,J=13.6Hz,1H),7.74(d,J=8.2Hz,1H),7.64–7.60(m,2H),7.24(t,J =7.8Hz,1H),6.88(d,J=3.1Hz,1H),4.23(t,J=7.1Hz,2H),2.17(t,J=7.3Hz,2H),1.80–1.72(m,2H),1.55–1.48(m,2H),1.24–1.23(m,2H). MS(ESI)m / z:301.2[MH] - .

[0138] Example 17

[0139] S1: The preparation method is the same as in Example 1S1. Indole-4-carboxaldehyde and 7-bromohexanoic acid were used to separate and purify 234 mg of brown solid int-17, with a yield of 62.1%. 1H NMR(500MHz,Chloroform-d)δ10.24(s,1H),7.65–7.59(m,2H),7.36–7.32(m,1H),7.30(d,J=3.1Hz,1H),7.28(d,J=3.1Hz, 1H), 4.18 (t, J = 7.1Hz, 2H), 2.39–2.30 (m, 2H), 1.90–1.82 (m, 2H), 1.69–1.57 (m, 2H), 1.51–1.42 (m, 2H), 1.41–1.34 (m, 2H). MS(ESI)m / z:272.1[MH] - .

[0140] S2: The preparation method is the same as in Example 16S2. Using int-17, 122 mg of dark orange solid cpd-17 was obtained by separation and purification, with a yield of 48.8%. 1 H NMR (500MHz, DMSO-d6) δ11.97(s,1H),8.39(d,J=13.6Hz,1H),8.18(d,J=13.6Hz,1H),7.74(d,J=8.2Hz,1H),7.65–7.59(m,2H),7.24(t,J =7.8Hz,1H),6.88(d,J=3.1Hz,1H),4.23(t,J=7.0Hz,2H),2.16(t,J=7.3Hz,2H),1.80–1.70(m,2H),1.48–1.41(m,2H),1.30–1.24(m,4H). MS(ESI)m / z:315.2[MH] - .

[0141] Example 18

[0142] S1: The preparation method is the same as in Example 1S1. Indole-4-carboxaldehyde and 7-bromo-n-heptanol were used to separate and purify 252 mg of pale yellow oily substance int-18, with a yield of 83.5%. 1H NMR(500MHz,Chloroform-d)δ10.25(s,1H),7.63(d,J=2.4Hz,1H),7.61(d,J=3.3Hz,1H),7.36–7.32(m,1H),7.30(d,J=3.1Hz,1H),7.28– 7.27(m,1H),4.18(t,J=7.1Hz,2H),3.61(t,J=6.6Hz,2H),1.89–1.82(m,2H),1.56–1.50(m,2H),1.35–1.30(m,6H),1.26(t,J=7.1Hz,1H). MS(ESI)m / z:260.1[M+H] + .

[0143] S2: The preparation method is the same as in Example 1S2. Using int-18, 71 mg of yellow solid cpd-18 was obtained by separation and purification, with a yield of 24.3%. 1 H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.7Hz,1H),7.80(d,J=13.6Hz,1H),7.50(d,J=8.2Hz,1H),7.37(d,J=7.4Hz,1H),7.28(d,J=3.2Hz,1H),7.27– 7.23(m,1H),6.70(d,J=3.2Hz,1H),4.17(t,J=7.1Hz,2H),3.62(t,J=6.5Hz ,2H),1.90–1.82(m,2H),1.57–1.50(m,2H),1.37–1.32(m,6H),1.26(s,1H). MS(ESI)m / z:303.08[M+H] + .

[0144] Example 19

[0145] S1: The preparation method is the same as in Example 1S1. Indole-4-carboxaldehyde and 4-chlorosulfonylbenzoic acid were used to separate and purify 79 mg of light brownish-yellow solid int-19, with a yield of 17.4%. 1 H NMR (500MHz, DMSO-d6) δ10.20(s,1H),8.29(d,J=8.3Hz,1H),8.16–8.13(m,2H),8.10(d,J=3. 6Hz,1H),8.09–8.07(m,2H),7.91(d,J=7.4Hz,1H),7.63–7.59(m,1H),7.46(d,J=3.7Hz,1H). MS(ESI)m / z:328.08[MH] - .

[0146] S2: The preparation method is the same as in Example 1S2. Using int-19, 30 mg of yellow solid cpd-19 was separated and purified to obtain a yield of 33.6%. 1 H NMR(500MHz, DMSO-d6)δ8.38(d,J=13.6Hz,1H),8.24(d,J=13.6Hz,1H),8.15–8.10(m,3H),8.08(d,J= 8.3Hz, 2H), 8.04 (d, J = 3.8Hz, 1H), 7.87 (d, J = 7.7Hz, 1H), 7.46 (t, J = 8.0Hz, 1H), 7.41 (d, J = 3.8Hz, 1H). MS(ESI)m / z:371.15[MH] - .

[0147] Example 20

[0148] S1: Tetrahydro-2H-pyran-4-ylmethanesulfonate (4 g, 22.2 mmol, 1.0 equivalent) and K2CO3 (5 g, 36.3 mmol, 3.0 equivalent) were dissolved in DMF (20 mL), and 2-hydroxy-5-iodobenzaldehyde (3 g, 12.1 mmol, 1.2 equivalent) was added. The mixture was stirred at 60 °C for 18 h. The mixture was extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine. The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 2.030 g of pale yellow solid int-20, yield 50.5%. 1 H NMR(500MHz,Chloroform-d)δ10.39(s,1H),8.10(d,J=2.2Hz,1H),7.77(dd,J=8.8,2.3Hz,1H),6.78(d,J= 8.8Hz,1H),4.65–4.60(m,1H),3.99–3.93(m,2H),3.65–3.58(m,2H),2.10–2.03(m,2H),1.89–1.81(m,2H). MS(ESI)m / z:333.0[M+H] + .

[0149] S2: The preparation method is the same as in Example 1S2. Using int-20, 137 mg of yellow solid cpd-20 was obtained by separation and purification, with a yield of 30.3%. 1H NMR(500MHz,Chloroform-d)δ8.06(d,J=13.6Hz,1H),7.79(d,J=13.6Hz,1H),7.76(d,J=2.2Hz,1H),7.67(dd,J=8.9,2.2Hz ,1H),6.75(d,J=8.8Hz,1H),4.65–4.60(m,1H),4.02–3.96(m,2H),3.64–3.59(m,2H),2.12–2.06(m,2H),1.91–1.83(m,2H).

[0150] Example 21

[0151] S1: K₂CO₃ (200 mg, 1.45 mmol, 1.0 equivalent) was dissolved in DMA (5 mL), and 2-fluoro-6-methylbenzaldehyde (171 μL, 1.45 mmol, 1.0 equivalent) and 3-methoxyphenol (167 μL, 1.52 mmol, 1.05 equivalent) were added. The mixture was stirred in a microwave at 165 °C for 2 h. The mixture was extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine. The mixture was dried over MgSO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 256 mg of a yellow oil, int-21, in yield 73.0%. 1 H NMR(500MHz,Chloroform-d)δ10.63(s,1H),7.36(t,J=7.9Hz,1H),7.27–7.23(m,1H),6.98(d,J=7 .6Hz,1H),6.81(d,J=8.3Hz,1H),6.72–6.67(m,1H),6.62–6.56(m,2H),3.79(s,3H),2.64(s,3H).

[0152] S2: The preparation method is the same as in Example 1S2. Using int-21, 194 mg of brownish-yellow solid cpd-21 was obtained by separation and purification, with a yield of 70.4%. 1 H NMR(500MHz,Chloroform-d)δ8.29(d,J=13.6Hz,1H),7.96(d,J=13.6Hz,1H),7.30–7.22(m, 3H), 7.01 (d, J = 7.5Hz, 1H), 6.76–6.72 (m, 2H), 6.61–6.57 (m, 2H), 3.80 (s, 3H), 2.55 (s, 3H). MS(ESI)m / z:286.1[M+H] + .

[0153] Example 22

[0154] S1: Indole-4-carboxaldehyde (200 mg, 1.38 mmol, 1.0 equivalent) was dissolved in DMF (3 mL). NaH (138 mg, 3.44 mmol, 2.5 equivalent, 60% in mineral oil) was added in portions under an ice-water bath, and stirring was continued for 0.5 h under an ice-water bath. Then, p-toluenesulfonyl chloride (356 mg, 1.52 mmol, 1.1 equivalent) was added, and the mixture was brought to room temperature and stirred for another 3 h. The mixture was quenched in ice water and extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was pre-purified using a Flash column chromatography system, followed by preparative liquid chromatography (C18, water / ACN) to obtain 94 mg of a white solid, int-22, in yield 22.8%. 1 H NMR(500MHz,Chloroform-d)δ10.18(s,1H),8.27(d,J=8.4Hz,1H),7.78–7.74(m, 3H),7.72(d,J=7.4Hz,1H),7.50–7.46(m,2H),7.24(d,J=8.2Hz,2H),2.35(s,3H). MS(ESI)m / z:300.0[M+H] + .

[0155] S2: Int-22 (94 mg, 0.31 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (10 mg, 0.13 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 4 h. The mixture was extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was pre-purified by Flash column chromatography, and then purified by preparative liquid chromatography (C18, water / ACN) to obtain 8 mg of yellow solid cpd-22, yield 7.4%. 1H NMR(500MHz,Chloroform-d)δ8.28(d,J=13.7Hz,1H),8.13(d,J=8.3Hz,1H),7.78(d,J=8.3Hz,2H),7.75(d,J=3.8Hz,1H),7 .66(d,J=13.7Hz,1H),7.48(d,J=7.6Hz,1H),7.37(t,J=8.0Hz,1H),7.26–7.23(m,2H),6.89(d,J=3.8Hz,1H),2.35(s,3H). MS(ESI)m / z:342.8[M+H] + .

[0156] Example 23

[0157] S1: The preparation method is as described in Example 22S1. Indole-4-carboxaldehyde and tert-butyl 4-(3-bromopropyl)piperidine-1-carboxylic acid were used to separate and purify the yellow oily substance int-23 with a yield of 73.7%. 1 H NMR (500MHz, Chloroform-d) δ10.25 (s, 1H), 7.63 (d, J = 7.4Hz, 1H), 7.61 (d, J = 8. 1Hz,1H),7.37–7.32(m,1H),7.30(d,J=3.1Hz,1H),7.28(d,J=3.1Hz,1H),4.18(t ,J=7.1Hz,2H),4.12–3.95(m,2H),2.69–2.56(m,2H),1.92–1.81(m,2H),1.62–1. 57(m,2H),1.43(s,9H),1.40–1.30(m,1H),1.26–1.24(m,2H),1.10–1.00(m,2H). MS(ESI) m / z: 271.08 [M-100+H] + .

[0158] S2: The preparation method is the same as in Example 22S2. Using int-23, 82 mg of yellow-brown oily substance cpd-23 was obtained by separation and purification, with a yield of 36.7%. 1H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.6Hz,1H),7.81(d,J=13.6Hz,1H),7.49( d,J=8.2Hz,1H),7.37(d,J=7.4Hz,1H),7.29–7.24(m,3H),6.70(d,J=3.1Hz,1H),4. 16(t,J=7.1Hz,2H),4.13–3.96(m,2H),2.70–2.57(m,2H),1.91–1.84(m,2H),1.63– 1.55(m,2H),1.44(s,9H),1.40–1.32(m,1H),1.29–1.25(m,3H),1.11–1.00(m,2H). MS(ESI)m / z:314.06[M-100+H] + .

[0159] Example 24

[0160] S1: The preparation method is as described in Example 22S1. Indole-4-carboxaldehyde and N-Boc-4-(2-bromoethyl)piperidine were used to separate and purify 253 mg of yellow oily substance int-24, with a yield of 91.2%. 1 H NMR (500MHz, Chloroform-d) δ10.25(s,1H),7.63(d,J=7.2Hz,1H),7.60(d,J=8.2Hz,1H),7.35(t,J=7.7Hz,1H),7.31–7.25(m,2H),4.23(t,J=7. 4Hz,2H),4.15–4.00(m,2H),2.65(t,J=13.1Hz,2H),1.81(q,J=7.2Hz,2H ),1.67–1.63(m,2H),1.45(s,9H),1.43–1.36(m,1H),1.22–1.13(m,2H). MS(ESI)m / z:257.07[M-100+H] + .

[0161] S2: The preparation method is as described in Example 22S2. Using int-24, 70 mg of yellow oily substance cpd-24 was obtained by separation and purification, with a yield of 25.0%. 1H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.7Hz,1H),7.80(d,J=13.6Hz,1H),7 .48(d,J=8.2Hz,1H),7.38(d,J=7.3Hz,1H),7.29–7.24(m,3H),6.71(d,J=2.9Hz ,1H),4.22(t,J=7.4Hz,2H),4.18–3.99(m,2H),2.72–2.60(m,2H),1.81(q,J=7. 2Hz,2H),1.76–1.68(m,2H),1.45(s,9H),1.44–1.38(m,1H),1.24–1.14(m,2H). MS(ESI) m / z: 300.66 [M-100+H] + .

[0162] Example 25

[0163] S1: Indole-4-carboxaldehyde (152 mg, 1.05 mmol, 1.05 equivalents) was dissolved in DMF (2 mL). NaH (100 mg, 2.5 mmol, 2.5 equivalents, 60% in mineral oil) was added in portions under an ice-water bath, and stirring was continued for 0.5 h under an ice-water bath. Then, bromomethylcyclopentane (163 mg, 1.0 mmol, 1.0 equivalents) was added, and the mixture was brought to room temperature and stirred for another 3 h. The mixture was quenched in ice water and extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 110 mg of a yellow oil, int-25, in yield 48.4%. MS (ESI) m / z: 228.06 [M+H] + .

[0164] S2: Int-25 (110 mg, 0.70 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (15 mg, 0.20 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 3 h. The mixture was extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 50 mg of yellow oily cpd-25, yield 38.5%. 1H NMR(500MHz,Chloroform-d)δ8.39(d,J=13.6Hz,1H),7.81(d,J=13.6Hz,1H),7.52(d,J=8.2Hz,1H),7.37(d,J=7.4Hz,1H),7.30(d,J= 3.2Hz,1H),7.27–7.23(m,1H),6.70(d,J=3.1Hz,1H),4.09(d,J=7.5Hz,2H),2.48–2.38(m,1H),1.68–1.72(m,2H),0.90–0.83(m,6H). MS(ESI)m / z:271.05[M+H] + .

[0165] Example 26

[0166] S1: NaH (67 mg, 1.66 mmol, 1.2 equivalents, 60% in mineral oil) was dissolved in DMF (2 mL) at 0 °C. Indole-4-carboxaldehyde (200 mg, 1.38 mmol, 1.0 equivalents) was added under argon protection, and the mixture was stirred in an ice-water bath for 0.5 h. Then, benzyl bromide (246 μL, 2.07 mmol, 1.5 equivalents) was added dropwise, and the mixture was brought back to room temperature and stirred overnight. The mixture was quenched in ice water and extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 278 mg of a yellow oil, int-26, in yield 85.5%. 1 H NMR (500MHz, DMSO-d6) δ10.20(s,1H),7.86(d,J=8.2Hz,1H),7.78(d,J=3.1Hz,1H),7. 71–7.67(m,1H),7.35–7.28(m,3H),7.26–7.22(m,1H),7.21–7.16(m,3H),5.52(s,2H). MS(ESI)m / z:236.1[M+H] + .

[0167] S2: The preparation method is as described in Example 25S2. Using int-26, 46 mg of yellow solid cpd-26 was obtained after separation and purification, with a yield of 38.4%. 1H NMR(500MHz,Chloroform-d)δ8.40(d,J=13.6Hz,1H),7.81(d,J=13.6Hz,1H),7.46-7.42(m,1H),7.38(d,J=7.4Hz,1 H),7.35-7.27(m,4H),7.22(t,J=7.8Hz,1H),7.10(dd,J=7.9,1.5Hz,2H),6.77(dd,J=3.3,0.9Hz,1H),5.38(s,2H). MS(ESI)m / z:279.01[M+H] + .

[0168] Example 27

[0169] S1: The preparation method was as described in Example 25S1, using indole-4-carboxaldehyde and 4-(2-bromoethyl)morpholine hydrobromide. 182 mg of a yellow oily substance, int-27, was obtained after separation and purification, with a yield of 70.5%. MS (ESI) m / z: 259.07 [M+H] + .

[0170] S2: The preparation method is the same as in Example 25S2. Using int-27, 169 mg of yellow solid cpd-27 was obtained by separation and purification, with a yield of 80.1%. 1 H NMR(500MHz,Chloroform-d)δ8.40–8.29(m,1H),7.81–7.75(m,1H),7.52(d,J=8.2Hz,1H),7.38–7.34(m,2H),7.27– 7.23(m,1H),6.71–6.68(m,1H),4.29(t,J=6.7Hz,2H),3.71–3.68(m,4H),2.76(t,J=6.7Hz,2H),2.50–2.46(m,4H). MS(ESI)m / z:302.09[M+H] + .

[0171] Example 28

[0172] S1: The preparation method is as described in Example 25S1. Indole-4-carboxaldehyde and 3-(difluoromethoxy)benzyl bromide were used to separate and purify 146 mg of yellow solid int-28, with a yield of 48.5%. 1H NMR(500MHz,Chloroform-d)δ10.26(s,1H),7.65(dd,J=7.3,1.0Hz,1H),7.53-7.50(m,1H),7.37(dd,J=3.1,0.8Hz,1H),7.35(d, J=3.1Hz,1H),7.32(dd,J=8.1,7.1Hz,1H),7.28(d,J=7.9Hz,1H),7.05-7.02(m,1H),6.90-6.86(m,2H),5.39(s,2H),1.61(s,1H). MS(ESI)m / z:302.1[M+H] + .

[0173] S2: The preparation method is the same as in Example 25S2. Using int-28, 37 mg of yellow solid cpd-28 was obtained by separation and purification, with a yield of 22.9%. 1 H NMR(500MHz,Chloroform-d)δ8.40(d,J=13.6Hz,1H),7.81(d,J=13.6Hz,1H),7.40(dd,J=7.9,3.2Hz,2H),7.34-7.32(m,1H),7.30(d,J=7.9Hz,1H),7.2 3(t,J=7.8Hz,1H),7.04(dd,J=8.2,2.4Hz,1H),6.91(d,J=7.8Hz,1H),6.88( d, J=2.4Hz, 1H), 6.79 (d, J=3.2Hz, 1H), 6.46 (t, J=73.6Hz, 1H), 5.38 (s, 2H). MS(ESI)m / z:345.1[M+H] + .

