Heteroaryl amide compounds, pharmaceutical composition and use

Abstract

Disclosed in the present invention are heteroaryl amide compounds, a pharmaceutical composition and the use thereof. Specifically, disclosed are compounds represented by formula I, pharmaceutically acceptable salts thereof, solvates thereof, stereoisomers thereof, tautomers thereof, prodrugs thereof, metabolites thereof, or isotopic compounds thereof. The compounds of the present invention have good antagonistic activity against MRGPRX2.

Description

A heteroarylamide compound, a pharmaceutical composition and its application

[0001] This application claims priority to Chinese Patent Application No. 2025103639551, filed March 25, 2025; Chinese Patent Application No. 2025104895860, filed April 17, 2025; Chinese Patent Application No. 2025108222130, filed June 18, 2025; Chinese Patent Application No. 2025109199979, filed July 3, 2025; and Chinese Patent Application No. 2025109199979, filed July 29, 2025. Priority claims are made to Chinese patent applications 2025110538273, 2025111659877 (filed August 19, 2025), 2025113485475 (filed September 21, 2025), 202511982115X (filed December 25, 2025), and 202610217025X (filed February 14, 2026). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a heteroarylamide compound, a pharmaceutical composition, and its application. Background Technology

[0003] MRGPRX2 (Mas-related G-protein coupled receptor member X2) is a G protein-coupled receptor (GPCR) that is highly expressed in mast cells and basophils. MRGPRX2 plays an important role in allergic reactions and inflammation by mediating peptide and drug signaling, triggering degranulation and cell activation.

[0004] WO2022067094A1 discloses a compound that regulates MRGPRX2 or its orthologs, which can treat diseases such as pseudoallergic reactions, itching, pain, inflammation, inflammatory bowel disease, urticaria, sinusitis, asthma, rosacea, endometriosis, and autoimmune diseases.

[0005] Symptoms related to pruritus include: chronic pruritus; contact dermatitis; allergic blepharitis; anemia; atopic dermatitis; bullous pemphigoid; candidiasis; chickenpox; end-stage renal failure; hemodialysis; chronic urticaria; contact dermatitis, atopic dermatitis; herpetic dermatitis; diabetes; drug allergy; dry skin; dyshidrotic dermatitis; atopic eczema; eosinophilic fasciitis; bullous epidermolysis; erythritis; food allergy; folliculitis; fungal skin infections; hemorrhoids; herpes; HIV infection; Hodgkin's disease; hyperthyroidism; allergy to iodinated contrast dyes; and deficiency. Iron anemia; kidney disease; leukemia, porphyria; lymphoma; malignant tumors; mastocytosis; multiple myeloma; neurodermatitis; onchocerciasis; Paget's disease; lice infestation; polycythemia vera; nodular prurigo; lichen planus; lichen sclerosus; anal prurigo; pseudorabies; psoriasis; rectal prolapse; sarcoidosis granuloma; scabies; schistosomiasis; scleroderma, severe stress, stasis dermatitis; swimming pruritus; thyroid disease; tinea cruris; rosacea; cutaneous amyloidosis; scleroderma; acne; wound healing; burn healing; pruritus; or urticaria. Preferably urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.

[0006] Pain-related symptoms include acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, joint fibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, ischemic necrosis, back pain, Behcet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical spinal stenosis, peroneal muscular atrophy (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, lung collapse (pneumothorax), and complex pain. Regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, toothache, Delken's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilic-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatitis (dermatomyositis), knee injury, leg pain, low back pain and hematuria syndrome, lupus. Lyme disease, medullary sponge kidney (MSK), paresthesia of the femoral head, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsons-Turner syndrome, pelvic pain, periodontal pain, peripheral neuropathy, phantom limb pain, nerve compression, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, postherpetic neuralgia, post-mastectomy pain syndrome, post-mastectomy pain, post-stroke pain, post-thoracotomy pain syndrome, postherpetic neuralgia (shingles), post-poliomyelitis syndrome Symptoms include: primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Shulman's kyphosis, sciatica, scoliosis, herpes zoster (herpes zoster), Sjögren's syndrome, spasmodic torticollis, sphincter insufficiency, spinocerebellar ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, Tarlov's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, or vulvar pain.

[0007] Inflammatory or autoimmune diseases include chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens Johnson syndrome, toxic epidermal necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (RSD / CRPS), rhinitis, tendinitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorders, and asthma. Airway infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, allergies, intestinal disorders, epithelial intestinal disorders, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, cardiovascular disease or vasculitis.

[0008] In recent years, MRGPRX2 has gradually become a hot topic in scientific research, and developing highly active MRGPRX2 antagonists is the direction that researchers in this field are striving for. Summary of the Invention

[0009] This invention provides a heteroarylamide compound, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, pharmaceutical composition, and application. The compounds of this invention exhibit superior antagonistic activity against MRGPRX2.

[0010] This invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotopic compound thereof:

[0011] Among them, ring A is a 5-14 membered heteroaryl, a 3-20 membered heterocyclic group, or a C3-C ring. 12 cycloalkyl, C6-C 14 The aryl group may not be present, and the heteroatoms in the heteroaryl or heterocyclic group are selected from one or more of N, O and S, with a number of 1-4 heteroatoms;

[0012] Ring B is a 3-20 membered heterocyclic group, C3-C 12 Cycloalkyl group, wherein the heteroatom in the heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0013] The ring C is a 5-14 membered heteroaryl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4;

[0014] L 1 for O, Connect key, -NR L1-1 , C1-C6 alkylene groups or none; wherein the a-end is connected to ring A and the b-end is connected to ring B;

[0015] R L1-1 It is H, C1-C6 alkyl;

[0016] L 2 For O, linking bond, S, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CR L2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups;

[0017] R L2-1 It is H, C1-C6 alkyl;

[0018] R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0019] R L2-4 It is a halogen;

[0020] X 1 It is C or does not exist;

[0021] X 2 It is C or does not exist;

[0022] X 3 For O, NR X3-1 S may not exist;

[0023] R X3-1 H, C1-C6 alkyl, C1-C6 alkoxy;

[0024] X 4 It is N or does not exist;

[0025] R 1 It is oxo, oxidized, halogenated, C1-C6 alkyl, or formed by one or more R 1-1 Substituted C1-C6 alkyl, cyano, -NR 1-2 R 1-3 hydroxyl group, 3-8 membered heterocyclic alkyl group, 3-8 membered cycloalkyl group, with one or more R 1-4 The substituted 3-8 membered cycloalkyl group may be absent, and the heteroatom in the heteroalkyl group is selected from one or more of N, O, and S, with 1-3 heteroatoms, -SO2R 1-5 ,

[0026] R 1-1 Halogen, hydroxyl, -NR 1-1-1 R 1-1-2 -NR 1-1-3 -(C=O)R 1-1-4 C3-C8 cycloalkyl groups, deuterium;

[0027] R 1-1-1 R 1-1-2 Each is independently H or C1-C6 alkyl;

[0028] R 1-1-3 It is H, C1-C6 alkyl;

[0029] R 1-1-4 It is a C1-C6 alkyl group;

[0030] R 1-2 R 1-3 Each is independently H or C1-C6 alkyl;

[0031] R 1-4 It is a hydroxyl group;

[0032] R 1-5 It is a C1-C6 alkyl group;

[0033] R 1-6 It is a C1-C6 alkyl group;

[0034] R 1-7 It is a C1-C6 alkyl group;

[0035] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, halogen, C3-C8 cycloalkyl, cyano, C2-C6 alkynyl, -COOH, hydroxyl;

[0036] R 2-1 Hydroxyl group, -NR 2-1-1 R 2-1-2 , cyano, -COOH, halogen;

[0037] R 2-1-1 R 2-1-2 Each is independently H or C1-C6 alkyl;

[0038] R 3 Halogen, oxo, cyano, C3-C8 cycloalkyl, C1-C6 alkyl, or with one or more R 3-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyl groups;

[0039] R 3-1 It is a halogen;

[0040] R4 R 5 Each is independently H, C1-C6 alkyl, and composed of one or more R groups. 4-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, or absent;

[0041] R 4-1 It consists of C1-C6 alkoxy, halogen, and hydroxyl groups;

[0042] Or R 4 R 5 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0043] R 6 It is H, C1-C6 alkyl;

[0044] R 7 For C6-C 14 aryl, with one or more R 7-1 Replacement C6-C 14 aryl, 5-14 heteroaryl, surrounded by one or more R 7-2 Substituted 5-14-membered heteroaryl, C1-C6 alkyl, or with one or more R 7-3 The substituted C1-C6 alkyl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0045] R 7-1 It can be halogen, C3-C8 cycloalkyl, C2-C6 ynyl, C1-C6 alkyl, or cyano;

[0046] R 7-2 It is a halogen;

[0047] R 7-3 It is a C3-C8 cycloalkyl group;

[0048] m can be 0, 1, 2, 3, 4, 5, or 6;

[0049] n can be 0, 1, 2, 3, 4, 5, or 6;

[0050] p can be 0, 1, 2, 3, 4, 5, or 6.

[0051] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound may be:

[0052] Among them, ring A is a 5-14 membered heteroaryl, a 3-20 membered heterocyclic group, or a C3-C ring. 12 cycloalkyl, C6-C 14The aryl group, wherein the heteroatom in the heteroaryl or heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4;

[0053] Ring B is a 3-20 membered heterocyclic group, C3-C 12 Cycloalkyl group, wherein the heteroatom in the heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0054] The ring C is a 5-14 membered heteroaryl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4;

[0055] L 1 for O, Connect key, -NR L1-1 , C1-C6 alkylene groups; wherein the a-end is connected to ring A and the b-end is connected to ring B;

[0056] R L1-1 It is H, C1-C6 alkyl;

[0057] L 2 For O, linking bond, S, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CR L2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups;

[0058] R L2-1 It is H, C1-C6 alkyl;

[0059] R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0060] R L2-4 It is a halogen;

[0061] X 1 It is C or does not exist;

[0062] X 2 It is C or does not exist;

[0063] X 3 For O, NR X3-1 S may not exist;

[0064] R X3-1 H, C1-C6 alkyl, C1-C6 alkoxy;

[0065] X 4 It is N or does not exist;

[0066] R 1 It is oxo, oxidized, halogenated, C1-C6 alkyl, or formed by one or more R 1-1 Substituted C1-C6 alkyl, cyano, -NR 1-2 R 1-3 hydroxyl group, 3-8 membered heterocyclic alkyl group, 3-8 membered cycloalkyl group, with one or more R 1-4 The substituted 3-8 membered cycloalkyl group, wherein the heteroatom in the heterocycloalkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3, -SO2R 1-5 ,

[0067] R 1-1 Halogen, hydroxyl, -NR 1-1-1 R 1-1-2 -NR 1-1-3 -(C=O)R 1-1-4 C3-C8 cycloalkyl groups;

[0068] R 1-1-1 R 1-1-2 Each is independently H or C1-C6 alkyl;

[0069] R 1-1-3 It is H, C1-C6 alkyl;

[0070] R 1-1-4 It is a C1-C6 alkyl group;

[0071] R 1-2 R 1-3 Each is independently H or C1-C6 alkyl;

[0072] R 1-4 It is a hydroxyl group;

[0073] R 1-5 It is a C1-C6 alkyl group;

[0074] R 1-6 It is a C1-C6 alkyl group;

[0075] R 1-7 It is a C1-C6 alkyl group;

[0076] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, halogen, C3-C8 cycloalkyl, cyano, C2-C6 alkynyl, -COOH;

[0077] R 2-1 Hydroxyl group, -NR 2-1-1 R 2-1-2 , cyano, -COOH, halogen;

[0078] R 2-1-1 R 2-1-2 Each is independently H or C1-C6 alkyl;

[0079] R 3 Halogen, oxo, cyano, C3-C8 cycloalkyl, C1-C6 alkyl, or with one or more R 3-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyl groups;

[0080] R 3-1 It is a halogen;

[0081] R 4 R 5 Each is independently H, C1-C6 alkyl, and composed of one or more R groups. 4-1 Substituted C1-C6 alkyl groups and C3-C8 cycloalkyl groups;

[0082] R 4-1 It consists of C1-C6 alkoxy, halogen, and hydroxyl groups;

[0083] Or R 4 R 5 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0084] R 6 It is H, C1-C6 alkyl;

[0085] R 7 For C6-C 14 aryl, with one or more R 7-1 Replacement C6-C 14 aryl, 5-14 heteroaryl, surrounded by one or more R 7-2 Substituted 5-14-membered heteroaryl, C1-C6 alkyl, or with one or more R 7-3 The substituted C1-C6 alkyl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0086] R 7-1 It can be halogen, C3-C8 cycloalkyl, C2-C6 ynyl, C1-C6 alkyl, or cyano;

[0087] R 7-2 It is a halogen;

[0088] R 7-3 It is a C3-C8 cycloalkyl group;

[0089] m can be 0, 1, 2, 3, 4, 5, or 6;

[0090] n can be 0, 1, 2, 3, 4, 5, or 6;

[0091] p can be 0, 1, 2, 3, 4, 5, or 6.

[0092] In one embodiment, the present invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotopic compound thereof:

[0093] Among them, ring A is a 5-14 membered heteroaryl, a 3-20 membered heterocyclic group, or a C3-C ring. 12 cycloalkyl, C6-C 14 The aryl group, wherein the heteroatom in the heteroaryl or heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4;

[0094] Ring B is a 3-20 membered heterocyclic group, C3-C 12 Cycloalkyl group, wherein the heteroatom in the heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0095] The ring C is a 5-14 membered heteroaryl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0096] L 1 for O, Connect key, -NR L1-1 , End a is connected to ring A, and end b is connected to ring B;

[0097] R L1-1 It is H, C1-C6 alkyl;

[0098] L 2 For O, linking bond, S, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CR L2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups;

[0099] R L2-1 It is H, C1-C6 alkyl;

[0100] R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0101] R L2-4 It is a halogen;

[0102] X 1 It is C or does not exist;

[0103] X 2 It is C or does not exist;

[0104] X 3 For O, NR X3-1 S may not exist;

[0105] R X3-1 H, C1-C6 alkyl, C1-C6 alkoxy;

[0106] X 4 It is N or does not exist;

[0107] R 1 It is oxo, oxidized, halogenated, C1-C6 alkyl, or formed by one or more R 1-1 Substituted C1-C6 alkyl, cyano, -NR 1-2 R 1-3 hydroxyl group, 3-8 membered heterocyclic alkyl group, 3-8 membered cycloalkyl group, with one or more R 1-4 The substituted 3-8 membered cycloalkyl group, wherein the heteroatom in the heterocycloalkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3, -SO2R 1-5 ,

[0108] R 1-1 Halogen, hydroxyl, -NR 1-1-1 R 1-1-2 -NR 1-1-3 -(C=O)R 1-1-4 C3-C8 cycloalkyl groups;

[0109] R 1-1-1 R 1-1-2 Each is independently H or C1-C6 alkyl;

[0110] R 1-1-3 It is H, C1-C6 alkyl;

[0111] R 1-1-4 It is a C1-C6 alkyl group;

[0112] R 1-2 R 1-3 Each is independently H or C1-C6 alkyl;

[0113] R 1-4 It is a hydroxyl group;

[0114] R 1-5 It is a C1-C6 alkyl group;

[0115] R 1-6 It is a C1-C6 alkyl group;

[0116] R1-7 It is a C1-C6 alkyl group;

[0117] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, halogen, C3-C8 cycloalkyl, cyano, C2-C6 alkynyl, -COOH;

[0118] R 2-1 Hydroxyl group, -NR 2-1-1 R 2-1-2 , cyano, -COOH, halogen;

[0119] R 2-1-1 R 2-1-2 Each is independently H or C1-C6 alkyl;

[0120] R 3 Halogen, oxo, cyano, C3-C8 cycloalkyl, C1-C6 alkyl, or with one or more R 3-1 Substituted C1-C6 alkyl groups and C3-C8 cycloalkyl groups;

[0121] R 3-1 It is a halogen;

[0122] R 4 R 5 Each is independently H, C1-C6 alkyl, and composed of one or more R groups. 4-1 Substituted C1-C6 alkyl groups and C3-C8 cycloalkyl groups;

[0123] R 4-1 It consists of C1-C6 alkoxy, halogen, and hydroxyl groups;

[0124] Or R 4 R 5 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0125] R 6 It is H, C1-C6 alkyl;

[0126] R 7 For C6-C 14 aryl, with one or more R 7-1 Replacement C6-C 14 aryl, 5-14 heteroaryl, surrounded by one or more R 7-2 Substituted 5-14-membered heteroaryl, C1-C6 alkyl, or with one or more R 7-3 The substituted C1-C6 alkyl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0127] R 7-1It can be halogen, C3-C8 cycloalkyl, C2-C6 ynyl, C1-C6 alkyl, or cyano;

[0128] R 7-2 It is a halogen;

[0129] R 7-3 It is a C3-C8 cycloalkyl group;

[0130] m can be 0, 1, 2, 3, 4, 5, or 6;

[0131] n can be 0, 1, 2, 3, 4, 5, or 6;

[0132] p can be 0, 1, 2, 3, 4, 5, or 6.

[0133] In one embodiment, the present invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotopic compound thereof:

[0134] Among them, ring A is a 5-14 membered heteroaryl, a 3-20 membered heterocyclic group, or a C3-C ring. 12 Cycloalkyl, wherein the heteroatom in the heteroaryl or heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4;

[0135] Ring B is a 3-20 membered heterocyclic group, wherein the heteroatom in the heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0136] The ring C is a 5-14 membered heteroaryl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0137] L 1 for O, Connection key;

[0138] L 2 For O, linking bond, sulfur atom, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CR L2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups;

[0139] R L2-1 It is H, C1-C6 alkyl;

[0140] R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0141] RL2-4 It is a halogen;

[0142] X 1 It is C or does not exist;

[0143] X 2 It is C or does not exist;

[0144] X 3 For O, NR X3-1 Or it may not exist;

[0145] R X3-1 H, C1-C6 alkyl, C1-C6 alkoxy;

[0146] X 4 It is N or does not exist;

[0147] R 1 It is oxo, oxidized, halogenated, C1-C6 alkyl, or formed by one or more R 1-1 Substituted C1-C6 alkyl, cyano, -NR 1-2 R 1-3 hydroxyl group, 3-8 membered heterocyclic alkyl group, 3-8 membered cycloalkyl group, with one or more R 1-4 The substituted 3-8 membered cycloalkyl group, wherein the heteroatom in the heterocycloalkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0148] R 1-1 Halogen, hydroxyl, -NR 1-1-1 R 1-1-2 -NR 1-1-3 -(C=O)R 1-1-4 C3-C8 cycloalkyl groups;

[0149] R 1-1-1 R 1-1-2 Each is independently H or C1-C6 alkyl;

[0150] R 1-1-3 It is H, C1-C6 alkyl;

[0151] R 1-1-4 It is a C1-C6 alkyl group;

[0152] R 1-2 R 1-3 Each is independently H or C1-C6 alkyl;

[0153] R 1-4 It is a hydroxyl group;

[0154] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl groups, halogens;

[0155] R 2-1 It is a hydroxyl group;

[0156] R 3 Halogen, oxo, cyano, C3-C8 cycloalkyl, C1-C6 alkyl, or with one or more R 3-1 Substituted C1-C6 alkyl groups and C3-C8 cycloalkyl groups;

[0157] R 3-1 It is a halogen;

[0158] R 4 R 5 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0159] Or R 4 R 5 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0160] R 6 It is H, C1-C6 alkyl;

[0161] R 7 For C6-C 14 aryl, with one or more R 7-1 Replacement C6-C 14 aryl, 5-14 heteroaryl, surrounded by one or more R 7-2 Substituted 5-14-membered heteroaryl, C1-C6 alkyl, or with one or more R 7-3 The substituted C1-C6 alkyl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0162] R 7-1 It can be halogen, C3-C8 cycloalkyl, C2-C6 ynyl, C1-C6 alkyl, or cyano;

[0163] R 7-2 It is a halogen;

[0164] R 7-3 It is a C3-C8 cycloalkyl group;

[0165] m can be 0, 1, 2, 3, 4, 5, or 6;

[0166] n can be 0, 1, 2, 3, 4, 5, or 6;

[0167] p can be 0, 1, 2, 3, 4, 5, or 6.

[0168] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I has a structure as shown in Formula Ia:

[0169] R 1 R 2 R 3 R 4 R 5 R 7 m, n, p, L 1 L 2 The definitions of ring A, ring B, and ring C are as described above.

[0170] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I has a structure as shown in Formula Ia-1:

[0171] R 1 R 2 R 3 R 4 R 5 R 7 m, n, p, L 1 L 2 The definitions of ring A, ring B, and ring C are as described above; t is 1, 2, 3, 4, 5, or 6.

[0172] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I has a structure as shown in Formula Ia-1-a:

[0173] R 1 R 2 R 3 R 4 R 5 R 7 m, n, p, L 1 L 2 The definitions of ring A and ring C are as described above;

[0174] t can be 1, 2, 3, 4, 5 or 6.

[0175] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I has a structure as shown in Formula Ib:

[0176] R 1 R 2 R 3 R 4 R 5 R 7-1 m, n, p, q, L 1 L 2 The definitions of ring A, ring B, and ring C are as described above;

[0177] Ring D is C6-C 14 The aryl group, preferably phenyl;

[0178] q can be 0, 1, 2, 3, 4, 5, or 6.

[0179] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I has a structure as shown in Formula Ib-1:

[0180] Among them, Y 1 For N or C;

[0181] Y 2 For N or C;

[0182] R 1 R 2 R 3 R 4 R 5 R 7-1 m, n, p, L 1 L 2 The definitions of ring A and ring B are as described above;

[0183] q can be 0, 1, 2, 3, 4, or 5.

[0184] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I has a structure as shown in Formula Id:

[0185] R 1 R2 R 3 R 7-1 m, n, p, L 1 L 2 The definitions of ring A, ring B, and ring C are as described above;

[0186] Ring D is C6-C 14 The aryl group, preferably phenyl;

[0187] q can be 0, 1, 2, 3, 4, 5, or 6.

[0188] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, is characterized in that the compound represented by Formula I has a structure as shown in Formula Id-1:

[0189] Among them, Y 1 For N or C;

[0190] Y 2 For N or C;

[0191] R 1 R 2 R 3 R 7-1 m, n, p, L 1 L 2 The definitions of ring A and ring B are as described above;

[0192] q can be 0, 1, 2, 3, 4, or 5.

[0193] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for

[0194] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein L 1 for O or -NH-.

[0195] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein ring B is... Where end a and L 1 Connected.

[0196] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Where end a and L 1 Connected.

[0197] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein L 2 For connecting bonds, S, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CR L2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups;

[0198] R L2-1 It is H, C1-C6 alkyl;

[0199] R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0200] R L2-4 It is a halogen.

[0201] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 4 It is a methyl group.

[0202] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, is characterized by R 5 It is hydrogen.

[0203] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, wherein the ring C is a 7-14 fused polycyclic heteroaryl group, and the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4.

[0204] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the ring C is as shown in the following structural formula C-1:

[0205] Among them, the cyclic Ca is a 5-membered monocyclic heteroaryl group;

[0206] The cyclic Cb is a 5-12 membered heterocyclic group;

[0207] Y c-1 For CR c-1-1 Or N;

[0208] Y c-2 For CR c-2-1 Or N;

[0209] Y c-3 For CR c-3-1 Or N;

[0210] Y c-4 For CR c-4-1 Or N;

[0211] R c-1-1 CR c-2-1 CR c-3-1 CR c-4-1 Each can be either hydrogen or non-existent independently;

[0212] Wherein, the heteroatoms in the heteroaryl and heterocyclic groups are selected from one or more of N, O and S, the number of heteroatoms in the ring C is 1-4, and the α-terminus is connected to the L-terminus. 2 Connected.

[0213] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the structural formula C-1 is shown below: Where end a and L 2 Connected.

[0214] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein L 1 for O or -NH;

[0215] L 2 For O, linking bond, S, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CRL2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups;

[0216] R L2-1 It is H, C1-C6 alkyl;

[0217] R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups;

[0218] R L2-4 It is a halogen.

[0219] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I has a structure as shown in Formula Ic:

[0220] Among them, R 2 R 3 R 4 R 5 R 6 R 7 n, p, L 2 X 1 X 2 X 3 X 4 The definitions of ring B and ring C are as described above.

[0221] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein the compound represented by Formula I is one of the following embodiments: Embodiment 1, Embodiment 2, or Embodiment 3:

[0222] Option 1:

[0223] for Where end a and L 1 Connected;

[0224] R 2 The definitions of n are as described above;

[0225] t1 can be 1, 2, 3, 4, 5, or 6;

[0226] t2 is 1, 2, or 3;

[0227] t3 is 1, 2, or 3;

[0228] t4 is 0, 1, or 2;

[0229] t5 is 1, 2, or 3;

[0230] Z 1 For N or CH;

[0231] Option 2:

[0232] for Where end a and L 1 Connected; ring C is Where end a and L 2 Connected;

[0233] Option 3:

[0234] for Where end a and L 1 Connected; R 2 It is a C1-C6 alkyl or cyano group; when R 2 When it is a C1-C6 alkyl group, the ring C is Where end a and L 2 Connected.

[0235] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, wherein in ring A, the 5-14 membered heteroaryl is a 3-8 membered monocyclic heteroaryl or a 7-12 membered polycyclic heteroaryl, preferably a 6 membered monocyclic heteroaryl.

[0236] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, wherein, in ring A, the 3-20 membered heterocyclic group is a 3-8 membered mono-heterocyclic group or a 5-20 membered fused heterocyclic group, preferably a 6 membered mono-heterocyclic group or a 7-12 membered fused heterocyclic group.

[0237] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein, in ring B, the 3-20 membered heterocyclic group is a 3-8 membered mono-heterocyclic group, a 5-20 membered spiro-heterocyclic group, a 5-20 membered bridged heterocyclic group, or a 5-20 membered fused heterocyclic group, preferably a 6 membered mono-heterocyclic group, an 8 membered mono-heterocyclic group, a 5 membered mono-heterocyclic group, a 7-12 membered spiro-heterocyclic group, a 7-12 membered bridged heterocyclic group, or a 7-12 membered fused heterocyclic group; more preferably a 7-12 membered fused heterocyclic group.

[0238] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, wherein the 5-14 membered heteroaryl in ring C is a 3-8 membered monocyclic heteroaryl or a 7-12 membered polycyclic heteroaryl, preferably a 6 membered heteroaryl, more preferably a pyridyl.

[0239] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 1 R 1-1 R 2 R 3 R 3-1 R 7-1 R 7-2 R 2-1 R 4-1 In this context, the halogen is independently F, Cl, Br, or I.

[0240] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R L2-1 R 1 R 1-1-1 R 1-1-2 R 1-1-3 R 1-1-4 R 1-2 R 1-3 R 2 R 3 R 4 R 5 R 6 R X3-1 R 7-1 R 7-2 R L1-1 R 1-5 R 1-6 R 1-7 R 2-1-1 R 2-1-2 In the C1-C6 alkyl group and the substituted C1-C6 alkyl group, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0241] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein L 1 L 2In the above, the C1-C6 alkylene groups are -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0242] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R L2-2 R L2-3 R 1-1 R 3 R 4 R 5 R 7-1 R 7-3 R 2 In this formulation, the C3-C8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, preferably cyclopropyl or cyclohexyl.

[0243] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R X3-1 R 4-1 In the context of the C1-C6 alkoxy group and the substituted C1-C6 alkoxy group, the C1-C6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0244] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 2 R 7-1 In this context, the C2-C6 ynyl group refers to ethynyl or propynyl.

[0245] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein ring A is a 5-14 membered heteroaryl, a 3-20 membered heterocyclic group, or a C6-C... 14 The aryl group, wherein the heteroatom in the heteroaryl or heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4.

[0246] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R1 Oxidation (the oxidation refers to the process where two R atoms are bonded to the same carbon atom on ring A) 1 When replacing, 2 R 1 (Together with the connected C, forming C=O), oxidation (the oxidation refers to the oxidation of N atoms on ring A by an R) 1 When replacing, 1 R 1 Together with the connected N, it forms C1-C6 alkyl groups, with one or more R 1-1 Substituted C1-C6 alkyl groups, -SO2R 1-5 or Preferably, it is oxidized, C1-C6 alkyl, or formed by one or more R groups. 1-1 Substituted C1-C6 alkyl or -SO2R 1-5 .

[0247] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 1-1 It is either a halogen or a hydroxyl group.

[0248] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 1-5 R 1-6 and R 1-7 It is a C1-C6 alkyl group.

[0249] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, wherein m is 1, 2, 3 or 4.

[0250] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein L 1 for O, Connect key, or -NR L1-1 .

[0251] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R L1-1 It is H or C1-C6 alkyl; preferably H.

[0252] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 2 It is a C1-C6 alkyl group, with one or more R 2-1 The substituted C1-C6 alkyl, halogen, or cyano group is preferred; preferably, it is a C1-C6 alkyl, halogen, or cyano group.

[0253] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 2-1 It is a hydroxyl group.

[0254] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, wherein n is 0, 1, 2, 3 or 4.

[0255] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein X 1 It is either C or does not exist.

[0256] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 4 R 5 Each is independently H or C1-C6 alkyl.

[0257] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein X 2 The answer is C.

[0258] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein X 3 It is O.

[0259] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein X 4 Let N be the number of elements in the array.

[0260] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 6 It is H or C1-C6 alkyl; preferably H.

[0261] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 3 It is a C1-C6 alkyl group.

[0262] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, wherein p is 0, 1, 2 or 3.

[0263] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein L 2 It is an O, a linker, an S, or a C1-C6 alkylene group; preferably an O, a linker, or a C1-C6 alkylene group.

[0264] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 7 For C6-C 14 aryl or aryl group with one or more R 7-1 Replacement C6-C 14 Aryl groups.

[0265] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein R 7-1 It is a halogen.

[0266] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 1 The following are possible meanings: Cl, oxo, methyl, -CF3, oxidized, -CN, -CH2CHF2, CH2CF3, -NH2, -CH2CH2OH, -CH2NHCH3. CH2OH, -OH, -CH2NH2, CH2NH-(C=O)CH3, -CD3, -CH2CH2F, CHF2, CH2CH3, Preferably, the derivatives are oxo, methyl, oxidized, -CH2CH2OH, CH2OH, etc. Or -CH2CH2F; more preferably oxo, methyl, oxidized, -CH2CH2OH, CH2OH, Or -CH2CH2F.

[0267] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 2 Methyl, ethyl, F, -CH2OH, -CH2NH2, -CN, -CH2CN, -CH2CH2OH, -COOH, -CH2COOH, -CH2OCH3, -CH2CHF2, -CH2CH2F, hydroxyl group; preferably methyl, F or -CN.

[0268] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 3 It can be methyl, -CF3, -CN, or oxo.

[0269] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 3 For methyl, -CF3, -CN, oxo, hydroxyl, -CHF2, F; preferably methyl.

[0270] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 4 Methyl, ethyl, -CH2CH2CH3, -CH2OCH3, -CH2CHF2, -CH2CH2F, -CH2CH2OH; preferably methyl.

[0271] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 5 It is H or methyl; preferably H.

[0272] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 4 and R5 The C atoms attached to it together form a cyclopropyl group.

[0273] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 6 For H.

[0274] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein L 1 for O, Connect key, NH may not be present; wherein end a is connected to ring A and end b is connected to ring B; preferably O, Connect key, Or NH.

[0275] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein L 2 For O, S, -CH2-, -NH-、 Connecting bond; preferably O, -CH2- or connecting bond.

[0276] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein L 2 For O, S, -CH2-, -NH-、 Connect key

[0277] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein R 7 for Preferred More preferably

[0278] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein ring A is... Preferred

[0279] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein ring A is...

[0280] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein ring A is... Where end a and m R 1 Substituents are connected, with the b-terminus connected to L. 1 Connected. When ring A is a multi-ring, This means it can be on any ring, for example It can represent On the left ring, that is It can also mean On the right ring, that is When ring A has no substituents, i.e., when m is 0, It does not exist.

[0281] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein, for Preferred More preferably

[0282] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein ring B is... Where end a and L 1 Connected.

[0283] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein ring B is... Where end a and L 1 Connected.

[0284] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein, for Where end a and L 1 Connected.

[0285] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Where end a and L 1 Connected.

[0286] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Where end a and L 1 Connected.

[0287] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Preferred Where end a and L 1 Connected.

[0288] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Where end a and L 1 Connected.

[0289] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Preferred Where end a and L 1 Connected.

[0290] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Where end a and L 1 Connected.

[0291] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Where end a and L 1 Connected.

[0292] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, wherein... for Where end a and L 1 Connected.

[0293] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein ring C is... Where end a and L 2 Connected.

[0294] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein ring C is... Preferred Where end a and L 2 Connected.

[0295] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein, for Preferred More preferably Where end a and L 2Connected.

[0296] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein X 1 It is either C or does not exist.