[0174] Example 29

[0175] S1: The preparation method was the same as in Example 25S1, using indole-4-carboxaldehyde and 3-bromomethylbenzoic acid. After separation and purification, 49 mg of a brown solid, int-29, was obtained, with a yield of 17.5%. MS (ESI) m / z: 280.1 [M+H] + .

[0176] S2: The preparation method is the same as in Example 25S2. Using int-29, 9 mg of yellow solid cpd-29 was separated and purified to obtain 15.5% yield. 1H NMR (500MHz, DMSO-d6) δ11.40(s,1H),8.40(d,J=13.2Hz,1H),7.96(d,J=13.2Hz,1H),7.75-7.73(m,1H),7.73-7.70(m,2H),7.59(d,J=8 .0Hz,1H),7.53(d,J=7.5Hz,1H),7.47(d,J=7.6Hz,1H),7.45(d,J=2.4Hz,1H),7.38(t,J=7.6Hz,1H),7.16(t,J=7.8Hz,1H),4.34(s,2H). MS(ESI)m / z:323.1[M+H] + .

[0177] Example 30

[0178] S1: The preparation method is as described in Example 25S1. Indole-4-carboxaldehyde and m-hydroxybenzyl bromide were used to separate and purify 138 mg of yellow solid int-30, with a yield of 54.9%. 1 H NMR(500MHz,Chloroform-d)δ10.14(d,J=4.4Hz,1H),7.59(d,J=7.4Hz,1H),7.54(d,J=8.2Hz,1H),7.33(dd,J=3.1,1.2Hz,1H), 7.28(dd,J=5.2,2.0Hz,2H),7.17(t,J=7.9Hz,1H),6.77(dd,J=8.1,2.5Hz,1H),6.69(d,J=7.6Hz,1H),6.50(s,1H),5.32(s,2H). MS(ESI)m / z:252.1[M+H] + .

[0179] S2: The preparation method is the same as in Example 25S2. Using int-30, 61 mg of red solid cpd-30 was obtained by separation and purification, with a yield of 37.7%. 1H NMR(500MHz,Chloroform-d)δ8.39(d,J=13.6Hz,1H),7.81(d,J=13.6Hz,1H),7.43(d,J=8.2Hz,1H),7.38(d,J=7.4Hz,1H),7.33(d,J=3.3H z,1H),7.24-7.16(m,2H),6.77(dd,J=3.2,0.9Hz,1H),6.74(dd,J=7.9,2.6Hz,1H),6.72-6.68(m,1H),6.50(t,J=2.1Hz,1H),5.33(s,2H). MS(ESI)m / z:295.1[M+H] + .

[0180] Example 31

[0181] S1: The preparation method is as described in Example 25S1. Indole-4-carboxaldehyde and 5-(bromomethyl)benzo(d)(1,3)dioxane were used to separate and purify 217 mg of yellow solid int-31, with a yield of 77.8%. 1 H NMR(500MHz,Chloroform-d)δ10.25(s,1H),7.67(d,J=8.2Hz,1H),7.63(d,J=7.3Hz,1H),7.40(d,J=3.1Hz, 1H),7.34-7.31(m,2H),6.77-6.71(m,2H),6.50(dd,J=7.6,1.5Hz,1H),6.00(d,J=1.2Hz,2H),5.32(s,2H). MS(ESI)m / z:280.1[M+H] + .

[0182] S2: The preparation method is the same as in Example 25S2. Using int-31, 69 mg of yellow solid cpd-31 was obtained by separation and purification, with a yield of 27.4%. 1 H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.6Hz,1H),7.80(d,J=13.5Hz,1H),7.55(d,J=8.2Hz,1H),7.40-7 .35(m,2H),7.23(d,J=7.9Hz,1H),6.78-6.72(m,3H),6.52(dd,J=7.5,1.8Hz,1H),6.01(s,2H),5.31(s,2H). MS(ESI)m / z:323.1[M+H] + .

[0183] Example 32

[0184] S1: 7-azaindole-4-carboxaldehyde (146 mg, 1.0 mmol, 1.0 equivalent) was dissolved in DMF (2 mL). NaH (100 mg, 2.5 mmol, 2.5 equivalent, 60% in mineral oil) was added in portions under an ice-water bath, and stirring was continued for 0.5 h under an ice-water bath. Benzyl bromide (188 mg, 1.1 mmol, 1.1 equivalent) was then added, and the mixture was brought to room temperature and stirred for another 3 h. The mixture was quenched in ice water and extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 35 mg of yellow solid int-32, yield 14.8%. 1 H NMR(500MHz,Chloroform-d)δ10.36(s,1H),8.57(d,J=4.8Hz,1H),7.52(d,J=4.8Hz,1H),7.4 3(d,J=3.4Hz,1H),7.33-7.27(m,3H),7.22-7.20(m,2H),7.15(d,J=3.5Hz,1H),5.56(s,2H). MS(ESI)m / z:237.1[M+H] + .

[0185] S2: The preparation method is the same as in Example 25S2. Using int-32, 6 mg of yellow solid cpd-32 was obtained by separation and purification, with a yield of 14.3%. 1 H NMR(500MHz,Chloroform-d)δ8.42(d,J=4.7Hz,1H),8.28(dd,J=13.7,2.3Hz,1H),7.83(dd,J=13.6,2.1Hz ,1H),7.38(t,J=3.0Hz,1H),7.34-7.28(m,3H),7.22(t,J=4.4Hz,3H),6.68(t,J=3.1Hz,1H),5.54(s,2H). MS(ESI)m / z:280.1[M+H] + .

[0186] Example 33

[0187] S1: The preparation method is as described in Example 25S1. Indole-4-carboxaldehyde and 3,4-dimethoxybenzyl bromide were used to separate and purify 540 mg of yellow solid int-33, with a yield of 91.4%. 1H NMR(500MHz,Chloroform-d)δ10.25(s,1H),7.63(dd,J=7.2,0.9Hz,1H),7.57(d,J=7.8Hz,1H),7.33(s,2H),7.30(dd,J=8.2, 7.3Hz, 1H), 6.79 (d, J = 8.1Hz, 1H), 6.66 (dd, J = 8.2, 2.0Hz, 1H), 6.63 (d, J = 2.1Hz, 1H), 5.32 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H). MS(ESI)m / z:296.1[M+H] + .

[0188] S2: The preparation method is the same as in Example 25S2. Using int-33, 388 mg of yellow solid cpd-33 was obtained by separation and purification, with a yield of 59.5%. 1 H NMR(500MHz,Chloroform-d)δ8.37(dd,J=13.7,3.1Hz,1H),7.79(dd,J=13.7,3.4Hz,1H),7.47(d,J=8.2Hz,1H),7.36(dd,J=7.5,2.9Hz,1H),7.31(d,J= 3.2Hz,1H),7.22(t,J=7.8Hz,1H),6.80(d,J=7.9Hz,1H),6.74(d,J=3.1Hz, 1H), 6.67 (d, J = 7.8Hz, 2H), 5.30 (s, 2H), 3.85 (d, J = 1.6Hz, 3H), 3.78 (s, 3H). MS(ESI)m / z:339.1[M+H] + .

[0189] Example 34

[0190] S1: 2-Bromo-3-hydroxyacetophenone (430 mg, 2.00 mmol, 1.0 equivalent) was dissolved in MeOH (5.0 mL), and NaBH4 (113 mg, 3.00 mmol, 1.5 equivalent) was added under ice-water bath. The reaction was then allowed to return to room temperature for 3 h. The mixture was quenched with ice water and extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 320 mg of pale yellow solid int-34a, yield 73.7%. 1H NMR(500MHz,DMSO-d6)δ9.34(s,1H),7.11(t,J=7.7Hz,1H),6.81-6.77(m,2H),6.67-6.63(m,1H),5 .72(d,J=4.7Hz,1H),4.70-4.66(m,1H),3.61(dd,J=10.2,4.3Hz,1H),3.51(dd,J=10.2,7.3Hz,1H). MS(ESI)m / z:214.95[M+H] + .

[0191] S2: The preparation method was the same as in Example 25S1, using indole-4-carboxaldehyde and int-34a. 15 mg of a yellow solid, int-34b, was obtained after separation and purification, with a yield of 5.3%. MS (ESI) m / z: 282.1 [M+H] + .

[0192] S3: The preparation method is the same as in Example 25S2. Using int-34b, 15 mg of yellow solid cpd-34 was obtained by separation and purification, with a yield of 86.6%. 1 H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.6Hz,1H),7.80(d,J=13.6Hz,1H),7.51(d,J=8.2Hz,1 H),7.38(d,J=7.4Hz,1H),7.27(s,1H),7.25(d,J=1.7Hz,1H),7.24-7.21(m,1H),6.88(d,J=7.6Hz ,1H),6.83(t,J=2.0Hz,1H),6.79(dd,J=8.0,2.9Hz,1H),6.70(d,J=3.2Hz,1H),5.02(dd,J=7.6, 4.3Hz, 1H), 4.39 (dd, J = 14.7, 4.3Hz, 1H), 4.33 (dd, J = 14.7, 7.6Hz, 1H), 2.96 (s, 1H), 2.88 (s, 1H). MS(ESI)m / z:325.1[M+H] + .

[0193] Example 35

[0194] S1: 3-Bromomethylbenzaldehyde (500 mg, 2.51 mmol, 1.0 equivalent) was dissolved in DMF (10 mL), followed by the addition of morpholine (245 μL, 2.76 mmol, 1.1 equivalent) and K₂CO₃ (347 mg, 2.51 mmol, 1.0 equivalent). The reaction was carried out overnight at 125 °C. The mixture was quenched with water and extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 434 mg of yellow solid int-35, yield 84.2%. 1 H NMR(500MHz,Chloroform-d)δ10.02(s,1H),7.85(s,1H),7.78(d,J=7.6Hz,1H),7.62(d,J=7 .6Hz, 1H), 7.49 (t, J = 7.6Hz, 1H), 3.71 (t, J = 4.7Hz, 4H), 3.57 (s, 2H), 2.46 (t, J = 4.6Hz, 4H). MS(ESI)m / z:206.01[M+H] + .

[0195] S2: The preparation method is the same as in Example 25S2. Using int-35, 5.2 mg of yellow oily substance cpd-35 was obtained by separation and purification, with a yield of 2.1%. 1 H NMR(500MHz,Chloroform-d)δ8.01(d,J=13.7Hz,1H),7.60(d,J=13.7Hz,1H),7.55(s,1H),7. 48–7.44(m,2H),7.43–7.39(m,1H),3.73(t,J=4.7Hz,4H),3.56(s,2H),2.49(t,J=4.6Hz,4H). MS(ESI)m / z:249.01[M+H] + .

[0196] Example 36

[0197] S1: 4-Bromoindole-3-carboxaldehyde (200 mg, 0.89 mmol, 1.0 equivalent) was dissolved in DME (9 mL), followed by the addition of 3-methoxybenzylboronic acid pinacol ester (243 mg, 0.98 mmol, 1.1 equivalent), K2CO3 (246 mg, 1.78 mmol, 2.0 equivalent), H2O (4.5 mL), and Pd(dppf)Cl2·CH2Cl2 (218 mg, 0.27 mmol, 0.3 equivalent). The reaction was carried out in a microwave oven at 90 °C for 2 h. The mixture was quenched with water and extracted with water and ethyl acetate. The combined organic phases were washed once with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by a Flash column chromatography (ethyl acetate / petroleum ether) to give 61.4 mg of a yellow solid, int-36, in yield 26.0%. 1 H NMR(500MHz,Chloroform-d)δ9.96(s,1H),9.29(s,1H),7.86(d,J=3.0Hz,1H),7.29(d,J=8.1Hz,1H),7.23(t,J=7.7Hz,1H),7.16( t,J=7.9Hz,1H),7.07(d,J=7.2Hz,1H),6.79(d,J=7.6Hz,1H),6.73(s,1H),6.70(dd,J=8.4,2.6Hz,1H),4.69(s,2H),3.73(s,3H). MS(ESI)m / z:266.02[M+H] + .

[0198] S2: Int-36 (60 mg, 0.23 mmol, 1.0 equivalent) was dissolved in CH3NO2 (4 mL), and ammonium acetate (18 mg, 0.23 mmol, 1.0 equivalent) was added. The mixture was stirred at 100 °C for 5 h. The mixture was quenched with water, extracted with water and ethyl acetate, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 41 mg of orange oily cpd-36, yield 58.7%. 1H NMR (500MHz, DMSO-d6) δ12.31(s,1H),8.40(d,J=13.1Hz,1H),8.36(s,1H),7.96(d,J=13.0Hz,1H),7.42(d,J=8.1Hz ,1H),7.22–7.13(m,2H),7.01(d,J=7.2Hz,1H),6.77–6.71(m,2H),6.67(d,J=7.6Hz,1H),4.39(s,2H),3.69(s,3H). MS(ESI)m / z:307.07[MH] - .

[0199] Example 37

[0200] S1: Indole-4-carboxaldehyde (250 mg, 1.72 mmol, 1.0 equivalent) was dissolved in DMF (5 mL). NaH (189 mg, 4.74 mmol, 2.5 equivalent, 60% in mineral oil) was added in portions under an ice-water bath, and stirring was continued for 0.5 h under an ice-water bath. Then, 5-chlorosulfonyl-2-methoxybenzoic acid (475 mg, 1.89 mmol, 1.1 equivalent) was added, and the mixture was brought back to room temperature and stirred for another 3 h. After quenching the mixture with ice water, it was purified by preparative liquid chromatography (C18, water / ACN) to obtain 508 mg of beige solid int-37, with a yield of 82.1%. 1 H NMR (500MHz, DMSO-d6) δ13.28(s,1H),10.20(s,1H),8.29(d,J=8.1Hz,1H),8.19–8.15(m,2H),8.11(d,J=3.7H z, 1H), 7.89 (d, J = 7.5Hz, 1H), 7.60 (t, J = 7.9Hz, 1H), 7.43 (d, J = 3.7Hz, 1H), 7.29 (d, J = 8.8Hz, 1H), 3.85 (s, 3H). MS(ESI)m / z:358.0[MH] - .

[0201] S2: Int-37 (489 mg, 1.36 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (42 mg, 0.54 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 4 h. After quenching the mixture in ice water, it was purified by preparative liquid chromatography (C18, water / ACN) to obtain 188 mg of yellow solid cpd-37, with a yield of 34.3%. 1HNMR(500MHz,DMSO-d6)δ8.38(d,J=13.6Hz,1H),8.24(d,J=13.5Hz,1H),8.18–8.14(m,2H),8.12(d,J=8.3Hz,1H),8.05( d,J=3.8Hz,1H),7.85(d,J=7.6Hz,1H),7.46(t,J=8.0Hz,1H),7.36(d,J=3.8Hz,1H),7.29(d,J=8.8Hz,1H),3.85(s,3H). MS(ESI)m / z:401.1[MH] - .

[0202] Example 38

[0203] S1: The preparation method is as described in Example 37S1. Indole-4-carboxaldehyde and methyl 3-(chlorosulfonyl)benzoate were used to separate and purify 58 mg of yellow solid int-38, with a yield of 9.8%. 1 H NMR (500MHz, DMSO-d6) δ11.58(s,1H),8.55(d,J=8.2Hz,1H),8.03(d,J=7.6Hz,1H),7.75(d,J=8.1Hz, 1H),7.54–7.51(m,2H),7.40(d,J=7.3Hz,1H),7.31–7.28(m,2H),6.36(t,J=2.5Hz,1H),2.69(s,3H).

[0204] S2: The preparation method is the same as in Example 37S2. Using int-38, 24 mg of yellow solid cpd-38 was obtained by separation and purification, with a yield of 41.8%. 1 H NMR (500MHz, DMSO-d6) δ8.42–8.35(m,2H),8.30–8.27(m,1H),8.24(d,J=13.6Hz,1H),8.22–8.19(m,1H),8.12(d,J=8.3H z, 1H), 8.10 (d, J = 3.8Hz, 1H), 7.87 (d, J = 7.7Hz, 1H), 7.75 (t, J = 7.9Hz, 1H), 7.47 (t, J = 8.0Hz, 1H), 7.41 (d, J = 3.8Hz, 1H). MS(ESI)m / z:371.0[MH] - .

[0205] Example 39

[0206] S1: The preparation method is as described in Example 37S1. Indole-4-carboxaldehyde and methyl 4-(chlorosulfonyl)benzoate were used to separate and purify 186 mg of grayish-white solid int-39, with a yield of 25.2%. 1 H NMR (500MHz, DMSO-d6) δ10.20(s,1H),8.28(d,J=8.3Hz,1H),8.17(d,J=8.6Hz,2H),8.12–8. 07(m,3H),7.90(d,J=7.4Hz,1H),7.60(t,J=7.9Hz,1H),7.46(d,J=3.7Hz,1H),3.83(s,3H). MS(ESI)m / z:344.0[M+H] + .

[0207] S2: The preparation method is as described in Example 37S2. Using int-39, 117 mg of yellow solid cpd-39 was obtained through separation and purification, with a yield of 57.1%. 1 H NMR (500MHz, DMSO-d6) δ8.38(d,J=13.6Hz,1H),8.23(d,J=13.6Hz,1H),8.16(d,J=8.2Hz,2H),8.12–8.08(m, 3H), 8.04 (d, J = 3.8Hz, 1H), 7.86 (d, J = 7.7Hz, 1H), 7.45 (t, J = 8.0Hz, 1H), 7.41 (d, J = 3.7Hz, 1H), 3.83 (s, 3H). MS(ESI)m / z:387.0[M+H] + .

[0208] Example 40

[0209] S1: The preparation method is as described in Example 37S1. Indole-4-carboxaldehyde and 5-chlorosulfonyl-2-methylbenzoic acid were used to separate and purify 372.5 mg of white solid int-40, with a yield of 28.0%. 1 H NMR(500MHz,DMSO-d6)δ10.20(s,1H),8.31–8.26(m,2H),8.11(s,1H),8.08(d,J=8.3Hz,1H),7.89 (d, J=7.6Hz, 1H), 7.60 (t, J=7.8Hz, 1H), 7.53 (d, J=8.3Hz, 1H), 7.44 (d, J=3.7Hz, 1H), 2.51 (s, 3H). MS(ESI)m / z:342.0[MH] - .

[0210] S2: Int-40 (368 mg, 1.07 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (33 mg, 0.43 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 2.5 h. After quenching the mixture in ice water, it was purified by preparative liquid chromatography (C18, water / ACN) to obtain 147 mg of yellow solid cpd-40, with a yield of 35.5%. 1 H NMR (500MHz, DMSO-d6) δ8.38(d,J=13.5Hz,1H),8.29(d,J=2.3Hz,1H),8.24(d,J=13.6Hz,1H),8.11(d,J=8.3Hz,1H),8. 09–8.04(m,2H),7.86(d,J=7.6Hz,1H),7.54(d,J=8.3Hz,1H),7.46(t,J=8.0Hz,1H),7.38(d,J=3.8Hz,1H),2.52(s,3H). MS(ESI)m / z:385.1[MH] - .

[0211] Example 41

[0212] S1: The preparation method is as described in Example 37S1. Indole-4-carboxaldehyde and 5-(chlorosulfonyl)-2,4-dimethylbenzoic acid were used to separate and purify 288 mg of brown solid int-41, with a yield of 22.0%. 1 H NMR (500MHz, DMSO-d6) δ10.23(s,1H),8.43(s,1H),8.12(d,J=3.7Hz,1H),7.95(d,J=8.3Hz,1H),7.89 (d, J = 7.4Hz, 1H), 7.55 (t, J = 7.9Hz, 1H), 7.46 (d, J = 3.6Hz, 1H), 7.37 (s, 1H), 2.52 (s, 3H), 2.41 (s, 3H). MS(ESI)m / z:356.0[MH] - .

[0213] S2: The preparation method is the same as in Example 37S2. Using int-41, 83 mg of light brownish-yellow solid cpd-41 was obtained by separation and purification, with a yield of 27.1%. 1H NMR(500MHz,DMSO-d6)δ8.45–8.39(m,2H),8.27(d,J=13.6Hz,1H),8.07(d,J=3.8Hz,1H), 7.85(d,J=7.7Hz,1H),7.77(d,J=8.3Hz,1H),7.43–7.37(m,3H),2.52(s,3H),2.41(s,3H). MS(ESI)m / z:399.1[MH] - .

[0214] Example 42

[0215] S1: The preparation method is as described in Example 37S1. Indole-4-carboxaldehyde and 3-(chlorosulfonyl)-4-methylbenzoic acid were used to separate and purify 84 mg of light brown solid int-42, with a yield of 11.4%. 1 H NMR (500MHz, DMSO-d6) δ13.54(s,1H),10.24(s,1H),8.41(d,J=1.7Hz,1H),8.15(d,J=3.7Hz,1H),8.12(dd,J=7.9,1. 8Hz, 1H), 7.99–7.95 (m, 1H), 7.91 (d, J = 7.3Hz, 1H), 7.60–7.54 (m, 2H), 7.48 (d, J = 3.7Hz, 1H), 3.51 (d, J = 17.9Hz, 3H). MS(ESI)m / z:342.1[MH] - .

[0216] S2: The preparation method is the same as in Example 37S2. Using int-42, 13.5 mg of yellow solid cpd-42 was obtained by separation and purification, with a yield of 16.0%. 1 H NMR(500MHz,DMSO-d6)δ8.43(d,J=13.7Hz,1H),8.41(d,J=1.8Hz,1H),8.30(d,J=7.1Hz,1H),8.13–8.10(m,2H) ,7.87(d,J=7.6Hz,1H),7.78(d,J=8.3Hz,1H),7.58(d,J=8.0Hz,1H),7.45–7.39(m,2H),3.51(d,J=19.9Hz,3H). MS(ESI)m / z:385.1[MH] - .

[0217] Example 43

[0218] S1: The preparation method is as described in Example 37S1. Indole-4-carboxaldehyde and 4-fluoro-2-methylbenzenesulfonyl chloride were used to separate and purify 589 mg of grayish-white solid int-43, with a yield of 70.4%. 1 H NMR(500MHz,DMSO-d6)δ10.23(s,1H),8.17–8.13(m,1H),8.12(d,J=3.7Hz,1H),8.02(d,J=8.3Hz,1H) ,7.89(d,J=7.4Hz,1H),7.54(t,J=7.9Hz,1H),7.45(d,J=3.7Hz,1H),7.36–7.31(m,2H),2.45(s,3H). MS(ESI)m / z:318.0[M+H] + .

[0219] S2: The preparation method is the same as in Example 37S2. Using int-43, 299 mg of yellow solid cpd-43 was obtained by separation and purification, with a yield of 46.4%. 1 H NMR(500MHz, DMSO-d6)δ8.42(d,J=13.6Hz,1H),8.27(d,J=13.6Hz,1H),8.16–8.12(m,1H),8.07(d,J=3.8 Hz,1H),7.86(d,J=7.6Hz,1H),7.83(d,J=8.3Hz,1H),7.41–7.37(m,2H),7.36–7.31(m,2H),2.45(s,3H). MS(ESI)m / z:361.0[M+H] + .

[0220] Example 44

[0221] S1: Indole-4-carboxaldehyde (250 mg, 1.72 mmol, 1.0 equivalent) was dissolved in DMF (3 mL). NaH (189 mg, 4.74 mmol, 2.5 equivalent, 60% in mineral oil) was added in portions under an ice-water bath, and stirring was continued for 0.5 h. Then, 4-chloro-5-(chlorosulfonyl)-2-hydroxybenzoic acid (250 mg, 0.92 mmol, 0.54 equivalent) was added, and the mixture was brought back to room temperature and stirred for another 3 h. After quenching the mixture with ice water, it was purified by preparative liquid chromatography (C18, water / ACN) to obtain 80 mg of dark brown solid int-44, with a yield of 22.8%. 1H NMR(500MHz,DMSO-d6)δ10.23(s,1H),8.62(s,1H),8.06(d,J=3.7Hz,1H),7.92–7 .87(m,2H),7.55(t,J=7.9Hz,1H),7.41(dd,J=3.8,0.8Hz,1H),7.13–7.09(m,1H). MS(ESI)m / z:378.0[MH] - .

[0222] S2: The preparation method is the same as in Example 37S2. Using int-44, 50 mg of reddish-brown oily substance cpd-44 was obtained by separation and purification, with a yield of 62.4%. 1 H NMR (500MHz, DMSO-d6) δ8.61(d,J=1.7Hz,1H),8.42(d,J=13.6Hz,1H),8.27(d,J=13.6Hz,1H),8.01(d,J=3.8Hz,1H) ,7.85(d,J=7.6Hz,1H),7.73(d,J=8.3Hz,1H),7.40(t,J=8.0Hz,1H),7.34(d,J=3.9Hz,1H),7.14(d,J=11.5Hz,1H). MS(ESI)m / z:421.0[MH] - .

[0223] Example 45

[0224] S1: K₂CO₃ (4.52 g, 19.9 mmol, 2.0 equivalents) was dissolved in acetone (20 mL), and salicylaldehyde (1.745 mL, 9.9 mmol, 1.0 equivalents) and benzyl bromide (2.954 mL, 24.9 mmol, 2.5 equivalents) were added. The mixture was stirred overnight at room temperature. The mixture was filtered, washed with dichloromethane, and the filtrate was collected and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 2.306 g of a colorless oil, int-45. 1 H NMR(500MHz,Chloroform-d)δ10.57(s,1H),7.87(dd,J=7.7,1.9Hz,1H),7.56–7. 52(m,1H),7.47–7.39(m,4H),7.38–7.34(m,1H),7.08–7.03(m,2H),5.20(s,2H). MS(ESI)m / z:213.11[M+H] + .

[0225] S2: Int-45 (400 mg, 1.88 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (58 mg, 0.75 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 4 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 359 mg of orange solid cpd-45, with a two-step yield of 81.5%. 1 H NMR(500MHz,Chloroform-d)δ8.19(d,J=13.6Hz,1H),7.86(d,J=13.6Hz,1H),7.48(dd,J =7.8,1.7Hz,1H),7.45–7.41(m,5H),7.40–7.36(m,1H),7.06–7.01(m,2H),5.22(s,2H). MS(ESI)m / z:254.0[MH] - .

[0226] Examples 46 and 47

[0227] S1: 4-Imidazole formaldehyde (200 mg, 2.08 mmol, 1.0 equivalent) was dissolved in DMF (3 mL), followed by the addition of 2-bromobenzyl bromide (285 μL, 2.08 mmol, 1.0 equivalent) and Na₂CO₃ (441 mg, 4.16 mmol, 2.0 equivalent). The mixture was stirred at 100 °C for 5.5 h. The mixture was quenched with water and extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 111 mg of brown solid int-46, yield 20.1%. 1 H NMR(500MHz,Chloroform-d)δ9.79(d,J=1.0Hz,1H),7.86(d,J=0.9Hz,1H),7.71(s,1H),7.62(dd, J=8.0,1.3Hz,1H),7.29–7.25(m,1H),7.23–7.18(m,1H),6.96(dd,J=7.6,1.8Hz,1H),5.63(s,2H). MS(ESI)m / z:264.91[M+H] + 181 mg of brown oily substance int-47, yield 32.8%. 1H NMR (500MHz, Chloroform-d) δ9.88 (s, 1H), 7.66–7.62 (m, 3H), 7.35 (t, J = 7.5Hz, 1H), 7.29–7.25 (m, 2H), 7.11 (dd, J = 7.6, 1.7Hz, 1H), 5.27 (s, 2H). MS(ESI)m / z:264.91[M+H] + .

[0228] S2-1: Int-46 (98 mg, 0.37 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (11 mg, 0.15 mmol, 0.4 equivalent) was added. The mixture was stirred at 100 °C for 4 h, and then ammonium acetate (28 mg, 0.37 mmol, 1.0 equivalent) was added, and stirring continued overnight. The mixture was quenched in ice water, extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative liquid chromatography (C18, water / ACN) to obtain 25 mg of brownish-yellow oily cpd-46, with a yield of 21.9%. 1 H NMR(500MHz,Chloroform-d)δ7.83(d,J=13.6Hz,1H),7.76(s,1H),7.70(s,1H),7.67(dd,J=7.8,1.4Hz,1H ),7.39(d,J=13.6Hz,1H),7.33–7.29(m,1H),7.28–7.24(m,1H),6.76(dd,J=7.6,1.8Hz,1H),5.32(s,2H). MS(ESI)m / z:307.91[M+H] + .

[0229] S2-2: Int-47 (459 mg, 1.73 mmol, 1.0 equivalent) was dissolved in CH3NO2 (3 mL), and ammonium acetate (133 mg, 1.73 mmol, 1.0 equivalent) was added. The mixture was stirred at 100 °C for 4 h. The mixture was quenched in ice water, extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative liquid chromatography (C18, water / ACN) to obtain 51 mg of brown oily cpd-47, with a yield of 9.6%. 1HNMR(500MHz,Chloroform-d)δ7.84(d,J=13.1Hz,1H),7.76(d,J=13.1Hz,1H),7.66–7.63(m,2H ),7.37–7.33(m,1H),7.30(s,1H),7.28–7.24(m,1H),7.08(dd,J=7.7,1.7Hz,1H),5.24(s,2H). MS(ESI)m / z:307.91[M+H] + .

[0230] Examples 48 and 49

[0231] S1: The preparation method is as described in Example 46S1. 4-Imidazole formaldehyde and benzyl bromide were used to separate and purify 140 mg of colorless solid int-48, with a yield of 25.4%. 1 H NMR (500MHz, Chloroform-d) δ9.74 (d, J = 1.0 Hz, 1H), 7.83 (d, J = 0.9 Hz, 1H), 7.71 (s, 1H), 7.48–7.45 (m, 2H), 7.09–7.06 (m, 2H), 5.46 (s, 2H). MS(ESI)m / z:264.02(M+H + 169 mg of colorless oily substance int-49, yield 30.6%. 1 H NMR (500MHz, Chloroform-d) δ9.86 (s, 1H), 7.60 (d, J = 1.4Hz, 1H), 7.58 (d, J = 1.3Hz, 1H), 7.54–7.51 (m, 2H), 7.08–7.05 (m, 2H), 5.12 (s, 2H). MS(ESI)m / z:264.02[M+H] + .

[0232] S2-1: The preparation method is the same as in Example 46S2. Using int-48, 73 mg of yellow solid cpd-48 was obtained by separation and purification, with a yield of 49.1%. 1 H NMR(500MHz,Chloroform-d)δ7.78(d,J=13.6Hz,1H),7.74(s,1H),7.67(s,1H ),7.54–7.51(m,2H),7.39(d,J=13.5Hz,1H),6.99–6.96(m,2H),5.21(s,2H). MS(ESI)m / z:307.88[M+H] + .

[0233] S2-2: The preparation method is the same as in Example 1S2. Using int-49, 13 mg of brown solid cpd-49 was obtained by separation and purification, with a yield of 7.3%. 1 H NMR(500MHz,Chloroform-d)δ7.83(d,J=13.1Hz,1H),7.76(d,J=13.1Hz,1H),7.6 0(s,1H),7.53(d,J=8.2Hz,2H),7.24(s,1H),7.06(d,J=8.4Hz,2H),5.10(s,2H). MS(ESI)m / z:307.91[M+H] + .

[0234] Examples 50 and 51

[0235] S1: The preparation method is as described in Example 46S1. 4-Imidazole formaldehyde and 3-bromobenzyl bromide were used to separate and purify 277 mg of colorless solid int-50, with a yield of 25.1%. 1 H NMR(500MHz,Chloroform-d)δ9.75(d,J=1.0Hz,1H),7.84(d,J=0.9Hz,1H),7.72(s,1H),7.4 5–7.43(m,1H),7.32(t,J=1.9Hz,1H),7.21(t,J=7.8Hz,1H),7.14–7.11(m,1H),5.49(s,2H). MS(ESI)m / z:264.02[M+H] + 247 mg of colorless solid int-51, yield 22.4%. 1 H NMR(500MHz,Chloroform-d)δ9.88(s,1H),7.63(d,J=1.3Hz,1H),7.61(d,J=1.3Hz,1H),7.51(d ,J=8.5Hz,1H),7.35(t,J=1.9Hz,1H),7.27(t,J=7.9Hz,1H),7.12(d,J=7.6Hz,1H),5.15(s,2H). MS(ESI)m / z:264.02[M+H] + .

[0236] S2-1: The preparation method is as described in Example 46S2. Using int-50, 57 mg of brown oily substance cpd-50 was obtained through separation and purification, with a yield of 17.7%. 1H NMR(500MHz,Chloroform-d)δ7.83(d,J=13.1Hz,1H),7.76(d,J=13.1Hz,1H),7.6 0(s,1H),7.53(d,J=8.2Hz,2H),7.24(s,1H),7.06(d,J=8.4Hz,2H),5.10(s,2H). MS(ESI)m / z:307.91[M+H] + .

[0237] S2-2: The preparation method is the same as in Example 1S2. Using int-51, 19 mg of brown solid cpd-51 was obtained by separation and purification, with a yield of 6.6%. 1 H NMR(500MHz,Chloroform-d)δ7.82(d,J=13.1Hz,1H),7.75(d,J=13.1Hz,1H),7.60(s,1H), 7.50(d,J=7.5Hz,1H),7.33(s,1H),7.28–7.24(m,2H),7.10(d,J=7.6Hz,1H),5.11(s,2H). MS(ESI)m / z:307.93[M+H] + .

[0238] Example 52

[0239] S1: PPh3 (262 mg, 1.00 mmol, 1.0 equivalent) and MgO (75 mg) were dissolved in DMF (5 mL). m-Phenoxybenzaldehyde (173 μL, 1.00 mmol, 1.0 equivalent) and methyl bromoacetate (95 μL, 1.00 mmol, 1.0 equivalent) were added, and the mixture was stirred at room temperature for 24 h. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, and the organic phases were combined and washed twice with water and once with saturated brine. The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 246 mg of a colorless oily substance, cpd-52, in 96.7% yield. 1 H NMR(500MHz,Chloroform-d)δ7.63(d,J=16.0Hz,1H),7.38–7.32(m,3H),7.27–7.22 (m,1H),7.17–7.12(m,2H),7.06–6.98(m,3H),6.38(d,J=15.8Hz,1H),3.79(s,3H). MS(ESI)m / z:255.1[M+H] + .

[0240] Example 53

[0241] S1: The preparation method is as described in Example 52S1. Using m-phenoxybenzaldehyde and bromoacetonitrile, 182 mg of colorless oily compound cpd-53 with E and Z configurations (E:Z = 1.00:0.95) was separated and purified, with a yield of 82.3%. 1 H NMR(500MHz,Chloroform-d)δ7.59(d,J=7.8Hz,1H,Z),7.43–7.32(m,8H),7.19–7. 13(m,3H),7.10–7.00(m,8H),5.83(d,J=16.6Hz,1H,E),5.46(d,J=12.1Hz,1H,Z). MS(ESI)m / z:222.1[M+H] + .

[0242] Example 54

[0243] S1: 173 μL m-phenoxybenzaldehyde (1.00 mmol, 1.0 equivalent), methyl cyanoacetate (88 μL, 1.00 mmol, 1.0 equivalent), and Et3N (14 μL, 0.10 mmol, 0.1 equivalent) were dissolved in NaCl (aq.) (3 mL) and reacted by microwave for 35 min. The mixture was extracted with water and ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 192 mg of white solid cpd-54, yield 68.7%. 1 H NMR(500MHz,Chloroform-d)δ8.19(s,1H),7.75(d,J=7.6Hz,1H),7.51(t,J=2.1Hz,1H),7.4 6(t,J=8.0Hz,1H),7.38(t,J=7.8Hz,2H),7.22–7.14(m,2H),7.08–7.02(m,2H),3.92(s,3H). MS(ESI)m / z:280.05[M+H] + .

[0244] Example 55

[0245] S2: The preparation method is the same as in Example 22S2. Salicylaldehyde was used to separate and purify 436 mg of yellow solid cpd-55, with a yield of 32.2%. 1H NMR (500MHz, DMSO-d6) δ10.88(s,1H),8.20(d,J=13.5Hz,1H),8.13(d,J=13.5Hz,1H),7. 69(d,J=7.7Hz,1H), 7.36(t,J=7.7Hz,1H), 6.98(d,J=8.3Hz,1H), 6.89(t,J=7.5Hz,1H). MS(ESI)m / z:166.0[M+H] + .