[0297] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein X 2 It is either C or does not exist.

[0298] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein X 3 For O, S, Or it may not exist.

[0299] In one embodiment, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein X 4 It is N or does not exist.

[0300] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein m is 0, 1, 2, or 3.

[0301] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt, solvate, prodrug, metabolite or isotopic compound thereof, wherein n is 0, 1, 2 or 3.

[0302] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, wherein p is 0 or 1.

[0303] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite, or isotopic compound, wherein the compound represented by Formula I is any one of the following compounds:

[0304] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite, or isotopic compound, wherein the compound represented by Formula I is any one of the following compounds:

[0305] The present invention also provides a pharmaceutical composition comprising the compound shown in Formula I above, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotopic compound thereof, preferably, the pharmaceutical composition further comprising pharmaceutical excipients.

[0306] The present invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound or the pharmaceutical composition thereof in the preparation of MRGPRX2 or its orthologous antagonist.

[0307] Alternatively, its use in the preparation of medicaments for the treatment or prevention of diseases or conditions mediated by MRGPRX2 or its orthologs.

[0308] In one embodiment, the described use, wherein the disease or condition mediated by MRGPRX2 or its ortholog is selected from pseudoallergic reactions, pruritus-related symptoms, pain-related symptoms, inflammatory or autoimmune conditions;

[0309] In one protocol, pruritus-related symptoms include: chronic pruritus; contact dermatitis; allergic blepharitis; anemia; atopic dermatitis; bullous pemphigoid; candidiasis; chickenpox; end-stage renal failure; hemodialysis; chronic urticaria; contact dermatitis, atopic dermatitis; herpetic dermatitis; diabetes; drug allergy, dry skin; dyshidrotic dermatitis; atopic eczema; eosinophilic fasciitis; bullous epidermolysis; erythritis; food allergy; folliculitis; fungal skin infection; hemorrhoids; herpes; HIV infection; Hodgkin's disease; hyperthyroidism; iodinated contrast dye allergy; iron deficiency anemia; kidney disease; leukemia, porphyria; lymphoma; malignant tumors; mastocytosis. Symptoms; multiple myeloma; neurodermatitis; onchocerciasis; Paget's disease; lice infestation; polycythemia vera; nodular prurigo; lichen planus; lichen sclerosus; anal pruritus; pseudorabies; psoriasis; rectal prolapse; sarcoidosis granuloma; scabies; schistosomiasis; scleroderma, severe stress, stasis dermatitis; swimming pruritus; thyroid disease; tinea cruris; rosacea; cutaneous amyloidosis; scleroderma; acne; wound healing; burn healing; pruritus; or urticaria; more preferably, the pruritus-related symptoms are urticaria, chronic urticaria, chronic spontaneous urticaria, severe chronic urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema;

[0310] In one protocol, the pain-related symptoms include acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, joint fibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, ischemic necrosis, back pain, Behcet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical spinal stenosis, peroneal muscular atrophy (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, and lung collapse. Pneumothorax, complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, toothache, Delken's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilic-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatitis (dermatomyositis), knee injury, leg pain, low back pain and hematuria syndrome Lupus, Lyme disease, medullary sponge kidney (MSK), paresthesia of the femoral head, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsons-Turner syndrome, pelvic pain, periodontal pain, peripheral neuropathy, phantom limb pain, nerve compression, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, postherpetic neuralgia, post-mastectomy pain syndrome, post-mastectomy pain, post-stroke pain, post-thoracotomy pain syndrome, postherpetic neuralgia (shingles), post-poliomyelitis Syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Shulman's kyphosis, sciatica, scoliosis, herpes zoster (Herpes Zoster), Sjögren's syndrome, spasmodic torticollis, sphincter insufficiency, spinocerebellar ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, Tarlov's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, or vulvar pain.

[0311] In one protocol, the inflammatory or autoimmune condition is chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens Johnson syndrome, toxic epidermal necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (RSD / CRPS), rhinitis, tendinitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, or reactive airway disease. Asthma, airway infection, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, allergies, intestinal diseases, epithelial intestinal diseases, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, cardiovascular disease or vasculitis.

[0312] Unless otherwise specified, the terms used in this invention have the following meanings:

[0313] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0314] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0315] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0316] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0317] The term "prodrug" refers to a compound obtained by chemically modifying a drug, which has no or low activity in vitro, but releases an active drug in vivo through enzymatic or non-enzymatic conversion to exert its pharmacological effect.

[0318] The term "metabolites" refers to intermediate and final metabolites in metabolism.

[0319] The term "isotopic compound" refers to a compound in which one or more atoms can exist in their non-natural abundance form. Taking hydrogen atoms as an example, their non-natural abundance form means that approximately 95% of them are deuterium.

[0320] The term "pharmaceutical excipients" can refer to those excipients widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0321] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0322] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0323] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the clinical symptoms to subside.

[0324] The "prevention" mentioned in this invention refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0325] The expression "a group substituted by one or more substituents" means that one or more hydrogen atoms in a group are independently replaced by the substituent. When multiple substituents appear simultaneously, unless otherwise specified, their definitions are independent and do not affect each other. Therefore, if a group is substituted by one, two, or three R groups... 1 Group substitution, meaning that the group can be replaced by up to 3 R groups. 1 Replace, the position R 1 Definition and other positions R 1 The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0326] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0327] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0328] The term "alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0329] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C1-C2). 20 Alkylenes. The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C1-C1). 12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C1-C6 alkylenes). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0330] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds with a specified number of carbon atoms (e.g., C2-C6, C2-C4 alkynyl). These carbon-carbon triple bonds can be internal or terminal, such as ethynyl or propynyl with the triple bond internal. Or a propynyl group at the end of the triple bond

[0331] The term "alkoxy group" refers to the group -OR X R X The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0332] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C3-C). 20 Cycloalkyl groups. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., C3-C4). 12 Cycloalkyl, more preferably cycloalkyl having 3 to 8 ring atoms (i.e., C3-C8 cycloalkyl), and most preferably cycloalkyl having 3 to 6 ring atoms (i.e., C3-C6 cycloalkyl).

[0333] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0334] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0335] The term "spirocycloalkyl" refers to a polycyclic system in which the rings share a single carbon atom (called the spiro atom), and the rings may contain one or more double bonds. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C5 to C6). 20 Spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C6-C). 14 Spirocycloalkyl, more preferably spirocycloalkyl having 7 to 10 ring atoms (i.e., C7-C14). 10Spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 monospirocycloalkyl. Non-limiting examples include:

[0336] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. It is a fusion of a monocyclic cycloalkyl group with one or more other monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group. The ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C5-C). 20 The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., C6 to C7). 14 fused cycloalkyl groups, more preferably fused cycloalkyl groups having 7 to 10 ring atoms (i.e., C7 to C14). 10 The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.), preferably bicyclic fused cyclic alkyl groups or tricyclic fused cyclic alkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cyclic alkyl groups. Non-limiting examples include:

[0337] The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon system in which two non-directly bonded carbon atoms are shared between the rings. The ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C5-C). 20 Bridged cycloalkyl group). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., C6 to C5). 14 Bridged cycloalkyl groups, more preferably bridged cycloalkyl groups having 7 to 12 carbon atoms (C7-C4). 12Bridged cycloalkyl groups). The bridged cycloalkyl groups include bicyclic bridged cycloalkyl groups and polycyclic bridged cycloalkyl groups (such as tricyclic bridged cycloalkyl groups, tetracyclic bridged cycloalkyl groups, etc.), preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples include:

[0338] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3-20 membered heterocyclic group). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3-12 membered heterocyclic group); more preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3-8 membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3-6 membered heterocyclic group), a heterocyclic group having 4 to 6 ring atoms (i.e., a 4-6 membered heterocyclic group), or a heterocyclic group having 5 to 7 ring atoms (i.e., a 5-7 membered heterocyclic group); most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heterocyclic group).

[0339] Non-limiting examples of the monocyclic heterocyclic group include:

[0340] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0341] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheterocyclic groups). The spiroheterocyclic group is preferably a spiroheterocyclic group with 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocyclic groups), and more preferably a spiroheterocyclic group with 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocyclic groups). The spiroheterocyclic group includes monospirocyclic and multispirocyclic groups (such as bispirocyclic groups), preferably monospirocyclic or bispirocyclic, and more preferably ternary / quadrivalent, ternary / pentarivalent, ternary / hexavalent, quadrivalent / quadrivalent, quadrivalent / pentarivalent, quadrivalent / pentarivalent, quadrivalent / pentarivalent, quadrivalent / pentarivalent, pentari ... or pentarivalent / pentarivalent monospirocyclic groups. Non-limiting examples include:

[0342] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur. This system is formed by the fusion of a monocyclic heterocyclic group with one or more monocyclic heterocyclic groups, or by the fusion of a monocyclic heterocyclic group with one or more cycloalkyl, aryl, or heteroaryl groups. The bonding point is located on the monocyclic heterocyclic group, and the system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclic group). The fused heterocyclic group is preferably a fused heterocyclic group with 6 to 14 ring atoms (i.e., a 6-14-membered fused heterocyclic group), more preferably a fused heterocyclic group with 6 to 10 ring atoms (i.e., a 6-10-membered fused heterocyclic group), and more preferably a 6- or 7-membered fused heterocyclic group. The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic or tricyclic fused heterocyclic groups, more preferably ternary / quadricyclic, ternary / pentaricyclic, ternary / hexacyclic, quadricyclic / quadricyclic, quadricyclic / pentaricyclic, quadricyclic / pentaricyclic, pentari ...

[0343] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur. The system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group is preferably a bridged heterocyclic group with 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), more preferably a bridged heterocyclic group with 6 to 10 ring atoms (i.e., 6 to 10-membered bridged heterocyclic groups), and more preferably a 6-, 7-, or 8-membered bridged heterocyclic group. Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), with bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples include:

[0344] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered aryl). The aryl is preferably an aryl having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl is, for example, phenyl. Non-limiting examples of the polycyclic aryl include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl also includes fusion of phenyl, naphthyl with one or more heterocyclic or cycloalkyl groups (i.e., fused polycyclic aryl), wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0345] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, wherein the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl) or a heteroaryl having 9 or 10 ring atoms (i.e., 9 or 10-membered heteroaryl). The polycyclic aryl group further includes fusion of a monocyclic heteroaryl group with one or more heterocyclic groups or cycloalkyl groups (i.e., fused polycyclic heteroaryl groups), wherein the connection point is on the monocyclic heteroaryl group (if there are two connection points, this connection point refers to the connection point at the left end), and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0346] In this invention, R 1 The "oxidation" mentioned above refers to the oxidation of heteroatoms on ring A, for example, when ring A is... When N on ring A is oxidized, it can become

[0347] In this invention, R 1 The "oxidation" mentioned above refers to the oxidation of ring A, for example, when ring A is... At that time, R 1 For oxidation, that is It can be oxidized to When ring A is R 1 For oxidation, that is It can be oxidized to

[0348] In this invention, the C-ring shown is At that time, in the ring Ca It can be a single bond or a double bond.

[0349] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0350] The reagents and raw materials used in this invention are all commercially available.

[0351] The positive and progressive effect of this invention is that the compound of this invention has better antagonistic activity against MRGPRX2. Detailed Implementation

[0352] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0353] The structures of all compounds in this invention can be identified by nuclear magnetic resonance (1H NMR) and / or mass spectrometry (MS).

[0354] ¹H NMR chemical shifts (δ) were recorded in ppm (10⁻⁶). NMR was performed using a Bruker AVANCE-400 spectrometer.

[0355] LC-MS was performed using an Agilent 1200 HPLC / 6120 mass spectrometer.

[0356] The abbreviations used in the following experiments have the following meanings: DBN: 1,5-diazabicyclo[4.3.0]non-5-ene; DCC: N,N'-dicyclohexylcarbodiimide; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; Boc: tert-butyloxycarbonyl; DIPEA: N,N-diisopropylethylamine; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; LDA: lithium diisopropylaminodimethylamine; m-CPBA: m-chloroperoxybenzoic acid; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; TBDPS: tert-butyldiphenylsilyl; T3P: 1-propylphosphonic anhydride;

[0357] Preparation Example 1: Synthesis of Intermediate IN-1

[0358] The synthetic route for the target intermediate IN-1 is shown below:

[0359] Step 1: In a 50 mL reaction flask, add IN-1-1 (1.00 g, 6.62 mmol) and dichloromethane (20 mL), then add m-CPBA (1.71 g, 9.92 mmol). Stir the reaction mixture at room temperature for 2 hours. After sampling and analysis, wash the reaction solution with saturated sodium bicarbonate solution (20 mL × 2), separate the organic phase, concentrate and mix it directly, and separate by silica gel column chromatography to obtain compound IN-1-2 (600 mg). LC-MS: 184.1 [M + H] + .

[0360] Step 2: In a 50 mL reaction flask, add IN-1-2 (400 mg, 2.19 mmol) and tetrahydrofuran (10 mL). While stirring, add LiOH·H₂O (250 mg, 5.98 mmol) and pure water (10 mL). The reaction mixture is stirred at room temperature for 2 hours. After sampling and testing, add hydrochloric acid (2 M) to the reaction solution to adjust the pH to 4-6. Then, concentrate the reaction solution directly to dryness. Add dichloromethane (30 mL) and methanol (5 mL) to the dried crude product, stir for 15 minutes, and filter. The filtrate is then directly concentrated to obtain product IN-1-3 (320 mg). LC-MS: 170.1 [M+H] + .

[0361] Step 3: In a 100 mL reaction flask, add IN-1-4 (3.00 g, 13.50 mmol) and (R)-2-(toluenesulfonyloxy)propionic acid (4.39 g, 18.00 mmol), then add ethyl acetate (50.00 mL) and pyridine (2.90 g, 40.5 mmol), and finally add 50% T3P solution (5.72 g, 18.00 mmol). Stir the reaction at room temperature for 18 hours, then collect a sample for analysis. After the reaction is complete, add 50 mL of pure water, stir, and separate the organic phase. Extract the aqueous phase again with ethyl acetate (50 mL). Combine the organic phases, concentrate, and pass through a column chromatography column to separate the compound IN-1 (2.2 g). LC-MS: 449.7 [M+H] + .

[0362] Preparation Example 2: Synthesis of Intermediate IN-2

[0363] The synthetic route for the target intermediate IN-2 is shown below:

[0364] Step 1: At 0°C, imidazole (13 g, 192 mmol) and tert-butyldiphenylchlorosilane (26.4 g, 96 mmol) were added sequentially to a DCM (120 mL) solution of 2-bromoethyl-1-ol (12 g, 96 mmol). The mixture was heated to room temperature and stirred for 3 hours. A saturated aqueous solution of NH4Cl was added to the reaction mixture, and the aqueous layer was extracted with DCM (120 mL x 3). The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain compound (2-bromoethoxy)(tert-butyl)diphenylsilane (28 g).

[0365] Step 2: NaI (14.8 g, 99 mmol), (2-bromoethoxy)(tert-butyl)diphenylsilane (24 g, 66 mmol), and K₂CO₃ (18.2 g, 132 mmol) were added to a DMF (240 mL) solution of methyl 6-oxo-1H-pyridine-3-carboxylate (10 g, 66 mmol) and K₂CO₃ (18.2 g, 132 mmol). The reaction mixture was stirred at 80°C for 12 h, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was poured into water (400 mL) and extracted with EA (200 mL × 3). The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain methyl 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (20 g). LC / MS: [M+H] + =436.2.

[0366] Step 3: At room temperature, methyl 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (16 g, 36.7 mmol) was added to MeOH (150 mL), THF (150 mL), and water (150 mL). LiOH (1.05 g, 44 mmol) was added in portions under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the pH was adjusted to 5-6 with 1N hydrochloric acid. The mixture was filtered to obtain a filter cake, which was then dried under vacuum to give compound 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid IN-2 (10.3 g). LC / MS: 422.2 [M+H] + .

[0367] Preparation Example 3: Synthesis of Intermediate IN-3

[0368] The synthetic route for the target intermediate IN-3 is shown below:

[0369] Step 1: Methyl 6-oxo-1H-pyridine-3-carboxylate (7.00 g, 45.40 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (13.03 g, 54.48 mmol) were dissolved in DMF (90 mL), and sodium iodide (1.36 g, 9.08 mmol) and potassium carbonate (12.55 g, 90.80 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and poured into ice water (200 mL). Extraction was performed with ethyl acetate (150 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (PE / EA = 1:1) to obtain methyl 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5-oxopyrazine-2-carboxylate (7.80 g). LCMS: 313.1 [M+H] + .

[0370] Step 2: Methyl 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5-oxopyrazine-2-carboxylic acid (8.20 g, 26.20 mmol) was dissolved in tetrahydrofuran (100 mL), and potassium trimethylsilanolate (4.37 g, 34.06 mmol) was added. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, the solution was evaporated to dryness and concentrated. It was then diluted with water (100 mL), and the pH was adjusted to 6-7 with dilute hydrochloric acid (1 M). The solid precipitated, filtered, and washed with water (10 mL × 3). The solid was dried to obtain 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyrazine-2-carboxylic acid IN-3 (5.40 g). LCMS: 299.1 [M+H] + .

[0371] Preparation Example 4: Synthesis of Intermediate IN-4

[0372] The synthetic route for the target intermediate IN-4 is shown below:

[0373] Step 1: Methyltriphenylphosphine bromide (39.29 g, 0.11 mol) was suspended in tetrahydrofuran (500 mL) solution. Under nitrogen protection at 0 °C, n-butyllithium (63.3 mL, 1.6 M, 0.10 mol) was added dropwise, and the mixture was stirred for 1 hour. Then, a tetrahydrofuran solution (50 mL) of 2,2-dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (10.00 g, 0.04 mol) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 15 hours. After the reaction was complete, the reaction solution was poured into an ice-cold saturated ammonium chloride aqueous solution (500 mL), extracted with ethyl acetate (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. Purification by silica gel column chromatography yielded 2,2-dimethyl-4-methylenepiperidine-1-carboxylic acid tert-butyl ester (5.00 g). LCMS: 170.1 [M+1-100] + .

[0374] Step 2: At room temperature, add rhodium dimer acetate (0.49 g, 1.11 mmol) to a dichloromethane solution of 2,2-dimethyl-4-methylenepiperidine-1-carboxylic acid tert-butyl ester (2.50 g, 11.10 mmol) (100 mL). Under nitrogen protection, add dichloromethane solution of ethyl diazonate (2.53 g, 22.20 mmol) (20 mL). After the addition is complete, continue stirring for 16 hours. After the reaction is complete, quench the reaction solution in an ice-cold aqueous acetic acid solution (1 M, 50 mL), extract with dichloromethane (100 mL × 3), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate by rotary evaporation, and purify by silica gel column chromatography to obtain 6-(tert-butyl)-1-ethyl 5,5-dimethyl-6-azaspiro[2.5]octane-1,6-dicarboxylic acid ester (3.20 g). LCMS: 212.1 [M+1-100] + .

[0375] Step 3: 6-(tert-butyl)-1-ethyl 5,5-dimethyl-6-azaspiro[2.5]octane-1,6-dicarboxylic acid ester (5.00 g, 16.10 mmol) was dissolved in ethanol (60 mL), and an aqueous solution of sodium hydroxide (1.93 g, 48.30 mmol) (20 mL) was added. The mixture was stirred at 45 °C for 16 hours. After the reaction was completed, the ethanol was removed, and the pH of the reaction solution was adjusted to 6-7 with dilute hydrochloric acid (1 M). The solution was concentrated by rotary evaporation and purified by silica gel column chromatography to obtain 6-(tert-butyloxycarbonyl)-5,5-dimethyl-6-azaspiro[2.5]octane-1-carboxylic acid (3.10 g). LCMS: 184.1 [M+1-100] + .

[0376] Step 4: Dissolve 6-(tert-butoxycarbonyl)-5,5-dimethyl-6-azaspiro[2,5]octane-1-carboxylic acid (2.73 g, 9.62 mmol) and 5-(2,4-difluorophenoxy)pyridine-2-amine (1.65 g, 7.40 mmol) in DMF (25 mL), add DIEA (2.87 g, 22.20 mmol) and HATU (4.22 g, 11.10 mmol), and stir at room temperature for 1 minute. After 6 hours of reaction, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to obtain tert-butyl-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)carbamoyl)-5,5-dimethyl-6-azaspiro[2,5]octane-6-carboxylic acid ester NI-4 (0.95 g). LCMS: 488.1 [M+1] + .

[0377] Example 1: Synthesis of Compound I-1

[0378] first step:

[0379] Compound I-1-1 (2 g, 12.62 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of compound I-1-2 (2.46 g, 18.93 mmol) and potassium carbonate (2.61 g, 18.93 mmol). The mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (100 mL × 3), and washed with saturated brine (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The solution was concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound I-1-3 (2.40 g, yield 76%). LC-MS: 252.8 [M + H] + .

[0380] Step Two:

[0381] Compound I-1-3 (2.40 g, 9.52 mmol) was dissolved in a mixed solution of ethanol (30 mL) and tetrahydrofuran (10 mL). Iron powder (1.86 g, 33.21 mmol) and glacial acetic acid (2 mL) were added sequentially, and the mixture was heated to 70 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and a saturated sodium carbonate aqueous solution was added to the reaction solution until neutral. The solution was extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give crude compound I-1-4 (2.0 g, 95% yield). LC-MS: 222.9 [M + H] + .

[0382] Step 3:

[0383] Compound I-1-4 (300 mg, 1.35 mmol) and (R)-(+)-2-bromopropionic acid (I-1-5, 370 mg, 2.42 mmol) were dissolved in dichloromethane (25 mL), followed by the sequential addition of silver nitrate (36 mg, 0.21 mmol) and N,N'-dicyclohexylcarbodiimide (500 mg, 2.43 mmol). The reaction was carried out overnight at room temperature under argon protection with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:20) to give compound I-1-6 (440 mg, yield 91%). LC-MS: 357.7 [M+H] + .

[0384] Step 4:

[0385] Compounds I-1-6 (200 mg, 0.56 mmol), I-1-7 (130 mg, 0.61 mmol), and triethylamine (65 mg, 0.64 mmol) were dissolved in DMF (2 mL) and reacted overnight at room temperature with stirring. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (50 mL × 4), then with saturated brine (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:25) to give I-1-8 (113 mg, yield 42%). LC-MS: 489.1 [M + H] + .

[0386] Step 5:

[0387] Compound I-1-8 (113 mg, 0.23 mmol) was dissolved in dichloromethane (1 mL), and a solution of 1,4-dioxane hydrogen chloride (0.3 mL, 1.18 mmol, 4 M) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solution was concentrated to give crude hydrochloride of compound I-1-9 (125 mg). LC-MS: 389.1 [M+H] + .

[0388] Step 6:

[0389] The hydrochloride salt (125 mg) of I-1-9 from the previous step and compound I-1-10 (50 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of HATU (130 mg, 0.34 mmol) and N,N-diisopropylethylamine (55 mg, 0.426 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate (60 mL) was added for dilution. The organic phase was washed with water (30 mL × 4) and saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (dichloromethane / methanol = 100:8) to give compound I-1 (37 mg, yield 24%). LC-MS: 510.0 [M + H] + . 1 H NMR (400MHz, CDCl3) δ13.05(s,1H),9.63(s,1H),8.22(d,J=9.0Hz,1H),8.09(d,J=2.5Hz,1H),7 .65(s,1H),7.58(d,J=9.3Hz,1H),7.32(dd,J=9.0,2.7Hz,1H),7.08(td,J=8.9,5.5Hz,1H),7.0 3–6.93(m,1H),6.89(t,J=7.6Hz,1H),6.60(d,J=9.4Hz,1H),4.3-3.78(m,1H),3.63-3.40(m,2H ),3.38-3.16(m,2H),3.15-3.0(m,1H),2.02(s,1H),1.92-1.50(m,4H),1.35(t,J=16.8Hz,3H).

[0390] Example 2 Synthesis of Compound I-2

[0391] first step:

[0392] Compound I-1-1 (1.58 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of I-2-1 (1.7 g, 15.14 mmol) and potassium carbonate (2.1 g, 15.22 mmol). The mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature and diluted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL × 3), then with saturated brine (100 mL × 3), and finally dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give I-2-2 (1.80 g, yield 77%). LC-MS: 234.8 [M + H] + .

[0393] Step Two:

[0394] Compound I-2-2 (1.80 g, 7.69 mmol) was dissolved in a mixture of ethanol (30 mL) and tetrahydrofuran (10 mL). Iron powder (1.3 g, 23.21 mmol) and glacial acetic acid (2 mL) were added sequentially, and the mixture was heated to 70 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and a saturated sodium carbonate aqueous solution was added to the reaction solution until neutral. The solution was extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give I-2-3 (1.44 g, 92% yield). LC-MS: 204.9 [M + H] + .

[0395] Step 3:

[0396] I-2-3 (300 mg, 1.47 mmol) and (R)-(+)-2-bromopropionic acid (I-1-5, 420 mg, 2.74 mmol) were dissolved in dichloromethane (25 mL), followed by the addition of silver nitrate (40 mg, 0.24 mmol) and N,N'-dicyclohexylcarbodiimide (590 mg, 2.87 mmol). The mixture was stirred overnight at room temperature under argon protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:20) to give I-2-4 (420 mg, yield 84%). LC-MS: 338.7 [M+H] + .

[0397] Step 4:

[0398] Compounds I-2-4 (200 mg, 0.59 mmol), I-2-5 (130 mg, 0.61 mmol), and triethylamine (78 mg, 0.77 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, ethyl acetate (60 mL) was added for dilution. The organic phase was washed with water (40 mL × 4), washed with saturated brine (30 mL × 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:35) to give compound I-2-6 (250 mg, yield 90%), LC-MS: 471.1 [M + H]. + .

[0399] Step 5:

[0400] Compound I-2-6 (250 mg, 0.53 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane hydrogen chloride (0.4 mL, 1.6 mmol, 4 M) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated and evaporated to dryness to give crude hydrochloride of compound I-2-7 (225 mg). LC-MS: 370.9 [M+H]+ .

[0401] Step 6:

[0402] The hydrochloride salt of compound I-2-7 (225 mg, 0.554 mmol) and I-1-10 (100 mg, 0.72 mmol) from the previous step were dissolved in N,N-dimethylformamide (2 mL). HATU (300 mg, 0.79 mmol) and N,N-diisopropylethylamine (120 mg, 0.93 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), then with saturated brine (30 mL × 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified sequentially by Pre-HPLC and silica gel chromatography (dichloromethane:methanol = 100:6) to give compound I-2 (18 mg, yield 7%). LC-MS: 492.1 [M + H] + . 1 H NMR (400MHz, CDCl3) δ9.41 (s, 1H), 8.21 (d, J = 8.6Hz, 1H), 8.11 (d, J = 12.6Hz, 1H),7.86(s,1H),7.80(d,J=9.2Hz,1H),7.36(d,J=7.7Hz,1H),7.05(d,J=7.5 Hz,2H),6.99(s,2H),6.60(d,J=9.2Hz,1H),4.05-3.80(m,2H),3.72-3.55(m ,2H),3.3-3.1(m,1H),2.97(s,2H),2.88-2.52(m,4H),1.43(d,J=5.4Hz,3H).

[0403] Example 3 Synthesis of Compound I-3

[0404] Step 1: I-1-4 (500 mg, 2.25 mmol) was dissolved in dichloromethane (10 mL). I-3-1 (1.40 g, 5.73 mmol), T3P (3.00 g, 50% ethyl acetate solution), and triethylamine (1.00 g) were added at room temperature, and the reaction was allowed to proceed for 22 hours at room temperature. After the reaction was complete, the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-3-2 (600 mg, yield 59.47%), LC-MS: 449.2 [M+H]. + .

[0405] Step 2: Compound 2-chloro-5-fluoropyridine (I-3-4, 1.50 g, 10 mmol) was added to DMF (30 mL). Sodium hydride (700 mg) and I-3-3 (2.63 g, 10 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. Water (50 mL) and ethyl acetate (200 mL) were added to the reaction mixture, and the mixture was separated. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-3-5 (2.00 g, yield 51.45%), LC-MS: 341.1 [M+H]. + .

[0406] Step 3: I-3-5 (2.00 g, 5.87 mmol) was dissolved in dioxane (25 mL), and potassium hydroxide (1.00 g), Pd2(dba)3 (0.50 g), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.50 g), and water (3 mL) were added at room temperature. The reaction mixture was reacted at 110 °C for 22 hours. After the reaction was complete, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-3-6 (1.50 g, yield 79.29%), LC-MS: 323.1 [M+H]. + .

[0407] Step 4: Dissolve I-3-6 (1.50 g, 4.65 mmol) in ethyl acetate (10 mL), add ethyl hydrochloride solution (10 mL, 2 M) at room temperature, and react for 22 hours at room temperature. Filter and dry to give white solid I-3-7 (1.00 g, yield 96.68%), LC-MS: 223.1 [M+H] + .

[0408] Step 5: Compound I-3-2 (100 mg, 0.22 mmol) was added to DMF (5 mL), and I-3-7 (60 mg, 0.27 mmol) and triethylamine (50 mg) were added to the reaction mixture. The reaction mixture was reacted at room temperature for 5 days. After the reaction was complete, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-3 (20 mg, yield 17.99%), LC-MS: 499.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.04(d,J=13.1Hz,1H),8.14(dd,J=12.2,6.0Hz,2H),7.50(ddd,J=10.9,7. 4,3.8Hz,2H),7.30(dt,J=9.9,5.2Hz,2H),7.19–7.03(m,2H),6.33(d,J=9.8Hz,1H),3.71–3.55(m,1H ),3.44(dd,J=16.7,7.0Hz,1H),2.76(s,1H),2.29(m,3H),2.14(dd,J=15.2,11.4Hz,1H),1.81(s,1H ), 1.64 (dd, J = 27.8, 10.0Hz, 1H), 1.16 (t, J = 6.2Hz, 3H), 1.08 (d, J = 4.9Hz, 3H), 1.01 (d, J = 6.8Hz, 3H).

[0409] Example 4: Synthesis of compounds I-4-a and I-4-b

[0410] Step 1: Compounds I-4-1 (300 mg, 1.44 mmol, prepared according to the method in patent WO2021092240A1) and I-1-5 (440 mg, 2.88 mmol) were dispersed in dichloromethane (15 mL), and triethylamine (550 mg, 5.4 mmol) and 50% 1-propylphosphonic anhydride (700 mg, 2.20 mmol) were added. The reaction was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 0-100% gradient). The product was collected and concentrated to give compound I-4-2 (450 mg, 91.4% yield), LC-MS: 342.7 [M+H]. + .

[0411] Step 2: Weigh palladium acetate (684 mg, 3.04 mmol) and sodium tert-butoxide (7.28 g, 75.80 mmol) into a round-bottom flask, and add tetrahydrofuran (80 mL). The system is protected with nitrogen and stirred at 45 °C for 10 minutes. Finally, I-4-3 (8.00 g, 30.29 mmol) and I-4-4 (9.05 g, 45.44 mmol) are added, and the mixture is stirred at 45 °C for 18 hours. After the reaction is complete, the reaction is quenched with water, and the mixture is extracted with ethyl acetate (80 mL × 3). The organic phases are combined and concentrated. The residue is purified by column chromatography (petroleum ether:ethyl acetate = 0%–100%, V / V) to give a white solid I-4-5 (4 g). LC-MS: 382.9 [M + H] + .

[0412] Step 3: Weigh compound I-4-5 (3 g, 7.84 mmol) into a round-bottom flask and add dichloromethane (30 mL). The reaction system was stirred in an ice bath for 5 minutes, and diethylaminotrifluoride (2.53 g, 15.69 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 18 hours. After the reaction was complete, the system was cooled in an ice bath and quenched by slowly adding ice water (5 mL). Extraction was performed with dichloromethane (50 mL × 3). The organic phases were combined and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 0%–50%, V / V) to give a colorless oily substance I-4-6 (1.80 g). LC-MS: 405.2 [M + H] + .

[0413] Step 4: Weigh compound I-4-6 (2 g, 4.94 mmol) into a round-bottom flask, add methanol (40 mL) and palladium on carbon (10 wt.%, 1 g), and react the system at room temperature for 2 hours under a hydrogen atmosphere. After the reaction is complete, filter the mixture, wash the filter cake with methanol (60 mL), concentrate the filtrate to obtain a racemic crude product (1 g), and separate it by supercritical fluid chromatography (1. Instrument: Waters 150SFC; 2. Column: Chiralpak IC, 3 × 15 cm, 5 μm; 3. Mobile phase A: carbon dioxide, mobile phase B: isopropanol; 4. Flow rate: 80 mL / min) to obtain compounds I-4-7-a and I-4-7-b.

[0414] Compound I-4-7-a: 420 mg, supercritical fluid (SFC) retention time = 4.12 min, LC-MS: 315.2 [M+H] + .

[0415] Compound I-4-7-b: 530 mg, supercritical fluid (SFC) retention time = 4.96 min, LC-MS: 315.2 [M+H] + .