[0246] Example 56

[0247] S1: 2-Iodoaniline (1.160 g, 5.30 mmol, 1.0 equivalent) and m-hydroxybenzaldehyde (1.003 g, 8.21 mmol, 1.55 equivalent) were dissolved in MeOH (10 mL), and glacial acetic acid (455 μL, 7.94 mmol, 1.5 equivalent) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was placed in an ice bath, and sodium cyanoborohydride (380 mg, 6.36 mmol, 1.2 equivalent) was added. The mixture was then slowly brought to room temperature and stirred overnight. The mixture was quenched with saturated sodium bicarbonate solution and extracted with water and ethyl acetate. The combined organic phases were washed once with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 1.723 g of a pale yellow oil, int-56a, in 100.0% yield. 1 H NMR(500MHz,Chloroform-d)δ7.68(dd,J=7.8,1.5Hz,1H),7.22(t,J=7.8Hz,1H),7.17–7.13(m,1H),6.92(d,J=7.6Hz,1H),6. 83(s,1H),6.75(dd,J=8.1,2.6Hz,1H),6.51(dd,J=8.1,1.5Hz,1H),6.47–6.43(m,1H),5.09(s,1H),4.64(s,1H),4.36(s,2H). MS(ESI)m / z:326.0[M+H] + .

[0248] S2: Int-56a (325 mg, 1.00 mmol, 1.0 equivalent), Pd(OAc)2 (7 mg, 0.03 mmol, 0.03 equivalent), N-formylsaccharin (317 mg, 1.50 mmol, 1.5 equivalent), dppb (19 mg, 0.045 mmol, 0.045 equivalent), and Na2CO3 (158 mg, 1.50 mmol, 1.5 equivalent) were dissolved in DMF (5 mL). The mixture was microwaved in a flask, purged with argon, and then Et3SiH (206 μL, 1.30 mmol, 1.3 equivalent) was added. The mixture was stirred in an oil bath at 75 °C for 5 h. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and extracted with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by a Flash column chromatography system (ethyl acetate / petroleum ether) to obtain 157 mg of the product, a yellow solid int-56b, with a yield of 68.2%. 1 H NMR(500MHz,Chloroform-d)δ9.85(s,1H),8.74(s,1H),7.49(dd,J=7.8,1.7Hz,1H),7.36–7.32(m,1H),7.21(t,J=7.9H z,1H),6.90(d,J=7.6Hz,1H),6.81(s,1H),6.75–6.70(m,2H),6.62(d,J=8.4Hz,1H),5.09(s,1H),4.44(d,J=5.8Hz,2H). MS(ESI)m / z:228.1[M+H] + .

[0249] S3: The preparation method is the same as in Example 38S2. Using int-56b, 16 mg of reddish-brown oily substance cpd-56 was obtained by separation and purification, with a yield of 16.6%. 1 H NMR(500MHz,Chloroform-d)δ8.21(d,J=13.3Hz,1H),7.57(d,J=13.3Hz,1H),7.36(dd,J=7.7,1.5Hz,1H),7.32–7.28(m ,1H),7.24(t,J=7.8Hz,1H),6.92(d,J=7.5Hz,1H),6.85(s,1H),6.79–6.74(m,2H),6.69(d,J=8.4Hz,1H),4.38(s,2H). MS(ESI)m / z:271.1[M+H] + .

[0250] Example 57

[0251] S1: 4-Bromo-6-fluoroindazole (800 mg, 3.72 mmol, 1.0 eq), Pd(OAc)₂ (25 mg, 0.11 mmol, 0.03 eq), John Phos (50 mg, 0.17 mmol, 0.045 eq), and Na₂CO₃ (392 mg, 3.72 mmol, 1.0 eq) were dissolved in DMF (8 mL). Under argon protection, tert-butyl isocyanate (505 μL, 4.46 mmol, 1.2 eq) and Et₃SiH (1.767 mL, 11.16 mmol, 3.0 eq) were added, and the mixture was stirred in an oil bath at 65 °C for 8 h. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and extracted with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by a Flash column chromatography system (ethyl acetate / petroleum ether) to obtain 249 mg of off-white solid int-57, with a yield of 40.8%. 1 H NMR (500MHz, DMSO-d6) δ13.13(s,1H),8.08(s,1H),7.81–7.77(m,1H),7.31(d,J=9.8Hz,1H),7.01–6.96(m,1H). LC-MS(ESI):m / z 165.0[M+H] + .

[0252] S2: PPh3 (248 mg, 0.94 mmol, 1.0 equivalent) and MgO (75 mg) were dissolved in DMF (5 mL), and int-57 (155 mg, 0.94 mmol, 1.0 equivalent) and bromoacetonitrile (65 μL, 0.94 mmol, 1.0 equivalent) were added. The mixture was microwaved at 40 °C for 3 h. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and concentrated under reduced pressure to remove the ethyl acetate, yielding a residue. The residue was purified by preparative liquid chromatography (C18, water / ACN) to give 13 mg of the cis compound as a white solid, cpd-57a, in 7.4% yield. 1 H NMR (500MHz, DMSO-d6) δ 13.42 (s, 1H), 8.36 (s, 1H), 7.92 (d, J = 12.0Hz, 1H), 7.62 (d, J = 10.4Hz, 1H), 7.51 (d, J = 9.0Hz, 1H), 6.16 (d, J = 12.1Hz, 1H). LC-MS(ESI):m / z 187.95[M+H] + The trans compound, 16 mg, was a white solid, cpd-57b, in 9.1% yield. 1H NMR (500MHz, DMSO-d6) δ13.46(s,1H),8.53(s,1H),8.03(d,J=16.8Hz,1H),7.50–7.42(m,2H),6.72(d,J=16.7Hz,1H). LC-MS(ESI):m / z 187.95[M+H] + .

[0253] Example 58

[0254] S1: 2-Bromobenzaldehyde (100 mg, 0.54 mmol, 1.0 eq) was dissolved in DME (6 mL), and 2-(3-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (147 mg, 0.594 mmol, 1.1 eq), potassium carbonate (149 mg, 1.08 mmol, 2.0 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (132 mg, 0.16 mmol, 0.3 eq), and water (3 mL) were added. The mixture was exchanged with nitrogen three times, and then the sealed vial was microwaved at 90 °C for 2 h. The mixture was extracted with water and ethyl acetate, the combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 111 mg of yellow oily substance int-58, with a yield of 90.7%. 1 H NMR(500MHz,Chloroform-d)δ10.25(s,1H),7.86(dd,J=7.6,1.5Hz,1H),7.55–7.51(m,1H),7.41(t,J=7.5Hz,1H ),7.27(d,J=8.1Hz,1H),7.20(t,J=7.9Hz,1H),6.72–6.77(m,2H),6.70–6.68(m,1H),4.43(s,2H),3.76(s,3H).

[0255] S2: Int-58 (50 mg, 0.22 mmol, 1.0 eq) was dissolved in CH3NO2 (4 mL), and ammonium acetate (17 mg, 0.22 mmol, 1.0 eq) was added. The mixture was stirred at 100 °C for 5 h. The mixture was extracted with water and ethyl acetate, and the combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative liquid chromatography (C18, water / ACN) to obtain 44.5 mg of yellow solid cpd-58, with a yield of 75.1%. 1H NMR(500MHz,Chloroform-d)δ8.33(d,J=13.5Hz,1H),7.53(d,J=7.4Hz,1H),7.48–7.40(m,2H),7.34–7.29(m,2H),7. 21(t,J=7.9Hz,1H),6.75(dd,J=8.2,2.6Hz,1H),6.72(d,J=7.6Hz,1H),6.68–6.62(m,1H),4.13(s,2H),3.77(s,3H). LC-MS(ESI):m / z 269.99[M+H] + .

[0256] Example 59

[0257] S1: Int-16 (81 mg, 0.31 mmol, 1.0 equivalent) was dissolved in nitrobane (3 mL), and ammonium acetate (6 mg, 0.08 mmol, 0.25 equivalent) was added. The mixture was reacted in an oil bath at 115 °C for 3 h. The mixture was concentrated under reduced pressure to remove the nitrobane, yielding a residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 62 mg of yellow solid cpd-65, yield 62.7%. 1 H NMR (500MHz, DMSO-d6) δ11.98(s,1H),8.38(s,1H),7.66–7.61(m,1H),7.54(d,J=3.1Hz,1H),7.28–7.24(m,2H),6.57(d,J=3. 1Hz,1H),4.21(t,J=7.0Hz,2H),2.42(s,3H),2.17(t,J=7.3Hz,2H),1.80–1.72(m,2H),1.55–1.48(m,2H),1.27–1.24(m,2H). LC-MS(ESI):m / z 315.2[M–H] - .

[0258] Example 60

[0259] S1: 173 μL of m-phenoxybenzaldehyde (1.00 mmol, 1.0 equivalent) was dissolved in nitrobenzene (3 mL), and ammonium acetate (39 mg, 0.50 mmol, 0.50 equivalent) was added. The mixture was reacted overnight in an oil bath at 115 °C. The mixture was concentrated under reduced pressure to remove nitrobenzene, yielding a residue. The residue was pre-purified using a Flash column chromatography system, followed by preparative liquid chromatography (C18, water / ACN) to obtain 226 mg of a yellow oily substance, cpd-66, in 88.5% yield.1 H NMR (500MHz, Chloroform-d) δ 8.02 (s, 1H), 7.43–7.35 (m, 3H), 7.19–7.13 (m, 2H), 7.08–7.02 (m, 4H), 2.41 (d, J = 1.2Hz, 3H).

[0260] Example 61

[0261] S1: 7-azaindole-4-carboxaldehyde (100 mg, 0.68 mmol, 1.0 equivalent) was dissolved in DMF (3 mL), and K2CO3 (284 mg, 2.05 mmol, 3.0 equivalent) was added. The mixture was stirred at room temperature for 0.5 h, and then 3,4-dimethoxybenzyl bromide (190 mg, 0.82 mmol, 1.2 equivalent) was added. The mixture was stirred overnight at room temperature. The mixture was extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine. The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 48 mg of yellow solid int-67, yield 23.7%. 1 H NMR(500MHz,Chloroform-d)δ10.34(d,J=1.2Hz,1H),8.56(d,J=4.8Hz,1H),7.50(dd,J=4.8,1.2Hz,1H) ,7.41(d,J=3.5Hz,1H),7.12(d,J=3.4Hz,1H),6.82–6.77(m,3H),5.47(s,2H),3.83(s,3H),3.78(s,3H). LC-MS(ESI):m / z 296.96[M+H] + .

[0262] S2: The preparation method is the same as in Example 1S2. Using int-67, 23 mg of orange-yellow solid cpd-67 was obtained by separation and purification, with a yield of 41.8%. 1 H NMR (500MHz, DMSO-d6) δ8.40–8.33(m,3H),7.85(d,J=3.6Hz,1H),7.59(d,J=5.0Hz,1H),7.03(d,J=2.0Hz,1H),6 .99(d,J=3.6Hz,1H),6.85(d,J=8.2Hz,1H),6.75(dd,J=8.2,2.0Hz,1H),5.43(s,2H),3.70(s,3H),3.69(s,3H). LC-MS(ESI):m / z 340.04[M+H] + .

[0263] Example 62

[0264] S1: In a 50 mL dry single-necked flask, 4-indolecarboxaldehyde (95.41 mg, 0.627 mmol, 1.0 equivalent) and 3-methoxybenzoic acid (100 mg, 0.627 mmol, 1.0 equivalent) were dissolved in 10 mL of acetonitrile and stirred until homogeneous. Then, 2,6-dimethylpyridine (4.36 μL, 0.032 mmol, 2.0 equivalent), 4-dimethylaminopyridine (7.04 mg, 0.06 mmol, 0.1 equivalent), and di-tert-butyl dicarbonate (0.377 mL, 1.64 mmol, 2.5 equivalent) were added. The mixture was reacted overnight at 30 °C, and the reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with water and ethyl acetate. The organic phases were combined, washed twice with water, washed once with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by a Flash column chromatography system (ethyl acetate / petroleum ether) to obtain 60 mg of yellow solid int-68, with a yield of 32.6%. 1 H NMR(500MHz,Chloroform-d)δ10.29(s,1H),8.73(dt,J=8.3,1.0Hz,1H),7.83(dd,J=7.4,1.0Hz,1H),7.58(dd,J=8.3,7.4Hz, 1H),7.54(d,J=3.7Hz,1H),7.48-7.46(m,2H),7.34-7.31(m,1H),7.31-7.30(m,1H),7.21-7.17(m,1H),3.90(s,J=1.9Hz,3H). MS(ESI)m / z:208.1[M+H] + .

[0265] S2: The preparation method is the same as in Example 1S2. Using int-68, 23 mg of orange-yellow solid cpd-68 was separated and purified, with a yield of 43.3%. 1 H NMR (500MHz, DMSO-d6) δ8.47(d,J=13.6Hz,1H),8.44(d,J=8.2Hz,1H),8.31(d,J=13.6Hz,1H),7.93(d,J= 7.7Hz,1H),7.61(d,J=3.8Hz,1H),7.56-7.47(m,2H),7.34-7.32(m,2H),7.29-7.26(m,2H),3.84(s,3H). MS(ESI)m / z:323.0[M+H] + .

[0266] Example 63

[0267] S1: 5 g of m-hydroxybenzoic acid (36.20 mmol, 1.0 equivalent) was dissolved in acetic anhydride (30 mL), and 4-dimethylaminopyridine (442.26 mg, 3.62 mmol, 1.0 equivalent) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. Ice water was added to the mixture to quench the reaction, resulting in the precipitation of a large amount of solid. The residue was collected by filtration and dried to obtain 3 g of white solid int-69-1, which was used without further purification.

[0268] S2: Preparation method as described in Example 62S1, using int-69-1 to separate 60 mg of yellow solid int-69-2, two-step yield 32.6%. MS (ESI) m / z: 308.01 [M+H] + .

[0269] S3: The preparation method is the same as in Example 62S1. 23 mg of orange-yellow solid cpd-69 was obtained by separation and purification, with a yield of 43.3%. 1 H NMR (500MHz, DMSO-d6) δ10.02(s,1H),8.47(d,J=13.6Hz,1H),8.41(d,J=8.2Hz,1H),8.31(d,J=13.6Hz,1H),7.92(d,J=7.6Hz,1H),7.62(d,J =3.8Hz,1H),7.48(t,J=8.0Hz,1H),7.42(t,J=8.0Hz,1H),7.27(d,J=3.7Hz,1H),7.20-7.16(m,1H),7.14(t,J=2.1Hz,1H),7.12-7.08(m,1H). MS(ESI)m / z:308.99[M+H] + .

[0270] Example 64

[0271] S1: 4-Methoxyformylphenylboronic acid pinacol ester (2 g, 7.63 mmol, 1.0 equivalent), 4-iodopyridine (1.56 g, 7.63 mmol, 1.0 equivalent), DPPF palladium dichloride (558.32 mg, 0.763 mmol, 0.1 equivalent), and sodium carbonate (43 g, 22.89 mmol, 3.0 equivalent) were dissolved in 24 mL of 1,4-dioxane and 6 mL of water. The mixture was reacted overnight at 80 °C under argon protection. After the reaction was completed by TLC monitoring, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 1.5 g of a brownish-yellow oil (int 70-1), yield 92.1%. MS (ESI) m / z: 214.1 [M+H] + .

[0272] S2: Add int-70-1 to a 50 mL dry single-necked flask, dissolve and stir in 5 mL methanol until homogeneous, add 5 mL of 3M sodium hydroxide aqueous solution, react at 50 °C for 2 h, monitor the reaction by TLC. After the reaction is complete, add 3M hydrochloric acid to adjust the pH to 5, evaporate the solvent and filter to obtain a yellowish-white solid int-70-2. This can be used without further purification.

[0273] S3: The preparation method is the same as in Example 62S1, using int-70-2 to separate and purify to obtain 60 mg of orange-yellow solid int-70-3, with a two-step yield of 32.6%. MS (ESI) m / z: 327.1 [M+H] + .

[0274] S4: The preparation method is the same as in Example 1S2. 37 mg of orange-yellow solid cpd-70 was obtained by separation and purification, with a yield of 47.3%. 1 H NMR (500MHz, DMSO-d6) δ8.70-8.66(m,2H),8.51-8.46(m,2H),8.32(d,J=13.6Hz,1H),8.21-8.13(m,2H),7.95(d,J=7 .7Hz,1H),7.91-7.87(m,1H),7.82-7.76(m,3H),7.67(d,J=3.9Hz,1H),7.51(t,J=8.0Hz,1H),7.28(d,J=3.8Hz,1H). MS(ESI):m / z 370.09[M+H] + .

[0275] Example 65

[0276] S1: Preparation method as described in Example 1S1, using 4-indolecarboxaldehyde and 3-bromobenzyl bromide, to separate and purify 154 mg of a pale yellow solid, int-71, with a yield of 61.2%. MS (ESI): m / z 313.91 [M+H] + .

[0277] S2: The preparation method is the same as in Example 1S2. Using int-71, 50 mg of yellow solid cpd-71 was separated and purified, with a yield of 47.2%. 1 H NMR (500MHz, DMSO-d6) δ8.41(d,J=13.6Hz,1H),8.22(d,J=13.6Hz,1H),7.80(d,J=3.2Hz,1H),7.74(d,J=8.2Hz,1H),7 .65(d,J=7.4Hz,1H),7.49-7.43(m,2H),7.30-7.22(m,2H),7.19(d,J=7.7Hz,1H),6.99(d,J=3.2Hz,1H),5.53(s,2H). MS(ESI):m / z 358.94[M+H] + .

[0278] Example 66

[0279] S1: Preparation method as described in Example 1S1, using 4-indolecarboxaldehyde and 3-bromobenzyl bromide, to separate and purify 154 mg of a pale yellow solid int-72-1, yield 61.2%. MS (ESI): m / z 313.91 [M+H] + .

[0280] S2: 4-(N,N-dimethylamino)phenylboronic acid pinacol ester (78.6 mg, 0.318 mmol, 1.0 equivalent), int-72-1 (100 mg, 0.318 mmol, 1.0 equivalent), DPPF palladium dichloride (23.2 mg, 0.031 mmol, 0.1 equivalent), and potassium carbonate (131.97 mg, 0.954 mmol, 3.0 equivalent) were dissolved in 24 mL of 1,4-dioxane and 6 mL of water. The mixture was reacted overnight at 80 °C under argon protection. After the reaction was completed by TLC monitoring, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 71 mg of yellow solid int 72-2, yield 65.2%. MS (ESI) m / z: 355.1 [M+H] + .

[0281] S3: The preparation method is the same as in Example 1S2. Using int-72, 41 mg of yellow solid cpd-72 was obtained by separation and purification, with a yield of 55.2%. 1 H NMR (500MHz, DMSO-d6) δ8.40(d,J=13.6Hz,1H),8.20(d,J=13.6Hz,1H),7.83(d,J=3.2Hz,1H),7.78(d,J=8.2Hz,1H),7.62(d,J=7.4Hz,1H),7.44-7 .41(m,2H),7.31(t,J=7.7Hz,1H),7.22(t,J=7.8Hz,1H),7.05(d,J=7.6Hz ,1H),6.97(d,J=3.2Hz,1H),6.80-6.74(m,2H),5.54(s,2H),2.92(s,6H). MS(ESI):m / z 398.09[M+H] + .

[0282] Example 67

[0283] S1: Preparation method as described in Example 1S1, using 4-indolecarboxaldehyde and 3-bromobenzyl bromide, to separate and purify 154 mg of a pale yellow solid int-73-1, yield 61.2%. MS (ESI): m / z 313.91 [M+H] + .

[0284] S2: The preparation method is as described in Example 66S2. Using 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)-1H-pyrazole, 195 mg of a pale yellow solid, int-73-1, was obtained after separation and purification, with a yield of 75.2%. MS (ESI) m / z: 344.1 [M+H] + .

[0285] S3: The preparation method is the same as in Example 1S2. Using int-73-2, 107 mg of yellow solid cpd-73 was obtained by separation and purification, with a yield of 75.2%. 1H NMR(500MHz,DMSO-d6)δ8.41(d,J=13.6Hz,1H),8.24-8.16(m,2H),7.83-7.79(m,2H),7.77(d,J=8.2Hz,1H),7.66-7.60(m ,2H),7.49-7.45(m,1H),7.29-7.20(m,2H),6.99-6.92(m,2H),5.49(s,2H),4.54-4.46(m,1H),1.45(s,3H),1.43(s,3H). MS(ESI):m / z 387.11[M+H] + .

[0286] Example 68

[0287] S1: Preparation method as described in Example 1S1, using 4-indolecarboxaldehyde and 4-bromo-2-bromomethyl-1-methoxybenzene, 164 mg of a pale yellow solid int-74-1 was obtained after separation and purification, with a yield of 85.2%. MS (ESI): m / z 343.93 [M+H] + .

[0288] S2: Preparation method as described in Example 66S2, using int-74-1, yielded 109 mg of yellow solid after separation and purification, with a yield of 65.2%. MS (ESI): m / z 384.1 [M+H] + .

[0289] S3: The preparation method is the same as in Example 1S2. Using int-74-2, 63 mg of yellow solid cpd-74 was obtained by separation and purification, with a yield of 55.2%. 1 H NMR(500MHz,DMSO-d6)δ8.41(d,J=13.6Hz,1H),8.20(d,J=13.6Hz,1H),7.78( d,J=8.2Hz,1H),7.73(d,J=3.2Hz,1H),7.63(d,J=7.5Hz,1H),7.47(dd,J=8.6, 2.4Hz,1H),7.29-7.23(m,3H),7.16(d,J=2.4Hz,1H),7.07(d,J=8.6Hz,1H),6. 95(d,J=3.2Hz,1H),6.74-6.71(m,2H),5.47(s,2H),3.88(s,3H),2.89(s,6H). MS(ESI): m / z 428.05 [M+H] + .

[0290] Example 69

[0291] S1: 3-Hydroxybenzyl alcohol (500 mg, 4.03 mmol, 1.0 equivalent) was dissolved in 20 mL of acetonitrile, followed by the addition of potassium carbonate (556 mg, 4.03 mmol, 1.0 equivalent) and 2-bromoacetamide (500 mg, 4.03 mmol, 1.0 equivalent). The mixture was stirred thoroughly and reacted overnight at room temperature. The solvent was removed by vacuum distillation, the product was dissolved in water, extracted with ethyl acetate, and the combined organic phases were dried. The residue was purified by Flash column chromatography (dichloromethane / methanol + 0.1% triethylamine) to obtain 350 mg of white solid int-75-1, yield 49.3%. MS (ESI) m / z: 363.01 [2M+H] + .

[0292] S2: Dissolve int-75-1 (75 mg, 0.413 mmol, 1.0 equivalent) in 5 mL of ultra-dry dichloromethane and stir until homogeneous under ice bath conditions. Dissolve phosphorus tribromide (12.84 μL, 0.136 mmol, 1.0 equivalent) in 3 mL of ultra-dry dichloromethane and add it slowly dropwise under ice bath conditions. After the addition is complete, remove the ice bath and react at room temperature for 2 h. Quench the mixture with water, extract with water and dichloromethane, dry to Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Separate and purify the residue using a preparative Flash column chromatography (dichloromethane / methanol + 0.1% triethylamine) to obtain 25 mg of white solid int-75-2, yield 24.7%. MS (ESI) m / z: 243.90 [M+H] + .

[0293] S3: Preparation method was the same as in Example 1S1, using 4-indolecarboxaldehyde and int-75-2. 20 mg of a pale yellow solid, int-75-3, was obtained after separation and purification, with a yield of 80.2%. MS (ESI): m / z 308.98 [M+H] + .

[0294] S4: The preparation method is the same as in Example 1S2. Using int-75-3, 12 mg of yellow solid cpd-75 was obtained by separation and purification, with a yield of 60.5%. 1H NMR (500MHz, DMSO-d6) δ8.41(d,J=13.6Hz,1H),8.21(d,J=13.6Hz,1H),7.76(d,J=3.2Hz,1H),7.71(d,J=8.2Hz,1H),7.63(d,J=7.4Hz,1H),7.5 0(s,1H),7.35(s,1H),7.25-7.19(m,2H),6.99-6.95(m,1H),6.89-6.85 (m,1H),6.85-6.80(m,1H),6.80-6.77(m,1H),5.47(s,2H),4.37(s,2H). MS(ESI):m / z 352.01[M+H] + .

[0295] Example 70

[0296] S1: Ligustrazine (1 g, 7.34 mmol, 1.0 equivalent) was dissolved in 20 mL of water, and KMnO4 (2.3 g, 14.68 mmol, 2.0 equivalent) was added in portions. The mixture was heated to 50 °C and reacted for 10 h. After cooling to room temperature, the mixture was extracted twice with ethyl acetate. The organic phase was discarded, and the aqueous phase was adjusted to pH 3 with 3 M hydrochloric acid. The aqueous phase was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 500 mg of a yellowish-white solid, int-76-1, was obtained, with a yield of 50.3%. MS (ESI) m / z: 167.0 [M+H] + .

[0297] S2: Preparation method was the same as in Example 1S2, using 7-azaindole-4-carboxaldehyde. 30.2 mg of a yellow solid, int-76-2, was obtained after separation and purification, with a yield of 43.5%. MS (ESI): m / z 190.15 [M+H] + .

[0298] S3: The preparation method is the same as in Example 62S1. Using int-76-1 and int-76-2, 20 mg of yellow solid cpd-76 was separated and purified to obtain a yield of 48.2%. 1 H NMR (500MHz, DMSO-d6) δ8.43-8.41(m,2H),8.21(d,J=4.2Hz,1H),8.15(d,J=5.1Hz,1H ),7.73(d,J=5.2Hz,1H),7.45(d,J=4.2Hz,1H),2.58(s,3H),2.42(s,3H),2.40(s,3H). MS(ESI)m / z:338.02[M+H] + .

[0299] Example 71

[0300] S1: Add tetramethylpyrazine (300 mg, 2.20 mmol, 1.0 equivalent) to a single-necked flask and dissolve it in 20 mL of CCl4. 4 N-bromosuccinimide (395.96 mg, 2.20 mmol, 1.0 equivalent) and catalytic amounts of benzoyl peroxide (26.68 mg, 0.11 mmol, 1.0 equivalent) were added in portions, and the mixture was heated to 80 °C for 6 h. After the reaction was complete, appropriate amounts of water and ethyl acetate were added for extraction, and the mixture was dried over anhydrous Na₂SO₄ and the solvent was evaporated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate) to give 70 mg of a clear oil, int-77-1, in yield 14.7%. MS (ESI) m / z: 214.91 [M+H] + .

[0301] S2: The preparation method is the same as in Example 61S1. 7-azaindole-4-carboxaldehyde and int-77-1 were used to separate and purify 20 mg of light yellow solid int-77-2, with a yield of 80.2%. 1 H NMR(500MHz,Chloroform-d)δ10.35(s,1H),8.56(d,J=4.9Hz,1H),7.53(d,J=3.6Hz,1H),7.5 0(d,J=4.9Hz,1H),7.12(d,J=3.6Hz,1H),5.65(s,2H),2.50(s,3H),2.49(s,3H),2.48(s,3H). MS(ESI):m / z208.9[M+H] + .

[0302] S3: The preparation method is the same as in Example 1S2. Using int-77-2, 45 mg of yellow solid cpd-77 was obtained by separation and purification, with a yield of 46.9%. 1 H NMR(500MHz,DMSO-d6)δ8.41-8.36(m,2H),8.34(d,J=5.0Hz,1H),7.72(d,J=3.6Hz,1H),7.58 (d,J=5.1Hz,1H),7.00(d,J=3.6Hz,1H),5.61(s,2H),2.52(s,3H),2.40(s,3H),2.31(s,3H).

[0303] Example 72

[0304] S1: The preparation method was as described in Example 69S1. After separation and purification, 350 mg of a white solid, int-78-1, was obtained, with a yield of 49.3%. MS (ESI) m / z: 363.01 [2M+H] + .

[0305] S2: The preparation method was the same as in Example 69S2. After separation and purification, 25 mg of a white solid, int-78-2, was obtained, with a yield of 24.7%. MS (ESI) m / z: 243.90 [M+H] + .

[0306] S3: The preparation method is the same as in Example 1S1. 7-azaindole-4-carboxaldehyde and int-78-2 were used to separate and purify 35 mg of light yellow solid int-78-3, with a yield of 63.5%. 1 H NMR (500MHz, DMSO-d6) δ10.37(s,1H),8.57(d,J=4.8Hz,1H),7.94(d,J=3.5Hz,1H),7.68(d,J=4.8Hz,1H),7.50(s,1H),7 .35(s,1H),7.23(t,J=7.9Hz,1H),7.07(d,J=3.5Hz,1H),6.90-6.86(m,1H),6.85-6.79(m,2H),5.54(s,2H),4.37(s,2H). MS(ESI):m / z 309.98[M+H] + .

[0307] S4: The preparation method is the same as in Example 1S2. Using int-78-3, 45 mg of yellow solid cpd-78 was separated and purified to obtain a yield of 60.5%. 1 H NMR (500MHz, DMSO-d6) δ8.42-8.35(m,3H),7.87(d,J=3.6Hz,1H),7.61(d,J=5.0Hz,1H),7.50(s,1H),7.35(s,1H ),7.23(t,J=7.9Hz,1H),7.03(d,J=3.6Hz,1H),6.88-6.87(m,1H),6.84-6.80(m,2H),5.51(s,2H),4.37(s,2H). MS(ESI):m / z 353.03[M+H] + .

[0308] Example 73

[0309] S1: The preparation method was the same as in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3-bromobenzyl bromide. After separation and purification, 154 mg of a pale yellow solid, int-79-1, was obtained, with a yield of 61.2%. MS (ESI): m / z 315.1 [M+H] + .

[0310] S2: The preparation method is the same as in Example 66S2. Using 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)-1H-pyrazole and int-79-1, 195 mg of a pale yellow solid, int-79-2, was obtained after separation and purification, with a yield of 75.2%. MS (ESI) m / z: 345.1 [M+H] + .

[0311] S3: The preparation method is the same as in Example 1S2. Using int-79-2, 78 mg of yellow solid cpd-79 was obtained by separation and purification, with a yield of 40.5%. 1 H NMR (500MHz, DMSO-d6) δ8.41-8.34(m,3H),8.18-8.16(m,1H),7.90(d,J=3.6Hz,1H),7.81-7.78(m,1H),7.61-7.58(m,2H),7.48-7.4 3(m,1H),7.25(t,J=7.7Hz,1H),7.03(d,J=3.6Hz,1H),6.98-6.94(m,1H),5.53(s,2H),4.52-4.45(m,1H),1.44(s,3H),1.42(s,3H). MS(ESI):m / z 388.1[M+H] + .

[0312] Example 74

[0313] S1: Preparation method as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3-bromobenzyl bromide, to separate and purify 154 mg of a pale yellow solid int-80-1, yield 61.2%. MS (ESI): m / z 315.1 [M+H] + .

[0314] S2: The preparation method is as described in Example 66S2. Using 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester and int-80-1, 155 mg of a pale yellow solid, int-80-2, was obtained after separation and purification, with a yield of 86.1%. MS (ESI) m / z: 375.1 [M+H]. + .

[0315] S3: The preparation method is the same as in Example 1S2. Using int-80-2, 100 mg of yellow solid cpd-80 was obtained by separation and purification, with a yield of 64.5%. 1 H NMR (500MHz, DMSO-d6) δ8.41-8.34(m,4H),7.91(d,J=3.6Hz,1H),7.89(s,1H),7.67-7.64(m,1H),7.61(d,J=5.0Hz,1H),7.51(d,J=7.7Hz,1H),7 .27(t,J=7.7Hz,1H),7.03(d,J=3.5Hz,1H),6.98(d,J=7.7Hz,1H),5.53 (s, 2H), 3.46-3.40 (m, 1H), 1.61 (d, J = 6.0Hz, 3H), 1.03 (t, J = 7.0Hz, 3H). MS(ESI)m / z:418.1[M+H] + .

[0316] Example 75

[0317] S1: The preparation method was as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3-bromobenzyl bromide. 154 mg of a pale yellow solid, int-81-1, was obtained after separation and purification, with a yield of 61.2%. MS (ESI): m / z 315.1 [M+H] + .

[0318] S2: The preparation method is the same as in Example 66S2. Using 2-furanboric acid and int-81-1, 60 mg of a pale yellow solid, int-81-2, was obtained after separation and purification, with a yield of 86.1%. MS (ESI) m / z: 303.1 [M+H]. + .

[0319] S3: The preparation method is the same as in Example 1S2. Using int-81-2, 35 mg of yellow solid cpd-81 was separated and purified to obtain a yield of 58.3%. 1 H NMR (500MHz, DMSO-d6) δ8.42-8.35(m,3H),7.92(d,J=3.6Hz,1H),7.73(m,1H),7.65-7.57(m,3H),7.35(t,J =7.7Hz, 1H), 7.13 (d, J = 7.7Hz, 1H), 7.04 (d, J = 3.6Hz, 1H), 6.90 (d, J = 3.4Hz, 1H), 6.58 (m, 1H), 5.58 (s, 2H). MS(ESI)m / z:346.12[M+H] + .

[0320] Example 76

[0321] S1: The preparation method was as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3-bromobenzyl bromide. 154 mg of a pale yellow solid, int-82-1, was obtained after separation and purification, with a yield of 61.2%. MS (ESI): m / z 315.1 [M+H] + .

[0322] S2: The preparation method is as described in Example 66S2. Using 1-methyl-1H-pyrazole-4-boric acid and int-82-1, 60 mg of a pale yellow solid, int-82-2, was obtained after separation and purification, with a yield of 63.2%. MS (ESI) m / z: 317.1 [M+H] + .

[0323] S3: The preparation method is the same as in Example 1S2. Using int-82-2, 32 mg of yellow solid cpd-82 was obtained by separation and purification, with a yield of 53.3%. 1 H NMR (500MHz, DMSO-d6) δ8.42-8.34(m,3H),8.08-8.05(m,1H),7.91(d,J=3.5Hz,1H),7.80-7.78(m,1H),7.61(d,J=5.0Hz,1H),7 .58-7.54(m,1H),7.47-7.42(m,1H),7.26(t,J=7.7Hz,1H),7.03(d,J=3.5Hz,1H),7.01-6.97(m,1H),5.54(s,2H),3.85(s,3H). MS(ESI)m / z:360.08[M+H] + .

[0324] Examples 77-90

[0325] general formula:

[0326] S1: The preparation method is as described in Example 66S1. 7-azaindole-4-carboxaldehyde and 3-bromopropyne were used to separate and purify 597 mg of a light yellow solid, int-Alkynyl, with a yield of 54.3%. 1 H NMR(500MHz,DMSO-d6)δ10.36(s,1H),8.58(d,J=4.8Hz,1H),7.91(d,J=3.5Hz,1H),7.6 9(d,J=4.8Hz,1H), 7.07(d,J=3.5Hz,1H), 5.21(d,J=2.6Hz,2H), 3.40(t,J=2.6Hz,1H). MS(ESI):m / z185.1[M+H] + .

[0327] S2: Add different substituted primary amine compounds (0.20 mmol, 1.5-2.0 equivalents), potassium bicarbonate (3 M in water, 0.80 mmol, 4.0 equivalents), FSO2N3 (350 mM in MTBE / DMSO, 0.20 mmol, 1.5-2.0 equivalents), and DMSO (2 mL) to a 10 mL round-bottom flask. Stir at room temperature for 6-12 h to generate an azide intermediate. Then, add buffer salt (1.0 mL) to the reaction solution and stir for 15 minutes. Add alkyne (0.10 mmol, 1.0 equivalent) and CuSO4 / THPTA (1 mL, 5 mM in water). Continue stirring the reaction solution overnight at room temperature. After the reaction is complete as monitored by MS, the reaction solution is separated and purified by Biotage column chromatography (FA in water / acetonitrile). Collect the fractions and concentrate to obtain the target product. Preparation of the buffer: Dissolve sodium ascorbate (1.240 g), disodium hydrogen phosphate (3.500 g), and citric acid (2.435 g) in 50 mL of water. Reaction yield: 10.0%-98.7%

[0328] S3: The preparation method is the same as in Example 1S2. Using int-trizaole, cpd-77-90 was isolated and purified in yields of 13.2%-53.3%. The specific compound structures and characterization data are shown in Table 2 below.

[0329] Table 2. Compound structures and characterization data from Examples 77-90

[0330] Example 91

[0331] S1: Preparation method as described in Example 66S1, using 4-indolecarboxaldehyde and (1-bromoethyl)benzene, yielded 56 mg of a pale yellow oily substance, int-97, with a yield of 46.8%. MS (ESI): m / z 280.9 [M+H] + .