[0416] Step 5: Compound I-4-7-a (420 mg, 0.48 mmol) was placed in a round-bottom flask, and 5 mL of hydrochloric acid-ethanol solution was added. The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the solution was concentrated to dryness to obtain 300 mg of I-4-8-a hydrochloride solid. LC-MS: 215.2 [M+H] + .

[0417] Compound I-4-7-b (530 mg, 1.68 mmol) was placed in a round-bottom flask, and 5 mL of hydrochloric acid-ethanol solution was added. The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the solution was concentrated to dryness to give 350 mg of I-4-8-b hydrochloride solid. LC-MS: 215.2 [M+H] + .

[0418] Step 6: Dissolve 100 mg of solid hydrochloride of compound I-4-8-a and 100 mg (0.30 mmol) of I-4-2 in N,N-dimethylformamide (5 mL), add N,N-diisopropylethylamine (260 mg, 1.99 mmol), and stir the reaction overnight at room temperature. After the reaction was complete, water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated. The residue was separated by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% TFA in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 30-95%; 5. Flow rate: 40 mL / min; 6. Retention time: 8.02 min). The product was collected, concentrated, and lyophilized to obtain compound I-4-a (25 mg). LC-MS: 477.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.71(d,J=108.2Hz,2H),7.44–7.32(m,2H),7.32–7.03(m,5H),6.29(d,J=9.5Hz,1H),4.12(s ,2H),3.71–3.57(m,1H),3.27–3.09(m,1H),2.94–2.70(m,3H),2.47(s,1H),2.08(s,2H),1.23(dd,J=16.7,7.0Hz,3H).

[0419] The hydrochloride solid of compound I-4-8-b (205 mg) and I-4-2 (200 mg, 0.60 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (500 mg, 3.9 mmol) was added. The reaction was stirred overnight at room temperature. After the reaction was complete, water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated. The residue was separated by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% TFA in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 30-95%; 5. Flow rate: 40 mL / min; 6. Retention time: 7.92 min). The product was collected, concentrated, and lyophilized to obtain compound I-4-b (25 mg). LC-MS: 477.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.62(d,J=11.6Hz,1H),7.44(s,1H),7.33(td,J=7.9,6.1Hz,1H),7.24(s,1H),7.10(d,J=7.4Hz,1H),6.99(dd,J=17.9,9.1Hz,2H ),6.52(d,J=9.5Hz,1H),4.14(s,2H),3.60(q,J=7.0Hz,1H),2.99(s,1H),2 .79(ddd,J=32.2,22.2,11.5Hz,3H),2.25–2.14(m,2H),1.41–1.29(m,4H).

[0420] Example 5: Synthesis of compounds I-5-a and I-5-b

[0421] Step 1: Compounds I-5-1 (10 g, 40 mmol) and I-5-2 (8.19 g, 40 mmol) were dissolved in methanol (180 mL), and stirred at 35 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, v / v) to give a white solid I-5-3 (9 g, yield: 47%). LC-MS: 396.1 [M+H] + .

[0422] Step 2: Compounds I-5-4 (6 g, 15.20 mmol) and I-5-4 (1.63 g, 15.20 mmol) were dissolved in 1,4-dioxane (70 mL), and cesium carbonate (7.43 g, 22.80 mmol) was added. The mixture was stirred at 110 °C for 16 hours under argon protection. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, V / V) to give I-5-5 (700 mg, yield: 10%). LC-MS: 319.2 [M+H] + .

[0423] Step 3: Compound I-5-5 (950 mg, 2.98 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperoxybenzoic acid (618 mg, 3.58 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1, v / v) to give a white solid I-5-6 (500 mg, yield: 45%). LC-MS: 335.2 [M+H] + .

[0424] Step 4: Compound I-5-6 (480 mg, 1.44 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and purified by prep-HPLC (ACN / H2O) to obtain the trifluoroacetate salt of compound I-5-7 (230 mg, yield: 66%). LC-MS: 235.1 [M+H] + .

[0425] Step 5: Weigh compound I-3-2 (350 mg, 0.78 mmol), trifluoroacetate of I-5-7 (814 mg, 2.34 mmol), and lithium trifluoromethanesulfonate (122 mg, 0.78 mmol) into a round-bottom flask, add acetonitrile (5.00 mL), then add triethylamine (438.49 μL, 3.12 mmol), protect the system with nitrogen, and stir at 30 °C for 48 hours. After the reaction was complete, the mixture was concentrated, and the residue was sent for high-performance liquid chromatography (HPLC) separation (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% TFA in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 15-95%; 5. Flow rate: 40mL / min), separating two components:

[0426] Component 1 was collected, concentrated, and lyophilized to give compound I-5-a (7.93 mg), retention time: 5.957 min. LC-MS: 511.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.19(d,J=6.9Hz,2H),8.16(d,J=3.0Hz,1H),8.13 (d,J=9.1Hz,1H),7.54–7.45(m,2H),7.40(d,J=6.5Hz,2H),7.35–7.26(m,1H),7.18–7.07 (m,1H),3.85(s,1H),3.44(q,J=7.0Hz,1H),2.91–2.79(m,1H),2.44(d,J=10.9Hz,1H),2. 38–2.27(m,3H),1.33(d,J=13.7Hz,1H),1.20(d,J=6.9Hz,3H),1.04(s,3H),0.39(s,3H).

[0427] Component 2 was collected, concentrated, and lyophilized to give compound I-5-b (9.72 mg), retention time: 6.353 min. LC-MS: m / z: (M+H) + =511.1. 1H NMR(400MHz, DMSO-d6)δ10.09(s,1H),8.18(d,J=6.6Hz,2H),8.14(d,J=12Hz,1H),8.14–8.1 1(m,1H),7.54–7.46(m,2H),7.39(d,J=6.5Hz,2H),7.34–7.27(m,1H),7.16–7.10(m,1H),3.8 6(s,1H),3.52(q,J=6.9Hz,1H),2.85(d,J=10.7Hz,1H),2.69–2.60(m,1H),2.47–2.38(m,1H) ,2.31–2.14(m,2H),1.32(d,J=14.1Hz,1H),1.18(d,J=6.9Hz,3H),1.04(s,3H),0.37(s,3H).

[0428] Example 6 Synthesis of compounds I-6-a and I-6-b

[0429] Step 1: Compounds I-1-4 (300 mg, 1.35 mmol) and I-6-1 (380 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (620 mg, 1.62 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, ethyl acetate (150 mL) was added for dilution. The organic phase was washed with water (60 mL × 4) and saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:20) to obtain I-6-2 (560 mg, yield 90%).

[0430] LC-MS: 460.1 [M+H] + .

[0431] Step 2: I-6-2 (560 mg, 1.22 mmol) was dissolved in dichloromethane (10 mL), and a hydrogen chloride-dioxane solution (2 mL, 4 M) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solution was concentrated to obtain I-6-3 hydrochloride (580 mg). LC-MS: 360.1 [M+H] + .

[0432] Step 3: Dissolve I-6-3 hydrochloride (0.20 g, 0.5 mmol) and I-1-10 (70 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL), then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (230 mg, 0.6 mmol) and N,N-diisopropylethylamine (200 mg, 1.55 mmol) in sequence, and stir the mixture at room temperature for 2 hours. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (50 mL × 4), then with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 100:8, V / V) to obtain a racemic mixture (95 mg). This racemic mixture was separated by supercritical fluid chromatography (1. Instrument: Waters 150SFC; 2. Column: Chiralpak IC, 3 × 15 cm, 5 μm; 3. Mobile phase A: carbon dioxide, mobile phase B: methanol; 4. Flow rate: 80 mL / min). Two components were separated:

[0433] Fraction 1 was collected, concentrated, and lyophilized to give compound I-6-b (35 mg), with a retention time of 7.02 min. LC-MS: 481.0 [M+H] + , 1 HNMR(400MHz, CDCl3)δ12.86(s,1H),9.24(s,1H),8.20(s,1H),8.04(s,1H),7.61(d,J=34.8Hz,2H),7.16–6.77(m,3H),6.58(s,1H),3.8 0-3.55(m,3H),3.53-3.40(m,1H),2.30-1.95(m,1H),1.91-1.80(m,2H),1.72(s,1H),1.63-1.51(m,1H),1.43-1.35(m,1H),1.03(s,1H).

[0434] Fraction 2 was collected, concentrated, and lyophilized to obtain compound I-6-a (32 mg), retention time: 8.07 min. LC-MS: 481.0 [M+H] + , 1HNMR (400MHz, CDCl3) δ12.99(s,1H),9.43(s,1H),8.20(s,1H),8.04(s,1H),7.57(s,2H),7.32(d,J=8.6Hz,1H),7.08(s,1H),6.98(s,1H),6.89(s ,1H),6.58(s,1H),3.85-3.55(m,3H),3.55-3.4(m,1H),2.6-1.98(m,1H) ,1.84(s,2H),1.74(s,1H),1.62-1.45(m,1H),1.39(s,1H),1.02(s,1H).

[0435] Example 7 Synthesis of Compound I-7

[0436] Step 1: Compounds I-1-6 (500 mg, 1.40 mmol) and I-7-1 (350 mg, 1.65 mmol) were added to DMF (5 mL), followed by triethylamine (500 mg). The reaction mixture was reacted at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-7-2 (250 mg, yield 37%). LC-MS: 489.2 [M+H] + .

[0437] Step 2: I-7-2 (250 mg, 0.51 mmol) was added to an ethyl hydrochloride solution (8 mL, 2 M), and the reaction was carried out at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was dried to give a white solid, I-7-3 hydrochloride (150 mg, yield 75%), LC-MS: 389.1 [M+H]. + .

[0438] Step 3: The I-7-3 hydrochloride (85 mg) and I-1-10 (35 mg, 0.25 mmol) obtained in the previous step were added to DMF (5 mL), followed by T3P (300 mg) and triethylamine (150 mg). The reaction mixture was reacted at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-7 (40 mg, yield 36%). LC-MS: 510.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.83(s,1H),9.95(s,1H),8.11(dd,J=25.4,6.0Hz,2H),7.50(ddd ,J=13.6,9.5,5.0Hz,4H),7.30(d,J=5.6Hz,1H),7.13(ddd,J=10.9,3.8,2.3Hz,1H),6.34(d ,J=9.4Hz,1H),3.88(d,J=6.9Hz,1H),3.59(s,2H),3.39(s,2H),3.19–2.97(m,1H),2.97–2. 81(m,1H),1.33(d,J=6.9Hz,3H),0.84(t,J=5.8Hz,1H),0.65(d,J=5.6Hz,2H),0.42(s,1H).

[0439] Example 8 Synthesis of Compounds I-8

[0440] Step 1: I-3-2 (300 mg, 0.67 mmol) and I-8-1 (264 mg, 1.33 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (173 mg, 1.34 mmol) was added. The mixture was stirred at 30 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%, V / V) to give a pale yellow liquid I-8-2 (290 mg, yield 92%). LC-MS: 475.1 [M+H] + .

[0441] Step 2: Compound I-8-2 (110 mg, 0.23 mmol) and ethyl acetate hydrochloride (5 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a yellow solid I-8-3 (80 mg, yield 92%), LC-MS: 375.2 [M+H]. + .

[0442] Step 3: Compound I-1-10 (36 mg, 0.26 mmol), N,N-dimethylformamide (2 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (106 mg, 0.28 mmol), N,N-diisopropylethylamine (55 mg, 0.43 mmol), and I-8-3 (80 mg, 0.21 mmol) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, and the sample was sent for preparative HPLC separation to obtain a white solid I-8 (13.60 mg). LC-MS: 496.2 [M+H] + ,1 HNMR(400MHz, CDCl3)δ9.62(s,1H),8.28(d,J=9.0Hz,1H),8.07(d,J=2.5Hz,3H),7.37(dd,J=9.0,2.5Hz,1H),7.17–6.85(m,3H), 6.62(d,J=9.5Hz,1H),4.10(s,1H),3.63–3.26(m,2H),3.07–2.73(m,3H),2.61(s,1H),1.53(dd,J=30.3,7.0Hz,3H),0.94(s,2H).

[0443] Example 9: Synthesis of Compounds I-9

[0444] Step 1: Compounds I-3-2 (150 mg, 0.33 mmol), I-9-1 (70 mg, 0.33 mmol), and N,N-diisopropylethylamine (55 mg, 0.426 mmol) were dissolved in dimethyl sulfoxide (3 mL) and reacted with the solution at room temperature for 72 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (80 mL). The organic phase was washed with water (50 mL × 4), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:35, v / v) to give I-9-2 (100 mg). LC-MS: 488.8 [M + H] + .

[0445] Step 2: Compound I-9-2 (100 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane hydrogen chloride (0.3 mL, 1.2 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated to obtain I-9-3 hydrochloride (100 mg). LC-MS: 388.8 [M+H] + .

[0446] Step 3: Dissolve I-9-3 hydrochloride (100 mg, 0.2 mmol) and I-1-10 (30 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL). Then, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (87 mg, 0.23 mmol) and N,N-diisopropylethylamine (55 mg, 0.426 mmol) sequentially to the reaction flask and stir at room temperature for 2 hours. After the reaction is complete, dilute with ethyl acetate (60 mL), wash the organic phase with water (30 mL × 4), wash with saturated brine (30 mL × 3), dry with anhydrous sodium sulfate, concentrate, and purify by high-performance silica gel chromatography (developing solvent: dichloromethane / methanol = 100:8) to obtain I-9 (35 mg, yield 34.38%). LC-MS: 510.1 [M + H] + , 1 H NMR (400MHz, CDCl3) δ12.57(s,1H),9.28(s,1H),8.21(d,J=7.4Hz,1H),8.08(t,J=3.0Hz,1 H),7.86-7.52(m,2H),7.33(s,1H),7.14–7.03(m,1H),6.99(t,J=9.5Hz,1H),6.89(t,J=7.7 Hz,1H),6.61(d,J=9.5Hz,1H),4.12-3.82(m,2H),3.47-3.32(m,1H),3.31-3.12(m,1H),3. 16-2.88(m,2H),2.28-2.12(s,1H),2.08-1.88(m,2H),1.7-1.62(m,2H),1.51–1.38(m,3H).

[0447] Example 10 Synthesis of compound I-10-a

[0448] Step 1: Weigh compound I-3-2 (500 mg, 1.12 mmol) into a round-bottom flask, add acetonitrile (3 mL) and triethylamine (0.19 mL, 1.34 mmol), then add I-10-1 (265 mg, 1.34 mmol). Stir the reaction mixture at room temperature for 18 hours. After the reaction is complete, concentrate the mixture directly. Separate the residue by silica gel column chromatography (dichloromethane:methanol = 0%–10%, V / V) to obtain compound I-10-2 (501 mg). LC-MS: 475.2 [M+H] + .

[0449] Step 2: Weigh compound I-10-2 (501 mg, 1.05 mmol) into a round-bottom flask, add dichloromethane (5 mL), then add tert-butyldimethylsilyltrifluoromethanesulfonate (365 mg, 1.45 mmol). Stir the reaction mixture at room temperature for 18 hours. After the reaction is complete, concentrate the solution to obtain crude compound I-10-3 (900 mg), which is used directly in the next step. LC-MS: 375.2 [M+H] + .

[0450] Step 3: Weigh compound I-1-10 (15 mg, 0.11 mmol) and N,N-diisopropylethylamine (28 mg, 0.22 mmol) into a round-bottom flask, then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (41.10 mg, 0.11 mmol). Protect the system with nitrogen and stir at room temperature for 5 minutes. Finally, add I-10-3 (48 mg, 0.13 mmol) and stir at room temperature for 18 hours after the addition is complete. After the reaction was complete, the mixture was concentrated, and the residue was separated by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 10-40%; 5. Flow rate: 40 mL / min; 6. Retention time: 7.62 min), yielding compound I-10-a (14.41 mg). LC-MS: 496.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.26(d,J=7.4Hz,1H),9.92(s,1H),8.22–8.12(m,2H),8 .12–8.03(m,1H),7.81–7.55(m,1H),7.54–7.43(m,2H),7.38–7.25(m,1H),7.19–7 .08(m,1H),6.40–6.30(m,1H),4.62–4.32(m,1H),3.80–3.65(m,1H),3.64–3.31(m ,3H),3.07–2.88(m,1H),2.88–2.62(m,1H),1.91–1.61(m,2H),1.31–1.18(m,3H).

[0451] Example 11 Synthesis of compounds I-11-a and I-11-b

[0452] Step 1: Compounds I-1-6 (400 mg, 1.12 mmol) and I-11-1 (280 mg, 1.30 mmol) were dispersed in N,N-dimethylformamide (10 mL), and triethylamine (340 mg, 3.30 mmol) was added. The reaction mixture was stirred at 25-30 °C for 18 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with 5% sodium chloride (20 mL). The organic phase was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100% gradient elution) to give I-11-2 (400 mg, yield 72.8%), LC-MS: 490.8 [M+H]. + .

[0453] Step 2: Compound I-11-2 (400 mg, 0.81 mmol) was dissolved in methanol (4 mL), and ethyl acetate hydrochloride solution (20 mL, 2 M) was added dropwise. The reaction was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane / methanol = 0%-10%, V / V). The column was washed to obtain compound I-11-3 (300 mg), LC-MS: 391.1 [M+H]. + .

[0454] Step 3: Disperse compounds I-11-3 (300 mg, 0.77 mmol) and I-1-10 (140 mg, 1 mmol) in N,N-dimethylformamide (8 mL), and add triethylamine (330 mg, 3.27 mmol) and HATU (620 mg, 1.64 mmol) in sequence. Stir the reaction at 5-15 °C for 18 hours. After the reaction was complete, 5% saline (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated, and the residue was separated by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% TFA in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 30-95%; 5. Flow rate: 40 mL / min). Two components were separated:

[0455] Component 1 was collected and lyophilized to obtain compound I-11-a (12 mg), retention time: 7.598 min. 1H NMR (400MHz, CD3OD) δ8.17(d,J=9.1Hz,1H),8.07(d,J=2.8Hz,1H),7.66(s,2H),7.43(dd,J=9.1,3 .0Hz,1H),7.29–7.13(m,2H),7.02(t,J=8.5Hz,1H),6.65–6.54(m,1H),4.55(d,J=17.4Hz,1H),3. 80(dd,J=32.1,11.7Hz,2H),3.51(q,J=7.1Hz,1H),3.17(d,J=15.5Hz,1H),3.05(dd,J=12.1,4.2H z, 1H), 2.54 (d, J = 12.1Hz, 1H), 1.53 (d, J = 6.8Hz, 3H), 1.38 (d, J = 7.0Hz, 3H), 1.13 (d, J = 6.6Hz, 3H). LC-MS: 512.2[M+H] + .

[0456] Component 2 was collected and lyophilized to obtain compound I-11-b (15 mg), retention time: 6.898 min. 1 H NMR (400MHz, CD3OD) δ8.07(d,J=2.6Hz,2H),7.67(s,2H),7.42(dd,J=9.0,2.9Hz,1H),7. 32–7.12(m,2H),7.02(t,J=8.2Hz,1H),6.59(d,J=10.3Hz,1H),4.44(s,1H),3.90(d,J=1 2.4Hz,1H),3.72(d,J=10.6Hz,1H),3.42(s,1H),3.16(q,J=6.7Hz,1H),2.93(dd,J=12.3 ,4.1Hz,1H),2.41(d,J=12.1Hz,1H),1.44(dd,J=15.8,6.8Hz,6H),1.05(d,J=6.5Hz,3H). LC-MS: 512.2[M+H] + .

[0457] Example 12 Synthesis of compound I-12-a

[0458] Step 1: Compound I-1-10 (2 g, 14.4 mmol) was dissolved in ethyl acetate (20 mL). I-12-1 (3.08 mg, 14.4 mmol), T3P (10 g, 50% ethyl acetate solution), and triethylamine (5.83 g) were added at room temperature. The mixture was stirred at room temperature for 16 hours after the addition was complete. After the reaction was complete, water (10 mL) was added to separate the layers. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 0–20%, V / V) to give a white solid I-12-2 (800 mg, yield 17%). LC-MS: 336.2 [M+H] + .

[0459] Step 2: Dissolve I-12-2 (800 mg, 2.38 mmol) in ethyl acetate (5 mL), add 10 mL of ethyl acetate solution of hydrogen chloride (2 mol / L), react at room temperature for 16 hours, filter, dry the filter cake to obtain a white solid, I-12-3 hydrochloride (500 mg, yield 78%), LC-MS: 236.1 [M+H] + .

[0460] Step 3: I-12-4 (1.98 g, 10.59 mmol) and I-12-5 (1.52 g, 11.65 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of cesium carbonate (6.90 g, 21.17 mmol), cuprous iodide (200 mg, 1.06 mmol), and N,N-dimethylglycine (220 mg, 2.12 mmol). The reaction mixture was stirred at 110 °C for 16 hours under an argon atmosphere. After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-80%, V / V) to give a yellow solid I-12-6 (400 mg, yield 15%). LC-MS: 236.9 [M + H] + .

[0461] Step 4: I-12-6 (368 mg, 1.56 mmol) and I-3-1 (761 mg, 3.12 mmol) were dispersed in ethyl acetate (10 mL), and N,N-diisopropylethylamine (242 mg, 1.87 mmol) and 1-n-propylphosphonic anhydride (548 mg, 1.72 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%, V / V) to give a yellow solid I-12-7 (740 mg, yield 96%). LC-MS: 463.2 [M + H] + .

[0462] Step 5: Dissolve 130 mg of I-12-3 hydrochloride and 130 mg (0.28 mmol) of I-12-7 in dimethyl sulfoxide (5 mL), add N,N-diisopropylethylamine (182 mg, 1.40 mmol), and stir at room temperature for 48 hours. After the reaction is complete, filter the reaction solution, concentrate the filtrate, and separate the residue by preparative HPLC to obtain I-12-a (16.40 mg, yield 11%). LC-MS: 526.3 [M+H] + , 1 H NMR(400MHz, CDCl3)δ8.13(s,1H),7.72(s,1H),7.61–7.52(m,1H),7.22(s,1H),7.09–6.93(m,3H),6.9 0(d,J=7.2Hz,1H),6.59(d,J=9.4Hz,1H),3.65(brs,4H),2.59-2.42(m,6H),1.62(s,6H),1.42(s,3H).

[0463] Example 13 Synthesis of compounds I-13-a and I-13-b

[0464] Step 1: Compounds I-1-6 (400 mg, 1.12 mmol) and I-13-1 (280 mg, 1.30 mmol) were dispersed in N,N-dimethylformamide (10 mL), and triethylamine (340 mg, 3.30 mmol) was added. The reaction mixture was stirred at 25-30 °C for 18 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with 5% sodium chloride (20 mL). The organic phase was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100% gradient elution) to give I-13-2 (520 mg, yield 94.6%), LC-MS: 490.8 [M+H]. + .

[0465] Step 2: Compound I-13-2 (450 mg, 0.92 mmol) was dissolved in methanol (4 mL), and ethyl acetate hydrochloride solution (20 mL, 2 M) was added dropwise. The reaction was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane / methanol = 0%-10%, V / V). The column was washed to obtain compound I-13-3 (350 mg), LC-MS: 391.1 [M+H]. + .

[0466] Step 3: Disperse compounds I-13-3 (350 mg, 0.83 mmol) and I-1-10 (140 mg, 1 mmol) in N,N-dimethylformamide (8 mL), and add triethylamine (330 mg, 3.27 mmol) and HATU (620 mg, 1.64 mmol) in sequence. Stir the reaction at 5-15 °C for 18 hours. After the reaction was complete, 5% saline (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated, and the residue was separated by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% TFA in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 30-95%; 5. Flow rate: 40 mL / min). Two components were separated:

[0467] Component 1 was collected and lyophilized to obtain I-13-a (58 mg), retention time: 7.820 min. 1H NMR(400MHz,CD3OD)δ8.10(dd,J=21.6,6.0Hz,2H),7.76–7.60(m,2H),7.51–7.42(m,1H) ,7.34–7.13(m,2H),7.07–6.95(m,1H),6.58(d,J=9.9Hz,1H),4.48(s,1H),3.87(s,1H),3 .67(d,J=7.1Hz,1H),3.12(d,J=11.9Hz,1H),3.00(d,J=3.7Hz,1H),2.92(d,J=11.8Hz,1H ),2.76–2.61(m,1H),1.53(d,J=6.8Hz,3H),1.35(d,J=7.1Hz,3H),1.05(d,J=6.2Hz,3H). LC-MS: 512.1[M+H] + .

[0468] Component 2 was collected and lyophilized to obtain I-13-b (15 mg), retention time: 8.053 min. 1 H NMR (400MHz, CD3OD) δ8.17(d,J=9.1Hz,1H),8.05(d,J=2.9Hz,1H),7.66(dd,J=9.4,2.7Hz, 2H),7.43(dd,J=9.1,3.0Hz,1H),7.32–7.14(m,2H),7.09–6.97(m,1H),6.58(d,J=9.4Hz,1 H),4.44(s,1H),4.05(q,J=6.9Hz,1H),3.18(d,J=24.7Hz,1H),3.01(d,J=7.3Hz,1H),2.70 (dd,J=11.9,3.6Hz,2H),2.50(d,J=12.0Hz,1H),1.46(d,J=6.8Hz,3H),1.28–1.14(m,6H). LC-MS: 512.1[M+H] + .

[0469] Example 14 Synthesis of compounds I-14-a and I-14-b

[0470] Step 1: Compounds I-1-6 (400 mg, 1.12 mmol) and I-14-1 (290 mg, 1.30 mmol) were dispersed in N,N-dimethylformamide (10 mL), and triethylamine (340 mg, 3.30 mmol) was added. The reaction mixture was stirred at 25-30 °C for 18 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with 5% sodium chloride (20 mL). The organic phase was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100% gradient elution) to give I-14-2 (420 mg), LC-MS: 476.8 [M + H]. + .

[0471] Step 2: Compound I-14-2 (400 mg, 0.81 mmol) was dissolved in methanol (4 mL), and ethyl acetate hydrochloride solution (20 mL, 2 M) was added dropwise. The reaction was stirred at room temperature for 4 hours. After the reaction was complete, the solution was concentrated to obtain the hydrochloride salt of compound I-14-3 (300 mg). LC-MS: 376.8 [M+H] + .

[0472] Step 3: Disperse compounds I-14-3 (140 mg, 0.34 mmol) and I-14-4 (50 mg, 0.25 mmol) in N,N-dimethylformamide (8 mL), and add triethylamine (200 mg, 1.9 mmol) and HATU (150 mg, 0.4 mmol) in sequence. Stir the reaction at 5-15 °C for 18 hours. After the reaction was complete, 5% saline (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated, and the residue was separated by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% TFA in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 30-95%; 5. Flow rate: 40 mL / min). Two components were separated:

[0473] Component 1 was collected and lyophilized to obtain I-14-a (39 mg), retention time: 7.513 min. 1H NMR (400MHz, DMSO-d6) δ8.14(dd,J=16.0,10.0Hz,2H),7.84(s,2H),7.52(d,J=8.2Hz,4H),7.31(d,J=5.7Hz,1H),7.14(s,1H),4.12( q,J=7.1Hz,1H),4.03(q,J=7.1Hz,2H),2.92–2.80(m,2H),2.76–2.65(m,2H),2.23(s,1H),1.68(d,J=13.4Hz,6H),1.26–1.08(m,6H). LC-MS: 557.1[M+H] + .

[0474] Component 2 was collected and lyophilized to obtain I-14-b (36 mg), retention time: 7.814 min. 1 H NMR(400MHz, DMSO-d6)δ10.15(s,1H),8.13(dd,J=16.7,8.8Hz,2H),7.84(dd,J=11.0,8.1Hz,2H),7.62–7.42(m,4H),7.39–7.26(m,1H),7.15 (d,J=7.9Hz,1H),3.55(s,2H),2.86(d,J=15.2Hz,2H),2.62(d,J=46.1Hz,1H),2.46–2.35(m,3H),1.68(d,J=13.4Hz,6H),1.44–1.06(m,6H). LC-MS: 557.0[M+H] + .

[0475] Example 15 Synthesis of Compound I-15

[0476] Step 1: Compounds I-12-1 (360 mg, 1.68 mmol) and I-1-6 (300 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (217 mg, 1.68 mmol) was added. The mixture was stirred at 50 °C for 72 hours. After the reaction was complete, saturated ammonium chloride (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%, V / V) to give I-15-1 (235 mg). LC-MS: 491.1 [M + H] + .

[0477] Step 2: Compound I-15-1 (235 mg) and ethyl acetate hydrochloride (5 mL) were added sequentially to a reaction flask and stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain I-15-2 hydrochloride (180 mg). LC-MS: 391.3 [M+H] + .

[0478] Step 3: I-1-10 (77 mg, 0.55 mmol), N,N-dimethylformamide (4 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (264 mg, 0.70 mmol), N,N-diisopropylethylamine (119.16 mg, 0.92 mmol), and I-15-2 hydrochloride (180 mg) were added sequentially to a reaction flask and stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain a white solid I-15 (150 mg).

[0479] LC-MS: 512.3 [M+H] + , 1 H NMR (400MHz, CD3OD) δ8.20(d,J=9.1Hz,1H),8.08(d,J=2.9Hz,1H),7.70(dt,J=9.2 ,2.1Hz,2H),7.45(dd,J=9.1,3.0Hz,1H),7.31–7.14(m,2H),7.08–6.98(m,1H),6. 59(dd,J=9.2,0.8Hz,1H),3.93(d,J=7.1Hz,3H),3.42(s,1H),3.32–3.17(m,1H),2 .98(d,J=3.1Hz,1H),2.61(s,1H),1.38(d,J=7.1Hz,3H),1.26(s,3H),1.16(s,3H).

[0480] Example 16 Synthesis of Compound I-16

[0481] Step 1: I-1-6 (300 mg, 1.35 mmol), I-16-1 (100 mg, 0.5 mmol), and N,N-diisopropylethylamine (80 mg, 0.62 mmol) were dissolved in DMF (3 mL). The reaction mixture was stirred at room temperature for 72 hours. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (50 mL × 4), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:50) to obtain I-16-2 (200 mg). LC-MS: 474.8 [M + H] + .

[0482] Step 2: Dissolve I-16-2 (200 mg, 0.42 mmol) in dichloromethane (5 mL), add a 1,4-dioxane solution of hydrogen chloride (0.5 mL, 2 mmol), and stir at room temperature for 3 hours. After the reaction is complete, concentrate the reaction solution to obtain I-16-3 hydrochloride (200 mg). LC-MS: 374.8 [M+H] + .

[0483] Step 3: Dissolve I-16-3 hydrochloride (200 mg, 0.42 mmol) and I-1-10 (75 mg, 0.54 mmol) in N,N-dimethylformamide (5 mL). Then, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (210 mg, 0.55 mmol) and N,N-diisopropylethylamine (150 mg, 1.16 mmol) sequentially to the reaction flask and stir at room temperature for 2 hours. After the reaction is complete, dilute with ethyl acetate (80 mL), wash the organic phase with water (50 mL × 4), wash with saturated brine (30 mL × 3), dry with anhydrous sodium sulfate, concentrate, and purify by high-performance silica gel chromatography (developing solvent: dichloromethane / methanol = 100:8) to obtain I-16 (55 mg). LC-MS: 496.0 [M + H] + , 1HNMR (400MHz, CDCl3) δ9.29 (s, 1H), 8.22 (s, 1H), 8.09 (d, J = 16.0Hz, 2H), 7.78 (s, 1 H),7.73(d,J=9.3Hz,1H),7.32(d,J=9.3Hz,1H),7.08(dd,J=13.9,8.8Hz,1H),6.9 9(t,J=9.4Hz,1H),6.91(d,J=7.4Hz,1H),6.66(d,J=8.0Hz,1H),4.02-3.68(m,5H) ,3.64-3.40(m,2H),2.85-2.7(m,1H),1.61(d,J=8.8Hz,1H),1.39(d,J=6.1Hz,3H).

[0484] Example 17 Synthesis of compounds I-17-a and I-17-b

[0485] Step 1: Compounds I-14-3 (200 mg, 0.48 mmol) and I-17-1 (140 mg, 0.70 mmol) were dispersed in N,N-dimethylformamide (8 mL), followed by the sequential addition of triethylamine (310 mg, 3 mmol) and HATU (380 mg, 1 mmol). The reaction was stirred at 5-15 °C for 18 hours. After the reaction was complete, the reaction solution was filtered and concentrated. The residue was separated by high performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% TFA in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 30-95%; 5. Flow rate: 40 mL / min). Two components were separated:

[0486] Component 1 was collected and lyophilized to obtain I-17-a (60 mg), retention time: 8.495 min.

[0487] 1H NMR (400MHz, CD3OD): δ8.15(d,J=9.0Hz,1H),8.08(d,J=7.7Hz,3H),7.70(d,J=8.1Hz,2H),7.43(dd,J=9.0,2.8Hz,1H),7.30– 7.14(m,2H),7.02(s,1H),3.51(s,1H),3.28–3.14(m,5H),2.88(s,1H),2.60(s,1H),1.61–1.40(m,6H),1.34(t,J=7.3Hz,3H). LC-MS: 559.0[M+H] + .