[0332] S2: The preparation method is the same as in Example 1S2. Using int-97, 25 mg of yellow oily substance cpd-97 was obtained by separation and purification, with a yield of 25.2%. 1H NMR(500MHz,Chloroform-d)δ8.41(d,J=4.9Hz,1H),8.29(d,J=13.7Hz,1H),7.84(d,J=13.7Hz,1H),7.48(d,J=3.7Hz,1H),7.32- 7.26(m,2H),7.23(d,J=4.9Hz,1H),6.70(d,J=3.7Hz,1H),4.90(q,J=6.5Hz,1H),3.84(s,3H),1.52(d,J=6.5Hz,2H).MS(ESI):m / z 323.8[M+H] + .

[0333] Example 92

[0334] S1: The preparation method was as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3-bromobenzyl bromide. 154 mg of a pale yellow solid, int-82-1, was obtained after separation and purification, with a yield of 61.2%. MS (ESI): m / z 315.1 [M+H] + .

[0335] S2: The preparation method is as described in Example 66S2. Using 1-methyl-1H-pyrazole-4-boric acid and int-82-1, 60 mg of a pale yellow solid, int-82-2, was obtained after separation and purification, with a yield of 63.2%. MS (ESI) m / z: 317.1 [M+H]. + .

[0336] S3: The preparation method is the same as in Example 1S2. Using int-82-2, 32 mg of yellow solid int-98-3 was obtained by separation and purification, with a yield of 53.3%.

[0337] S4: Int-98-3 (34 mg, 0.094 mmol, 1.0 equivalent) was dissolved in 2 mL of N,N-dimethylformamide, and 20 μL of acetic acid was added. After stirring at room temperature for 30 minutes, N-chlorosuccinimide (12.6 mg, 0.094 mmol, 1.5 equivalent) was added to the system. The reaction was carried out at 70 °C for 7 h, and the reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with water and ethyl acetate. The combined organic phases were washed twice with water and once with saturated brine. The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 15 mg of yellow solid cpd-98, with a yield of 40.2%. 1H NMR(500MHz,Chloroform-d)δ9.09(d,J=13.6Hz,1H),8.45(d,J=5.0Hz,1H),7.73(s,1H),7.70(d,J=13.6Hz,1H),7.60(s,1H), 7.43(d,J=7.7Hz,1H),7.39(s,1H),7.37-7.32(m,2H),7.30(d,J=5.3Hz,1H),7.10(d,J=7.6Hz,1H),5.51(s,2H),3.95(s,3H). MS(ESI):m / z 394.08[M+H] + .

[0338] Example 93

[0339] S1: The preparation method was as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3-bromobenzyl bromide. 154 mg of a pale yellow solid, int-82-1, was obtained after separation and purification, with a yield of 61.2%. MS (ESI): m / z 315.1 [M+H] + .

[0340] S2: Dissolve int-99-1 (50 mg, 0.158 mmol, 1.0 equivalent) in 5 mL of acetonitrile, add 1 mL of acetic acid, add selectflour (84 mg, 0.237 mmol, 1.5 equivalent), purge with nitrogen, and react overnight at 70 °C. Monitor the reaction by TLC. After the reaction is complete, extract the mixture with water and ethyl acetate. Combine the organic phases, wash twice with water, wash once with saturated brine, dry over Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Separate and purify the residue by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 25 mg of yellow solid int-99-2, yield 40.2%. 1 H NMR(500MHz,Chloroform-d)δ10.65(d,J=2.6Hz,1H),8.56(d,J=4.9Hz,1H),7.66(d,J=4.9Hz, 1H),7.46(d,J=8.0Hz,1H),7.40(s,1H),7.24–7.20(m,2H),7.16(d,J=7.7Hz,1H),5.50(s,2H). 19 F NMR (471MHz, Chloroform-d) δ-163.16. MS(ESI)m / z:333.0[M+H] + .

[0341] S3: The preparation method is the same as in Example 66S2. Using 1-methyl-1H-pyrazole-4-boric acid and int-99-2, 15 mg of a pale yellow solid, int-99-3, was obtained after separation and purification, with a yield of 63.2%. MS (ESI) m / z: 335.1 [M+H]. + .

[0342] S4: The preparation method is the same as in Example 1S2. Using int-99-3, 10 mg of yellow solid int-98-3 was obtained by separation and purification, with a yield of 50.3%. 1 H NMR(500MHz,Chloroform-d)δ8.46(d,J=5.0Hz,1H),8.40(d,J=13.8Hz,1H),7.88(d,J=13.8Hz,1H),7.73(s,1H),7.59(s,1H),7.42(d,J=7. 6Hz,1H),7.37(s,1H),7.34(t,J=7.6Hz,1H),7.27(d,J=5.0Hz,1H),7.17(d,J=2.1Hz,1H),7.08(d,J=7.7Hz,1H),5.51(s,2H),3.95(s,3H). 19 F NMR (471MHz, Chloroform-d) δ-166.05. MS(ESI):m / z 377.13[M+H] + .

[0343] Example 94

[0344] S1: Ligustrazine (300 mg, 2.20 mmol, 1.0 equivalent) was dissolved in 20 mL of CCl4 in a single-necked flask. N-bromosuccinimide (395.96 mg, 2.20 mmol, 1.0 equivalent) and a catalytic amount of benzoyl peroxide (26.68 mg, 0.11 mmol, 1.0 equivalent) were added in portions. The mixture was heated to 80 °C and reacted for 6 h. After the reaction was complete, appropriate amounts of water and ethyl acetate were added for extraction. The mixture was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate) to obtain 70 mg of a clear oil, int-100-1, with a yield of 14.7%. MS (ESI) m / z: 214.91 [M+H] + .

[0345] S2: The preparation method is the same as in Example 61S1. 7-azaindole-4-carboxaldehyde and int-100-1 were used to separate and purify 20 mg of light yellow solid int-100-2, with a yield of 80.2%. 1H NMR(500MHz,Chloroform-d)δ10.35(s,1H),8.56(d,J=4.9Hz,1H),7.53(d,J=3.6Hz,1H),7.5 0(d,J=4.9Hz,1H),7.12(d,J=3.6Hz,1H),5.65(s,2H),2.50(s,3H),2.49(s,3H),2.48(s,3H). MS(ESI):m / z 208.9[M+H] + .

[0346] S3: The preparation method is the same as in Example 92S4. Using int-100-2, 206 mg of light yellow solid int-100-3 was obtained by separation and purification, with a yield of 91.7%. 1 H NMR(500MHz,Chloroform-d)δ11.19(s,1H),8.53(d,J=4.9Hz,1H),7.68(d,J= 4.9Hz,1H),7.53(s,1H),5.63(s,2H),2.56(s,3H),2.51(s,3H),2.50(s,3H). MS(ESI)m / z 314.97[M+H] + .

[0347] S4: The preparation method is the same as in Example 1S2. Using int-100-3, 60 mg of yellow solid cpd-100 was obtained by separation and purification, with a yield of 25.2%. 1 H NMR(500MHz,Chloroform-d)δ9.08(d,J=13.7Hz,1H),8.42(d,J=5.1Hz,1H),7.69(d,J=13.6Hz ,1H),7.45(s,1H),7.27(d,J=5.1Hz,1H),5.59(s,2H),2.55(s,3H),2.51(s,3H),2.51(s,3H). MS(ESI):m / z 358.03[M+H] + .

[0348] Example 95

[0349] S1: Preparation method is the same as in Example 1S2, using indole-6-carboxaldehyde. 526 mg of reddish-brown solid int-101-1 was obtained after separation and purification, with a yield of 40.6%. MS (ESI): m / z 189.1 [M+H] + .

[0350] S2: Int-101-1 (150 mg, 0.80 mmol, 1.0 equivalent) was dissolved in 5 mL of acetonitrile solution. 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (172 mg, 0.80 mmol, 1.0 equivalent), 4-dimethylaminopyridine N-oxide (3 mg, 0.02 mmol, 0.026 equivalent), triethylamine (222 μL, 1.59 mmol, 2.0 equivalent), and di-tert-butyl dicarbonate (261 mg, 1.0 equivalent) were added, and the mixture was stirred overnight at room temperature. The resulting reaction mixture was then concentrated under vacuum, and the residue was purified by Flash column chromatography (petroleum ether / ethyl acetate) to give 146 mg of yellow solid int-101-2, yield 47.5%. 1 H NMR(500MHz,Chloroform-d)δ8.76(d,J=1.6Hz,1H),8.13(d,J=13.6Hz,1H),7.69(d,J=13.6Hz,1H),7.65-7. 57(m,2H),7.47(dd,J=8.2,1.6Hz,1H),6.76-6.70(m,1H),3.91-3.47(m,6H),2.49-2.26(m,2H),1.48(s,9H). LC-MS(ESI):m / z 286.1[M-99] + .

[0351] S3: Using int-101-2 (24 mg, 0.06 mmol), dissolved in 0.4 mL of 1,4-dioxane in 4 M hydrochloric acid and 1 mL of dichloromethane. The mixture was stirred at room temperature for 0.5 h. The resulting reaction mixture was filtered to give 16 mg of a yellow solid, yield 79.9%. 1 H NMR(500MHz,DMSO-d6)δ8.70(s,1H),8.28-8.23(m,1H),8.20-8.16(m,2H),7.85-7.81(m,1H),7.76-7.72(m,1H), 6.93-6.88(m,1H),4.25-4.18(m,1H),3.64-3.55(m,3H),3.31-3.24(m,2H),2.48-2.40(m,1H),2.19-2.11(m,1H). MS(ESI):m / z 286.1[M+H] + .

[0352] Example 96

[0353] S1: Preparation method as described in Example 1S1, using indole-6-carboxaldehyde and tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate, 141 mg of a clear oily substance int-102-1 was obtained after separation and purification, with a yield of 43.3%. MS (ESI): m / z 329.1 [M+H] + .

[0354] S2: Preparation method was the same as in Example 1S2. Using int-102-1, 151 mg of yellow solid cpd-102 was obtained through separation and purification, with a yield of 94.7%. MS (ESI): m / z 272.0 [M+H] + .

[0355] Example 97

[0356] S1: Preparation method as described in Example 1S1, using indole-6-carboxaldehyde and N-Boc-bromoethylamine, yielded 207 mg of a white solid int-103-1 after separation and purification, with a yield of 34.7%. MS (ESI): m / z 289.1 [M+H] + .

[0357] S2: The preparation method is the same as in Example 1S2. Using int-103-1, 178 mg of yellow solid cpd-103 was obtained by separation and purification, with a yield of 74.8%. 1 H NMR(500MHz,DMSO-d6)δ8.29-8.19(m,2H),8.15(d,J=5.1Hz,1H),7.65-7.57(m,2H),7.49(dd,J=8.3,1.5Hz,1H),6.54(d,J=3.0Hz,1H),4.32-4.1 7(m,2H),3.40-3.22(m,2H),3.21-3.13(m,1H),3.04-2.95(m,1H),2.79- 2.65(m,1H),1.82-1.73(m,1H),1.66-1.54(m,1H),1.36(d,J=9.2Hz,9H). MS(ESI):m / z 272.0[M-99] + .

[0358] Examples 98-99

[0359] S1-1: Palladium acetate (6 mg, 0.02 mmol, 0.03 equivalents), 3-bromocarbazole (200 mg, 0.81 mmol, 1.0 equivalents), 1,4-bis(diphenylphosphine)butane (23.2 mg, 0.031 mmol, 0.1 equivalents), N-formylsaccharin (257 mg, 1.22 mmol, 1.5 equivalents), and sodium carbonate (131.97 mg, 0.954 mmol, 3.0 equivalents) were added to a 50 mL dry single-necked flask. The mixture was dissolved in ultradry N,N-dimethylformamide, and the mixture was heated to 70 °C under argon protection for 10 h. The reaction was monitored by TLC until completion. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 23 mg of a yellow solid, int-104-2, in yield 13.9%. 1 H NMR (500MHz, DMSO-d6) δ11.69(s,1H),10.12(s,1H),8.31(d,J=8.0Hz,1H),8.23(d,J=7.9Hz,1H) ,8.05(s,1H),7.71(d,J=8.0Hz,1H),7.58(d,J=8.2Hz,1H),7.52-7.47(m,1H),7.26-7.20(m,1H). LC-MS(ESI):m / z 196.0[M+H] + .

[0360] S1-2: The preparation method is the same as in Example 1S2. Using int-104-1, 19 mg of yellow solid cpd-104 was obtained by separation and purification, with a yield of 74.8%. 1 H NMR(500MHz,DMSO-d6)δ11.59(s,1H),8.36-8.28(m,2H),8.22(d,J=8.2Hz,1H),8.18(d,J=7.9Hz,1H),7.98 (d,J=1.4Hz,1H),7.69(dd,J=8.3,1.5Hz,1H),7.52(d,J=8.1Hz,1H),7.48-7.43(m,1H),7.22-7.18(m,1H). LC-MS(ESI):m / z 239.1[M+H] + .

[0361] S2-1: Preparation method is as described in Example 98S1-1, using 4-bromocarbazole. 42 mg of a yellow solid was obtained after separation and purification. MS (ESI): m / z 196.0 [M+H] + .

[0362] S2-2: The preparation method is the same as in Example 1S2. Using int-105-1, 33 mg of yellow solid cpd-104 was obtained by separation and purification, with a yield of 64.4%. 1 H NMR (500MHz, DMSO-d6) δ11.66(s,1H),8.97(d,J=13.3Hz,1H),8.31(d,J=13.3Hz,1H),8.14(d,J =8.0Hz,1H),7.71-7.67(m,2H),7.58(d,J=8.1Hz,1H),7.51-7.45(m,2H),7.28(t,J=7.5Hz,1H). LC-MS(ESI):m / z 239.1[M+H] + .

[0363] Example 100

[0364] S1: 4-Indolecarbaldehyde (1.450 g, 10.00 mmol, 1.0 equivalent) was dissolved in acetic acid. Sodium cyanoborohydride (1.495 mg, 6.36 mmol, 1.2 equivalent) was added in portions at 0 °C, and the reaction was allowed to proceed for 1.5 h at room temperature. The reaction mixture was adjusted to neutral with 2 M sodium hydroxide aqueous solution, and extracted with appropriate amounts of water and ethyl acetate. The extract was dried over anhydrous Na₂SO₄, and the solvent was evaporated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate) to give 1.14 g of a colorless oil, int-106-1, in yield 32.7%. 1 H NMR (500MHz, Chloroform-d) δ7.56-7.52 (m, 2H), 7.42-7.35 (m, 3H), 6.46 (d, J = 2.3Hz, 1H), 2.66 (d, J = 2.3Hz, 1H), 2.11 (s, 3H). MS(ESI):m / z 150.1[M+H] + .

[0365] S2: 1-Phenylacetyl-1-ol (1.450 g, 10.00 mmol, 1.0 equivalent), acetic acid (1.260 mL, 1.10 mmol, 10.0 equivalent), and 4-dimethylaminopyridine (244 mg, 2.19 mmol, 0.1 equivalent) were dissolved in 10 mL of ultra-dry dichloromethane and stirred at 0 °C until homogeneous. N,N'-dicyclohexylcarbodiimide (4.540 g, 22.00 mmol, 1.1 equivalent) was added, and the reaction was carried out at room temperature for 24 h. The solvent was evaporated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate) to give 1.14 g of colorless oil int-106-2, yield 32.7%. 1H NMR (500MHz, DMSO-d6) δ6.86(t,J=7.6Hz,1H),6.54(d,J=7.6Hz,1H),6.38(d,J=7.8Hz,1H),5.38( s, 1H), 4.91 (t, J = 5.6Hz, 1H), 4.36 (d, J = 5.6Hz, 2H), 3.39 (t, J = 8.5Hz, 2H), 2.86 (t, J = 8.5Hz, 2H). LC-MS(ESI):m / z 150.1[M+H] + .

[0366] S3: Int-106-2 (1.028 g, 6.89 mmol, 1.0 equivalent) and cuprous chloride (68 mg, 0.69 mmol, 0.1 equivalent) were dissolved in 10 mL of ultra-dry tetrahydrofuran and stirred at room temperature for 5 min. N,N-diisopropylethylamine (1.319 mL, 7.58 mmol, 1.1 equivalent) was added, and stirring was continued at room temperature for another 5 min. Int-106-1 (1.308 g, 7.51 mmol, 1.09 equivalent) was added, and the mixture was stirred at 66 °C for 6 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 1.25 g of yellow solid int-106-4, yield 69.1%. 1 H NMR(500MHz,Chloroform-d)δ7.68-7.63(m,2H),7.42-7.38(m,2H),7.36-7.31(m,1H),7.13(t,J=7.7Hz,1H),6.79(d,J=7.6Hz,1H),6.61(d,J=7 .9Hz,1H),5.63(d,J=2.3Hz,1H),4.62(s,2H),3.42-3.34(m,1H),3.21-3 .14(m,1H),3.06-2.98(m,1H),2.96-2.84(m,1H),2.41(d,J=2.3Hz,1H). MS(ESI):m / z 263.9[M+H] + .

[0367] S4: Int-106-4 (600 mg, 2.28 mmol, 1.0 equivalent) was dissolved in 20 mL of ultra-dry dichloromethane. 2,3-Dichloro-5,6-dicyanobenzoquinone (776 mg, 3.42 mmol, 1.5 equivalent) was added at -30 °C. The reaction was carried out at -30 °C for 0.5 h, then transferred to 0 °C and reacted for another 1.5 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to obtain 195 mg of yellow solid int-106-4, yield 32.6%. 1 H NMR(500MHz,Chloroform-d)δ10.24(s,1H),7.63(dd,J=7.3,0.9Hz,1H),7.61(d,J=8.3Hz,1H),7.52(d ,J=3.2Hz,1H),7.36(d,J=3.3Hz,1H),7.35-7.28(m,6H),6.46(d,J=2.5Hz,1H),2.75(d,J=2.5Hz,1H). LC-MS(ESI):m / z 259.9[M+H] + .

[0368] S5: The preparation method is the same as in Example 1S2. Using int-106-4, 87 mg of yellow oily substance cpd-104 was obtained by separation and purification, with a yield of 93.3%. 1 H NMR(500MHz,Chloroform-d)δ8.39(d,J=13.6Hz,1H),7.79(d,J=13.7Hz,1H),7.52-7.48(m,2H),7.41- 7.32 (m, 6H), 7.22 (t, J = 7.9Hz, 1H), 6.78 (d, J = 3.4Hz, 1H), 6.44 (d, J = 2.5Hz, 1H), 2.76 (d, J = 2.5Hz, 1H). LC-MS(ESI):m / z 302.8[M+H] + .