[0488] Component 2 was collected and lyophilized to obtain I-17-b (75 mg), retention time: 8.727 min.

[0489] 1 H NMR (400MHz, CD3OD) δ8.21–8.03(m,4H),7.69(d,J=8.2Hz,2H),7.43(dd,J=9.1,3.0Hz,1H),7.30–7.1 4(m,2H),7.10–6.97(m,1H),3.54(d,J=29.4Hz,3H),3.18(s,3H),2.85(m,5H),1.51(d,J=5.0Hz,6H). LC-MS: 559.0[M+H] + .

[0490] Example 18 Synthesis of compound I-18-a

[0491] Step 1: Compounds I-18-1 (2 g, 10.69 mmol) and I-12-5 (1.53 g, 11.77 mmol) were dissolved in 1,4-dioxane (20 mL). Cesium carbonate (6.97 g, 21.39 mmol), cuprous iodide (200 mg, 1.07 mmol), and N,N-dimethylglycine (220 mg, 2.14 mmol) were added sequentially. The system was protected with argon and stirred at 110 °C for 16 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-80%, V / V) to give compound I-18-2 (300 mg). LC-MS: 237.1 [M + H] + .

[0492] Step 2: Compounds I-18-2 (230 mg, 0.97 mmol) and I-3-1 (476 mg, 1.95 mmol) were dispersed in ethyl acetate (5 mL) under ice bath conditions. N,N-diisopropylethylamine (152 mg, 1.17 mmol) and 1-n-propylphosphoric anhydride (343 mg, 1.08 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%, V / V) to give I-18-3 (170 mg). LC-MS: 463.2 [M + H] + .

[0493] Step 3: I-12-3 (114 mg, 0.49 mmol) and I-18-3 (150 mg, 0.32 mmol) were dissolved in dimethyl sulfoxide (4 mL), and N,N-diisopropylethylamine (209 mg, 1.62 mmol) was added. The mixture was stirred at 30 °C for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain I-18-a (15.45 mg). LC-MS: 526.3 [M+H] + , 1 H NMR (400MHz, CD3OD) δ8.15(s,1H),7.76(s,1H),7.69(s,2H),7.17(ddd,J=11.2,8. 6,2.9Hz,1H),7.07(td,J=9.1,5.4Hz,1H),7.01–6.93(m,1H),6.54(d,J=9.4Hz,1H ),3.61–3.49(m,2H),3.37(d,J=7.0Hz,1H),2.86–2.79(m,1H),2.69(dt,J=11.4,3 .6Hz, 1H), 2.51 (s, 2H), 2.37 (s, 3H), 1.56 (d, J = 3.6Hz, 6H), 1.35 (d, J = 7.0Hz, 3H).

[0494] Example 19 Synthesis of compound I-19-a

[0495] Step 1: Compounds I-19-1 (1.00 g, 4.94 mmol) and I-1-10 (890 mg, 6.43 mmol) were dispersed in N,N-dimethylformamide (10 mL), followed by the sequential addition of triethylamine (2.13 g, 21.04 mmol) and HATU (4.00 g, 10.53 mmol). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, 50 mL of pure water was added, and the reaction solution was concentrated. The residue was separated by silica gel column chromatography (dichloromethane / methanol = 0-10%, V / V) to obtain I-19-2 (800 mg), LC-MS: 338.1 [M+H]. + .

[0496] Step 2: Compound I-19-2 (800 mg, 2.40 mmol) was dissolved in methanol (5 mL), and ethyl acetate hydrochloride solution (20 mL, 2 M) was added dropwise. The reaction was stirred at room temperature for 4 hours. After the reaction was complete, the solution was concentrated to obtain the hydrochloride salt of compound I-19-3 (550 mg). LC-MS: 238.0 [M+H] + .

[0497] Step 3: The hydrochloride salt of compound I-19-3 (500 mg, 2.0 mmol) and I-1-6 (1.0 g, 2.0 mmol) were dispersed in N,N-dimethylformamide (10 mL), and triethylamine (510 mg, 5.0 mmol) was added. The reaction mixture was stirred at 25-30 °C for 18 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with 5% sodium chloride (20 mL). The organic phase was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%, V / V) to give I-19-a (420 mg), LC-MS: 514.0 [M+H]. + .

[0498] 1H NMR (400MHz, CD3OD): δ8.41(s,1H),8.27(s,1H),8.15(d,J=9.1Hz,1H),8.08–7.98(m,1H),7.42(d d,J=9.1,2.9Hz,1H),7.31–7.14(m,2H),7.03(s,1H),6.52(dd,J=9.6,1.9Hz,1H),4.45(dd,J=15. 9,5.6Hz,2H),3.63(d,J=7.0Hz,1H),3.53–3.41(m,1H),3.22(dd,J=22.7,17.1Hz,1H),2.97(s,2H ),2.82–2.69(m,1H),2.62(dd,J=21.2,9.9Hz,1H),2.53–2.41(m,1H),1.36(dd,J=7.0,1.7Hz,3H).

[0499] Example 20 Synthesis of compounds I-20-a, I-20-b, I-20-c and I-20-d

[0500] Step 1: Under nitrogen protection at 0°C, 1,1,3,3-tetramethyldisiloxane (4.03 g, 30.00 mmol) was added dropwise to a dichloromethane (40 mL) solution of compound I-20-1 (3.16 g, 10.00 mmol, synthesized according to patent CN116514847A) and IrCl(CO)(PPh3)2 (780 mg, 1.00 mmol). The mixture was stirred at room temperature for 1.5 hours until the reaction solution became clear. The reaction solution was then cooled to -78°C, and methyl Grignard reagent (14 mL, 14.00 mmol, 1 M in THF) was slowly added dropwise. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for another 2.5 hours. After the reaction was complete, the reaction solution was poured into an ammonium chloride aqueous solution (100 mL), extracted with dichloromethane (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give I-20-2 (2.40 g, colorless oil), yield 68%. LC-MS: 317.5 [M + H] + .

[0501] Step 2: I-20-2 (1.80 g, 5.70 mmol) was dissolved in ethanol (50 mL), and Pd(OH)2 / C (400 mg, 2.85 mmol) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to produce I-20-3 (1.36 g), yield: 94.74%. LC-MS: 227.2 [M+H] + .

[0502] Step 3: I-20-3 (1.26 g, 5.60 mmol) and I-1-10 (780 mg, 5.60 mmol) were dissolved in DMF (30 mL), and triethylamine (1.70 g, 16.80 mmol), EDCI (1.29 g, 6.72 mmol), and HOBt (0.91 g, 6.72 mmol) were added sequentially. The mixture was stirred overnight at 30 °C under nitrogen protection. After the reaction was complete, the mixture was concentrated and separated sequentially by silica gel column chromatography (dichloromethane / methanol = 10:1) and preparative high performance liquid chromatography (ACN / H2O) to obtain I-20-4 (1.48 g, white solid), yield: 68%. LC-MS: 348.1 [M+H] + .

[0503] Step 4: Dissolve I-20-4 (300 mg, 0.86 mmol) in dichloromethane (2 mL), add a dioxane solution of hydrogen chloride (10 mL, 4 mol / L), and stir at room temperature for 2 hours. After the reaction is complete, concentrate the reaction solution to obtain I-20-5 hydrochloride (270 mg, white solid). LC-MS: 248.2 [M+H] + .

[0504] Step 5: Weigh 332 mg (1.34 mmol) of I-20-5 hydrochloride into a round-bottom flask, and add acetonitrile (5.00 mL), triethylamine (227 mg, 2.24 mmol), and silver nitrate (210 mg, 1.23 mmol) sequentially. Stir at room temperature for 5 minutes, then add I-1-6 (400 mg, 1.12 mmol). Stir the reaction mixture at 50 °C for 48 hours. After the reaction is complete, concentrate the mixture, and separate the residue by silica gel column chromatography (dichloromethane:methanol = 0%–20%, V / V) to obtain racemic I-20 (270 mg). LC-MS: m / z: (M+H) + =524.1.

[0505] Step 6: The racemic mixture obtained in Step 5 was separated. The first separation (1. Instrument: Waters 150SFC; 2. Chiralpak OD, 2×15cm, 5um; 3. Mobile phase A: carbon dioxide, mobile phase B: isopropanol; 4. Flow rate: 50mL / min) yielded two components. Component 1 was a mixture of I-20-a and I-20-b (50mg), with a retention time of 3.852min; Component 2 was a mixture of I-20-c and I-20-d (49mg), with a retention time of 5.851min.

[0506] Component 1 underwent secondary separation (1. Instrument: Waters 150 SFC; 2. Chiralpak SA, 2×15cm, 5µm; 3. Mobile phase A: carbon dioxide, mobile phase B: isopropanol; 4. Flow rate: 50mL / min). The compound with a retention time of 3.186 min was collected and concentrated to give I-20-a (2.33mg). LC-MS: m / z: (M+H) + =524.1. 1 H NMR (400MHz, CD3OD) δ8.18(d,J=9.1Hz,1H),8.09(d,J=3.0Hz,1H),7.71–7.61(m,2H),7.45(dd,J =9.0,3.0Hz,1H),7.25(td,J=9.1,5.4Hz,1H),7.18(ddd,J=11.2,8.6,3.0Hz,1H),7.07–7.00(m,1 The chromatogram values ​​were 6.63–6.51 (m, 1H), 4.69–4.59 (m, 1H), 3.92–3.75 (m, 1H), 3.57–3.42 (m, 2H), 3.31–3.14 (m, 1H), 3.11–3.01 (m, 1H), 2.04–1.87 (m, 2H), 1.81–1.59 (m, 2H), 1.53–1.46 (m, 3H), and 1.38–1.33 (m, 3H). The compound with a retention time of 4.121 min was collected and concentrated to give I-20-b (2.54 mg). LC-MS: m / z: (M+H) + =524.1. 1 H NMR (400MHz, CD3OD) δ8.18(d,J=9.1Hz,1H),8.09(d,J=3.0Hz,1H),7.71–7.61(m,2H),7.45(dd,J =9.1,3.0Hz,1H),7.25(td,J=9.1,5.4Hz,1H),7.18(ddd,J=11.2,8.6,3.0Hz,1H),7.08–6.99(m,1 H),6.63–6.51(m,1H),4.68–4.59(m,1H),3.91–3.75(m,1H),3.55–3.39(m,2H),3.30–3.15(m,1H ),3.11–3.02(m,1H),2.02–1.90(m,2H),1.79–1.61(m,2H),1.52–1.46(m,3H),1.37–1.32(m,3H).

[0507] Component 2 underwent a second separation (1. Instrument: Waters 150SFC; 2. Chiralpak IC, 3×15cm, 5µm; 3. Mobile phase A: carbon dioxide, mobile phase B: isopropanol:acetonitrile (7:3); 4. Flow rate: 80mL / min). The compound with a retention time of 8.226 min was collected and concentrated to give I-20-c (2.31mg). LC-MS: m / z: (M+H) + =524.1. 1 H NMR(400MHz,CD3OD)δ8.17(d,J=9.1Hz,1H),8.07(s,1H),7.67–7.63(m,2H),7.47–7.37(m,1H) ,7.24(td,J=9.2,5.5Hz,1H),7.21–7.14(m,1H),7.05–6.98(m,1H),6.58(d,J=10.2Hz,1H),4. 57–4.47 (m, 1H), 3.79–3.72 (m, 1H), 3.71–3.50 (m, 2H), 3.17–3.10 (m, 1H), 3.08–3.00 (m, 1H), 2.18–2.06 (m, 1H), 1.89–1.73 (m, 1H), 1.73–1.54 (m, 2H), 1.50–1.42 (m, 3H), 1.40–1.34 (m, 3H). The compound with a retention time of 12.033 min was collected and concentrated to give I-20-d (2.43 mg), retention time: 12.033 min. LC-MS: m / z: (M+H) + =524.1. 1 H NMR(400MHz,CD3OD)δ8.17(d,J=9.1Hz,1H),8.07(s,1H),7.67–7.63(m,2H),7.47–7.37(m,1H) ,7.24(td,J=9.2,5.5Hz,1H),7.21–7.14(m,1H),7.05–6.98(m,1H),6.58(d,J=10.2Hz,1H),4. 57–4.47(m,1H),3.79–3.72(m,1H),3.71–3.50(m,2H),3.17–3.10(m,1H),3.08–3.00(m,1H),2 .18–2.06(m,1H),1.89–1.73(m,1H),1.73–1.54(m,2H),1.50–1.42(m,3H),1.40–1.34(m,3H).

[0508] Example 21 Synthesis of Compound I-21

[0509] Step 1: Compounds I-4-2 (260 mg, 0.76 mmol) and I-1-7 (202 mg, 0.95 mmol) were added to DMF (3 mL), followed by triethylamine (300 mg). The reaction mixture was reacted at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-21-1 (200 mg, yield 55.59%), LC-MS: 475.2 [M+H]. + .

[0510] Step 2: I-21-1 (200 mg, 0.42 mmol) was added to an ethyl acetate solution of hydrogen chloride (5 mL, 2 mol / L), and the reaction was carried out at room temperature for 2 hours. The mixture was filtered and dried to give a white solid, I-21-2 hydrochloride (100 mg, yield 63.43%). LC-MS: 375.1 [M+H] + .

[0511] Step 3: The hydrochloride salt of compound I-21-2 (80 mg, 0.21 mmol) and I-1-10 (30 mg, 0.22 mmol) were added to DMF (4 mL), followed by T3P (250 mg) and DIPEA (200 mg). The reaction mixture was reacted at room temperature for 26 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0–100%, V / V) to give a white solid I-21 (20 mg). LC-MS: 496.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.78(s,2H),7.53(d,J=2.3Hz,1H),7.47(dd,J=9.5,2.6Hz, 1H),7.42–7.33(m,1H),7.30(s,1H),7.17–6.98(m,3H),6.33(d,J=9.4Hz,1H),4.12(s ,2H),3.40(s,1H),3.24(d,J=6.6Hz,2H),3.11(s,2H),1.95–1.79(m,1H),1.72(dd,J =12.0, 6.8Hz, 1H), 1.42 (dd, J = 34.9, 20.7Hz, 2H), 1.24 (s, 2H), 1.21 (d, J = 6.6Hz, 3H).

[0512] Example 22 Synthesis of Compound I-22

[0513] Step 1: Compounds I-22-2 (2.64 g, 11.57 mmol), I-22-1 (1.98 g, 10.52 mmol), cesium carbonate (4.46 g, 13.67 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G3, 260 mg, 0.32 mmol), and toluene (30 mL) were sequentially added to a round-bottom flask (100 mL). The system was reacted at 115 °C for 16 hours under an argon atmosphere. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give a yellow liquid I-22-3 (950 mg, yield 27%). LC-MS: 336.3 [M+H] + .

[0514] Step 2: Compound I-22-3 (900 mg, 2.68 mmol) and hydrochloric acid (5 mL) were added sequentially to a reaction flask, and the mixture was stirred at 100 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound I-22-4 (560 mg). LC-MS: 222.2 [M+H] + .

[0515] Step 3: I-22-4 hydrochloride (121 mg, 0.55 mmol) and I-1-6 (150 mg, 0.42 mmol) were dissolved in dimethyl sulfoxide (3 mL), and N,N-diisopropylethylamine (271 mg, 2.10 mmol) was added. The mixture was reacted at 30 °C for 16 hours. After the reaction was complete, the reaction solution was filtered and preparatively separated by high performance liquid chromatography (HPLC) to obtain compound I-22 (11 mg). LC-MS: 498.1 [M+H] + , 1H NMR (400MHz, CD3OD) δ8.17 (dd, J=9.0, 2.3Hz, 1H), 8.06 (s, 1H), 7.43 (dt, J=5.9, 2.7Hz, 2H), 7.29–7. 14(m,2H),7.06–6.98(m,1H),6.76(d,J=2.9Hz,1H),6.50(d,J=9.6Hz,1H),3.52–3.36(m,1H),3.26( d,J=7.0Hz,1H),2.91(s,1H),2.81(d,J=10.6Hz,1H),2.58–2.43(m,1H),2.35–2.25(m,1H),1.86(s, 1H), 1.71 (dd, J = 24.4, 11.4Hz, 1H), 1.34–1.28 (m, 3H), 1.18 (d, J = 4.4Hz, 3H), 1.01 (d, J = 3.6Hz, 3H).

[0516] Example 23 Synthesis of compound I-23

[0517] Step 1: Compounds I-1-6 (404 mg, 1.13 mmol) and I-23-1 (200 mg, 0.94 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (244 mg, 1.88 mmol) was added. The mixture was stirred at 30 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound I-23-2 (400 mg, yield 87%), LC-MS: 488.8 [M+H]. + .

[0518] Step 2: Compound I-23-2 (200 mg, 0.41 mmol) and ethyl acetate hydrochloride (2 mol / L, 5 mL) were added sequentially to a reaction flask and stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound I-23-3 (150 mg). LC-MS: 388.8 [M+H] + .

[0519] Step 3: Compound I-1-10 (150 mg, 1.08 mmol), N,N-dimethylformamide (2 mL), HATU (221.67 mg, 0.58 mmol), N,N-diisopropylethylamine (100 mg, 0.77 mmol), and the hydrochloride salt of I-23-3 (150 mg, 0.39 mmol) were sequentially added to a reaction flask, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound I-23 (85 mg). LC-MS: 510.1 [M+H] + ,1H NMR(400MHz, CD3OD)δ8.08(d,J=3.1Hz,2H),7.75–7.62(m,2H),7.44(ddd,J=9.0,7.8,4.8H z,1H),7.23(ddt,J=21.4,19.5,5.6Hz,2H),7.02(t,J=7.0Hz,1H),6.61–6.52(m,1H),4.12( d,J=7.1Hz,1H),3.61(d,J=7.0Hz,1H),3.54–3.43(m,1H),3.30–2.97(m,2H),2.65(dd,J=2 5.9, 16.1Hz, 1H), 2.49 (d, J = 9.3Hz, 1H), 2.26–2.06 (m, 1H), 1.90 (s, 1H), 1.43–1.27 (m, 5H).

[0520] Example 24 Synthesis of compound I-24-a

[0521] Step 1: Compound I-24-1 (1.37 g, 9.86 mmol), N,N-dimethylformamide (20 mL), HATU (4.50 g, 11.84 mmol), N,N-diisopropylethylamine (2.55 g, 19.73 mmol), and I-12-1 (2.33 g, 10 mmol) were added sequentially to a reaction flask and stirred at room temperature for 4 hours. After the reaction was complete, saturated ammonium chloride (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-70%) to give compound I-24-2 (900 mg, yield 24%), LC-MS: 336.2 [M + H]. + .

[0522] Step 2: Compound I-24-2 (860 mg, 2.55 mmol) and ethyl acetate hydrochloride solution (4 mol / L, 10 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain I-24-3 hydrochloride (600 mg, yield 90%), LC-MS: 236.2 [M+H]. + .

[0523] Step 3: Compound I-24-4 (108 mg, 0.22 mmol, prepared according to patent WO2025064534) and the hydrochloride salt of compound I-24-3 (160 mg, 0.67 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (140 mg, 1.12 mmol) was added. The mixture was stirred at 30 °C for 48 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and separated by preparative HPLC to obtain compound I-24-a (31 mg, yield 27%). LC-MS: 525.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.17(d,J=4.83Hz,2H),7.96(d,J=4.84Hz,2H ),7.09(m,1H),6.98(m,2H),6.64(s,1H),4.59(t,J=2.3Hz,1H),4.33(dd,J=2.9,1. 4Hz,1H),4.21–4.19(m,1H),3.58–3.43(m,2H),3.29(q,J=6.8Hz,1H),2.86–2.73(m ,2H),2.66–2.56(m,1H),2.47(m,3H),1.62(d,J=2.4Hz,6H),1.37(d,J=7.0Hz,3H).

[0524] Example 25 Synthesis of Compound I-25

[0525] Step 1: Compounds I-25-1 (215 mg, 1.02 mmol) and I-1-10 (70 mg, 0.33 mmol) were dissolved in DMF (5 mL). HATU (0.5 g, 1.3 mmol) and N,N-diisopropylethylamine (200 mg, 1.55 mmol) were added sequentially, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (50 mL × 4), then with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 100:8, V / V) to obtain compound I-25-2 (160 mg). LC-MS: 332.9 [M + H] + .

[0526] Step 2: Compound I-25-2 (160 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.3 mL, 3.92 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude trifluoroacetate of I-25-3 (170 mg). LC-MS: 232.9 [M+H] + .

[0527] Step 3: Crude trifluoroacetate of I-25-3 (170 mg, 0.48 mmol) and I-1-6 (170 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of N,N-diisopropylethylamine (100 mg, 0.78 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, ethyl acetate (60 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), then with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by PTLC (dichloromethane / methanol = 100:8, V / V) to obtain I-25 (5 mg). LC-MS: 509.0 [M + H] + , 1H NMR(400MHz, CDCl3)δ9.58-9.5(br,1H),8.20(d,J=8.4Hz,1H),8.10(s,1H),7.77(s,1H) ,7.59(s,1H),7.32(s,1H),7.08(s,1H),6.98(d,J=8.4Hz,1H),6.89(s,1H),6.63(s,1H), 5.53(s,1H),4.07-3.92(m,1H),3.83-3.65(m,1H),3.55-3.40(m,1H),3.25–3.05(m,1H) ,3.0-2.87(m,1H),2.86-2.77(m,1H),2.76-2.56(m,1H),2.51-2.40(m,1H),1.39(s,3H).

[0528] Example 26 Synthesis of compounds I-26-a, I-26-b, I-26-c and I-26-d

[0529] Step 1: Compound I-20-1 (3.16 g, 10.00 mmol) and 2,6-di-tert-butyl-4-methylpyridine (2.46 g, 12.00 mmol) were dissolved in dichloromethane (100 mL). Trifluoromethanesulfonic anhydride (3.39 g, 12.00 mmol) was added dropwise to the reaction solution under nitrogen protection at -78 °C. The mixture was stirred for 1 hour after the addition was complete. Then, methyl Grignard reagent (30 mL, 30 mmol, 1 M in THF) was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was stirred for another 0.5 hours. The reaction solution was then slowly brought to room temperature and stirred overnight. After the reaction was complete, the reaction solution was poured into an ammonium chloride aqueous solution (100 mL), extracted with dichloromethane (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain I-26-1 (2.87 g), LC-MS: 331.2 [M + H]. + .

[0530] Step 2: Compound I-26-1 (2.80 g, 8.50 mmol) was dissolved in ethanol (60 mL), and Pd / C (10%) (450 mg) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere at one atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated by rotary evaporation to obtain I-26-2 (1.90 g). LC-MS: 241.2 [M+H] + .

[0531] Step 3: Compound I-1-10 (1.32 g, 9.50 mmol) was dissolved in DMF (30 mL). Triethylamine (1.60 g, 15.80 mmol), EDCI (1.82 g, 9.50 mmol), HOBt (1.28 g, 9.50 mmol), and I-26-2 (1.90 g, 7.90 mmol) were added sequentially at room temperature. The reaction mixture was stirred at 30 °C for 16 hours. The reaction mixture was concentrated by rotary evaporation, and the residue was prepared by C18 reversed-phase chromatography (CH3CN / H2O = 2%-35%) to give I-26-3 (1.0 g), LC-MS: 306.1 [M+H]. + .

[0532] Step 4: Compound I-26-3 (350 mg, 0.97 mmol) and a solution of dioxane hydrochloric acid (10 mL, 4 M) were placed in a reaction flask and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness and concentrated to obtain I-26-4 hydrochloride (298 mg), LC-MS: 262.1 [M+H] + .

[0533] Step 5: Place I-26-4 hydrochloride (311 mg) in a round-bottom flask, and add N,N-dimethylformamide (3 mL), triethylamine (198 mg, 1.96 mmol), and silver nitrate (202 mg, 1.19 mmol) sequentially. After stirring at 30°C for 5 minutes, add I-1-6 (350 mg, 0.98 mmol), and stir the system at 30°C for 72 hours. After the reaction is complete, perform preparative separation by reverse-phase chromatography (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 35-65%; Flow rate: 35 mL / min). Retention times: 4.05 min and 7.25 min), yielding two components: Component 1 was a mixture of I-26-a and I-26-b (40 mg) with a retention time of 4.05 min; Component 2 was a mixture of I-26-c and I-26-d (49 mg) with a retention time of 7.25 min.

[0534] Component 1 underwent secondary separation (1. Instrument: Waters 150SFC; 2. Column: Chiralpak SA, 2×15cm, 5µm; 3. Mobile phase A: carbon dioxide, mobile phase B: 40% ethanol; 4. Flow rate: 50mL / min). The compound with a retention time of 3.311 min was collected and concentrated to obtain I-26-a (2.52 mg). LC-MS: m / z: (M+H) + =538.1. 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),9.86(s,1H),8.15(d,J=3.0Hz,1H),8.13(d,J=9. 1Hz,1H),7.55–7.48(m,3H),7.48–7.41(m,1H),7.37–7.26(m,1H),7.19–7.08(m,1H),6 3.35 (d, J = 9.4 Hz, 1H), 3.52–3.39 (m, 2H), 3.22 (d, J = 12.5 Hz, 1H), 3.08–2.99 (m, 1H), 2.66 (d, J = 5.8 Hz, 1H), 2.04–1.66 (m, 4H), 1.50 (s, 3H), 1.38 (s, 3H), 1.24 (d, J = 6.7 Hz, 3H). The compound with a retention time of 7.121 min was collected and concentrated to give I-26-b (2.42 mg). LC-MS: m / z: (M+H) + =538.1. 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),9.86(s,1H),8.15(d,J=3.0Hz,1H),8.13(d,J=9. 1Hz,1H),7.54–7.49(m,3H),7.49–7.41(m,1H),7.35–7.28(m,1H),7.17–7.09(m,1H),6 .35(d,J=9.4Hz,1H),3.50–3.39(m,2H),3.22(d,J=12.5Hz,1H),3.08–2.99(m,1H),2.6 6(d,J=5.8Hz,1H),2.04–1.69(m,4H),1.50(s,3H),1.38(s,3H),1.24(d,J=5.8Hz,3H).

[0535] Component 2 underwent secondary separation (1. Instrument: Waters 150SFC; 2. Column: Chiralpak IC, 3×15cm, 5µm; 3. Mobile phase A: carbon dioxide, mobile phase B: 50% methanol; 4. Flow rate: 80mL / min). The compound with a retention time of 6.912 min was collected and concentrated to give I-26-c (2.64 mg). LC-MS: m / z: (M+H) + =538.1. 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),9.97(s,1H),8.15(d,J=3.0Hz,1H),8.09(d,J=9.1Hz ,1H),7.53–7.45(m,3H),7.43–7.38(m,1H),7.33–7.23(m,1H),7.16–7.08(m,1H),6.32(d, J = 9.4 Hz, 1H), 3.42–3.35 (m, 1H), 3.15–3.09 (m, 2H), 3.08–3.01 (m, 1H), 2.98 (d, J = 6.2 Hz, 1H), 2.09–1.89 (m, 2H), 1.73–1.60 (m, 2H), 1.52 (s, 3H), 1.47 (s, 3H), 1.22 (d, J = 6.7 Hz, 3H). The compound with a retention time of 9.411 min was collected and concentrated to give I-26-d (2.41 mg). LC-MS: m / z: (M+H) + =538.1, 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),9.98(s,1H),8.15(d,J=3.0Hz,1H),8.09(d,J=9.0H z,1H),7.55–7.44(m,3H),7.44–7.37(m,1H),7.33–7.23(m,1H),7.17–7.07(m,1H),6.32( d,J=9.5Hz,1H),3.42–3.35(m,1H),3.17–3.09(m,2H),3.09–3.02(m,1H),3.02–2.95(m,1 H), 2.08–1.91 (m, 2H), 1.72–1.60 (m, 2H), 1.52 (s, 3H), 1.47 (s, 3H), 1.23 (d, J = 6.9Hz, 3H).

[0536] Example 27 Synthesis of compound I-27-a

[0537] Step 1: Compound I-27-1 (1.50 g, 13.26 mmol) was dispersed in acetonitrile (50 mL), followed by the sequential addition of potassium carbonate (1.83 g, 13.26 mmol), potassium iodide (23 mg, 0.14 mmol), and I-27-2 (2.78 g, 13.41 mmol). The reaction was stirred at 70 °C. After the reaction was complete, the mixture was filtered directly, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to obtain compound I-27-3 (2.20 g), LC-MS: 239.8 [M+H]. + .

[0538] Step 2: Compound I-27-3 (1.00 g, 4.18 mmol) was dispersed in ethanol (20 mL), followed by the addition of ammonium chloride (70 mg, 1.25 mmol), water (3 mL), and iron powder (700 mg, 12.54 mmol). The reaction was stirred at 70 °C. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and concentrated. The residue was extracted with water (40 mL) and then with ethyl acetate (40 mL × 2). The combined organic phases were washed with water (40 mL) and then concentrated. The residue was separated by silica gel column chromatography to obtain compound I-27-4 (600 mg), LC-MS: 209.9 [M + H]. + .

[0539] Step 3: Compounds I-27-4 (600 mg, 2.87 mmol) and I-3-1 (900 mg, 3.68 mmol) were dispersed in ethyl acetate (40 mL). Pyridine (950 mg, 12.22 mmol) and T3P (2.32 g, 6.10 mmol, 50% ethyl acetate solution) were added sequentially, and the reaction was stirred at room temperature. After the reaction was complete, ethyl acetate (50 mL) was added. The organic phase was washed with hydrochloric acid (30 mL × 2, 1 mol / L) and concentrated. The residue was separated by silica gel column chromatography to obtain compound I-27-5 (450 mg), LC-MS: 435.7 [M + H]. + .

[0540] Step 4: Compounds I-27-5 (200 mg, 0.46 mmol) and I-12-3 (100 mg, 0.42 mmol) were dispersed in DMF (8 mL), and triethylamine (300 mg, 2.94 mmol) was added. The reaction was stirred at 30 °C. After the reaction was complete, the mixture was concentrated, and the residue was separated by high performance liquid chromatography to obtain compound I-27-a (45 mg). LC-MS: 499.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.74–7.63(m,3H),7.34(d,J=1.4Hz,1H),6.98–6.87(m,3H),6.54(d,J=9.4Hz,1H),5.24(s,2H),3.5 3(dd,J=13.9,6.9Hz,3H),2.79(s,1H),2.67(s,1H),2.51(q,J=11.9Hz,2H),1.56(d,J=4.9Hz,6H),1.33(d,J=6.9Hz,3H).

[0541] Example 28 Synthesis of compound I-28-a

[0542] Following the synthetic method of Example I-19, replacing starting material I-19-1 with (S)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (I-28-1) yields compound I-28-a. LC-MS: 528.1 [M+H] + . 1 HNMR (400MHz, CD3OD): δ8.48 (s, 1H), 8.21–8.08 (m, 2H), 7.99 (ddd, J=12.2, 10.0, 2.8Hz, 2H),7.41(dd,J=9.1,3.0Hz,1H),7.24(dd,J=20.5,15.3Hz,2H),7.03(d,J=1.4Hz,1H),6. 49(dd,J=11.7,9.7Hz,1H),4.42(t,J=6.0Hz,2H),3.58–3.37(m,2H),3.31–2.96(m,3H), 2.88–2.74(m,1H),2.68–2.39(m,2H),2.09(d,J=3.7Hz,2H),1.36(dd,J=7.0,2.3Hz,3H).

[0543] Example 29 Synthesis of compounds I-29-a, I-29-b, I-29-c and I-29-d

[0544] Step 1: Weigh compound I-1-6 (700 mg, 1.96 mmol) into a round-bottom flask, add compound I-29-1 (477 mg, 2.38 mmol) and triethylamine (397 mg, 3.92 mmol), then add acetonitrile (5 mL). Stir the system at 50 °C. After the reaction is complete, evaporate to dryness, and separate the residue by silica gel column chromatography to obtain two fractions.

[0545] Component 1 was a mixture of I-29-1-a and I-29-1-b (379 mg), with a retention time of 9.362 min (1. Column: XBridgee Shield RP185um, 4.6x150mm Column; 2. Gradient for 10 min, 5% to 95%; 3. Flow rate 1 mL / min, phase a: 0.1% formic acid in water, phase b: acetonitrile), LC-MS: m / z: 477.1 [M+H] + Component 2 was a mixture of I-29-1-c and I-29-1-d (199 mg), retention time: 8.686 min (1. Column: XBridgee Shield RP185um, 4.6 x 150 mm Column; 2. Gradient 10 min, 5% to 95%; 3. Flow rate 1 mL / min, phase a: 0.1% formic acid in water, phase b: acetonitrile), LC-MS: m / z: 477.1 [M+H] + .

[0546] Step Two:

[0547] Component 1 (343 mg, 0.72 mmol) obtained in the first step was dispersed in dichloromethane (5 mL), and 2,6-dimethylpyridine (154 mg, 1.44 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (381 mg, 1.44 mmol) were added. The system was stirred at room temperature for 2 hours, and then cesium fluoride (109 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature. After the reaction was complete, the solution was directly evaporated to dryness to obtain a crude product (620 mg), which was a mixture of I-29-2-a and I-29-2-b, and could be used directly in the next step. LC-MS: m / z: 377.2 [M+H] + .

[0548] Component 2 (193 mg, 0.40 mmol) obtained in the first step was dispersed in dichloromethane (5 mL), and 2,6-dimethylpyridine (87 mg, 0.81 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (214 mg, 0.81 mmol) were added. The mixture was stirred at room temperature for 2 hours, followed by the addition of cesium fluoride (62 mg, 0.40 mmol) and stirring at room temperature. After the reaction was complete, the mixture was directly evaporated to dryness to obtain a crude product (380 mg), which was a mixture of I-29-2-c and I-29-2-d and could be used directly in the next step. LC-MS: m / z: 377.2 [M+H] + .

[0549] Step 3:

[0550] Weigh compound I-1-10 (100 mg, 0.72 mmol) and DIPEA (186 mg, 1.44 mmol) into a round-bottom flask, add HATU (273 mg, 0.72 mmol), and stir at room temperature for 10 minutes under nitrogen protection. Finally, add the mixture of I-29-2-a and I-29-2-b obtained in the second step (271 mg, 0.72 mmol) and stir at room temperature. After the reaction was complete, reverse-phase preparative separation was performed (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 20-50%; Flow rate: 35 mL / min; 5. Retention time: 6.77 min), yielding a mixture of I-29-a and I-29-b (8.5 mg). LC-MS: m / z: 498.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),9.97(s,1H),8.16(d,J=2.9Hz,1H),8.10(d,J=9. 1Hz,1H),7.58(s,1H),7.56–7.46(m,3H),7.37–7.25(m,1H),7.20–7.07(m,1H),6.35(d ,J=9.4Hz,1H),3.98–3.74(m,3H),3.27–3.16(m,1H),3.11–2.98(m,1H),2.75–2.64(m, 1H), 2.62–2.55 (m, 1H), 2.45–2.31 (m, 1H), 1.12 (d, J = 6.7Hz, 3H), 1.07 (d, J = 6.1Hz, 3H).

[0551] Weigh compound I-1-10 (60 mg, 0.43 mmol) and DIPEA (111 mg, 0.86 mmol) into a round-bottom flask, add HATU (164 mg, 0.43 mmol), purify the system with nitrogen, and stir at room temperature for 10 minutes. Finally, add the mixture of I-29-2-c and I-29-2-d obtained in the second step (206 mg) and stir at room temperature. After the reaction was complete, reverse-phase preparative separation was performed (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 15-45%; Flow rate: 40 mL / min; 5. Retention time: 6.61 min), yielding a mixture of I-29-c and I-29-d (19 mg). LC-MS: m / z: 498.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.87 (s, 1H), 10.22 (s, 1H), 8.15 (d, J = 3.1Hz, 1H), 8.0 9(d,J=9.1Hz,1H),7.61–7.55(m,1H),7.54–7.45(m,3H),7.36–7.24(m,1H),7.1 7–7.09(m,1H),6.35(d,J=9.4Hz,1H),3.89–3.64(m,3H),3.31–3.22(m,1H),3.0 3–2.86(m,2H),2.78–2.59(m,2H),1.25(d,J=6.2Hz,3H),0.98(d,J=6.2Hz,3H).

[0552] Example 30 Synthesis of compound I-25-a

[0553] Step 1: I-30-1 (820 mg, 3.89 mmol) and I-1-10 (630 mg, 4.53 mmol) were dissolved in DMF (5 mL), followed by the addition of HATU (500 mg, 1.3 mmol) and DIPEA (1.90 g, 5.0 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with ethyl acetate (120 mL). The organic phase was washed with water (50 mL × 4), then with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain compound I-30-2 (1.1 g). LC-MS: 332.9 [M + H]+ .

[0554] Step 2: Compound I-30-2 (330 mg, 1.0 mmol) was dissolved in acetonitrile (5 mL), and p-toluenesulfonic acid (520 mg, 3.0 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, sodium bicarbonate aqueous solution was added to adjust the pH to neutral. The system was filtered, and the filtrate was concentrated and purified by reversed-phase column chromatography to obtain compound I-30-3 (600 mg). LC-MS: 232.9 [M+H] + .

[0555] Step 3: Compounds I-30-3 (600 mg) and I-3-2 (180 mg, 0.4 mmol) obtained in Step 2 were dissolved in acetonitrile (5 mL), and then DIPEA (100 mg, 0.78 mmol) was added. The mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the mixture was concentrated, and the residue was separated by silica gel chromatography to obtain compound I-25-a (20 mg). LC-MS: 509.0 [M+H] + , 1 H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 8.09 (d, J = 13.0Hz, 2H), 7.99 (s, 1H), 7.50 (d, J = 8.3Hz, 1 H),7.08(dd,J=14.1,8.6Hz,1H),6.98(t,J=7.9Hz,1H),6.89(s,1H),6.70(d,J=9.4Hz,1H) ,5.87(d,J=7.1Hz,1H),5.42(s,1H),3.93(d,J=13.4Hz,1H),3.45(t,J=11.5Hz,1H),3.35( d, J=13.1Hz, 1H), 3.09 (dd, J=24.2, 13.0Hz, 2H), 2.85 (t, J=11.4Hz, 1H), 1.82-1.70 (m, 5H).

[0556] Example 31 Synthesis of compounds I-31-a, I-31-b, I-31-c and I-31-d

[0557] Step 1: Compound I-31-0 (2.37 g, 10.56 mmol) was dissolved in tetrahydrofuran (30 mL). Under nitrogen protection, n-butyllithium (4.6 mL, 2.5 M, 11.52 mmol) was slowly added dropwise at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. Then, a tetrahydrofuran solution of I-31-1 (2.18 g, 9.60 mmol) was added dropwise to the reaction mixture. After the addition was complete, the mixture was slowly brought to room temperature overnight. After the reaction was complete, the reaction mixture was poured into an ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The solution was concentrated by rotary evaporation, and the residue was separated by silica gel column chromatography to obtain I-31-2 (2.60 g), MS (ESI): 198.4 [M + H - 100]. + .

[0558] Step 2: Compound I-31-2 (1.50 g, 5.00 mmol) was dissolved in ethanol (30 mL), and Pd / C (270 mg, 2.50 mmol) was added. The system was stirred at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain I-31-3 (1.50 g), MS (ESI): 244.0 [M+H-56]. + .

[0559] Step 3: I-31-3 (1.40 g, 4.70 mmol) was dissolved in tetrahydrofuran (25 mL). Under nitrogen protection, LDA (3.05 mL, 2 M, 6.11 mmol) was slowly added dropwise at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. Then, iodomethane (2.00 g, 14.10 mmol) was added dropwise, and the mixture was stirred for 2 hours after the addition was complete. After the reaction was complete, the reaction solution was poured into an ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by silica gel column chromatography to obtain I-31-4 (1.30 g), MS (ESI): 314.2 [M + H]. + .

[0560] Step 4: Dissolve I-31-4 (800 mg, 2.55 mmol) in dichloromethane (2 mL), add dioxane (20 mL, 4 M) of hydrogen chloride, and stir at room temperature. After the reaction is complete, concentrate to obtain I-31-5 hydrochloride (700 mg), MS (ESI): 214.2 [M+H]. + .

[0561] Step 5: Dissolve I-31-5 hydrochloride (691 mg, 2.77 mmol) and I-1-10 (350 mg, 2.52 mmol) in DMF (15 mL), then add triethylamine (1.27 g, 12.58 mmol), EDCI (579 mg, 3.02 mmol), and HOBt (408 mg, 3.02 mmol) sequentially. Stir overnight at room temperature under nitrogen protection. The reaction solution is concentrated by rotary evaporation and purified by silica gel column chromatography to obtain I-31-6 (492 mg), MS (ESI): 335.0 [M+H]. + .

[0562] Step 6: Dissolve I-31-6 (492 mg, 1.47 mmol) in ethanol / water (10 mL / 5 mL), add lithium hydroxide hydrate (247 mg, 5.88 mmol), and stir overnight at 45 °C. After the reaction is complete, remove the ethanol, adjust the pH to 5 with dilute hydrochloric acid (1 mol / L), concentrate by rotary evaporation, and prepare diastereomers P1 (a mixture of I-31-7-a and I-31-7-b) and P2 (a mixture of I-31-7-c and I-31-7-d) by prep-HPLC.

[0563] 225 mg of component P1 was obtained. 1 H NMR (400MHz, DMSO-d6): 7.55 (s, 1H), 7.45 (d, J = 9.2Hz, 1H), 6.31 (d, J = 9.6Hz, 1H), 6.19 (s, 1H), 3.49 (d, J = 14.4Hz, 1H), 3.02 (d, J = 10.8Hz, 1H),2.04-2.00(m,1H),1.83-1.82(m,1H),1.69(d,J=9.6Hz,1H),1.43-1.37(m,5H),1.32(s,3H),1.26-1.21(m,1H),1.00(d,J=6.8Hz,3H). LCMS:307.1[M+H] + Retention time: 1.004 minutes (mobile phase A: CH3CN, mobile phase B: acetonitrile).

[0564] 165 mg of component P2 was obtained. 1H NMR (400MHz, DMSO-d6): 7.59(d,J=1.6Hz,1H),7.45(dd,J=9.6,2.4Hz,1H),6.30(d,J=9.2Hz,1H),6.21(s,1H),3.51-3.47(m,1H),3.00(d,J=11. 2Hz,1H),2.04-2.01(m,1H),1.77-1.75(m,1H),1.66-1.63(m,1H),1.51- 1.45(m,4H),1.33-1.27(m,5H),1.00(d,J=6.8Hz,3H).LCMS:307.1[M+H] + Retention time: 1.032 minutes (mobile phase A: CH3CN, mobile phase B: acetonitrile).

[0565] Step 7: Add sodium hydrogen hydride (24.55 mg, 1.02 mmol) to a round-bottom flask, then add tetrahydrofuran (4 mL) and I-1-4 (227 mg, 1.02 mmol) under nitrogen protection, and stir at room temperature for 1 hour. In another round-bottom flask, weigh out the isomer P1 (a mixture of I-31-7-a and I-31-7-b) obtained in Step 6 (100 mg, 0.33 mmol), add tetrahydrofuran (0.40 mL) under nitrogen protection, then add diethylaminotrifluoride (158 mg, 0.98 mmol), and stir at room temperature. After the reaction is complete, add triethylamine (165 mg, 1.63 mmol), and add this reaction solution to the first round-bottom flask, stirring at room temperature. After the reaction was complete, the mixture was concentrated, and the residue was separated by reverse-phase chromatography (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 30-60%; 5. Flow rate: 40 mL / min. Retention time: 8.31 min), yielding a mixture of I-31-a and I-31-b (4.70 mg). LC-MS: m / z: 511.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.77(s,1H),10.53(s,1H),8.19–8.11(m,2H),7.55(d,J=2.6Hz ,1H),7.53–7.44(m,3H),7.34–7.26(m,1H),7.17–7.08(m,1H),6.33(d,J=9.5Hz,1H),3.5 9–3.48(m,1H),3.13–3.01(m,1H),2.49–2.39(m,1H),1.99–1.88(m,1H),1.88–1.75(m,1H ),1.51–1.44(m,1H),1.43(s,3H),1.41–1.35(m,2H),1.33(s,3H),1.10(d,J=6.8Hz,3H).

[0566] Following the above steps, replacing isomer P1 (a mixture of I-31-7-a and I-31-7-b) with isomer P2 (a mixture of I-31-7-c and I-31-7-d) obtained in step six yields a mixture of I-31-c and I-31-d. LC-MS: m / z: = 511.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.54(s,1H),8.17–8.10(m,2H),7.55–7.50( m,2H),7.50–7.40(m,2H),7.35–7.25(m,1H),7.18–7.06(m,1H),6.32(d,J=9.5Hz,1 H),3.56–3.45(m,1H),3.07–2.93(m,1H),2.49–2.40(m,1H),1.92–1.78(m,1H),1.6 9–1.57(m,2H),1.48(s,3H),1.35(s,3H),1.32–1.26(m,2H),1.09(d,J=6.8Hz,3H).

[0567] Example 32 Synthesis of compound I-32

[0568] Following the synthesis method of Example 25, replacing starting material I-25-1 with I-32-1 yields compound I-32. LC-MS: 526.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.75(s,1H),10.33(s,1H),8.19(d,J=3.0Hz,1H),8.12(d,J=9.1Hz ,1H),7.57–7.43(m,4H),7.30(td,J=9.2,5.6Hz,1H),7.13(t,J=8.6Hz,1H),6.34(d,J=10.0H z,1H),4.34(t,J=5.1Hz,1H),3.70(q,J=6.9Hz,1H),3.45(dd,J=7.0,5.1Hz,2H),2.83(s,2H) ,2.66(dd,J=13.1,6.9Hz,2H),1.72(s,2H),1.51(s,3H),1.38(s,3H),1.22(d,J=6.9Hz,3H).

[0569] Example 33 Synthesis of compound I-33

[0570] Step 1: Compounds I-33-1 (1 g, 5.75 mmol) and I-33-2 (1.0 g, 6.5 mmol) were dissolved in 1,4-dioxane (35 mL), followed by the addition of Pd2(dba)3 (120 mg, 0.13 mmol), XantPhos (120 mg, 0.2 mmol), and DIPEA (1.5 mL, 8.6 mmol). The system was heated to 110 °C and stirred under argon protection. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain I-33-3 (1.17 g), LC-MS: 247.9 [M+H]. + .

[0571] Step 2: Compound I-33-3 (500 mg, 2.02 mmol) was dissolved in glacial acetic acid (6 mL) and water (1.5 mL). The reaction system was cooled to 0 °C, and N-chlorosuccinimide (760 mg, 5.7 mmol) was added in portions. After the addition was complete, the mixture was stirred at 0 °C. After the reaction was complete, ethyl acetate (100 mL) was added. The organic phase was washed successively with water (50 mL × 3), saturated sodium bicarbonate aqueous solution (50 mL × 3), and saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain I-33-4 (250 mg), LC-MS: 194.0 [M + H]. + .

[0572] Step 3: Dissolve I-12-1 (320 mg, 0.15 mmol) and triethylamine (0.28 mL, 2.0 mmol) in dichloromethane (10 mL), then add a solution of I-33-4 (0.25 g, 1.3 mmol) in dichloromethane (2 mL). Stir at room temperature after addition. Once the reaction is complete, concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain I-33-5 (140 mg). LC-MS: 315.8 [M+H-56] + .

[0573] Step 4: Dissolve I-33-5 (140 mg, 0.38 mmol) in dichloromethane (3 mL), then add trifluoroacetic acid (0.5 mL). Stir at room temperature after the addition is complete. Concentrate the solution to obtain crude trifluoroacetate of I-33-6 (110 mg). LC-MS: 271.9 [M+H] + .

[0574] Step 5: I-1-6 (140 mg, 0.39 mmol) and crude trifluoroacetate of I-33-6 (110 mg) were dissolved in DMF (2 mL), and DIPEA (110 mg, 0.8 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, ethyl acetate (60 mL) was added for dilution. The organic phase was washed with water (40 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated using silica gel agar plates to obtain I-33 (35 mg). LC-MS: 548.1 [M + H] + . 1 H NMR (400MHz, CDCl3) δ12.48(s,1H),9.50(s,1H),8.20(d,J=9.0Hz,1H),8.05(d,J=2.9Hz, 1H),8.00(d,J=2.2Hz,1H),7.69(dd,J=9.7,2.4Hz,1H),7.31(dd,J=9.1,2.9Hz,1H),7.08( td,J=9.0,5.4Hz,1H),7.03–6.93(m,1H),6.93–6.84(m,1H),6.66(d,J=9.7Hz,1H),3.65(s ,2H),3.28(s,1H),2.83(s,1H),2.64(s,1H),2.38(s,2H),1.50(s,6H),1.39–1.31(m,3H).

[0575] Example 34 Synthesis of compound I-34

[0576] Following the synthesis method of Example 9, replacing starting material I-9-1 with I-34-1 yields compound I-34. LC-MS: 496.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.10(d,J=2.9Hz,2H),7.88(s,2H),7.42(dd,J=9.0,2.9Hz,1H),7.29–7.13(m,2H),7.02(d d,J=18.5,10.2Hz,1H),6.56(d,J=9.6Hz,1H),4.42(dd,J=48.2,10.8Hz,8H),4.25(s,1H),1.55(d,J=6.9Hz,3H).

[0577] Example 35 Synthesis of Compound I-35

[0578] Following the synthesis method of Example 9, replacing starting material I-9-1 with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylic acid (I-35-1) yields compound I-35. LC-MS: 524.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.30(s,1H),8.10(dd,J=15.3,6.0Hz,2H),7.66(dt,J=9.2,2.1Hz,2H),7.42(dd,J=9.1,3.0Hz,1H),7.30–7 .15(m,2H),7.03(ddd,J=10.9,4.6,2.4Hz,1H),6.57(d,J=9.2Hz,1H),3.60(d,J=5.5Hz,9H),1.92(s,4H),1.39(d,J=6.8Hz,3H).

[0579] Example 36 Synthesis of Compound I-36

[0580] Following the synthetic method of Example 19, replacing I-19-1 with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylic acid (I-35-1) yields compound I-36. LC-MS: 524.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.35–7.25(m,2H),7.12–7.04(m,2H),6.62(dd,J=9.1, 3.0Hz,1H),6.45(t,J=4.5Hz,1H),6.38(ddd,J=11.0,7.2,2.9Hz,1H),6.22(t ,J=8.5Hz,1H),5.74(d,J=9.5Hz,1H),3.40(s,2H),3.11(s,2H),2.72(dd,J= 24.5,22.9Hz,2H),2.36–2.31(m,1H),2.07(s,4H),1.58(s,1H),1.23(s,4H).

[0581] Example 37 Synthesis of compounds I-3-a and I-3-b

[0582] Step 1: Compound I-3 (270 mg, 0.54 mmol) was weighed and separated by supercritical fluid chiral chromatography (1. Column: Chiralpak SA, 3 × 15 cm, 5 μm; 2. Mobile phase A: carbon dioxide, mobile phase B: methanol; 3. Flow rate: 50 mL / min; reaction time: 30 min) to obtain two fractions. I-3-a (fraction 1, 64 mg) was obtained with a retention time of 2.83 min. LC-MS: 499.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.17(d,J=9.1Hz,1H),8.07(d,J=2.9Hz,1H),7.52(dd,J=9.8,3.2Hz,1H),7.43(dd, J=9.1,3.0Hz,1H),7.30–7.11(m,3H),7.02(ddd,J=10.8,4.6,2.3Hz,1H),6.55(d,J=9.8Hz,1H),3.74(dd ,J=8.6,3.8Hz,1H),3.30(s,1H),2.92–2.83(m,1H),2.53(s,1H),2.40(t,J=8.9Hz,1H),2.27(d,J=11.4H z,1H),2.02(dd,J=13.6,9.9Hz,1H),1.91–1.78(m,1H),1.31(d,J=7.0Hz,3H),1.20(s,3H),1.13(s,3H).

[0583] The retention time of I-3-b (component 2, 77 mg) was 3.58 min. LC-MS: 499.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.17(d,J=9.1Hz,1H),8.07(d,J=2.9Hz,1H),7.51(dd,J=9.8,3.2Hz,1H), 7.43(dd,J=9.1,3.0Hz,1H),7.30–7.09(m,3H),7.07–6.98(m,1H),6.55(d,J=9.8Hz,1H),3.74(d d,J=8.5,4.1Hz,1H),3.37(d,J=7.0Hz,1H),2.80(s,1H),2.64–2.54(m,1H),2.50(d,J=11.4Hz, 1H), 2.21 (d, J = 11.4Hz, 1H), 2.02-1.85 (m, 2H), 1.29 (d, J = 7.0Hz, 3H), 1.20 (s, 3H), 1.12 (s, 3H).

[0584] Example 38 Synthesis of Compound I-38

[0585] Step 1: Compound I-38-1 (4.0 g, 22.33 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) and cooled to 0°C in an ice-water bath. Methyl magnesium bromide solution (3 M, 7.5 mL, 22.35 mmol) was slowly added dropwise under argon protection, and the mixture was stirred at 0°C for 2 hours after the addition was complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution (15 mL), followed by ethyl acetate (400 mL). The organic phase was washed with water (100 mL × 3), then with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain compound I-38-2 (2.26 g). LC-MS: 195.9 [M + H] + .

[0586] Step 2: Compound I-38-2 (2.26 g, 10.59 mmol) was dissolved in dichloromethane (30 mL), and DIPEA (3.0 g, 23.18 mmol) was added. The system was cooled to 0 °C in an ice-water bath, and tert-butyldimethylsilyltrifluoromethanesulfonate (4.2 g, 15.84 mmol) was slowly added dropwise under argon protection. After the addition was complete, the reaction was allowed to proceed for 2 hours, quenched with water (50 mL), and then diluted with ethyl acetate (400 mL). The organic phase was washed with water (100 mL × 3), washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain compound I-38-3 (3.5 g). LC-MS: 309.9 [M + H] + .

[0587] Step 3: I-38-3 (1.5 g, 4.85 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (75%, 1.25 g, 5.43 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The solution was diluted with ethyl acetate (120 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), then with saturated brine (50 mL × 3). After drying over anhydrous sodium sulfate, the solution was concentrated, and the residue was purified by silica gel column chromatography to give compound I-38-4 (1.5 g). LC-MS: 325.9 [M + H] + .

[0588] Step 4: Compound I-38-4 (600 mg, 1.85 mmol) was dissolved in methanol (6 mL), lithium hydroxide monohydrate (233 mg, 5.55 mmol) was added, followed by water (2 mL). The mixture was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid (1 N) was added to adjust the pH to approximately 6. The system was concentrated, and the residue was purified by silica gel column chromatography to obtain compound I-38-5 (520 mg). LC-MS: 311.9 [M+H] + .

[0589] Step 5: At room temperature, trimethylsilyl iodide (800 mg, 3.9 mmol) was dissolved in anhydrous DMSO (12 mL), and sodium hydrogen hydride (153 mg, 3.84 mmol) was added under argon protection. Stirring continued for 1 hour. Compound I-31-2 (900 mg, 3.0 mmol) was dissolved in anhydrous DMSO (3 mL), and this solution was added to the aforementioned reaction mixture. The mixture was stirred overnight at room temperature. The system was quenched with saturated ammonium chloride, diluted with ethyl acetate (100 mL), washed with water (50 mL × 6), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain compound I-38-6 (210 mg). LC-MS: 212.0 [M + H - 100] + .

[0590] Step 6: Compound I-38-6 (210 mg, 0.68 mmol) was dissolved in methanol (3 mL), and sodium hydroxide (82 mg, 2.04 mmol) and water (1 mL) were added. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to approximately 6.0 with dilute hydrochloric acid (1 N). The system was concentrated, and the residue was purified by silica gel column chromatography to obtain compound I-38-7 (105 mg). LC-MS: 185.0 [M + H - 100] + .

[0591] Step 7: Compounds I-38-7 (105 mg, 0.37 mmol), I-1-4 (160 mg, 0.4 mmol), DMF (2 mL), HTAU (160 mg, 0.42 mmol), and DIPEA (60 mg, 0.46 mmol) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, ethyl acetate (60 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), then with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give compound I-38-8 (100 mg). LC-MS: 487.8 [M + H] + .

[0592] Step 8: Compound I-38-8 (100 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (182 mg, 1.60 mmol) was added. The mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated, and the residue was added to methanol (10 mL). The pH was adjusted to neutral with sodium carbonate aqueous solution, and the system was concentrated. The residue was purified by silica gel column chromatography to give compound I-38-9 (75 mg). LC-MS: 387.8 [M+H] + .

[0593] Step 9: Compounds I-38-9 (75 mg, 0.194 mmol), I-38-5 (72 mg, 0.23 mmol), DMF (2 mL), HATU (100 mg, 0.26 mmol), and DIPEA (50 mg, 0.39 mmol) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, ethyl acetate (60 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), then with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give compound I-38-10 (80 mg). LC-MS: 680.8 [M + H] + .

[0594] Step 10: Compound I-38-10 (80 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), and then triethylamine hydrofluoric acid (200 mg, 1.2 mmol) was added. The system was heated to 50 °C for reaction. After the reaction was complete, it was cooled to room temperature, quenched with water, diluted with ethyl acetate (80 mL), washed with water (50 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound I-38 (53 mg). LC-MS: 567.3 [M + H] + . 1H NMR (400MHz, CDCl3) δ8.28–8.23(m,1H),8.22(d,J=3.2Hz,1H),8.18(d,J=7.6Hz,1H),8.02(d,J=2.8Hz,1H),7 .47(d,J=2.4Hz,1H),7.32(dd,J=9.2,2.8Hz,1H),7.27(d,J=2.4Hz,1H),7.09(td,J=9.0,5.4Hz,1H),7.04–6. 95(m,1H),6.90(ddd,J=10.8,4.6,2.2Hz,1H),5.53(s,1H),3.45-3.30(m,2H),3.22(q,J=6.8Hz,1H),2.8-2.2 1(m,1H),2.19–2.11(m,1H),1.69(s,6H),1.66(s,3H),1.65(s,3H),1.41(d,J=7.2Hz,3H),1.28-1.26(m,1H).

[0595] Example 39 Synthesis of Compound I-39

[0596] Step 1: Compound I-26-1 (17.70 g, 0.05 mol) was dissolved in dioxane (20 mL), and a solution of dioxane containing hydrogen chloride (100 mL, 4 mol / L) was added. The mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated, and the residue was diluted with ice water (100 mL). The pH was adjusted to approximately 9 with sodium bicarbonate aqueous solution, resulting in the precipitation of a white solid. The system was filtered, the filter cake was washed with water, and dried under vacuum to obtain compound I-39-1 (10.78 g). LCMS: 231.2 [M+H] + .

[0597] Step 2: Compound I-39-2 (8.02 g, 0.05 mol) was added to dioxane (100 mL), followed by I-1-2 (6.00 g, 0.05 mol), N,N-dimethylglycine (1.43 g, 0.01 mol), cuprous iodide (1.32 g, 6.92 mmol), and cesium carbonate (30.05 g, 0.09 mol). The system was heated to 110 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain I-39-3 (5.47 g). LC-MS: 224.0 [M+H] + .

[0598] Step 3: Compounds I-39-3 (2.74 g, 11.20 mmol), I-3-1 (2.74 g, 11.20 mmol), and pyridine (0.36 mL, 4.48 mmol) were dispersed in ethyl acetate (20 mL), cooled to 0 °C, and T3P (1.43 g, 4.48 mmol) was added. The mixture was then slowly heated to room temperature with stirring. After the reaction was complete, the mixture was concentrated, and the residue was purified by silica gel column chromatography to give I-39-4 (1.20 g) as a white solid. LC-MS: 450.1 [M+H] + .

[0599] Step 4: Compound I-39-1 (500 mg, 1.11 mmol) was dispersed in DMF (10 mL), and triethylamine (225 mg, 2.23 mmol) and I-39-4 (282 mg, 1.22 mmol) were added. The mixture was stirred at room temperature. After the reaction was complete, the mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain I-39-5 (125 mg). LC-MS: 508.1 [M+H] + .

[0600] Step 5: Compound I-39-5 (120 mg, 0.24 mmol) was placed in a round-bottom flask, and palladium on carbon (126 mg, 1.18 mmol) and methanol (10 mL) were added. The system was reacted at room temperature under hydrogen atmosphere. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (alkaline alumina packing) to give compound I-39-6 (59 mg). LC-MS: 418.2 [M+H] + .

[0601] Step 6: Weigh compound I-38-5 (35 mg, 0.11 mmol) into a round-bottom flask, add DMF (3 mL), DIPEA (0.10 mL, 0.56 mmol), and HATU (45 mg, 0.12 mmol) sequentially, stir at room temperature for 0.5 hours, then add compound I-39-6 (53 mg, 0.13 mmol), and react at room temperature for 1 hour. After the reaction is complete, quench with water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography to obtain compound I-39-7 (200 mg). LC-MS: 711.4 [M+H] + .

[0602] Step 7: Weigh I-39-7 (30 mg, 0.04 mmol) into a round-bottom flask, add tetrahydrofuran (3 mL), then add triethylamine trihydrofluoride (340 mg, 2.10 mmol), and heat to 50 °C with stirring. After the reaction is complete, concentrate the solution, and separate the residue by reversed-phase column chromatography to obtain I-39 (20 mg). LC-MS: 596.7 [M+H]+ . 1 H NMR (400MHz, CD3OD) δ8.91–8.83(m,1H),8.37–8.26(m,2H),7.77–7.69(m,1H),7. 51–7.41(m,1H),7.38–7.28(m,1H),7.19–7.09(m,1H),7.08–6.98(m,1H),3.56–3. 46(m,1H),3.26–3.19(m,4H),3.19–3.11(m,1H),2.32–2.19(m,1H),2.17–2.00(m, 2H),2.00–1.83(m,1H),1.75–1.60(m,10H),1.48–1.43(m,1H),1.39–1.35(m,3H).

[0603] Example 40 Synthesis of Compound I-40

[0604] Step 1: Compound I-39-3 (1.4 g, 6.27 mmol) was dissolved in dichloromethane (15 mL). I-1-5 (1.23 g, 7.53 mmol), DCC (1.67 g, 7.53 mmol), and silver nitrate (120 mg, 0.63 mmol) were added at room temperature, and the mixture was stirred for 3 hours at room temperature. Then, dichloromethane (15 mL) and water (10 mL) were added and stirred. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to give compound I-40-1 (1 g). LC-MS: 358.0 [M+H] + .

[0605] Step 2: Compound 1-5-1 (5 g, 22 mmol) was dissolved in tetrahydrofuran (30.00 mL), and (-)-diisopinepine chloroborane (23.29 mL, 40 mmol) was slowly added dropwise at 0 °C. The reaction was carried out at 5 °C for 16 hours. After the reaction was completed, ethyl acetate (120 mL) and diethanolamine (4 g) were added, and the mixture was stirred vigorously at room temperature for three hours. The mixture was filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to give compound I-40-2 (3.68 g), LC-MS: 174.2 [M+H-56]. + .

[0606] Step 3: Compound I-3-4 (1.72 g, 13 mmol) was added to DMF (30 mL). Sodium hydride (1.57 g) and compound I-40-2 (3 g, 13 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) and ethyl acetate (200 mL) were added to the reaction mixture, and the mixture was separated. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound I-40-3 (4.41 g), LC-MS: 285.10 [M+H-56]. + .

[0607] Step 4: Compound I-40-3 (2.11 g, 6.19 mmol) was dissolved in dioxane (25 mL). Potassium hydroxide (690 mg, 12.37 mmol), tris(dibenzylacetone)dipalladium (580 mg, 60.63 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.26 g, 0.63 mmol), and water (4 mL) were added at room temperature. The reaction mixture was heated to 110 °C and stirred. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound I-40-4 (1.37 g), LC-MS: 267.20 [M+H-56]. + .

[0608] Step 5: Dissolve compound I-40-4 (720 mg, 2.23 mmol) in acetic acid (5 mL), add 10% palladium on carbon (55% water, 360 mg), and stir the mixture at room temperature under hydrogen protection. After the reaction is complete, filter the reaction solution, concentrate the filtrate to obtain crude I-40-5 (730 mg), which can be used directly in the next step. LC-MS: 227.20 [M + H - 100] + .

[0609] Step 6: The compound I-40-5 (730 mg) obtained in the previous step was dissolved in ethyl acetate (5 mL), and a solution of ethyl acetate containing hydrogen chloride (5 mL, 2 mol / L) was added at room temperature. The mixture was stirred at room temperature. After the reaction was complete, the mixture was filtered, and the filter cake was dried to obtain I-40-6 hydrochloride (500 mg). LC-MS: 227.20 [M+H] + .

[0610] Step 7: Compound I-40-1 (200 mg, 0.56 mmol) and I-40-6 hydrochloride (127 mg) obtained in Step 6 were dissolved in DMF (1 mL), and triethylamine (232 μL, 1.67 mmol) was added. The mixture was heated to 40 °C and stirred. After the reaction was complete, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain I-40 (110 mg). LC-MS: 504.3 [M+H] + .1 H NMR (400MHz, CDCl3) δ9.73 (d, J = 13.4Hz, 1H), 9.05 (s, 1H), 8.19 (s, 1H), 7.23 ( td,J=8.7,5.3Hz,1H),7.10–6.80(m,2H),5.84(s,1H),3.80(t,J=4.6Hz,1H), 3.54–3.16(m,3H),3.08(td,J=8.6,4.3Hz,1H),2.85(s,1H),2.68–2.23(m,4H ),2.21–2.03(m,1H),2.02–1.87(m,3H),1.31–1.28(m,3H),1.18–0.96(m,6H).