[0369] Examples 101-102

[0370] S1: Under ice bath conditions, piperic acid (2 g, 12.04 mmol, 1.0 equivalent) was dissolved in 20 mL of ultradry tetrahydrofuran solution, and sodium borohydride (1.822 g, 48.16 mmol, 4.0 equivalent) was added in portions. After 30 minutes, trifluoroboroethyl ether (4.457 mL, 36.12 mmol, 3.0 equivalent) was added dropwise to the mixture under ice bath conditions. The reaction mixture was stirred at room temperature for 3 h, and then quenched by adding ice water. The resulting reaction mixture was extracted with ethyl acetate (×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and removed under vacuum to give a colorless oily substance int-107-1 at 2.072 g. 1 H NMR (500MHz, Chloroform-d) δ6.87 (s, 1H), 6.81 (d, J = 7.9 Hz, 2H), 6.78 (d, J = 7.8 Hz, 2H), 5.95 (s, 2H), 4.58 (s, 2H), 1.68 (s, 1H).

[0371] S2: Dissolve 2.072 g of int-107-1 in 20 mL of ultra-dry acetonitrile, and add manganese dioxide (5.233 g, 60.19 mmol, 5.0 equivalent). Stir the mixture at 80 °C for 2.5 h. Then filter the resulting reaction mixture through diatomaceous earth and remove it under vacuum to obtain a residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 1.491 g of yellow solid int-107-2, with a two-step yield of 82.5%. 1 H NMR (500MHz, Chloroform-d) δ9.81 (s, 1H), 7.41 (dd, J = 7.9, 1.6 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.07 (s, 2H). MS(ESI):m / z 151.1[M+H] + .

[0372] S3: Under ice bath conditions, int-107-2 (2.078 g, 13.84 mmol, 1.0 equivalent) was dissolved in 20 mL of ultra-dry tetrahydrofuran solution, and magnesium acetylene bromide (35.987 mL, 17.99 mmol, 1.3 equivalent) was added. The reaction was stirred at room temperature for 3 h. The reaction was then quenched by adding saturated ammonium chloride solution. Tetrahydrofuran was removed under reduced pressure, and the aqueous phase was extracted with water and ethyl acetate (×3). The combined organic layers were washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and removed under vacuum. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 2.327 g of yellow oil int-107-3, yield 95.5%. 1H NMR(500MHz,Chloroform-d)δ7.07-7.03(m,1H),7.02-6.99(m,1H),6.79(d,J=8.0 Hz, 1H), 5.97 (s, 2H), 5.38-5.35 (m, 1H), 2.66 (d, J = 2.3Hz, 1H), 2.35-2.27 (m, 1H).

[0373] S4: Int-107-3 (1 g, 5.68 mmol, 1.0 equivalent), N,N'-dicyclohexylcarbodiimide (1.288 g, 6.24 mmol, 1.1 equivalent), and 4-dimethylaminopyridine (69 mg, 0.57 mmol, 0.1 equivalent) were dissolved in 10 mL of ultradry dichloromethane, and acetic acid (715 μL, 12.49 mmol, 2.2 equivalent) was added. The mixture was stirred at room temperature for 3 h, and then the reaction mixture was removed under vacuum. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 988 mg of yellow oil int-107-4, in yield 79.8%. 1 H NMR (500MHz, Chloroform-d) δ7.04-6.99 (m, 2H), 6.79 (d, J = 7.9Hz, 1H), 6.36 (d, J = 2.3Hz, 1H), 5.98 (s, 2H), 2.64 (d, J = 2.3Hz, 1H), 2.10 (s, 3H).

[0374] S5: The preparation method is the same as in Example 100S1.

[0375] S6: The preparation method is the same as in Example 100S3. 831 mg of yellow oily substance int-107-5 was obtained by separation and purification, with a yield of 79.4%. 1 H NMR(500MHz,Chloroform-d)δ7.16-7.09(m,3H),6.81(d,J=8.0Hz,1H),6.78(d,J=7.6Hz,1H),6.58(d,J=7.8Hz,1H),5.97(s,2H),5. 51(d,J=2.3Hz,1H),4.61(s,2H),3.38-3.31(m,1H),3.22-3.16(m,1H),3.04-2.97(m,1H),2.93-2.85(m,1H),2.39(d,J=2.3Hz,1H). MS(ESI):m / z 308.1[M+H] + .

[0376] The preparation method of S7 is as described in Example 100S4. 118 mg of yellow oily substance int-107-6 was obtained by separation and purification, with a yield of 26.5%.1 H NMR(500MHz,Chloroform-d)δ10.24(s,1H),7.65-7.62(m,2H),7.51(d,J=3.3Hz,1H),7.35(d,J=3.0Hz,1H),7.34-7.30(m,1H ), 6.89-6.86 (m, 1H), 6.80 (d, J = 1.9Hz, 1H), 6.76 (d, J = 8.0Hz, 1H), 6.36 (d, J = 2.5Hz, 1H), 5.95 (s, 2H), 2.74 (d, J = 2.5Hz, 1H). MS(ESI):m / z 304.1[M+H] + .

[0377] S8: The preparation method is the same as in Example 1S2. Using int-107-7, 97 mg of yellow solid cpd-107 was obtained by separation and purification, with a yield of 75.2%. 1 H NMR(500MHz,Chloroform-d)δ8.38(d,J=13.7Hz,1H),7.78(d,J=13.7Hz,1H),7.51(d,J=8.2Hz,1H),7.49(d,J=3.3Hz,1H),7.39(d,J =7.4Hz,1H),7.23(t,J=7.8Hz,1H),6.90–6.88(m,1H),6.81–6.76(m,3H),6.34(d,J=2.5Hz,1H),5.96(s,2H),2.76(d,J=2.5Hz,1H). MS(ESI):m / z 347.1[M+H] + .

[0378] S9: The preparation method is the same as in Example 92S4. Using int-107-7, 59 mg of yellow solid int-107-8 was obtained by separation and purification, with a yield of 62.3%. 1 H NMR(500MHz,Chloroform-d)δ11.21(s,1H),7.90(d,J=7.5Hz,1H),7.62(d,J=8.2Hz,1H),7.43(s,1H),7.32(t,J=7.9Hz,1H),6.9 1(dd,J=8.1,1.9Hz,1H),6.82(d,J=1.9Hz,1H),6.79(d,J=8.0Hz,1H),6.30(d,J=2.5Hz,1H),5.97(s,2H),2.77(d,J=2.5Hz,1H). MS(ESI):m / z 338.0[M+H] + .

[0379] S10: The preparation method is the same as in Example 1S2. Using int-107-8, 41 mg of yellow solid cpd-108 was obtained by separation and purification, with a yield of 66.5%. 1 H NMR(500MHz,Chloroform-d)δ9.29(d,J=13.5Hz,1H),7.59(d,J=13.5Hz,1H),7.50(d,J=8.3Hz,1H),7.43(d,J=7.5Hz,1H),7.38(s,1H),7.27–7 .23(m,2H),6.91(dd,J=8.0,1.9Hz,1H),6.81(d,J=1.9Hz,1H),6.79(d,J=8.1Hz,1H),6.27(d,J=2.5Hz,1H),5.97(s,2H),2.76(d,J=2.4Hz,1H). MS(ESI):m / z 381.0[M+H] + .

[0380] Example 103

[0381] S1: The preparation method is as described in Examples 101-102 and S3. Using int-109-1, 100 mg of yellow solid int-109-2 was obtained by separation and purification, with a yield of 66.5%. 1 H NMR(500MHz,DMSO-d6)δ7.04(d,J=2.0Hz,1H),6.99(dd,J=8.2,2.0Hz,1H),6.93(d,J=8.2Hz,1H),5 .93(d,J=6.0Hz,1H),5.28(dd,J=6.0,2.3Hz,1H),3.76(s,3H),3.75(s,3H),3.46(d,J=2.2Hz,1H). MS(ESI)m / z:174.98[M-OH] + .

[0382] S2: The preparation method is as described in Examples 101-102 and S4. Using int-109-2, 41 mg of yellow solid int-109-3 was obtained by separation and purification, with a yield of 46.5%. 1 H NMR (500MHz, Chloroform-d) δ7.12 (dd, J=8.3, 2.1Hz, 1H), 7.08 (d, J=2.1Hz, 1H), 6.88 (d, J=8. 3Hz,1H),6.42(d,J=2.3Hz,1H),3.93(s,3H),3.90(s,3H),2.68(d,J=2.3Hz,1H),2.12(s,3H).

[0383] S3: The preparation method is the same as in Example 100S1.

[0384] S4: The preparation method was the same as in Example 100S3. After separation and purification, 31 mg of a yellow solid int-109-5 was obtained, with a yield of 82.4%. MS (ESI) m / z: 324.1 [M+H] + .

[0385] S5: The preparation method is the same as in Example 100S4. 15 mg of yellow oily substance int-109-6 was obtained by separation and purification, with a yield of 53.2%.

[0386] S6: The preparation method is the same as in Example 1S2. Using int-109-6, 10 mg of yellow solid cpd-109 was separated and purified to obtain 10 mg of cpd-109, with a yield of 66.5%. 1 H NMR(500MHz,Chloroform-d)δ8.41(d,J=13.7Hz,1H),7.81(d,J=13.6Hz,1H),7. 57–7.54(m,1H),7.47(d,J=3.4Hz,1H),7.42(dd,J=7.4,0.8Hz,1H),7.28–7.24(m ,1H),6.97–6.94(m,1H),6.90(d,J=2.2Hz,1H),6.86(d,J=8.3Hz,1H),6.80–6.7 7(m,1H),6.41(d,J=2.5Hz,1H),3.89(s,3H),3.83(s,3H),2.77(d,J=2.5Hz,1H). MS(ESI): m / z 363.1 [M+H] + .

[0387] Examples 104-107

[0388] S1: The preparation method of intermediate int-10-4a is as described in Example 100S1.

[0389] S2: K3[Fe(CN)6] (0.57 equivalents) and K4[Fe(CN)6] (0.43 equivalents) were dissolved in 0.2 mL of acetic acid and 3 mL of water. Benzaldehyde derivatives (1.0 equivalents) and int-10-4a (1.0 equivalents) were dissolved in ethyl acetate and added to the system. The mixture was then stirred at 80 °C for 6 h in the dark. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with water and ethyl acetate (×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and removed under vacuum. The residue was purified by a Flash column chromatography (ethyl acetate / petroleum ether) to obtain yellow oily substances int-110b, int-111-2b, and int-113-4b, with yields ranging from 39.4% to 73.5%.

[0390] S3: The preparation method is the same as in Example 100S4. Yellow oily substances int-110c, int-111c, and int-113c were obtained by separation and purification, with a yield of 38.0-42.3%.

[0391] S4: Preparation method of indole ring with 3-position substituted chlorine atom, Example 92S4. Int-112c and int-114c were obtained by separation and purification, with yields of 66.2%-71.9%.

[0392] S5: The preparation method is the same as in Example 1, S2. The target compounds cpd110-cpd114 were isolated and purified, with yields of 40.1%-44.9%.

[0393] cpd-110: 1 H NMR(500MHz,Chloroform-d)δ8.36(d,J=13.7Hz,1H),7.76(d,J=13.7Hz,1H),7.50–7.43 (m,5H),7.41–7.37(m,2H),7.33–7.28(m,2H),6.84(dd,J=3.4,0.7Hz,1H),6.57(s,1H). MS(ESI):m / z 304.1[M+H] + .

[0394] cpd-111: 1H NMR(500MHz,Chloroform-d)δ8.37(d,J=13.7Hz,1H),7.76(d,J=13.7Hz,1H),7.49(d,J=8.3Hz,1H),7.45(d,J=7.4Hz,1H),7.34–7.29(m,2H),6.97(dd,J=8.2,1.4Hz,1H),6.86(d,J=8.1Hz,1H),6.84(d,J=3.3Hz,1H),6.76(d,J=1.4Hz,1H),6.44(s,1H),6.03–6.00(m,2H)。MS(ESI):m / z 348.1[M+H] + 。

[0395] cpd-112: 1 H NMR(500MHz,Chloroform-d)δ9.25(d,J=13.5Hz,1H),7.59(d,J=13.5Hz,1H),7.52–7.47(m,2H),7.34(t,J=7.9Hz,1H),7.18(s,1H),7.00(dd,J=8.1,1.6Hz,1H),6.88(d,J=8.1Hz,1H),6.79(d,J=1.6Hz,1H),6.38(s,1H),6.04–6.03(m,2H)。MS(ESI):m / z 381.1[M+H] + 。

[0396] cpd-113: 1 H NMR(500MHz,Chloroform-d)δ8.28(d,J=13.6Hz,1H),7.68(d,J=13.6Hz,1H),7.52(d,J=8.2Hz,1H),7.39(d,J=7.5Hz,1H),7.30–7.23(m,2H),7.00(dd,J=8.4,2.3Hz,1H),6.88(d,J=8.4Hz,1H),6.84(d,J=2.3Hz,1H),6.76(d,J=3.4Hz,1H),6.53(s,1H),3.86(s,3H),3.79(s,3H),2.02(s,1H)。MS(ESI):m / z 364.1[M+H] + 。

[0397] cpd-114: 1H NMR(500MHz,Chloroform-d)δ9.27(d,J=13.5Hz,1H),7.61(d,J=13.5Hz,1H),7.56(d,J=8.3Hz,1H),7.52(d,J=7.5Hz,1H),7.37(t,J=8. 0Hz,1H),7.14(s,1H),7.07(dd,J=8.3,2.3Hz,1H),6.96(d,J=8.4Hz,1H),6.89(d,J=2.3Hz,1H),6.45(s,1H),3.94(s,3H),3.88(s,3H). MS(ESI)m / z:398.1[M+H] + .

[0398] Example 108

[0399] S1: Preparation method as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3,4-dimethoxybenzyl bromide, to separate and purify 150 mg of a pale yellow solid, int-115, with a yield of 54.3%. MS (ESI) m / z: 296.99 [M+H] + .

[0400] S2: Int-115 (80 mg, 0.269 mmol, 1.0 equivalent) was dissolved in 3 mL of saturated sodium chloride solution, and methyl 2-cyanoacetate (23.82 μL, 0.269 mmol, 1.0 equivalent) and triethylamine (3.7 μL, 0.027 mmol, 0.1 equivalent) were added. The mixture was stirred in a microwave at 85 °C for 50 min. The resulting reaction mixture was then extracted with water and ethyl acetate (×3), and the combined organic layers were washed with water and saturated brine and dried over anhydrous Na₂SO₄. The solvent was removed by filtration and vacuum. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 50 mg of a yellow solid in 62.5% yield. 1 H NMR(500MHz,Chloroform-d)δ8.71(s,1H),8.52(d,J=5.2Hz,1H),8.01(d,J=5.2Hz,1H),7.39(d,J=3.6Hz,1H ), 6.84 (d, J = 7.3Hz, 3H), 6.71 (d, J = 3.6Hz, 1H), 5.48 (s, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 3.83 (d, J = 3.5Hz, 3H). MS(ESI)m / z:378.07[M+H] + .

[0401] Example 109

[0402] S1: Preparation method as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3-bromobenzyl bromide, to separate and purify 154 mg of a pale yellow solid int-116-1, yield 61.2%. MS (ESI): m / z 315.1 [M+H] + .

[0403] S2: The preparation method is as described in Example 66S2. Using 1-methyl-1H-pyrazole-4-boric acid and int-116-1, 60 mg of a pale yellow solid, int-116-2, was obtained after separation and purification, with a yield of 63.2%. MS (ESI) m / z: 317.1 [M+H]. + .

[0404] S3: The preparation method is the same as in Example 108S2. Using int-116-2, 50 mg of yellow solid cpd-116 was separated and purified to obtain cpd-116, with a yield of 69.2%. 1 H NMR(500MHz,Chloroform-d)δ8.72(s,1H),8.53(d,J=5.1Hz,1H),8.01(d,J=5.1Hz,1H),7.73(s,1H),7.58(s,1H),7.44-7.39(m,2H),7.37-7.35 (m,1H),7.35-7.30(m,1H),7.09(dt,J=7.8,1.4Hz,1H),6.73(d,J=3.6H z,1H),5.57(s,2H),4.01(s,3H),3.94(s,3H).MS(ESI)m / z:398.11[M+H] + .

[0405] Example 110

[0406] S1: Preparation method as described in Example 66S1, using 7-azaindole-4-carboxaldehyde and 3,4-dimethoxybenzyl bromide, to separate and purify 150 mg of a pale yellow solid, int-117, with a yield of 54.3%. MS (ESI) m / z: 296.99 [M+H] + .

[0407] S2: 2-(triphenyl-15-phosphononitrile)acetonitrile (208.8 mg, 0.693 mmol, 1.3 equivalents) was added to a solution of int-117 (158 mg, 0.533 mmol, 1.0 equivalents) in 9 mL of tetrahydrofuran. The mixture was stirred overnight at 60 °C. The resulting reaction mixture was then extracted with water and ethyl acetate (×3). The combined organic layers were washed with water and saturated brine and dried over anhydrous Na₂SO₄. The mixture was filtered, and the solvent was removed under vacuum. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to a yellow solid in 53.1% yield. 1 H NMR(500MHz,Chloroform-d)δ8.41(d,J=5.0Hz,1H),7.74(d,J=16.7Hz,1H),7.35(d,J=3.6Hz,1H),7.19-7.14( m,1H),6.86-6.78(m,3H),6.63(d,J=3.6Hz,1H),6.22(d,J=16.7Hz,1H),5.47(s,2H),3.87(s,3H),3.82(s,3H). MS(ESI)m / z:320.1[M+H] + .

[0408] Example 111

[0409] S1: The preparation method is as described in Example 52S1. 2-Naphthaldehyde was used to separate and purify 108 mg of white solid cpd-118, with a yield of 69.2%. 1 H NMR (500MHz, Chloroform-d) δ7.93 (s, 1H), 7.90-7.80 (m, 4H), 7.67 (d, J = 8.6Hz, 1H), 7.56-7.48 (m, 2H), 6.56 (d, J = 16.0Hz, 1H), 3.84 (s, 3H).