[0611] Example 41 (Compounds I-38-a and I-38-b)

[0612] Step 1: Compound I-38 (65 mg) was separated by supercritical fluid chromatography (1. Instrument: Waters 150SFC; 2. Column: Chiralpak IG, 10 μm, 20 × 150 mm; 3. Mobile phase A: carbon dioxide, mobile phase B: (ethanol: acetonitrile = 70:30); 4. Gradient: 50% B; 5. Flow rate: 50 mL / min; after 30 min).

[0613] The fraction with a retention time of 3.837 min was collected. After concentration and lyophilization, I-38-a (16.7 mg) was obtained. LC-MS: 567.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.31–8.12(m,3H),8.02(s,1H),7.49(s,1H),7.34(d,J=9.0 Hz,1H),7.10(dd,J=14.3,8.8Hz,1H),7.00(t,J=8.0Hz,1H),6.92(d,J=7.4Hz,1H) ,5.54(s,1H),3.48-3.30(m,2H),3.27-3.15(m,1H),2.34-2.20(m,1H),2.20-2.1 0(m,1H),1.90-1.75(br,3H),1.69(s,6H),1.67(s,6H),1.43(s,1H),1.41(s,1H).

[0614] The fraction retained for 5.110 min was collected. After concentration and lyophilization, I-38-b (24.18 mg) was obtained. LC-MS: 567.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.27-8.16(m,3H),8.02(d,J=2.4Hz,1H),7.48(d,J=1.8Hz,1H),7.35(dd, J=9.1,2.6Hz,1H),7.10(td,J=9.0,5.5Hz,1H),7.00(ddd,J=10.7,8.3,2.8Hz,1H),6.91(t,J=8 .1Hz,1H),5.54(s,1H),3.47–3.32(m,2H),3.27–3.18(m,1H),2.26(d,J=16.3Hz,1H),2.16(d,J =16.9Hz,1H),1.89-1.73(br,3H),1.69(s,6H),1.67(d,J=2.4Hz,6H),1.43(s,1H),1.41(s,1H).

[0615] Example 42

[0616] Step 1: Compound I-41-1 (1.0 g, 6.62 mmol) was dispersed in dichloromethane (20 mL), followed by the addition of m-CPBA (1.71 g, 9.92 mmol). The mixture was stirred at room temperature. After the reaction was complete, saturated sodium bicarbonate solution (40 mL) was added. The aqueous phase was separated and extracted with dichloromethane (20 mL × 10). The organic phases were combined and concentrated. The residue was separated by silica gel column chromatography to obtain compound I-41-2 (600 mg). LC-MS: 184.1 [M + H] + .

[0617] Step 2: Compound I-41-2 (400 mg, 2.19 mmol) was dispersed in tetrahydrofuran (10 mL), and LiOH·H₂O (250 mg, 5.98 mmol) and water (10 mL) were added. The mixture was stirred at room temperature. After the reaction was complete, hydrochloric acid (2 M) was added to adjust the pH of the reaction solution to 4-6. The system was concentrated under reduced pressure, and the residue was dissolved in water (15 mL). The residue was extracted with ethyl acetate (20 mL × 15). The organic phases were combined and concentrated to obtain compound I-41-3. LC-MS: 170.0 [M + H₂] + .

[0618] Step 3: Compounds I-38-9 (80 mg, 0.21 mmol), I-41-3 (42 mg, 0.25 mmol), DMF (3 mL), HATU (110 mg, 0.29 mmol), and DIPEA (100 mg, 0.80 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), then with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel plate preparation to obtain I-41 (55 mg). LC-MS: 539.1 [M + H] + .

[0619] Step 4: Compound I-41 (55 mg) was separated by supercritical fluid chromatography (1. Instrument: Waters 150SFC; 2. Column: Chiralpak IG, 10 μm, 20 × 150 mm; 3. Mobile phase A: carbon dioxide, mobile phase B: methanol; 4. Gradient: 50% B; 5. Flow rate: 50 mL / min; 30 min).

[0620] The fraction with a retention time of 5.859 min was collected. After concentration and lyophilization, I-41-a (17 mg) was obtained. LC-MS: 539.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),8.23(d,J=9.0Hz,2H),8.02(s,1H),7.47(s,1H),7.35(d,J=9.0Hz,2H),7.15–7.05(m,1H),7.04–6.95(m,1H),6. 91(t,J=8.0Hz,1H),5.48(s,1H),4.83(s,2H),3.39(s,2H),3.22(d,J=6.8 Hz,1H),2.21(m,3H),1.63(s,6H),1.42(s,1H),1.40(s,1H),1.26(m,1H).

[0621] The fraction with a retention time of 7.482 min was collected. It was concentrated and lyophilized to obtain I-41-b (15 mg). LC-MS: 539.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 8.22 (d, J = 9.0Hz, 2H), 8.03 (d, J = 2.6Hz, 1H), 7.46 (s,1H),7.34(dd,J=9.1,2.8Hz,2H),7.10(td,J=9.0,5.4Hz,1H),7.04–6.95(m,1H),6 .94–6.86(m,1H),5.47(s,1H),4.82(s,2H),3.39(t,J=4.8Hz,2H),3.22(q,J=6.7Hz, 1H), 2.32–2.09 (m, 3H), 1.63 (d, J = 2.4Hz, 6H), 1.42 (s, 1H), 1.40 (s, 1H), 1.29 (m, 1H).

[0622] Example 43

[0623] Step 1: Weigh compound I-1-10 (50 mg, 0.33 mmol) into a round-bottom flask, add DMF (0.50 mL) and DIPEA (0.28 mL, 1.64 mmol), then add HATU (136 mg, 0.36 mmol). Stir the mixture at room temperature for 30 minutes, then add compound I-39-6 (138 mg, 0.33 mmol) and stir at room temperature. After the reaction is complete, concentrate the reaction solution directly, and separate the residue by reversed-phase column chromatography to obtain the crude product. The crude product was prepared and separated by high performance liquid chromatography (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 40mL / min).

[0624] The fraction retained for 3.465 min was collected. After concentration and lyophilization, I-42-a (33.34 mg) was obtained. LC-MS: 553.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.85(s,1H),8.47(s,1H),7.92(s,1H),7.55–7.38(m,3H),7.24–7.14(m,1H),6.40(d,J=9.3Hz,1H),3.4 7(s,3H),3.44–3.39(m,1H),3.27–3.20(m,1H),3.13–3.02(m,1H),2.7 2–2.64(m,1H),2.03–1.58(m,4H),1.45(d,J=42.2Hz,6H),1.26(s,3H).

[0625] The fraction with a retention time of 7.267 min was collected. It was concentrated and lyophilized to obtain I-42-b (18 mg). LC-MS: 553.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),8.80(d,J=1.4Hz,1H),8.45(d,J=1.4Hz,1H),7.89(d,J=2.5Hz,1H),7.54–7.36(m,3H),7.24 –7.11(m,1H),6.37(d,J=9.3Hz,1H),3.43–2.96(m,8H),2.13–1.91(m,2H),1.82–1.66(m,2H),1.51(d,J=13.8Hz,6H),1.26(s,3H).

[0626] Example 44

[0627] Step 1: At room temperature, I-43-1 (1.50 g, 9.80 mmol) and 1-fluoro-2-iodoethane (2.04 g, 11.75 mmol) were added to DMF (20 mL), followed by potassium carbonate (4.06 g, 29.38 mmol). The reaction mixture was heated to 75 °C and stirred. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (50 mL × 6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give compound I-43-2 (1.52 g). LC / MS: [M+H] + =200.0.

[0628] Step 2: At room temperature, I-43-2 (1.8 g, 9.0 mmol) and lithium hydroxide monohydrate (0.76 g, 18.0 mmol) were added to methanol (30 mL) and water (5 mL). The reaction mixture was stirred at 40 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated, the residue was dissolved in water, and the pH was adjusted to approximately 4 with dilute hydrochloric acid. A large amount of solid precipitated from the reaction mixture. After filtration, the filter cake was collected to obtain compound I-43-3 (1.30 g). LC / MS: [M+H] + =186.05.

[0629] Step 3: Weigh compound I-43-3 (50 mg, 0.27 mmol) into a round-bottom flask, add DMF (0.50 mL) and DIPEA (0.09 mL, 0.54 mmol), then add HATU (103 mg, 0.27 mmol). Stir the mixture at room temperature for 30 minutes, then add compound I-39-6 (90 mg, 0.22 mmol) and stir at room temperature. After the reaction is complete, the reaction solution is directly concentrated, and the residue is separated by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Deter; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35 mL / min).

[0630] The fractions with shorter retention times were collected, concentrated, and lyophilized to obtain I-43-a (29.77 mg). LC-MS: 585.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.86(s,1H),8.27(d,J=1.3Hz,1H),7.83(d,J=2.5Hz,1H),7.61–7.49(m,1H), 7.37–7.27(m,1H),7.18–7.08(m,1H),7.08–6.97(m,1H),6.59(d,J=9.3Hz,1H),4.80–4.69(m,1H), 4.69–4.57(m,1H),4.52–4.22(m,2H),3.60–3.49(m,1H),3.45–3.36(m,1H),3.29–3.04(m,3H),2.3 1–2.20(m,1H),2.14–2.01(m,1H),1.94–1.77(m,2H),1.65(d,J=19.7Hz,6H),1.39(d,J=6.7Hz,3H).

[0631] The fraction with the longest retention time was collected. After concentration and lyophilization, I-43-b (7.94 mg) was obtained. LC-MS: 585.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.90(s,1H),8.31(s,1H),7.90(s,1H),7.67–7.57(m,1H),7.39–7.28(m,1H),7.21–7.10(m,1H),7.08–7.01(m,1H), 6.62(d,J=9.4Hz,1H),4.82–4.74(m,1H),4.71–4.61(m,1H),4.51–4.26(m,2H),4.01–3.35(m,5H),2.41–1.91(m,4H),1.74–1.39(m,9H).

[0632] Example 45

[0633] Step 1: Compound I-41-2 (3.00 g, 16.38 mmol) was dispersed in dichloromethane (30 mL), and imidazole (1.34 g, 0.02 mol) and tert-butyldiphenylchlorosilane (5.41 g, 19.69 mmol) were added. The mixture was stirred at room temperature. After the reaction was complete, the mixture was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography to give I-44-1 (6 g). LC-MS: 422.1 [M+H] + .

[0634] Step 2: Compound I-44-1 (6 g, 14.23 mmol) was dispersed in acetonitrile (60 mL), and lithium bromide (7.42 g, 85.40 mmol) and DBN (10.61 g, 85.40 mmol) were added. The mixture was stirred at room temperature. After the reaction was complete, the mixture was concentrated, the residue was cooled in an ice bath, quenched with water, and then an aqueous formic acid solution (0.5%, 100 mL) was added. A large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with water. The filter cake was dissolved in methanol and separated by reversed-phase column chromatography to give compound I-44-2 (1.32 g). LC-MS: 409.0 [M+H] + .

[0635] Step 3: Compound I-44-2 (293 mg, 0.72 mmol), DMF (3 mL), DIPEA (0.26 mL, 1.49 mmol), and HATU (273 mg, 0.72 mmol) were added sequentially to a round-bottom flask and stirred at room temperature for 5 minutes. Then, compound I-39-6 (150.00 mg, 0.36 mmol) was added and stirred at room temperature. After the reaction was complete, the mixture was quenched with water, extracted three times with ethyl acetate, and the organic layers were combined and concentrated. The residue was separated by silica gel column chromatography to obtain compound I-44-3 (250 mg). LC-MS: 807.4 [M+H] + .

[0636] Step 4: Compound I-44-3 (250 mg, 0.31 mmol) was dispersed in DMF (4 mL), and ammonium fluoride (115 mg, 3.10 mmol) was added. The mixture was stirred at room temperature. After the reaction was complete, the mixture was preparatively separated by high performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35 mL / min), yielding two fractions.

[0637] Fraction 1 (I-44-a, 43.46 mg) was collected and analyzed by LC-MS: 569.3 [M+H]. + . 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.85(s,1H),8.48(s,1H),8.28(d,J=6.5Hz,1H),7.55–7.41(m,3H),7.40–7.28(m,1H),7.24–7.1 2(m,1H),4.60(s,2H),3.43–3.34(m,3H),3.18–3.01(m,1H),2.77–2.63(m,1H),2.11–1.65(m,4H),1.50(d,J=24.8Hz,6H),1.25(s,3H).

[0638] Component 2 (I-44-b, 37.65 mg) was collected and analyzed by LC-MS: 569.3 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ10.29 (s, 1H), 8.79 (d, J = 1.4Hz, 1H), 8.46 (d, J = 1. 4Hz,1H),8.25(d,J=6.6Hz,1H),7.53–7.40(m,3H),7.35–7.28(m,1H),7.21 –7.11(m,1H),4.57(s,2H),3.35–3.02(m,5H),2.19–2.05(m,1H),2.05–1.9 2(m,1H),1.82–1.61(m,2H),1.56(d,J=4.1Hz,6H),1.26(d,J=14.8Hz,3H).

[0639] Example 46

[0640] Step 1: Weigh compound I-45-1 (88 mg, 0.48 mmol) into a round-bottom flask, add DMF (0.50 mL) and DIPEA (0.17 mL, 1.0 mmol), then add HATU (182 mg, 0.48 mmol). Stir the mixture at room temperature for 30 minutes, then add compound I-39-6 (100 mg, 0.24 mmol) and stir at room temperature. After the reaction is complete, concentrate the reaction solution, and separate the residue by high-performance liquid chromatography (HPLC). (1. Instruments: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 40 mL / min).

[0641] Component 1 was collected, concentrated, and lyophilized to obtain I-45-a (41.77 mg). LC-MS: 583.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.90 (s, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 9. 6Hz,1H),7.40–7.29(m,1H),7.19–7.11(m,1H),7.09–7.01(m,1H),6.60(d ,J=9.4Hz,1H),4.81–4.30(m,2H),4.30–4.20(m,1H),4.13–4.00(m,1H),3 .94–3.73(m,3H),3.70–3.44(m,2H),2.37–1.96(m,4H),1.75–1.38(m,9H).

[0642] Component 2 was collected, concentrated, and lyophilized to obtain I-45-b (44.41 mg). LC-MS: 583.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.87(s,1H),8.28(s,1H),7.88–7.81(m,1H),7.61–7.53(m,1H),7.38 –7.27(m,1H),7.19–7.09(m,1H),7.07–6.98(m,1H),6.57(d,J=9.3Hz,1H),4.70–4.29(m,1H ),4.29–4.15(m,1H),4.15–4.00(m,1H),3.90–3.75(m,2H),3.71–3.56(m,1H),3.54–3.37(m ,2H),3.27–3.10(m,1H),2.30–1.79(m,4H),1.66(d,J=18.8Hz,6H),1.39(d,J=30.4Hz,3H).

[0643] Example 47

[0644] Step 1: Compound I-3-3 (4.50 g, 19.62 mmol) was dissolved in DMF (80 mL) under ice bath conditions. Sodium hydride (60%, 494.46 mg, 20.60 mmol) and compound I-46-1 (2.40 g, 19.62 mmol) were added, and the mixture was stirred at room temperature. After the reaction was complete, saturated ammonium chloride (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give I-46-2 (6.20 g). LC-MS: 331.8 [M + H] + .

[0645] Step 2: Compound I-46-2 (6 g, 18.10 mmol) and concentrated hydrochloric acid (30 mL) were added sequentially to a reaction flask, and the mixture was heated to 110 °C. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain compound I-46-3 (4.20 g). LC-MS: 251.1 [M+H] + .

[0646] Step 3: Compound I-46-3 (4 g, 15.98 mmol), triethylamine (4.85 g, 47.94 mmol), di-tert-butyl dicarbonate (4.19 g, 19.18 mmol), and tetrahydrofuran (50 mL) were added sequentially to a reaction flask and stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give a white solid I-46-4 (5.20 g). LC-MS: 350.8 [M + H] + .

[0647] Step 4: Compound I-46-4 (5.20 g, 14.84 mmol) was dispersed in tetrahydrofuran (80 mL), cooled to 0 °C, and lithium aluminum hydride solution (1 M, 37.10 mL, 37.10 mmol) was slowly added dropwise while stirring at 0 °C. After the reaction was complete, a saturated potassium sodium tartrate solution (100 mL) was added to quench the reaction. The system was filtered, and the filtrate was concentrated under reduced pressure to obtain I-46-5 (3.10 g). LC-MS: 337.1 [M+H] + .

[0648] Step 5: Compound I-46-5 (3 g, 8.92 mmol) and tert-butyldimethylchlorosilane (1.62 g, 10.72 mmol) were dissolved in DMF (50 mL), and DIPEA (1.73 g, 13.39 mmol) was added. The mixture was stirred at room temperature. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound I-46-6 (3.70 g). LC-MS: 451.1 [M+H] + .

[0649] Step 6: Compound I-46-6 (3.10 g, 6.88 mmol) was dispersed in dichloromethane (60 mL), and m-CPBA (1.78 g, 10.32 mmol) was added under ice bath conditions. The mixture was stirred at room temperature. After the reaction was complete, the mixture was diluted with dichloromethane (200 mL), washed successively with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound I-46-7 (3 g). LC-MS: 466.9 [M+H] + .

[0650] Step 7: Compound I-46-7 (1.10 g, 2.36 mmol) and dichloromethane (15 mL) were added sequentially to a reaction flask. Trifluoroacetic acid (3 mL) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound I-46-8 (850 mg). LC-MS: 366.9 [M+H] + .

[0651] Step 8: Compound I-3-2 (300 mg, 0.37 mmol) and compound I-46-8 (293 mg, 0.80 mmol) were dissolved in acetonitrile (5 mL), and DIPEA (259 mg, 2.01 mmol) was added. The mixture was stirred at room temperature. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain crude I-46-9 (430 mg), which was directly used in the next step of the reaction. LCMS: 643.1 [M+H] + .

[0652] Step 9: Crude I-46-9 (300 mg, 0.47 mmol) and tetrahydrofuran (5 mL) were added sequentially to a reaction flask. Triethylamine trihydrofluoride (3 mL) was added under ice bath conditions. The ice bath was removed, and the mixture was brought to room temperature with stirring. After the reaction was complete, the mixture was filtered. The filtrate was separated into two products by preparative HPLC. Product I-46-a (62.04 mg), LC-MS: 529.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.09 (d, J=16.3Hz, 1H), 8.22–8.02 (m, 3H), 7.52 (dd, J=5. 9,3.0Hz,2H),7.31(d,J=5.6Hz,1H),7.11(d,J=21.5Hz,3H),5.65(s,1H),4.55(s, 2H),4.16(s,1H),3.49(s,1H),2.90–2.54(m,1H),2.49–2.35(m,2H),2.23(d,J=10 .8Hz,1H),1.92(s,1H),1.76(s,1H),1.18(d,J=5.8Hz,3H),1.05(d,J=53.0Hz,6H). Product I-46-b (42.54mg), LC-MS: 529.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.24–8.04(m,3H),7.56–7.44(m,2H),7.3 2(s,1H),7.08(d,J=3.1Hz,3H),5.63(s,1H),4.54(d,J=3.9Hz,2H),4.20–4.10(m ,1H),3.46(d,J=7.1Hz,1H),2.78(s,1H),2.39(d,J=44.0Hz,2H),2.26(s,1H),1 .93(s,1H),1.67(d,J=9.3Hz,1H),1.19(d,J=6.9Hz,3H),1.05(d,J=37.2Hz,6H).

[0653] Example 48

[0654] Step 1: Weigh compound IN-2 (404.90 mg, 0.960 mmol) into a round-bottom flask, add N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (0.42 mL, 2.438 mmol), then add compound I-48-2 (200 mg, 0.480 mmol, prepared as I-39-6), and finally add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (309.127 mg, 0.813 mmol). React at room temperature for 48 hours. After the reaction is complete, quench with water, extract three times with ethyl acetate, combine the organic layers, evaporate to dryness, and separate the residue by silica gel column chromatography to obtain compound I-48-3 (100 mg). LC-MS: 820.5 [M+H] + .

[0655] Step 2: Weigh compound I-48-3 (162 mg, 0.198 mmol) into a round-bottom flask, add N,N-dimethylformamide (4 mL), then add ammonium fluoride (73.339 mg, 1.980 mmol), and stir at room temperature for 18 hours. After the reaction is complete, preparative separation is performed by high performance liquid chromatography (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35 mL / min).

[0656] The fraction retained for 2.778 min was collected, concentrated, and lyophilized to obtain I-48-a (26.31 mg). LC-MS: 582.3 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.15(d,J=9.1Hz,1H),8.06(d,J=2.9Hz,1H),7.81(d,J=2.5Hz,1H),7.58–7.53(m,1H) ,7.45–7.40(m,1H),7.28–7.14(m,2H),7.06–6.98(m,1H),6.56(d,J=9.3Hz,1H),4.26–4.16(m,1H),4.10–4. 01(m,1H),3.87–3.77(m,2H),3.62–3.55(m,1H),3.46–3.38(m,1H),3.17(d,J=6.7Hz,1H),3.14–3.06(m,2H ),2.25–2.15(m,1H),2.12–1.99(m,1H),1.89–1.75(m,2H),1.68(s,3H),1.62(s,3H),1.36(d,J=6.8Hz,3H).

[0657] The fraction retained for 3.077 min was collected, concentrated, and lyophilized to obtain I-48-b (26.47 mg). LC-MS: 582.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.17(d,J=9.1Hz,1H),8.07(d,J=3.0Hz,1H),7.84(d,J=2.5Hz,1H),7.61–7.55(m,1H ),7.47–7.40(m,1H),7.29–7.15(m,2H),7.07–6.98(m,1H),6.59(d,J=9.3Hz,1H),4.29–4.17(m,1H),4.12 –4.02(m,1H),3.89–3.81(m,2H),3.71–3.63(m,1H),3.57(s,1H),3.47–3.38(m,1H),3.16–3.06(m,1H),2. 75(d,J=6.2Hz,1H),2.19–2.09(m,1H),2.05–1.87(m,3H),1.64(s,3H),1.51(s,3H),1.37(d,J=6.8Hz,3H).

[0658] Example 49

[0659] Step 1: Weigh compound IN-3 (200 mg, 0.670 mmol) into a round-bottom flask, add N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (0.350 mL, 2.010 mmol), then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (254.754 mg, 0.670 mmol), stir at room temperature for 5 minutes, then add compound I-48-2 (279.630 mg, 0.671 mmol), and react at room temperature for 18 hours. After the reaction is complete, quench with water, extract three times with ethyl acetate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography to obtain compound I-49-3 (223 mg). LC-MS: 698.4 [M+H] + .

[0660] Step 2: Weigh compound I-49-3 (200 mg, 0.287 mmol) into a round-bottom flask, add N,N-dimethylformamide (5 mL), then add ammonium fluoride (106.300 mg, 2.870 mmol), and stir at room temperature for 18 hours. After the reaction is complete, preparative separation is performed by high-performance liquid chromatography (HPLC) (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35 mL / min).

[0661] The fraction retained for 1.789 min was collected, concentrated, and lyophilized to obtain I-49-a (44.46 mg). LC-MS: 582.3 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.17(d,J=9.0Hz,1H),8.07(d,J=3.0Hz,1H),8.02(d,J=1.0Hz,1H),7.93 (d,J=1.0Hz,1H),7.48–7.40(m,1H),7.30–7.14(m,2H),7.08–6.98(m,1H),4.17–4.07(m,2H),4 .05–3.97(m,1H),3.91–3.81(m,2H),3.63–3.54(m,1H),3.38(d,J=12.9Hz,1H),3.19–3.08(m, 1H),2.76(d,J=6.4Hz,1H),2.25–1.84(m,4H),1.64(s,3H),1.52(s,3H),1.38(d,J=6.8Hz,3H).

[0662] The fraction retained for 2.985 min was collected, concentrated, and lyophilized to obtain I-49-b (37.81 mg). LC-MS: 582.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.15(d,J=9.1Hz,1H),8.05(d,J=3.0Hz,1H),7.99(d,J=1.1Hz,1H ),7.91(d,J=1.1Hz,1H),7.45–7.40(m,1H),7.27–7.13(m,2H),7.04–6.97(m,1H),4.15– 4.05(m,2H),3.96–3.88(m,1H),3.87–3.80(m,2H),3.41–3.35(m,1H),3.18–3.13(m,1H) ,3.12–3.05(m,2H),2.17–1.74(m,4H),1.68(s,3H),1.62(s,3H),1.36(d,J=6.8Hz,3H).

[0663] Example 50

[0664] Step 1: Weigh compound IN-3 (140.00 mg, 0.47 mmol) into a round-bottom flask, add N,N-dimethylformamide (0.50 mL) and N,N-diisopropylethylamine (0.25 mL, 1.41 mmol), then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (178.33 mg, 0.47 mmol), stir at room temperature for 5 minutes, then add compound I-39-6 (196.21 mg, 0.47 mmol), and react at room temperature for 18 hours. After the reaction is complete, quench with water, extract three times with ethyl acetate, combine the organic layers, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography to obtain compound I-50-3 (243.00 mg). LC-MS: 698.4 [M+H] + .

[0665] Step 2: Weigh compound I-50-3 (210.00 mg, 0.30 mmol) into a round-bottom flask, add N,N-dimethylformamide (0.50 mL), then add ammonium fluoride (111.49 mg, 3.01 mmol), and react at room temperature for 14 hours. After the reaction is complete, preparative separation is performed by high-performance liquid chromatography (HPLC). (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35 mL / min).

[0666] The fraction retained for 7.696 min was collected, concentrated, and lyophilized to obtain I-50-a (41.60 mg). LC-MS: 583.7 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.86(s,1H),8.26(d,1H),7.99(s,1H),7.92(s,1H) ,7.37–7.25(m,1H),7.20–7.08(m,1H),7.07–6.96(m,1H),4.18–4.03(m, 2H),3.96–3.87(m,1H),3.87–3.79(m,2H),3.37–3.34(m,1H),3.22–3.02 (m,3H),2.23–1.73(m,4H),1.64(d,J=21.2Hz,6H),1.35(d,J=6.8Hz,3H).

[0667] The fraction retained for 8.700 min was collected, concentrated, and lyophilized to obtain I-50-b (63.70 mg). LC-MS: 583.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.89(d,J=1.4Hz,1H),8.29(d,J=1.4Hz,1H),8.02(d,J=1.0Hz,1H),7. 93(d,J=1.1Hz,1H),7.39–7.29(m,1H),7.19–7.10(m,1H),7.07–6.99(m,1H),4.16–4.08(m, 2H),4.03–3.95(m,1H),3.92–3.83(m,2H),3.60–3.54(m,1H),3.40–3.36(m,1H),3.20–3.08 (m,1H),2.79–2.70(m,1H),2.25–1.77(m,4H),1.58(d,J=52.9Hz,6H),1.38(d,J=6.9Hz,3H).

[0668] Example 51

[0669] Step 1: Weigh compound I-44-2 (140.00 mg, 0.34 mmol) into a round-bottom flask, add N,N-dimethylformamide (0.50 mL) and N,N-diisopropylethylamine (0.12 mL, 0.69 mmol), then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (130.80 mg, 0.34 mmol), stir at room temperature for 5 minutes, then add compound I-48-2 (71.38 mg, 0.17 mmol), and react at room temperature for 18 hours. After the reaction is complete, quench with water, extract three times with ethyl acetate, combine the organic layers, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography to obtain compound I-51-3 (73.00 mg). LC-MS: 806.4 [M+H] + .

[0670] Step 2: Weigh compound I-51-3 (55.00 mg, 0.07 mmol) into a round-bottom flask, add N,N-dimethylformamide (0.50 mL), then add ammonium fluoride (25.19 mg, 0.68 mmol), and stir at room temperature for 18 hours. After the reaction is complete, preparative separation is performed by high-performance liquid chromatography (HPLC). (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35 mL / min).

[0671] The fraction retained for 3.629 min was collected, concentrated, and lyophilized to obtain I-51-a (6.36 mg). LC-MS: 567.7 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.37(d,J=6.6Hz,1H),8.17(d,J=9.0Hz,1H),8.08(s,1H) ,7.69(d,J=2.4Hz,1H),7.48–7.41(m,2H),7.29–7.14(m,2H),7.06–6.98(m,1H ),4.83(s,2H),3.59–3.52(m,1H),3.48–3.39(m,2H),3.15–3.05(m,1H),2.81– 2.73(m,1H),2.20–1.81(m,4H),1.63(d,J=29.1Hz,6H),1.36(d,J=6.8Hz,3H).

[0672] The fraction retained for 3.631 min was collected, concentrated, and lyophilized to obtain I-51-b (6.18 mg). LC-MS: 567.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.33(d,J=6.6Hz,1H),8.15(d,J=9.1Hz,1H),8.09–8.03(m,1H),7.66(d,J=2.4Hz,1H),7.46–7.39(m,2H),7.28–7.12(m ,2H),7.07–6.95(m,1H),4.80(s,2H),3.50–3.35(m,2H),3.24–3.01(m ,3H),2.29–1.77(m,4H),1.70(d,J=6.7Hz,6H),1.36(d,J=6.8Hz,3H).

[0673] Example 52

[0674] Step 1: Weigh compound I-43-3 (50.00 mg, 0.27 mmol) into a round-bottom flask, add N,N-dimethylformamide (2.50 mL) and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol), then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (102.66 mg, 0.27 mmol), stir at room temperature for 5 minutes, then add compound I-48-2 (89.54 mg, 0.22 mmol), and react at room temperature for 18 hours. After the reaction was completed, the mixture was preparatively separated by high performance liquid chromatography (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35mL / min).

[0675] The fraction retained for 3.139 min was collected, concentrated, and lyophilized to obtain I-52-a (29.95 mg). LC-MS: 584.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.16(d,J=9.1Hz,1H),8.08(d,J=3.0Hz,1H),7.91–7.84(m,1H ),7.61(dd,J=9.3,2.5Hz,1H),7.43(dd,J=9.0,3.1Hz,1H),7.29–7.15(m,2H),7.07– 6.97(m,1H),6.61(d,J=9.3Hz,1H),4.82–4.75(m,1H),4.70–4.63(m,1H),4.51–4.24 (m,2H),3.89–3.34(m,4H),3.24–3.02(m,1H),2.31–1.92(m,4H),1.73–1.44(m,9H).

[0676] The fraction retained for 6.724 min was collected, concentrated, and lyophilized to obtain I-52-b (28.02 mg). LC-MS: 584.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.14(d,J=9.1Hz,1H),8.06(d,J=3.0Hz,1H),7.87–7.82(m,1H ),7.58(dd,J=9.3,2.5Hz,1H),7.43(dd,J=9.1,3.0Hz,1H),7.28–7.13(m,2H),7.05– 6.98(m,1H),6.59(d,J=9.4Hz,1H),4.81–4.73(m,1H),4.70–4.60(m,1H),4.51–4.22 (m,2H),3.76–3.34(m,4H),3.21–3.00(m,1H),2.37–1.83(m,4H),1.74–1.38(m,9H).

[0677] Example 53

[0678] Step 1: Add compound I-38-7 (300 mg, 1.06 mmol) and dichloromethane (10 mL) to a single-necked flask. While stirring, add oxaloyl chloride (200 mg, 1.6 mmol) dropwise. After the addition is complete, add one drop of N,N-dimethylformamide as a catalyst. Stir at room temperature for 1 hour and concentrate to obtain crude compound I-53-2 (360 mg).

[0679] Step 2: 5-[(2,4-difluorophenyl)oxy]pyrazine-2-amine I-39-3 (200 mg, 0.9 mmol) was dissolved in dry pyridine (3 mL) and added to compound I-53-2. The mixture was stirred overnight at room temperature. After the reaction was complete, compound I-53-3 (105 mg) was obtained by reversed-phase column chromatography. LC-MS: 388.8 [M + H - 100] + .

[0680] Step 3: Compound I-53-3 (105 mg, 0.215 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL, 6.6 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to obtain crude compound I-53-4 (130 mg). LC-MS: 388.8 [M+H] + .

[0681] Step 4: Compound I-53-4 (75 mg, 0.19 mmol), 4-carboxy-2-(hydroxymethyl)pyridine-1-oxide I-41-3 (40 mg, 0.24 mmol), N,N-dimethylformamide (3.0 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 mg, 0.80 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography to obtain I-53 (85 mg). LC-MS: 540.3 [M + H] + .

[0682] Separation by supercritical fluid chromatography (1. Instrument: Waters 150SFC; 2. Column: (5μm, 20×150mm); 3. Mobile phase A: carbon dioxide, mobile phase B: methanol; 4. Gradient: mobile phase B content 20%; 5. Flow rate: 50mL / min).

[0683] The fraction retained for 8.712 min was collected, concentrated, and lyophilized to obtain I-53-a (13 mg). LC-MS: 540.3 [M+H] + . 1H NMR(400MHz, CDCl3)δ9.01(s,1H),8.45-8.12(br,2H),7.96(s,1H),7.78-7.32(br,2H),7.2 5-7.15(m,1H),7.05–6.84(m,2H),5.54(s,1H),5.20-4.50(br,2H),3.62-3.32(m,2H),3.31 -3.15(m,1H),2.40-2.25m,3H),1.67(s,6H),1.48-1.35(m,3H).

[0684] The fraction with a retention time of 10.064 was collected, concentrated, and lyophilized to obtain I-53-b (16 mg). LC-MS: 540.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ9.01(s,1H),8.16(br,2H),7.98(s,1H),7.72-7.32(br,2H),7.26-7.16(m,1H),7.04–6.87(m,2H),5 .54(s,1H),5.10-4.65(br,2H),3.57-3.32(m,2H),3.30-3.20(m,1H),2.35-2.00(m,3H),1.66(s,6H),1.45–1.37(m,3H).

[0685] Example 54

[0686] Compound I-38-9 (120 mg, 0.31 mmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (47 mg, 0.31 mmol), N,N-dimethylformamide (3.0 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (140 mg, 0.37 mmol), and N,N-diisopropylethylamine (100 mg, 0.80 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography to obtain compound I-54 (120 mg). Further separation was performed by supercritical fluid chromatography (1. Instrument: Waters 150 SFC; 2. Column: (5μm, 20×250mm); 3. Mobile phase A: carbon dioxide, mobile phase B: methanol; 4. Gradient: mobile phase B content 12%; 5. Flow rate: 50mL / min).

[0687] The fraction with a retention time of 9.737 min was collected, concentrated, and lyophilized to obtain I-54-a (45 mg).

[0688] LC-MS: 523.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.20(d,J=9.1Hz,1H),8.08–7.99(m,2H),7.74(d,J=2.3Hz,1H),7.37 (dd,J=9.4,2.5Hz,1H),7.31(dd,J=9.2,2.9Hz,1H),7.12-7.04(m,1H),6.93-6.85(m,1H),6 .93–6.84(m,1H),6.53(d,J=9.4Hz,1H),5.50(s,1H),3.58(s,3H),3.52-3.37(m,2H),3.21 (q,J=7.0Hz,1H),2.33–2.22(m,1H),2.22-2.10(m,1H),1.61(s,6H),1.41(d,J=7.0Hz,3H).

[0689] The fraction with a retention time of 10.915 min was collected, concentrated, and lyophilized to obtain I-54-b (42 mg). LC-MS: 523.3 [M+H]+. 1 H NMR (400MHz, CDCl3) δ8.20(d,J=9.1Hz,1H),8.06(s,1H),8.03(d,J=2.7Hz,1H),7.74(d,J=2.2H z,1H),7.37(dd,J=9.1,2.2Hz,1H),7.31(dd,J=9.2,2.9Hz,1H),7.13-7.04(m,1H),7.02–6.94( m,1H),6.93-6.86(m,1H),6.53(d,J=9.4Hz,1H),5.51(s,1H),3.58(s,3H),3.53–3.38(m,2H),3 .21(q,J=6.8Hz,1H),2.34–2.22(m,1H),2.22–2.11(m,1H),1.62(s,6H),1.42(d,J=7.0Hz,3H).

[0690] Example 55

[0691] Step 1: Compound I-38-9 (120 mg, 0.31 mmol), 1-(5,5-dimethyl-

[0692] 4,4-Diphenyl-3-oxa-4-silazhex-1-yl)-6-oxomylidene-3-carboxylic acid I-44-2 (145 mg, 0.34 mmol), N,N-dimethylformamide (3.0 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (140 mg, 0.37 mmol), and N,N-diisopropylethylamine (100 mg, 0.80 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography to obtain compound I-55-2 (240 mg). LC-MS: 790.6 [M + H] + .

[0693] Step 2: Compound I-55-2 (240 mg, 0.3 mmol) was dissolved in 5 mL of tetrahydrofuran, and then triethylamine hydrofluoric acid (400 mg, 2.4 mmol) was added. After the addition was complete, the reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water, and then diluted with ethyl acetate (80 mL). The solution was washed with water (50 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain compound I-55 (120 mg). LC-MS: 553.3 [M + H] + . 1 H NMR (400MHz, CDCl3) δ8.356-8.15(m,2H),8.02(d,J=2.8Hz,1H),7.78(d,J=2.2Hz,1H),7.48–7.39(m,1H),7 .37–7.30(m,1H),7.14–7.04(m,1H),6.99(ddd,J=10.9,5.7,2.8Hz,1H),6.94–6.85(m,1H),6.60–6.50(m,1 H),5.49(d,J=8.1Hz,1H),4.20-4.10(m,2H),4.0-3.9(m,2H),3.56–3.38(m,2H),3.21(d,J=6.8Hz,1H),2.3 5-2.22(m,1H),2.20-2.10(m,1H),2.01-1.82(brs,1H),1.60(d,J=5.5Hz,6H),1.41(dd,J=6.9,3.9Hz,3H).

[0694] Example 56

[0695] Step 1: Compounds I-38-9 (500 mg, 1.291 mmol) and I-50-1 (385 mg, 1.291 mmol) were dissolved in DMF (2 mL), and DIPEA (0.67 mL, 3.873 mmol) and HATU (736 mg, 1.937 mmol) were added. The reaction mixture was reacted at 25 °C for 16 hours. The reaction solution was directly concentrated, and the crude product was purified by rapid silica gel column chromatography to obtain compound I-56-2 (377 mg). LC-MS: 688.4 [M+H] + .

[0696] Step 2: Compound I-56-2 (360 mg, 0.539 mmol) was dissolved in DMF (2 mL), and fluoroamine (188 mg, 5.390 mmol) was added. The reaction mixture was reacted at 25 °C for 16 hours. The reaction solution was filtered and separated by high performance liquid chromatography. After lyophilization, I-56 (86.7 mg) was obtained. LC-MS: 554.3 [M+H] + .

[0697] Compound I-56 was resolved by supercritical fluid chromatography (1. Instrument: Waters 150SFC; 2. Column: (S,S)Whelk-O 1 (5μm, 30×150mm); 3. Mobile phase A: carbon dioxide, mobile phase B: methanol; 4. Gradient: mobile phase B content 30%; 5. Flow rate: 80mL / min).

[0698] The fraction with a retention time of 5.187 min was collected, concentrated, and lyophilized to obtain I-56-a (34.5 mg). 1 H NMR (400MHz, CDCl3) δ8.21(d,J=9.1Hz,1H),8.08(s,1H),8.05–8.01(m,2H),7.94(d,J=1.1Hz,1H),7.31(dd,J=9.1,3.0Hz ,1H),7.08(td,J=9.0,5.4Hz,1H),6.98(ddd,J=10.8,8.3,2.9Hz,1H),6.89(dddd,J=9.2,7.7,3.0,1.7Hz,1H),5.49(s,1H ),4.13(dd,J=5.8,4.0Hz,2H),3.99(d,J=4.9Hz,2H),3.60(ddd,J=13.3,6.0,3.9Hz,1H),3.47(ddd,J=13.3,7.4,3.7Hz,1 H), 3.20 (q, J = 7.0Hz, 1H), 2.69 (s, 1H), 2.43–2.29 (m, 1H), 2.29–2.12 (m, 1H), 1.62 (d, J = 5.2Hz, 6H), 1.41 (d, J = 7.0Hz, 3H).

[0699] The fraction with a retention time of 5.814 min was collected, concentrated, and lyophilized to obtain I-56-b (30 mg). 1 H NMR (400MHz, CDCl3) δ8.21(d,J=9.1Hz,1H),8.15(s,1H),8.03(d,J=1.4Hz,2H),7.95(d,J=1.1Hz,1H),7.31(dd,J=9.1,3.0 Hz,1H),7.08(td,J=9.0,5.4Hz,1H),6.98(ddd,J=10.8,8.3,2.9Hz,1H),6.89(dddd,J=9.2,7.7,3.0,1.8Hz,1H),5.47(s,1 H),4.12(dd,J=5.7,3.9Hz,2H),3.99(t,J=4.6Hz,2H),3.59(ddd,J=13.3,6.1,4.0Hz,1H),3.46(ddd,J=13.3,7.3,3.7Hz,1 H), 3.20 (q, J = 7.0Hz, 1H), 2.91 (s, 1H), 2.47–2.31 (m, 1H), 2.28–2.12 (m, 1H), 1.61 (d, J = 6.5Hz, 6H), 1.40 (d, J = 7.0Hz, 3H).

[0700] Example 57

[0701] Step 1: Add N,N-dimethylformamide (50.00 mL) to a round-bottom flask under nitrogen protection. Add sodium hydride (410 mg, 17.11 mmol). At room temperature, add compound I-57-2 (2.61 g, 11.40 mmol). Stir for 1 hour at the same temperature. Then add compound I-57-1 (1.50 g, 11.40 mmol). React at room temperature for 18 hours. After the reaction is complete, quench with water, extract three times with ethyl acetate, combine the organic layers, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain compound I-57-3 (3.20 g). LC-MS: 285.0 [M+H] + .

[0702] Step 2: Weigh compound I-57-3 (3.20 g) and potassium hydroxide (1.58 g, 28.16 mmol) into a round-bottom flask, add 1,4-dioxane (0.80 mL), then add water (0.10 mL), and finally add tris(dibenzylene-BASE-acetone)dipalladium (409.32 mg, 447.00 μmol) and 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (460.56 mg, 0.96 mmol). Stir at 110 °C for 18 hours. After the reaction is complete, evaporate to dryness and purify by silica gel column chromatography to obtain compound I-57-4 (3.10 g) as a blue solid. LC-MS: 267.2 [M+H] + .

[0703] Step 3: Add N,N-dimethylformamide (100.00 mL) to a round-bottom flask under nitrogen protection. Add compound I-57-4 (3.00 g, 9.31 mmol). At room temperature, add cesium carbonate (6.06 g, 18.61 mmol) and potassium iodide (159.53 mg, 0.96 mmol), followed by tert-butyl(2-iodoethoxy)dimethylsilane (4.00 g, 13.98 mmol). React at 80 °C for 3 hours. After the reaction is complete, quench with water, extract three times with ethyl acetate, combine the organic layers, dry to anhydrous sodium sulfate, evaporate the organic phase to dryness, dissolve in methanol, filter, and directly pass through a reversed-phase column to obtain compound I-57-5 (1.89 g). LC-MS: 481.1 [M+H] + .

[0704] Step 4: Weigh compound I-57-5 (1.87 g, 3.89 mmol) into a round-bottom flask, add dichloromethane (50.00 mL) and trifluoroacetic acid (2.68 mL, 31.12 mmol), and stir at room temperature for 1 hour. After the reaction is complete, evaporate to dryness, dissolve in methanol, filter, and pass directly through a reversed-phase column to obtain compound I-57-6 (1.20 g). LC-MS: 267.1 [M+H] + .

[0705] Step 5: Weigh compound I-57-6 (170 mg, 0.378 mmol) into a round-bottom flask, add N,N-dimethylformamide (0.3 mL) and triethylamine (0.265624 mL, 1.890 mmol), then add compound IN-1 (140.894 mg, 0.529 mmol), and react at room temperature for 18 hours. After the reaction is complete, evaporate to dryness, and purify the residue by silica gel column chromatography to obtain I-57 (78.31 mg). LC-MS: 544.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.89(t,J=1.7Hz,1H),8.28(d,J=1.4Hz,1H),7.49–7.44(m,1H),7.39–7.36(m,1H) ,7.36–7.30(m,1H),7.20–7.10(m,1H),7.08–7.00(m,1H),6.56(d,J=9.7Hz,1H),4.17–4.04(m,2H),3.8 5(t,J=5.2Hz,2H),3.80–3.73(m,1H),3.55–3.39(m,1H),3.01–2.84(m,1H),2.76–2.42(m,2H),2.36–2. 24(m,1H),2.11–1.99(m,1H),1.99–1.81(m,1H),1.39–1.27(m,3H),1.20(s,3H),1.14(d,J=2.9Hz,3H).

[0706] Example 58

[0707] Step 1: Compound I-57-4 (720 mg, 2.23 mmol) was dissolved in acetic acid (5.00 mL), and wet palladium on carbon (360 mg) was added. The reaction was carried out under hydrogen protection at 25 °C for 16 hours. The reaction solution was directly filtered and concentrated to obtain compound I-58-5 (730 mg). LC-MS: 227.20 [M + H - 100] + .

[0708] Step 2: Compound I-58-5 (730 mg, 2.23 mmol) was dissolved in ethyl acetate (5 mL), and ethyl hydrochloride solution (5 mL, 2 M) was added at room temperature. The reaction was allowed to proceed for 22 hours at room temperature. After filtration and drying, compound I-58-6 (500 mg) was obtained. LC-MS: 227.20 [M+H] + .

[0709] Step 3: Compound IN-1 (210 mg, 0.46 mmol) and compound I-58-6 (106.93 mg, 0.46 mmol) were dissolved in N,N-dimethylformamide (1.00 mL), and triethylamine (224.03 μL, 1.40 mmol) was added. The reaction was carried out at 40 °C for 16 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound I-58 (74 mg), LC-MS: 504.3 [M+H]. + .

[0710] 1H NMR (400MHz, CDCl3) δ9.73(d,J=13.5Hz,1H),9.05(d,J=1.4Hz,1H),8.19(d,J=1.4H z,1H),7.23(td,J=8.8,5.4Hz,1H),7.05–6.88(m,2H),5.81(s,1H),3.88–3.72(m,1H ),3.53–3.17(m,3H),3.08(td,J=8.7,4.4Hz,1H),2.92–2.71(m,1H),2.71–2.20(m, 4H), 2.19–2.03 (m, 1H), 2.01–1.78 (m, 4H), 1.30 (t, J = 6.6Hz, 3H), 1.17–0.88 (m, 6H).

[0711] Example 59

[0712] Step 1: Compound IN-1 (300.00 mg, 669.00 μmol) and compound I-46-8 (296.60 mg, 0.81 mmol) were dissolved in acetonitrile (5.00 mL), and N,N-diisopropylethylamine (259.00 mg, 2.00 mmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered to obtain crude product I-59 (430.00 mg), which was directly used in the next step of the reaction. LC-MS: 644.1 [M+H] + .

[0713] Step 2: Crude I-59 (300.00 mg, 0.47 mmol) and tetrahydrofuran (5.00 mL) were added sequentially to the reaction flask. Triethylamine trihydrofluoride (3.00 mL) was added under ice bath conditions. The ice bath was removed, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was separated by preparative HPLC (1. Instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; 2. Column: Xbridge@Prep Shield RP185um OBD 30×150mm Column; 3. Mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; 4. Gradient: Mobile phase B content 5-95%; 5. Flow rate: 35 mL / min).

[0714] The fraction retained for 7.20 min was collected. After concentration and lyophilization, I-59-a (51.70 mg) was obtained.

[0715] LC-MS: 530.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.90(s,1H),8.29(s,1H),8.21(d,J=7.2Hz,1H),7.31(d,J=3.7Hz,2H),7 .15(ddd,J=14.4,7.4,3.2Hz,2H),7.04(t,J=8.5Hz,1H),4.80(s,2H),4.32(dd,J=8.1,3.4Hz,1 H),3.52(dd,J=24.7,7.9Hz,1H),2.85(d,J=28.6Hz,2H),2.65(d,J=11.3Hz,1H),2.47–2.38(m ,1H),2.13(s,1H),2.00(dd,J=17.8,9.3Hz,1H),1.36(d,J=6.9Hz,3H),1.17(d,J=36.6Hz,6H).

[0716] The fraction with a retention time of 7.33 min was collected. After concentration and lyophilization, I-59-b (36.81 mg) was obtained. LC-MS: 530.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.90(s,1H),8.29(s,1H),8.21(d,J=7.2Hz,1H),7.38–7.29(m,2H),7.19–7.09(m,2H),7.04(s,1H),4.80(s,2H),4.33 (s,1H),3.50(s,1H),3.10(d,J=46.5Hz,1H),2.68(s,2H),2.58–2.42(m,1H),2.17(s,1H),1.96(s,1H),1.40(s,3H),1.18(d,J=33.7Hz,6H).

[0717] Example 60

[0718] Step 1: Weigh compound I-57-6 (1.2 g, 4.506 mmol) into a round-bottom flask, add palladium on carbon (359.80 mg, 3.381 mmol), and methanol (10 mL). React at room temperature for 18 hours under hydrogen atmosphere. After the reaction is complete, filter and evaporate to dryness to obtain compound I-60-2 (930 mg). LC-MS: 271.1 [M+H] + .

[0719] Step 2: Weigh compound I-60-2 (194.76 mg, 0.680 mmol) into a round-bottom flask, add N,N-dimethylformamide (0.3 mL) and triethylamine (0.31 mL, 2.230 mmol), then add compound I-3-2 (200 mg, 0.446 mmol), and react at room temperature for 8 days. After the reaction is complete, directly send to preparative chromatography (instrument: 3767 Sample Manager, Waters 2489 UV / Visible Detergent; column: Xbridge@Prep Shield RP18 5um OBD 30×150mm Column; mobile phase: A for 0.1% HCOOH in H2O, B for CH3CN; gradient: mobile phase B content 5-95%; flow rate: 40 mL / min). After rotary evaporation, purify by thin-layer chromatography to obtain I-60 (30 mg). LC-MS: 547.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.16(d,J=9.0Hz,1H),8.10–8.02(m,1H),7.48–7.38(m, 1H),7.29–7.13(m,2H),7.07–6.97(m,1H),3.96–3.86(m,1H),3.78–3.38(m,6 H),3.30–3.12(m,2H),2.92–2.75(m,1H),2.63–2.29(m,4H),2.24–2.08(m,1H ),2.08–1.90(m,3H),1.87–1.72(m,1H),1.31–1.24(m,3H),1.13–0.97(m,6H).

[0720] Example 61

[0721] In a 50 mL reaction flask, I-57-6 (0.22 g, 0.84 mmol) and I-3-2 (0.25 g, 0.56 mmol) were added, followed by DMF (10 mL) and triethylamine (0.22 g, 2.23 mmol). The reaction was carried out overnight at 30 °C. Pure water (60 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 2). The organic phases were combined, concentrated, and then sent to high-performance liquid chromatography (HPLC) for separation. The product was collected to obtain I-61 (50 mg). LC-MS: 543.1 [M + H] +. 1H NMR (400MHz, CD3OD) δ8.17(d,J=9.0Hz,1H),8.06(d,J=2.7Hz,1H),7.53–7.41(m,2H),7.37(d,J=2.8Hz, 1H),7.30–7.12(m,2H),7.02(t,J=8.4Hz,1H),6.56(d,J=9.7Hz,1H),4.10(d,J=3.8Hz,2H),3.85(t,J=5. 1Hz,2H),3.74(dd,J=8.4,3.7Hz,1H),3.37(d,J=7.0Hz,1H),2.80(s,1H),2.58(t,J=8.7Hz,1H),2.50(d, J=11.2Hz,1H),2.21(d,J=11.4Hz,1H),2.09–1.83(m,2H),1.29(d,J=7.0Hz,3H),1.16(d,J=28.9Hz,6H).

[0722] Example 62

[0723] Step 1: Intermediate IN-4 (200 mg; 0.41 mmol) was dissolved in 2 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by concentration to obtain I-62-2 (240 mg, crude product). LC-MS: 388.2 [M+H]+.

[0724] Step 2: Compound I-62-2 (240 mg crude) and compound I-62-3 (81 mg, 0.53 mmol), N,N-dimethylformamide (3.0 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (230 mg, 0.6 mmol), and N,N-diisopropylethylamine (260 mg, 2.0 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. I-62-4 (150 mg) was obtained by silica gel column chromatography. LC-MS: 523.3 [M + H]+.

[0725] Step 3: Compound I-62-4 (150 mg, 0.287 mmol) was separated by supercritical fluid chiral chromatography (1. Instrument: Waters 150SFC; 2. Column: (S,S)Whelk-O 1 (5 μm, 30 × 150 mm); 3. Mobile phase A: carbon dioxide, mobile phase B: methanol; 4. Gradient: mobile phase B content 30%; 5. Flow rate: 80 mL / min).

[0726] The fraction retained for 7.674 min was collected, concentrated, and lyophilized to obtain I-62-a (55 mg). LC-MS: 523.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.43(s,1H),8.30-8.10(m,1H),8.04(s,1H),7.78(s,1H),7.50-7.37(m ,1H),7.32(d,J=7.0Hz,1H),7.15-7.05(m,1H),7.03-6.94(m,1H),6.94-6.85(m,1H),6.54(d ,J=7.5Hz,1H),3.59(s,3H),3.47(s,2H),1.95(d,J=14.4Hz,1H),1.85(d,J=13.9Hz,2H),1.8 0-1.65(m,2H),1.55(s,3H),1.53–1.50(m,1H),1.47(s,3H),1.44–1.38(m,1H),1.07(s,1H).

[0727] The fraction with a retention time of 9.057 min was collected, concentrated, and lyophilized to obtain I-62-b (65 mg). 1 H NMR (400MHz, CDCl3) δ8.55-8.35(m,1H),8.20-8.10(m,1H),8.05(s,1H),7.78(s,1H),7.43(d ,J=8.0Hz,1H),7.38-7.30(m,1H),7.10-7.03(m,1H),7.03-6.94(m,1H),6.94-6.80(m,1H),6 .54(d,J=8.2Hz,1H),3.59(s,3H),3.47(s,2H),1.95(d,J=13.7Hz,1H),1.85(d,J=14.0Hz,1H ),1.80-1.66(m,2H),1.55(s,3H),1.53–1.50(m,1H),1.46(s,3H),1.28(s,1H),1.06(s,1H).

[0728] Example 63

[0729] Step 1: N-{5-[(2,4-difluorophenyl)oxy]pyridin-2-yl}-5,5-dimethyl-6-azaspiro[2.5]octane-1-carboxamide I-62-2 (110 mg), 4-carboxy-2-(hydroxymethyl)pyridine-1-oxide I-41-3 (42 mg, 0.25 mmol), N,N-dimethylformamide (3.0 ml), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 0.29 mmol), and N,N-diisopropylethylamine (130 mg, 1.0 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), then with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography to obtain I-63 (60 mg). LC-MS: 539.0 [M + H] + .

[0730] Step 2: Compound I-63 (60 mg) was separated by supercritical fluid chiral chromatography (1. Instrument: Waters 150SFC; 2. Column: OD column (5 μm, 20 × 150 mm); 3. Mobile phase A: carbon dioxide, mobile phase B: isopropanol; 4. Gradient: mobile phase B content 30%; 5. Flow rate: 50 mL / min).

[0731] The fraction retained for 7.080 min was collected, concentrated, and lyophilized to obtain I-63-a (16 mg). LC-MS: 539.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.69(s,1H),8.26(s,1H),8.20(d,J=8.8Hz,1H),8.02(s,1H),7.49(s,1H),7 .41-7.30(m,2H),7.10(dd,J=14.5,8.8Hz,1H),6.99(t,J=9.2Hz,1H),6.95-6.85(m,1H),4.84(s,2 H),3.55-3.35(m,2H),2.8-2.25(br,1H),2.01(d,J=14.5Hz,1H),1.90(d,J=14.5Hz,1H),1.75(s, 1H),1.60(s,3H),1.58–1.55(m,1H),1.52(s,3H),1.45(s,1H),1.36–1.21(m,1H),1.1-1.0(m,1H).

[0732] The fraction retained for 9.809 min was collected, concentrated, and lyophilized to obtain I-63-b (20 mg). LC-MS: 539.3 [M+H] + .

[0733] 1 H NMR (400MHz, CDCl3) δ8.49(s,1H),8.26(d,J=5.9Hz,1H),8.18(d,J=9.0Hz,1H),8.03(d,J=2.3Hz,1H),7 .48(s,1H),7.39–7.30(m,2H),7.09(td,J=8.8,5.4Hz,1H),7.03–6.95(m,1H),6.95-6.85(m,1H),4.84(s ,2H),3.55-3.38(m,2H),2.75-2.22(br,1H),2.01(d,J=14.6Hz,1H),1.94–1.85(m,1H),1.76-1.70(m,1H ),1.60(s,3H),1.57-1.52(m,1H),1.52(s,3H),1.48–1.43(m,1H),1.16-1.05(m,1H),0.95–0.81(m,1H).

[0734] Example 64

[0735] Step 1: Dissolve the starting material IN-4 (250 mg, 0.51 mmol) in dichloromethane (3 mL), add 0.5 mL of trifluoroacetic acid, stir at room temperature for 1 hour, and concentrate after the reaction is complete to obtain 270 mg of crude product 2. LC-MS: 388.2 [M+H]+

[0736] Step 2: Compound 2 (270 mg), compound 1-50-1 (180 mg, 0.60 mmol), N,N-dimethylformamide (3.0 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (230 mg, 0.60 mmol), and N,N-diisopropylethylamine (260 mg, 2.0 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was separated by a rapid silica gel preparative chromatography column to obtain compound 3 (300 mg). LC-MS: 667.8 [M + H] +

[0737] Step 3: Compound 3 (300 mg, 0.45 mmol) was dissolved in 10 mL of tetrahydrofuran, and triethylamine-hydrofluoride (720 mg, 4.5 mmol) was added. The mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, washed once with 30 mL of water, and three times with 30 mL of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and mixed. The mixture was then purified by silica gel column chromatography to obtain 190 mg of compound 4. LC-MS: 554.3 [M+H]+

[0738] I-64 (65 mg, retention time 2.498 min) was obtained after chiral separation (1. Instrument: Waters Acquity UPCC; 2. Column: Daicel CHIRALPAK IE_3, 3.0*150 mm, 3 μm; 3. Mobile phase: CO2 / MeOH (0.1% DEA) = 50 / 50; 4. Flow rate: 1.5 ml / min). LC-MS: 554.3 [M+H] +

[0739] 1 H NMR (400MHz, CDCl3) δ9.06(s,1H),8.24(d,J=9.2Hz,1H),8.06(s,1H),8.00(d,J=2.8Hz,1H),7.97(s,1H),7.38(dd,J =9.1,2.9Hz,1H),7.10(td,J=9.0,5.4Hz,1H),7.04–6.96(m,1H),6.91(ddd,J=7.7,5.5,1.7Hz,1H),4.18-4.05(m,2H) ,4.03–3.91(m,2H),3.65–3.52(m,2H),2.30(s,1H),1.98(d,J=14.4Hz,1H),1.90(d,J=14.4Hz,1H),1.85-1.74(m,1H ),1.73-1.64(m,1H),1.63-1.59(m,1H),1.57(s,3H),1.46(s,3H),1.43(t,J=5.0Hz,1H),1.08(dd,J=7.9,4.6Hz,1H).

[0740] Example 65

[0741] Step 1: Dissolve raw material 1-1 (5g; 27.32mmol) in 100mL of dichloromethane, add...

[0742] Add N,N-diisopropylethylamine (5.29 g; 41 mmol), and while stirring, add dropwise a solution of tert-butyldimethoxytrifluoromethanesulfonate (9 g, 34.5 mmol) dissolved in 35 mL of dichloromethane. After the addition is complete, stir overnight at room temperature. After the reaction is complete, concentrate, mix, and purify by silica gel column chromatography to obtain 7.2 g of product 1-2. LC-MS: 297.9 [M+H]+.

[0743] Step 2: Dissolve 1-2 (7.2 g; 24.24 mmol) in 60 mL of methanol, add lithium hydroxide monohydrate (1.22 g, 29 mmol), then add 10 mL of water. Stir at room temperature for 1 hour. LC-MS analysis indicates the reaction is complete. Adjust the pH of the reaction solution to neutral by adding 2N dilute hydrochloric acid. After concentrating to remove most of the solvent, add 200 mL of ethyl acetate and wash once with 50 mL of water. Dry the organic phase with anhydrous sodium sulfate and concentrate to obtain 5.3 g of product 1-3. LC-MS: 283.9 [M+H]+

[0744] Step 3: Take crude product 5 (500 mg, 1.25 mmol, preparation method as described in Example 66 for compound 5), acids 1-3 (530 mg, 1.88 mmol), N,N-dimethylformamide (20.00 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (715 mg, 1.88 mmol), and N,N-diisopropylethylamine (260 mg, 2.0 mmol), and add them sequentially to a reaction flask. Stir overnight at room temperature. After the reaction is complete, dilute with ethyl acetate (120 mL), wash the organic phase with water (50 mL × 4), wash with saturated brine (30 mL × 3), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by silica gel plate separation to obtain compound 6 (600 mg). LC-MS: 653 [M + H] +.

[0745] Step 4: Chiral resolution (1. Instrument: Waters Acquity UPCC; 2. Column: Daicel CHIRALPAK IE_3, 3.0*150mm, 3μm; 3. Mobile phase: CO2 / MeOH (0.1% DEA) = 60 / 40; 4. Flow rate: 1.5ml / min) yielded compound 7 (148mg, retention time 2.518min).

[0746] Step 5: Compound 7 (148 mg, 0.23 mmol) was dissolved in 10 mL of tetrahydrofuran, and triethylamine-hydrofluoride (182 mg, 1.13 mmol) was added. The mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, washed once with 30 mL of water, and three times with 30 mL of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain 70 mg of I-65. LC-MS: 524.3 [M+H] +

[0747] 1 H NMR(400MHz, CDCl3)δ8.98(s,1H),8.45(s,1H),8.38-8.20(m,1H),8.16(s,1H),7.60-7.4 7(m,1H),7.47-7.54(m,1H),7.23(dd,J=14.3,8.7Hz,1H),6.96(dt,J=13.7,8.4Hz,2H),4. 84(s,2H),3.45(s,2H),2.2.70-2.2(brs,3H),2.00(d,J=14.7Hz,1H),1.90(d,J=14.5Hz, 1H),1.82-1.70(m,1H),1.60(brs,3H),1.52(s,3H),1.49-1.42(m,1H),1.12-1.02(m,1H).

[0748] Example 66

[0749] Step 1: Dissolve starting material 1 (0.18 g, 0.64 mmol; starting material 1 is derived from compound 5 in the IN-4 synthetic route) in dichloromethane (5 mL), add oxalyl chloride (120 mg, 0.95 mmol) dropwise, and then add one drop of N,N-dimethylformamide as a catalyst. React at room temperature for 1 hour, and concentrate to dryness after the reaction is complete. Acyl chloride 2 (0.22 g, crude product) is obtained.

[0750] Step 2: Amine IN-1-4 (170 mg, 0.76 mmol) was dissolved in anhydrous pyridine (2 mL), and acyl chloride 2 was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated to obtain the crude product. The crude product was separated by silica gel plate chromatography to obtain compound 4 (70 mg). LC-MS: 388.8 [M + H - 100] + .

[0751] Step 3: Dissolve isomer P of compound 4 (70 mg, 0.14 mmol; isomer with Rf 0.43) in dichloromethane (3 mL), add 0.5 mL of trifluoroacetic acid, stir at room temperature for 1 hour, and concentrate after the reaction is complete to obtain 82 mg of crude product 5.

[0752] Step 4: Add crude product 5 (82 mg, 0.14 mmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (28 mg, 0.18 mmol), N,N-dimethylformamide (2.00 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80 mg, 0.20 mmol), and N,N-diisopropylethylamine (60 mg, 0.47 mmol) sequentially to a reaction flask and stir overnight at room temperature. After the reaction is complete, dilute with ethyl acetate (60 mL), wash the organic phase with water (30 mL × 4), wash with saturated brine (30 mL × 3), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by silica gel plate separation to obtain compound 6 (70 mg).

[0753] Compound 6 was resolved by supercritical fluid chromatography (1. Instrument: Waters 150SFC; 2. Column: SA column (5μm, 20×150mm); 3. Mobile phase A: carbon dioxide, mobile phase B: methanol; 4. Gradient: mobile phase B content 30%; 5. Flow rate: 50mL / min).

[0754] The fraction retained for 5.680 min was collected, concentrated, and lyophilized to give compound I-66-a (26 mg). LC-MS: 524.3 [M+H]+

[0755] 1 H NMR (400MHz, CDCl3) δ8.99(s,1H),8.15(d,J=11.0Hz,2H),7.77(s,1H),7.43(d,J=9.5Hz ,1H),7.27–7.18(m,1H),7.02-6.90(m,2H),6.54(d,J=9.1Hz,1H),3.59(s,3H),3.53-3.4 0(m,2H),1.94(d,J=14.1Hz,1H),1.84(d,J=14.3Hz,1H),1.79-1.72(m,1H),1.62-1.57(m ,1H),1.55(s,3H),1.50-1.48(m,1H),1.46(s,3H),1.29-1.27(m,1H),1.12-1.05(s,1H).

[0756] The fraction retained for 3.764 min was collected, concentrated, and lyophilized to give compound I-66-b (22 mg). LC-MS: 524.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.99(s,1H),8.17(s,1H),8.10(s,1H),7.77(s,1H),7.48-7.37(m ,1H),7.26-7.17(m,1H),7.03–6.90(m,2H),6.60-6.52(m,1H),3.60(s,3H),3.52-3.40( m,2H),1.94(d,J=14.4Hz,1H),1.86(d,J=14.2Hz,1H),1.80-1.70(m,1H),1.61-1.57(m, 1H),1.55(s,3H),1.46(s,3H),1.45–1.42(m,1H),1.30-1.25(m,1H),1.12-1.05(s,1H).