[0410] Example 112

[0411] S1: The preparation method is as described in Example 52S1. 2-Naphthaldehyde and bromoacetonitrile were used to separate and purify 79 mg of white solid cpd-119, with a yield of 44.1%. 1 H NMR (500MHz, Chloroform-d) δ7.89-7.83 (m, 4H), 7.59-7.51 (m, 4H), 5.97 (d, J = 16.6Hz, 1H).

[0412] Example 113

[0413] S1: The preparation method is the same as 108S2. 2-Naphthaldehyde and methyl cyanoacetate were used to separate and purify 140 mg of white solid cpd-120, with a yield of 59.0%. 1 H NMR(500MHz,Chloroform-d)δ8.42(s,1H),8.40(s,1H),8.19(dd,J=8.7,1.9Hz,1H),7.9 7-7.92(m,2H),7.89(d,J=8.1Hz,1H),7.66-7.61(m,1H),7.60-7.55(m,1H),3.97(s,3H).

[0414] Example 114

[0415] S1: A solution of quinoxaloline-6-carboxaldehyde (75 mg, 0.47 mmol, 1.0 equivalent) in 3 mL of ethanol was dissolved, and malononitrile (34 mg, 0.52 mmol, 1.1 equivalent) and piperidine (5 μL, 0.05 mmol, 0.1 equivalent) were added. The mixture was stirred at room temperature for 1 h, and then the resulting reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 69 mg of a yellow solid, in 70.6% yield. 1 H NMR (500MHz, Chloroform-d) δ 8.97 (s, 2H), 8.55 (d, J = 2.1 Hz, 1H), 8.37 (dd, J = 8.9, 2.1 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 8.02 (s, 1H). LC-MS(ESI):m / z 207.0[M+H] + .

[0416] Example 115

[0417] S1: The preparation method is the same as 114S1. 2-Naphthaldehyde was used, and the yellow solid was separated and purified to obtain 206 mg, with a yield of 99.9%. 1 H NMR (500MHz, Chloroform-d) δ8.28 (s, 1H), 8.07 (dd, J = 8.8, 2.0Hz, 1H), 7.97–7.88 (m, 4H), 7.68 (t, J = 7.4Hz, 1H), 7.61 (t, J = 7.5Hz, 1H).

[0418] Example 116

[0419] S1: Cyanogen bromide (282 mg, 2.66 mmol, 1.0 equivalent), 2-vinylnaphthalene (493 mg, 3.20 mmol, 1.2 equivalent), and tris(pentafluorophenyl)borane (136 mg, 0.27 mmol, 0.1 equivalent) were dissolved in 5 mL of toluene solution, and 500 mg of 4A molecular sieve was added. The mixture was stirred at room temperature for 20 h. The resulting reaction mixture was then filtered through diatomaceous earth, extracted with water and ethyl acetate (×3), and the combined organic layers were washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether) to give 388 mg of a yellow solid, in 56.0% yield. 1 H NMR (500MHz, Chloroform-d) δ7.90 (d, J = 8.6Hz, 1H), 7.88-7.82 (m, 3H), 7.58-7.52 (m, 3H), 5.35-5.28 (m, 1H), 3.43-3.30 (m, 2H).

[0420] S2: Dissolve int-123 (135 mg, 0.52 mmol) in 2 mL of acetic acid, and add sulfuric acid (150 μL). Stir at 118 °C for 1 h. Then quench the reaction with saturated sodium bicarbonate solution, extract with water and ethyl acetate (×3), dry the combined organic layers with anhydrous Na2SO4, filter and remove under vacuum. The residue was purified by Biotage C18 reversed-phase chromatography to give 98 mg of yellow solid, yield 96.0%. 1 H NMR (500MHz, DMSO-d6) δ8.05 (s, 1H), 7.96-7.89 (m, 3H), 7.75-7.71 (m, 1H), 7.65-7.51 (m, 4H), 7.15 (s, 1H), 6.75 (d, J = 15.8Hz, 1H). MS(ESI):m / z 198.1[M+H] + .

[0421] Examples 117-120

[0422] The preparation method is the same as in Example 1S2. The specific compound structure and characterization data are shown in Table 3 below:

[0423] Table 3. Compound structures and characterization data from Examples 117-120

[0424] Example 121: Mant-GDP Exchange Experiment

[0425] Using EDTA to chelate Mg 2+This can accelerate the substrate exchange rate of RhoA. In a system containing excess EDTA, the addition of fluorescently labeled substrates (mant-GDP / -GTP / -GMPPMP / -GTPγS, etc.) allows the labeled substrates to bind into the RhoA substrate pocket, resulting in enhanced fluorescence intensity. Therefore, the level of inhibition of the RhoA substrate exchange process by small molecules can be detected by measuring the amplitude of the fluorescence signal change.

[0426] This patent uses RhoAWT and RhoA Y42C RhoA A161P The inhibitory activity of small molecule compounds against wild-type and mutant RhoA proteins was tested using mutants. 0.5–2 μM RhoA protein was incubated with the compounds for 30 min, followed by the addition of twice the volume of Mg. 2+ Fluorescence signal changes were immediately detected using mant-GDP at concentrations of EDTA (1000 ppm) and RhoA (2 times the concentration). DMSO was used as a control group, and the inhibition rate was calculated based on the magnitude of signal changes in the experimental groups. RhoA... A161P Due to decreased substrate affinity, in the presence of Mg 2+ The substrate exchange rate is relatively fast in the system, so EDTA is not added during the test.

[0427] Fitting IC using this method 50 At the same time, with a fixed RhoA concentration of 1 μM, 11-12 compound concentration gradients were set up using 2-fold serial dilutions, with 3 replicates for each concentration gradient. The inhibitory activity against RhoA protein was calculated based on the inhibition rate of each compound concentration gradient, and the IC50 was fitted. 50 Because small molecules react with different RhoAWT and RhoA... Y42C and RhoA A161P The activities differ, using RhoAWT and RhoA Y42C Test IC 50 The highest concentration of the compound was set at 512 μM, and RhoA was tested. A161P The maximum concentration of the compound was set to 120 μM.

[0428] The bioactivity assay of the compounds disclosed herein is for RhoA A161P The inhibitory activity of the protein substrate exchange was classified into four levels based on the level of inhibition of the substrate exchange process at a concentration of 30 μM. Among them, A represents an inhibition rate ≥90% at 30 μM; B represents an inhibition rate ≥75% at 30 μM (90% > 75%); C represents an inhibition rate ≥50% at 30 μM (75% > 50%); and D represents an inhibition rate <50% at 30 μM.

[0429] Table 4. The effects of the small molecule compounds prepared in this invention on RhoA A161P Inhibition level of protein substrate exchange

[0430] The bioactivity assay of the compounds disclosed herein is for RhoA A161P Inhibitory activity of protein substrate exchange IC 50 The values ​​are listed in Table 5.

[0431] Table 5. The effects of the small molecule compounds prepared in this invention on RhoA A161P IC50 of protein inhibitory activity 50 value

[0432] The bioactivity assay of the compounds in this application is performed on RhoA wild-type (WT) protein and RhoA Y42C The inhibitory activities of protein substrate exchange are listed in Table 6.

[0433] Table 6. Inhibitory activity of the small molecule compounds prepared in this invention on RhoA protein substrate exchange.

[0434] It can be seen that the compounds of the present invention have significant inhibitory effects on both wild-type and pathogenic mutant RhoA protein, and some compounds (such as compounds cpd37 / 38 / 43 / 44, etc.) show significant inhibitory effects on RhoA. A161P It exhibits outstanding selective inhibitory activity, while other compounds (such as cpd77 / 83 / 84 / 85 / 93 / 98 / 100 / 109 / 110 / 111 / 125 / 127, etc.) show strong selective inhibitory activity against RhoA wild-type (WT) and RhoA. Y42C It exhibits superior inhibitory activity.

[0435] 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), or a pharmaceutically acceptable salt, stereoisomer, or isotopologue thereof, in: R 1 and R 2 are independently selected from the group consisting of H, CN, COOH, halogen or unsubstituted C1-C6alkyl, NO2, -COOC1-C6alkyl, -CON(C1-C6alkyl) 0-2 ; A is selected from substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted phenyl-5-6-membered heterocyclic phenyl; wherein the substitution means that one or more (e.g., 2, 3 or 4) H on the group are independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl; L is selected from unsubstituted, substituted, or unsubstituted C1-C8 alkylene, substituted, or unsubstituted (C0-C4 alkylene)X1-(C0-C4 alkylene), wherein X1 is selected from the group consisting of -O-, -S-, -NH-, CO, -SO-, and -SO2-; wherein substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of halogen, -OH, -CN, C1-C4 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo- or unsubstituted C2-C6 alkenyl, halo- or unsubstituted C2-C6 alkynyl; and B is selected from H, halogen, OH, CN, COOH, halo- or unsubstituted C1-C6alkyl, halo- or unsubstituted C2-C6alkenyl, halo- or unsubstituted C2-C6alkynyl, halo- or unsubstituted C1-C6alkoxy, -COOC1-C6alkyl, -NHCOC1-C6alkyl, -NHCOOC1-C6alkyl, -N(C1-C6alkyl) 0-2 , -OC1-C6alkyleneN(C1-C6alkyl) 0-2 , substituted or unsubstituted C1-C6alkyleneCOOC1-C6alkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution means that one or more (such as 2, 3, or 4) H on the group are independently replaced with a moiety selected from the group consisting of halogen, OH, CN, COOH, halo- or unsubstituted C1-C6alkyl, halo- or unsubstituted C2-C6alkenyl, halo- or unsubstituted C2-C6alkynyl, halo- or unsubstituted C1-C6alkoxy, -COOC1-C6alkyl, -NHCOC1-C6alkyl, -NHCOOC1-C6alkyl, -N(C1-C6alkyl) 0-2 , -OC1-C6alkyleneN(C1-C6alkyl) 0-2 , -C1-C4alkyleneOC1-C4alkyl, substituted or unsubstituted C1-C6alkyleneCOOC1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, -L1-substituted or unsubstituted C3-C6cycloalkyl, -L1-substituted or unsubstituted 3-6 membered heterocyclyl, -L1-N(substituted or unsubstituted benzyl) 1-2 , -L1-COO(substituted or unsubstituted benzyl) 1-2 , -L1-substituted or unsubstituted phenyl, -L1-substituted or unsubstituted 5-6 membered heteroaryl, or two substituents on the same or adjacent ring atoms of ring B together with the ring atoms to which they are attached form a C3-C6cycloalkyl or 3-6 membered heterocyclyl; wherein the substitution means that one or more (such as 2, 3, or 4) H on the group are independently replaced with a moiety selected from the group consisting of halogen, OH, CN, COOH, halo- or unsubstituted C1-C6alkyl, halo- or unsubstituted C2-C6alkenyl, halo- or unsubstituted C2-C6alkynyl, halo- or unsubstituted C1-C6alkoxy, -COOC1-C6alkyl, -C1-C4alkyleneOC1-C4alkyl, -NHCOC1-C6alkyl, -NHCOOC1-C 6alkyl, -OC1-C6alkyleneN(C1-C6alkyl) 0-2 ; Each L1 is independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkylene-, substituted or unsubstituted C1-C6 alkylene NHCO-; wherein the substitution refers to one or more (e.g., 2, 3 or 4) H on the group being independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy.

2. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue thereof of claim 1, wherein, in: R 1 and R 2 are independently selected from the group consisting of H, CN, COOH, halogen or unsubstituted C1-C6alkyl, NO2, -COOC1-C6alkyl; A is selected from substituted or unsubstituted 5-10-membered heteroaryl groups and substituted or unsubstituted C6-C10 aryl groups; wherein the substitution means that one or more (e.g., 2, 3 or 4) H on the group are independently substituted by a group selected from the group consisting of: halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C2-C6 alkenyl, halogenated or unsubstituted C2-C6 alkynyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOOC1-C6 alkyl, -NHCOOC1-C6 alkyl; L is selected from unsubstituted, substituted, or unsubstituted C1-C8 alkylene, substituted, or unsubstituted (C0-C4 alkylene)X1-(C0-C4 alkylene), wherein X1 is selected from the group consisting of -O-, -S-, -NH-, -SO-, and -SO2-; wherein substitution refers to one or more (e.g., 2, 3, or 4) H atoms on the group being independently substituted by a group selected from the group consisting of halogen, -OH, -CN, C1-C4 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and B is selected from the group consisting of H, halogen, OH, CN, COOH, halo- or un-substituted C1-C6alkyl, halo- or un-substituted C2-C6alkenyl, halo- or un-substituted C2-C6alkynyl, halo- or un-substituted C1-C6alkoxy, -COOC1-C6alkyl, -NHCOC1-C6alkyl, -NHCOOC1-C6alkyl, substituted or un-substituted C3-C10cycloalkyl, substituted or un-substituted 3-10 membered heterocyclyl, substituted or un-substituted C6-C10aryl, substituted or un-substituted 5-10 membered heteroaryl; wherein the substitution means one or more (such as 2, 3 or 4) H on the group are independently replaced with a group selected from the group consisting of halogen, OH, CN, COOH, halo- or un-substituted C1-C6alkyl, halo- or un-substituted C2-C6alkenyl, halo- or un-substituted C2-C6alkynyl, halo- or un-substituted C1-C6alkoxy, -COOC1-C6alkyl, -NHCOC1-C6alkyl, -NHCOOC1-C6alkyl.

3. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue thereof of claim 1, wherein, R 1 is H, R 2 is independently selected from the group consisting of CN, NO2, -COOC1-C6alkyl.

4. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue of claim 1, wherein, A is selected from the group consisting of substituted or un-substituted benzo 5-6 membered heteroaryl containing 1 or 2 nitrogen atoms each, substituted or un-substituted C6-C10aryl.

5. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue thereof of claim 1, wherein, A is selected from the group consisting of substituted or unsubstituted:

6. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue thereof of claim 1, wherein, A is selected from the group consisting of substituted or unsubstituted:

7. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue of claim 1, wherein B is selected from the group consisting of substituted or un-substituted phenyl, substituted or un-substituted 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, N and S, substituted or un-substituted C5-C6cycloalkyl, or substituted or un-substituted 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, N and S.

8. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue of claim 7, wherein, B is substituted with a group selected from the group consisting of substituted or unsubstituted C1-C6alkyleneCOOC1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, -L1-substituted or unsubstituted C3-C6cycloalkyl, -L1-substituted or unsubstituted 3-6 membered heterocyclyl, -L1-N(substituted or unsubstituted benzyl) 1-2 , -L1-COO(substituted or unsubstituted benzyl) 1-2 , -L1-substituted or unsubstituted phenyl, -L1-substituted or unsubstituted 5-6 membered heteroaryl; or two substituents on adjacent ring atoms of ring B, together with the ring atoms to which they are attached, form a C5-C6cycloalkyl or 5-6 membered heterocyclyl; wherein the substitution means that one or more (such as 2, 3, or 4) H on the group is independently replaced with a group selected from the group consisting of halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6alkyl, halogenated or unsubstituted C1-C6alkoxy, -COOC1-C6alkyl, -C1-C4alkyleneOC1-C4alkyl, -OC1-C6alkyleneN(C1-C6alkyl) 0-2 ; wherein each L1is independently selected from the group consisting of substituted or un-substituted C1-C6alkylene-, substituted or un-substituted C1-C6alkyleneNHCO-; wherein the substitution means one or more (such as 2, 3 or 4) H on the group are independently replaced with a group selected from the group consisting of halogen, OH, CN, COOH, halo- un-substituted C1-C6alkyl, halo- or un-substituted C1-C6alkyl, halo- or un- substituted C2-C6alkenyl, halo- or un-substituted C2-C6 alkynyl, halo- or un- substituted C1-C6alkoxy.

9. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue of claim 1, wherein, L is substituted or un-substituted Cl-C4alkylene, CO, O or SO2; wherein substitution means one or more (such as 2, 3 or 4) H on a group are independently replaced with a group selected from the group consisting of halogen, -OH, -CN, C1-C2alkyl, C1-C2haloalkyl, C1-C2alkoxy, C1-C2haloalkoxy, halo- or un-substituted C2-C3alkenyl, halo- or un-substituted C2-C3alkynyl.

10. The compound of claim 1, a pharmaceutically acceptable salt, stereoisomer or isotopically enriched compound thereof, wherein, R 1 is H, R 2 is NO2; A is substituted or un-substituted indolyl; wherein the substitution means one or more (such as 2, 3 or 4 ) H on the group are independently replaced with a group selected from the group consisting of halogen, halo- or un-substituted C1-C6alkyl; L is CH2, CH2CH2, CH2CHOH, or SO2; A is substituted or un-substituted indolyl; wherein the substitution means one or more H on the group are independently replaced with a group selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C2-C3alkenyl, C2-C3alkynyl. B is substituted or unsubstituted phenyl; the substitution means one or more (such as 2, 3, or 4) H on the group is independently replaced with a group selected from the group consisting of halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOC1-C6 alkyl, -NHCOOC1-C6 alkyl.

11. The compound of claim 1, pharmaceutically acceptable salt, stereoisomer or isotopologue thereof, wherein, R 1 is H, R 2 is NO2; A is substituted or unsubstituted phenyl; L is nothing, O, or S; B is substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; the substitution means one or more (such as 2, 3, or 4) H on the group is independently replaced with a group selected from the group consisting of halogen, OH, CN, COOH, halogenated or unsubstituted C1-C6 alkyl, halogenated or unsubstituted C1-C6 alkoxy, -COOC1-C6 alkyl, -NHCOC1-C6 alkyl, -NHCOOC1-C6 alkyl.

12. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopologue of claim 1, wherein, The compound is selected from the group consisting of:

13. A pharmaceutical composition, characterized by, The pharmaceutical composition of claim 13, wherein the compound is a compound of any one of claims 1-12, a pharmaceutically acceptable salt, stereoisomer or isotopologue thereof.

14. Use of the compound of any one of claims 1-12, a pharmaceutically acceptable salt, stereoisomer or isotopologue thereof; or the pharmaceutical composition of claim 13 in the manufacture of a medicament for RhoA inhibitor or for the prevention and / or treatment of a disease or disorder mediated by RhoA.

15. Use according to claim 14, characterized in that, The disease or disorder mediated by RhoA is selected from the group consisting of hematological neoplasms, gastric cancer, adult medulloblastoma, diffuse large B-cell lymphoma, colon cancer, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, cholangiocarcinoma and gallbladder cancer, bladder cancer; brain tumors, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma; cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma, cardiovascular disease, neurodegenerative disease, malaria, AIDS, gout, diabetes, renal failure, chronic pulmonary disease.

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