[0757] Example 67

[0758] Step 1: Compound IN-4 (394 mg, 0.84 mmol) was dissolved in 3 ml of dichloromethane, and 0.5 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated to obtain 350 mg of crude product 3. LC-MS: 369.9 [M+H]+.

[0759] Step 2: Crude product 3 (350 mg, 0.84 mmol), 4-carboxy-2-(hydroxymethyl)pyridine-1-oxide (185 mg, 1.1 mmol), N,N-dimethylformamide (5.00 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (456 mg, 1.2 mmol), and N,N-diisopropylethylamine (540 mg, 4.2 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (100 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel plate separation to obtain compound 4 (150 mg).

[0760] Step 3: Compound 4 was separated by supercritical fluid chromatography (1. Instrument: Waters)

[0761] Acquity UPCC; 2. Chromatographic column: Daicel CHIRALPAK OJ_3, 3*150m / m, 3um, CO2 / / MeOH (0.1% DEA)=75 / 25, 2ml / min) to obtain I-67 (45mg, retention time 1.912min). LC-MS: 521.3 [M+H]+. 1H NMR (400MHz, CDCl3) δ 8.66(s,1H), 8.26(s,1H), 8.38-8.23(m,1H), 8.23-8.12(m,1H), 7.50(s,1H), 7.44-7.32(m,2H), 7.13-7.03(m,2H), 7.03-6.88(m,2H), 4.84(s,2H), 3.60-3.35(m,2H) ),2.55-2.20(brs,1H)2.01(d,J=13.2Hz,1H),1.91(d,J=14.2Hz,1H),1.74(s,1H),1.60(s,3 H),1.58–1.55(m,1H),1.52(s,3H),1.48-1.40(m,1H),1.38-1.22(m,1H),1.17-0.98(m,1H).

[0762] Example 68

[0763] Step 1: Dissolve the raw material IN-4 (250 mg, 0.51 mmol) in dichloromethane (3 mL), add 0.5 mL of trifluoroacetic acid, stir at room temperature for 1 hour, and concentrate after the reaction is complete to obtain 270 mg of crude product 2. LC-MS: 388.2 [M+H]+.

[0764] Step 2: Compound 2 (270 mg crude) and compound IN-2 (250 mg, 0.66 mmol), N,N-dimethylformamide (3.0 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (250 mg, 0.66 mmol), and N,N-diisopropylethylamine (260 mg, 2.0 mmol) were added sequentially to a reaction flask and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (80 mL) was added for dilution. The organic phase was washed with water (30 mL × 4), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Separation by silica gel column chromatography yielded 3 (400 mg), LC-MS: 790.8 [M + H] +.

[0765] Step 3: Compound 3 (400 mg, 0.51 mmol) was dissolved in 10 mL of tetrahydrofuran, and triethylamine-hydrofluoride (815 mg, 5.1 mmol) was added. The mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, washed once with 30 mL of water, and three times with 30 mL of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain 260 mg of white solid. LC-MS: 553.3 [M+H]+.

[0766] Chiral resolution (1. Instrument: Waters Acquity UPCC; 2. Column: Daicel CHIRALPAK IE_3, 3.0*150mm, 3μm; 3. Mobile phase: CO2 / MeOH (0.1% DEA) = 45 / 55; 4. Flow rate: 1.5ml / min) yielded a white solid I-63 (75mg, retention time 2.282min). LC-MS: 553.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.09(s,1H),8.25(s,1H),7.98(d,J=2.9Hz,1H),7.81(d,J=2.3Hz,1H),7.49(dd,J=9.4,2.5Hz,1H ),7.44–7.38(m,1H),7.12(d,J=5.4Hz,1H),7.01(s,1H),6.92(t,J=8.4Hz,1H),6.57(d,J=9.4Hz,1H),4.21-4.12(m,2H ),3.98(t,J=4.8Hz,2H),3.57-3.50(m,1H),3.50–3.40(m,1H),2.40-2.05(brs,2H),1.94(d,J=14.1Hz,1H),1.84(d,J= 14.4Hz,1H),1.81-1.72(m,1H),1.64-1.59(m,1H),1.55(s,3H),1.46(s,3H),1.43(d,J=4.9Hz,1H),1.12-1.06(m,1H).

[0767] Biological test example:

[0768] Test Example 1: Calcium Flow Detection

[0769] Cells overexpressing human MRGPRX2 (provided by Shanghai WuXi AppTec Co., Ltd.) were seeded into 96-well plates at 100,000 cells per well and then incubated at 37°C in a 5% CO2 incubator for 1 hour. Fluorescent Ca2+ was then added to the cells. 2+The probe Fluo-4AM (1:1000, S1060; Beyotime Institute of Biotechnology) and 0.04% Pluoronic-F127 (ST501; Beyotime Institute of Biotechnology) were used, followed by incubation at 37°C in the dark for 30 minutes. Then, different concentrations of antagonists were added to the cells. The agonists were added automatically using a FlexStation 3 multimode microplate reader (Molecular Devices, Sunnyvale, CA, USA), and the fluorescence intensity of the samples was detected at an excitation wavelength of 494 nm and an emission wavelength of 516 nm. The IC50 value of the compounds was calculated using GraphPad Prism software to analyze ΔF (ΔF = maximum fluorescence intensity after agonist addition minus minimum fluorescence intensity before agonist addition). Data are shown in Table 1.

[0770] Table 1:

[0771] Conclusion: The compounds of this invention have strong MRGPRX2 antagonistic activity.

[0772] Test Example 2: Mast Cell β-Hexosaminease Release Assay

[0773] Mast cells (catalog number: T8157; purchased from Wuhan AmyJet Scientific Co., Ltd.) were seeded into 96-well plates at 20,000 cells per well. After adding the antagonist to the cells, the plates were incubated at 37°C for 1 hour. Then, the agonist was added and incubated for 30 minutes. The cell culture plates were removed and centrifuged at 450g and 4°C for 5 minutes. The culture supernatant was transferred to another assay plate. 0.1% Triton-X 100 was added to the cell pellet to induce complete cell lysis, and the cell lysis buffer was transferred to another assay plate. The substrate 4-nitrophenyl-N-acetyl-β-d-glucosamine (1.3 mg / ml; N9376; Sigma-Aldrich) was dissolved in citrate buffer (20 mM Na2HPO4·7H2O and 40 mM citric acid, pH 4.5). An appropriate amount of substrate was added to the assay plate containing the cell supernatant and cell pellet, mixed well, and incubated at 37°C for 90 minutes. The reaction was then terminated by adding 0.4 M Glycine buffer (pH = 10.7). The absorbance of the supernatant and cell pellet at 405 nm was read using a FlexStation 3 multimode microplate reader (Molecular Devices, Sunnyvale, CA, USA). The percentage of mast cell degranulation (percentage of β-hexosaminease release) = (supernatant β-hexosaminease / (supernatant β-hexosaminease + cell pellet β-hexosaminease)) × 100%. The IC50 value of each compound was calculated using GraphPad Prism software. Data are shown in Table 2.

[0774] Table 2

[0775] Conclusion: The compounds of this invention can effectively inhibit the degranulation reaction of human mast cells. Most of the compounds showed stronger inhibitory activity than the control compound (the control compound was selected from Example 65 of WO2024226914). ).

[0776] Test Example 3: Pharmacokinetic (PK) Study in Mice

[0777] Pharmacokinetic evaluation in mice

[0778] Selected strains of mice (weighing 20-22g, n=3 per group) were randomly divided into an intravenous injection group and an oral administration group. The intravenous injection group received a tail vein injection of the test compound solution (dose 3mg / kg, administration volume 10mL / kg, solvent formulation 5% DMSO + 10% Solutol + 85% physiological saline); the oral administration group received a gavage administration of the test compound solution (dose 10mg / kg, administration volume 20mL / kg, solvent formulation 10% propylene glycol + 30% PEG400 + 10% Cremophor EL + 50% water). Blood samples of 30 μL were collected via the mandibular vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h after administration (intravenous group) or 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h after administration (oral group). The samples were placed in anticoagulant tubes containing EDTA-K2, and the blood samples were centrifuged at 8000 rpm for 5 min to separate the plasma. The plasma samples were stored at -20℃ for analysis.

[0779] Plasma sample pretreatment

[0780] Quantitatively pipette 10 μL of plasma sample into a 96-well plate (samples from the intravenous administration group 1 hour prior were diluted 10-fold with blank plasma), add 500 μL of acetonitrile containing internal standard to precipitate proteins, vortex for 10 min, and centrifuge at 4℃ and 6000g for 10 min; accurately transfer 45 μL of supernatant to a 96-well plate, add 45 μL of pure water to reconstitute, vortex for 10 min, centrifuge at 4℃ and 6000g for 10 min, and take the supernatant for LC-MS / MS analysis.

[0781] Preparation of standard curve and quality control samples

[0782] Take 9 μL of blank mouse plasma and add 1 μL of standard curve working solution to prepare a series of standard curve samples containing compound concentrations of 3000, 1000, 300, 100, 30, 10, 5, 2, and 1 ng / mL, as well as quality control (QC) samples of 240, 80, 5, and 3 ng / mL. After vortexing, add 50 μL of acetonitrile containing internal standard to precipitate the protein, vortex for 10 min, and centrifuge at 4℃ and 6000g for 10 min. Take 20 μL of the supernatant into a 96-well plate, add 80 μL of pure water to reconstitute, centrifuge at 4℃ and 6000g for 10 min, and perform LC-MS / MS analysis under the above conditions.

[0783] LC-MS / MS detection conditions

[0784] A Waters Acquity UPLC system (equipped with a binary infusion pump, autosampler, column oven, and degasser) was used in tandem with a SCIEX 7500Q-Trap triple quadrupole mass spectrometer, equipped with an electrospray ionization (ESI) source. Data acquisition was performed using SCIEX OS software. The chromatographic column was an ACQUITY UPLC BEH C18 (1.7 μm), the column temperature was 45 °C, mobile phase A was an aqueous solution containing 0.1% formic acid (1 mL formic acid was added to 1000 mL of water and sonicated), mobile phase B was an acetonitrile solution containing 0.1% formic acid (1 mL formic acid was added to 1000 mL of acetonitrile and sonicated), the flow rate was 0.6 mL / min, the injection volume was 5 μL, the autosampler temperature was 8 °C, the weak wash solution was 5% acetonitrile, the strong wash solution was 95% acetonitrile, and the plunger seal cleaning solution was 10% acetonitrile.

[0785] Data Analysis

[0786] Phoenix WinNonlin software (version 8.3.5) was used to process the blood drug concentration-time data using a non-compartmental model (NCA) to calculate the AUC. last C max T max Elimination half-life (T) 1 / 2 Pharmacokinetic parameters such as Pharmacokinetics (AUC) are also considered. Oral bioavailability (BA) is calculated using the following formula: BA (%) = [AUC last] PO ×Dose IV ] / [mean AUClast IV ×Dose PO ]×100%

[0787] Table 3

[0788] Conclusion: Compound I-41-a in this application is superior to the control compound (the control compound is selected from Example 144 in WO2024226914). It has higher drug exposure in mice, greater bioavailability, and better pharmacokinetic properties.

[0789] Test Example 4: Pharmacokinetic (PK) Study in Rats

[0790] Pharmacokinetic evaluation in rats

[0791] Rats of the selected strain (weighing 200-220g, n=3 per group) were randomly divided into an intravenous injection group and an oral administration group. The intravenous injection group received a tail vein injection of the test compound solution (dose 3mg / kg, administration volume 3mL / kg, solvent formulation: 5% DMSO + 10% Solutol + 85% physiological saline, prepared by vortexing for 6 min and sonication for 15 min to obtain a colorless and transparent solution); the oral administration group received a gavage administration of the test compound solution (dose 6mg / kg, administration volume 8mL / kg, solvent formulation: 10% propylene glycol + 30% PEG400 + 10% Cremophor EL + 50% water, prepared by vortexing for 6 min and sonication for 10 min to obtain a colorless and transparent solution). 100 μL of blood was collected via the jugular vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h after administration (intravenous group) or 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h after administration (oral group). The blood samples were placed in anticoagulant tubes containing EDTA-K2, and the plasma was separated by centrifugation at 8000 rpm for 5 min and stored at -20℃ for analysis.

[0792] Plasma sample pretreatment

[0793] Quantitatively, 10 μL of rat plasma sample was drawn into a 96-well plate (samples from the intravenously administered group were diluted 10-fold with blank rat plasma 1 hour prior). 500 μL of acetonitrile containing internal standard was added to precipitate the protein. The plate was vortexed for 10 min and centrifuged at 4℃ and 6000g for 10 min. 45 μL of the supernatant was accurately transferred to a 96-well plate, reconstituted with 45 μL of pure water, vortexed for 10 min, and centrifuged at 4℃ and 6000g for 10 min. The supernatant was then analyzed by LC-MS / MS.

[0794] Preparation of standard curve and quality control samples

[0795] Take 9 μL of blank rat plasma and add 1 μL of standard curve working solution to prepare a series of standard curve samples containing compound concentrations of 3000, 1000, 300, 100, 30, 10, 5, 2, and 1 ng / mL, as well as quality control (QC) samples of 240, 80, 5, and 3 ng / mL. After vortexing, add 50 μL of acetonitrile containing internal standard to precipitate the protein, vortex for 10 min, and centrifuge at 4℃ and 6000g for 10 min. Take 20 μL of the supernatant into a 96-well plate, add 80 μL of pure water to reconstitute, centrifuge at 4℃ and 6000g for 10 min, and perform LC-MS / MS analysis under the above conditions.

[0796] LC-MS / MS detection conditions

[0797] A Waters Acquity UPLC system (equipped with a binary infusion pump, autosampler, column oven, and degasser) was used in tandem with a SCIEX 7500Q-Trap triple quadrupole mass spectrometer, equipped with an electrospray ionization (ESI) source. Data acquisition was performed using SCIEX OS software. The chromatographic column was an ACQUITY UPLC BEH C18 (1.7 μm), the column temperature was 45 °C, mobile phase A was an aqueous solution containing 0.1% formic acid (1 mL formic acid was added to 1000 mL of water and sonicated), mobile phase B was an acetonitrile solution containing 0.1% formic acid (1 mL formic acid was added to 1000 mL of acetonitrile and sonicated), the flow rate was 0.6 mL / min, the injection volume was 5 μL, the autosampler temperature was 8 °C, the weak wash solution was 5% acetonitrile, the strong wash solution was 95% acetonitrile, and the plunger seal cleaning solution was 10% acetonitrile.

[0798] Data Analysis

[0799] Phoenix WinNonlin software (version 8.3.5) was used to process plasma drug concentration-time data using a non-compartmental (NCA) model to calculate pharmacokinetic parameters such as AUClast, Cmax, Tmax, and elimination half-life (T1 / 2). Oral bioavailability (BA) was calculated using the following formula: BA (%) = [AUClast] / [Cmax] / [Cmax] / [Cmax] / [Cmax] / [Cmax] / [Cmax] / [Cmax] / [Cmax] / [Cmax] / [Cmax]] PO ×Dose IV ] / [mean AUClast IV ×Dose PO ]×100%

[0800] Table 4

[0801] Conclusion: Compared with the control compound (selected from Example 75 in WO2024226914), the compounds in this application are superior. It has higher drug exposure in rats and better pharmacokinetic properties.

Claims

Compounds represented by Formula I, their pharmaceutically acceptable salts, their solvates, their stereoisomers, their tautomers, their prodrugs, their metabolites, or their isotopic compounds: in, Ring A is a 5-14 membered heteroaryl, 3-20 membered heterocyclic, C3-C 12 cycloalkyl, C6-C 14 The aryl group may not be present, and the heteroatoms in the heteroaryl or heterocyclic group are selected from one or more of N, O and S, with a number of 1-4 heteroatoms; Ring B is a 3-20 membered heterocyclic group, C3-C 12 Cycloalkyl group, wherein the heteroatom in the heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3; The ring C is a 5-14 membered heteroaryl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4; L 1 for O, Connect key, NR L1-1 、 C1-C6 alkylene groups or none; wherein the a-end is connected to ring A and the b-end is connected to ring B; R L1-1 It is H or C1-C6 alkyl; L 2 For O, linking bond, S, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CR L2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups; R L2-1 It is H or C1-C6 alkyl; R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups; R L2-4 It is a halogen; X 1 It is C or does not exist; X 2 It is C or does not exist; X 3 For O, NR X3-1 S may not exist; R X3-1 H, C1-C6 alkyl, C1-C6 alkoxy; X 4 It is N or does not exist; R 1 It is oxo, oxidized, halogenated, C1-C6 alkyl, or formed by one or more R 1-1 Substituted C1-C6 alkyl, cyano, -NR 1-2 R 1-3 hydroxyl group, 3-8 membered heterocyclic alkyl group, 3-8 membered cycloalkyl group, with one or more R 1-4 The substituted 3-8 membered cycloalkyl group may be absent, and the heteroatom in the heteroalkyl group is selected from one or more of N, O, and S, with 1-3 heteroatoms, -SO2R 1-5 , R 1-1 Halogen, hydroxyl, -NR 1-1-1 R 1-1-2 -NR 1-1-3 -(C=O)R 1-1-4 C3-C8 cycloalkyl groups, deuterium; R 1-1-1 R 1-1-2 Each is independently H or C1-C6 alkyl; R 1-1-3 It is H, C1-C6 alkyl; R 1-1-4 It is a C1-C6 alkyl group; R 1-2 R 1-3 Each is independently H or C1-C6 alkyl; R 1-4 It is a hydroxyl group; R 1-5 It is a C1-C6 alkyl group; R 1-6 It is a C1-C6 alkyl group; R 1-7 It is a C1-C6 alkyl group; R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, halogen, C3-C8 cycloalkyl, cyano, C2-C6 alkynyl, -COOH, hydroxyl; R 2-1 Hydroxyl group, -NR 2-1-1 R 2-1-2 , cyano, -COOH, halogen; R 2-1-1 R 2-1-2 Each is independently H or C1-C6 alkyl; R 3 Halogen, oxo, cyano, C3-C8 cycloalkyl, C1-C6 alkyl, or with one or more R 3-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyl groups; R 3-1 It is a halogen; R 4 R 5 Each is independently H, C1-C6 alkyl, and composed of one or more R groups. 4-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, or absent; R 4-1 It consists of C1-C6 alkoxy, halogen, and hydroxyl groups; Or R 4 R 5 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups; R 6 It is H, C1-C6 alkyl; R 7 For C6-C 14 aryl, with one or more R 7-1 Replacement C6-C 14 aryl, 5-14 heteroaryl, surrounded by one or more R 7- 2 Substituted 5-14-membered heteroaryl, C1-C6 alkyl, or with one or more R 7-3 The substituted C1-C6 alkyl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3; R 7-1 It can be halogen, C3-C8 cycloalkyl, C2-C6 ynyl, C1-C6 alkyl, or cyano; R 7-2 It is a halogen; R 7-3 It is a C3-C8 cycloalkyl group; m can be 0, 1, 2, 3, 4, 5, or 6; n can be 0, 1, 2, 3, 4, 5, or 6; p can be 0, 1, 2, 3, 4, 5, or 6. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, The compounds represented by Formula I have structures represented by Formula Ia, Formula Ib, Formula Ic, or Formula Id: In equations Ib and Id, ring D is C6-C 14 The aryl group is preferably phenyl; q is 0, 1, 2, 3, 4, 5 or 6. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, The compounds represented by Formula I have structures as shown in Formula Ia-1, Formula Ib-1, or Formula Id-1: In equation Ia-1: t is 1, 2, 3, 4, 5 or 6; In equations Ib-1 and Id-1: Y 1 For N or C; Y 2 It can be N or C; q can be 0, 1, 2, 3, 4 or 5. The compound of Formula I as claimed in claim 2, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, It meets one or more of the following conditions: (1) for (2)L 1 for O or -NH-; (3) Ring B is Where end a and L 1 Connected; (4)L 2 For connecting bonds, O, S, C1-C6 alkylene, deuterated C1-C6 alkylene, -NR L2-1 -、-CR L2-2 R L2-3 - by one or more R L2-4 Substituted C1-C6 alkylene groups; R L2-1 It is H, C1-C6 alkyl; R L2-2 R L2-3 Together with the C atoms attached thereto, they form C3-C8 cycloalkyl groups; R L2-4 It is a halogen; (5)R 4 It is methyl; (6)R 5 It is hydrogen; (7) The ring C is a 7-14 fused polycyclic heteroaryl group, wherein the heteroatom in the heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4. The compound of Formula I as claimed in claim 2, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, for Where end a and L 1 Connected. The compound of Formula I as claimed in claim 4, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, The ring C is shown in the following structural formula C-1: Among them, the cyclic Ca is a 5-membered monocyclic heteroaryl group; The cyclic Cb is a 5-12 membered heterocyclic group; Y c-1 For CR c-1-1 Or N; Y c-2 For CR c-2-1 Or N; Y c-3 For CR c-3-1 Or N; Y c-4 For CR c-4-1 Or N; R c-1-1 CR c-2-1 CR c-3-1 CR c-4-1 Each can be either hydrogen or non-existent independently; Wherein, the heteroatoms in the heteroaryl and heterocyclic groups are selected from one or more of N, O and S, the number of heteroatoms in the ring C is 1-4, and the α-terminus is connected to the L-terminus. 2 Connected. The compound of Formula I as claimed in claim 6, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, The structural formula C-1 is shown below: Where end a and L 2 Connected. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, The compound represented by Formula I is one of Scheme 1, Scheme 2, or Scheme 3: Option 1: for Where end a and L 1 Connected; t1 can be 1, 2, 3, 4, 5, or 6; t2 is 1, 2, or 3; t3 is 1, 2, or 3; t4 is 0, 1, or 2; t5 is 1, 2, or 3; Z 1 For N or CH; Option 2: for Where end a and L 1 Connected; ring C is Where end a and L 2 Connected; Option 3: for Where end a and L 1 Connected; R 2 It is a C1-C6 alkyl or cyano group; when R 2 When it is a C1-C6 alkyl group, the ring C is Where end a and L 2 Connected. The compound of Formula I as claimed in claim 8, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, It satisfies one or more of the following conditions: (1) for Where end a and L 1 Connected; (2) for Where end a and L 1 Connected; (3) for Preferred Where end a and L 1 Connected; (4) for Where end a and L 1 Connected; (5) for Preferred Where end a and L 1 Connected; (6) for Where end a and L 1 Connected; (7) for Where end a and L 1 Connected; (8) for Where end a and L 1 Connected. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound, is characterized in that, It satisfies one or more of the following conditions: (1) In ring A, the 5-14 member heteroaryl is a 3-8 member monocyclic heteroaryl or a 7-12 member polycyclic heteroaryl, preferably a 6 member monocyclic heteroaryl; (2) In ring A, the 3-20 member heterocyclic group is a 3-8 member mono-heterocyclic group or a 5-20 member fused heterocyclic group, preferably a 6 member mono-heterocyclic group or a 7-12 member fused heterocyclic group; (3) In ring B, the 3-20 member heterocyclic group is a 3-8 member monocyclic group, a 5-20 member spirocyclic group, a 5-20 member bridged heterocyclic group, or a 5-20 member fused heterocyclic group, preferably a 6 member monocyclic group, an 8 member monocyclic group, a 5 member monocyclic group, a 7-12 member spirocyclic group, a 7-12 member bridged heterocyclic group, or a 7-12 member fused heterocyclic group; more preferably a 7-12 member fused heterocyclic group; (4) In ring C, the 5-14 member heteroaryl is a 3-8 member monocyclic heteroaryl or a 7-12 member polycyclic heteroaryl, preferably a 6 member heteroaryl, more preferably a pyridyl; (5)R 1 R 1-1 R 2 R 3 R 3-1 R 7-1 R 7-2 R 2-1 R 4-1 In this context, the halogen is independently F, Cl, Br, or I; (6)R L2-1 R 1 R 1-1-1 R 1-1-2 R 1-1-3 R 1-1-4 R 1-2 R 1-3 R 2 R 3 R 4 R 5 R 6 R X3-1 R 7-1 R 7- 2 R L1-1 R 1-5 R 1-6 R 1-7 R 2-1-1 R 2-1-2 In the C1-C6 alkyl group and the substituted C1-C6 alkyl group, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (7)L 1 L 2 In the above, the C1-C6 alkylene groups are -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-. (8)R L2-2 R L2-3 R 1-1 R 3 R 4 R 5 R 7-1 R 7-3 R 2 In this context, the C3-C8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl, preferably cyclopropyl or cyclohexyl; (9)R X3-1 R 4-1 In the above, the C1-C6 alkoxy group and the substituted C1-C6 alkoxy group are independently methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy. (10)R 2 R 7-1 In this context, the C2-C6 ynyl group refers to ethynyl or propynyl. The compound of Formula I as claimed in claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, is characterized in that, It meets one or more of the following conditions: (1) Ring A is a 5-14 membered heteroaryl, a 3-20 membered heterocyclic group, or a C6-C ring. 14 The aryl group, wherein the heteroatom in the heteroaryl or heterocyclic group is selected from one or more of N, O and S, and the number of heteroatoms is 1-4; (2)R 1 Oxidation (the oxidation refers to the process where two R atoms are bonded to the same carbon atom on ring A) 1 When replacing, 2 R 1 (Together with the connected C, forming C=O), oxidation (the oxidation refers to the oxidation of N atoms on ring A by an R) 1 When replacing, 1 R 1 Together with the connected N, it forms C1-C6 alkyl groups, with one or more R 1-1 Substituted C1-C6 alkyl groups, -SO2R 1-5 or Preferably, it is oxidized, C1-C6 alkyl, or formed by one or more R groups. 1-1 Substituted C1-C6 alkyl or -SO2R 1-5 ; (3)R 1-1 It is a halogen or a hydroxyl group; (4)R 1-5 R 1-6 and R 1-7 It is a C1-C6 alkyl group; (5) m can be 1, 2, 3 or 4; (6)L 1 for O, Connect key, or -NR L1-1 ; (7)R L1-1 It is H or C1-C6 alkyl; preferably H; (8)R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, halogen, or cyano groups; preferably C1-C6 alkyl, halogen, or cyano groups; (9)R 2-1 It is a hydroxyl group; (10) n can be 0, 1, 2, 3 or 4; (11)X 1 It is C or does not exist; (12)R 4 R 5 Each is independently H or C1-C6 alkyl; (13)X 2 The answer is C; (14)X 3 It is O; (15)X 4 Let N be the number of people in the group. (16)R 6 It is H or C1-C6 alkyl; preferably H; (17)R 3 It is a C1-C6 alkyl group; (18) p can be 0, 1, 2 or 3; (19)L 2 It is an O, a linking bond, an S, or a C1-C6 alkylene group; preferably an O, a linking bond, or a C1-C6 alkylene group. (20)R 7 For C6-C 14 aryl or aryl group or one or more R 7-1 Replacement C6-C 14 aryl; (21)R 7-1 It is a halogen. The compound of Formula I as claimed in claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, is characterized in that, It meets one or more of the following conditions: (1)R 1 The following are possible meanings: Cl, oxo, methyl, -CF3, oxidized, -CN, -CH2CHF2, -CH2CF3, -NH2, -CH2CH2OH, -CH2NHCH3. -CH2OH、-OH、-CH2NH2、CH2NH-(C=O)CH3、 -CD3、-CH2CH2F、CHF2、CH2CH3、 Preferably, the derivatives are oxo, methyl, oxidized, -CH2CH2OH, CH2OH, etc. Or -CH2CH2F; more preferably oxo, methyl, oxidized, -CH2CH2OH, CH2OH, Or -CH2CH2F; (2)R 2 Methyl, ethyl, F, -CH2OH、-CH2NH2、-CN、-CH2CN、 -CH2CH2OH, -COOH, -CH2COOH, -CH2OCH3, -CH2CHF2, -CH2CH2F, hydroxyl group; preferably methyl, F or -CN; (3)R 3 For methyl, -CF3, -CN, oxo, hydroxyl, -CHF2, F; preferably methyl; (4)R 4 Methyl, ethyl, -CH2CH2CH3, -CH2OCH3, -CH2CHF2, -CH2CH2F, -CH2CH2OH; preferably methyl; (5)R 5 H or methyl; preferably H; (6)R 4 and R 5 Together with the C atoms attached to it, they form a cyclopropyl group; (7)R 6 For H; (8)L 1 for O, Connect key, NH may not be present; wherein end a is connected to ring A and end b is connected to ring B; preferably O, Connect key, Or NH; (9)L 2 For O atoms, S, -CH2-, -NH-、 Connect key Preferably, it is O, -CH2-, or a linker bond; (10)R 7 for Preferred More preferably (11) Ring A is Preferred (12) Ring B is Where end a and L 1 Connected; (13) Ring C is Where end a and L 2 Connected; preferably (14)X 1 It is C or does not exist; (15)X 2 It is C or does not exist; (16)X 3 For O, S, Or it may not exist; (17)X 4 It is N or does not exist; (18) m can be 0, 1, 2 or 3; (19) n can be 0, 1, 2 or 3; (20) p is 0 or 1. The compound of Formula I as claimed in claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof, is characterized in that, It meets one or more of the following conditions: (1) for Preferred More preferably (2) for Where end a and L 1 Connected; (3) for Where end a and L 2 Connected; preferably More preferably The compound of Formula I as claimed in claim 1, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite, or isotopic compound, is characterized in that, The compound represented by Formula I is any of the following compounds: A pharmaceutical composition comprising a compound of Formula I as described in any one of claims 1-14, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotopic compound thereof, preferably, the pharmaceutical composition further comprising a pharmaceutical excipient. Use of the compound of Formula I as described in any one of claims 1-14, or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, or its isotopic compound, or the pharmaceutical composition as described in claim 15, in the preparation of MRGPRX2 or its orthologous antagonist. Alternatively, its use in the preparation of medicaments for the treatment or prevention of diseases or conditions mediated by MRGPRX2 or its orthologs; The diseases or conditions mediated by MRGPRX2 or its orthologs are preferably selected from pseudoallergic reactions, pruritus-related symptoms, pain-related symptoms, inflammatory or autoimmune diseases; More preferably, The pruritus-related symptoms include: chronic pruritus; contact dermatitis; allergic blepharitis; anemia; atopic dermatitis; bullous pemphigoid; candidiasis; chickenpox; end-stage renal failure; hemodialysis; chronic urticaria; contact dermatitis, atopic dermatitis; herpetic dermatitis; diabetes; drug allergy; dry skin; dyshidrosis; atopic eczema; eosinophilic fasciitis; bullous epidermolysis; erythritis; food allergy; folliculitis; fungal skin infection; hemorrhoids; herpes; HIV infection; Hodgkin's disease; hyperthyroidism; iodinated contrast dye allergy; iron deficiency anemia; kidney disease; leukemia, porphyria; lymphoma; malignant tumors; mastocytosis; multiple myelopathy. Tumors; neurodermatitis; onchocerciasis; Paget's disease; lice; polycythemia vera; nodular prurigo; lichen planus; lichen sclerosus; anal pruritus; pseudorabies; psoriasis; rectal prolapse; sarcoidosis granuloma; scabies; schistosomiasis; scleroderma, severe stress, stasis dermatitis; swimming pruritus; thyroid disease; tinea cruris; rosacea; cutaneous amyloidosis; scleroderma; acne; wound healing; burn healing; pruritus; or urticaria; more preferably, the pruritus-related symptoms are urticaria, chronic urticaria, chronic spontaneous urticaria, chronic induced urticaria, severe chronic urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema; Alternatively, the pain-related symptoms may include acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, joint fibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, ischemic necrosis, back pain, Behcet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical spinal stenosis, peroneal muscular atrophy (CMT), chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, and pulmonary collapse (pneumothorax). Complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, toothache, Delken's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilic-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatitis (dermatomyositis), knee injury, leg pain, low back pain and hematuria syndrome, lupus. Sores, Lyme disease, medullary cavernous kidney (MSK), paresthesia of the femoral head, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsons-Turner syndrome, pelvic pain, periodontal pain, peripheral neuropathy, phantom limb pain, nerve compression, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, postherpetic neuralgia, post-mastectomy pain syndrome, post-mastectomy pain, post-stroke pain, post-thoracotomy pain syndrome, postherpetic neuralgia (shingles), post-poliomyelitis syndrome Combination syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Shulman's kyphosis, sciatica, scoliosis, herpes zoster (herpes zoster), Sjögren's syndrome, spasmodic torticollis, sphincter insufficiency, spinocerebellar ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, Tarlov's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain or vulvar pain; Alternatively, the inflammatory or autoimmune condition may be chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens Johnson syndrome, toxic epidermal necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (RSD / CRPS), rhinitis, tendinitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorders, asthma. Asthma, airway infection, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, allergies, intestinal disorders, epithelial intestinal disorders, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis media, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, cardiovascular disease or vasculitis.

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