Oxime-containing compound with STING inhibition effect as well as pharmaceutical composition and application of oxime-containing compound

Abstract

The invention relates to a compound with an STING inhibiting effect, a pharmaceutical composition of the compound and application of the compound and the pharmaceutical composition in preparation of drugs for preventing and / or treating diseases related to abnormal expression of STING. Specifically, the compound has a structure as shown in a formula (I-A). # imgabs0 #

Description

Oxime-containing compounds with STING inhibitory effect and pharmaceutical compositions and uses thereof Technical Field

[0001] The present application relates to compounds having an inhibitory effect on stimulator of interferon genes (STING) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, pharmaceutical compositions containing the same, and their use in preventing and / or treating diseases associated with abnormal STING expression. Background Art

[0002] The stimulator of interferon genes (STING), also known as transmembrane protein 173, regulatory activator of interferon regulatory factor 3, and endoplasmic reticulum interferon-stimulated protein, is primarily expressed on the outer membranes of the rough endoplasmic reticulum, mitochondria, and microsomes of human macrophages, T lymphocytes, dendritic cells, endothelial cells, epithelial cells, and fibroblasts. It specifically recognizes and binds to bacterial second messengers (cyclic di-AMP, cyclic di-GMP, and cyclic 3',3'-cGAMP) and natural cyclic dinucleotide (CDN) ligands synthesized by cyclic GMP-AMP synthase (cGAS). cGAS is involved in detecting self- and foreign DNA, such as pathogen DNA, tumor-derived DNA, and leaked mitochondrial or nuclear DNA. Upon recognizing dsDNA, cGAS catalyzes the synthesis of 2',3'-cGAMP from GTP and ATP, leading to STING activation. Ligand-bound STING is transported to the Golgi apparatus and initiates a cascade of downstream signaling, including the recruitment of serine / threonine protein kinase (TBK1), phosphorylation of interferon-regulated transcription factor 3 (IRF3) and nuclear factor κB (NF-κB), and the production of type I interferons and proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα).

[0003] STING plays a crucial role in the innate immune response triggered by viral, bacterial, and parasitic infections, the body's tumor immunity, and cellular autophagy. It regulates protein synthesis and IFN expression through its own phosphorylation, ubiquitination, and dimerization, playing a key role in multiple immune processes. Many viruses can interact with signaling proteins in the cGAS-STING pathway, stimulating the body to produce interferon in amounts that vary from normal immune responses, leading to viral proliferation or autoimmune diseases. Tumor cell proliferation can activate STING in antigen-presenting cells, thereby activating T cell-mediated adaptive immunity and exerting anti-tumor effects.

[0004] In the existing technology, there are two main categories of STING agonists: cyclic dinucleotide (CDN) derivatives and non-nucleotide small molecules, and two main categories of STING inhibitors: covalent inhibitors and non-covalent inhibitors. In addition, there are also some STING indirect regulators whose mechanisms are not clear.

[0005] Summary of the Invention

[0006] In one aspect, the present application provides a compound of the present invention (such as a compound of formula IA as defined below) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof. The compounds of the present invention have STING inhibitory activity and can be used to prevent and / or treat STING-mediated diseases or conditions, including conditions, diseases or disorders (e.g., autoimmune diseases or cancer) involving STING activation (e.g., overactivated STING signaling). The compounds of the present invention have improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), less prone to drug resistance and other more excellent properties.

[0007] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0008] In another aspect, the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a drug.

[0009] In another aspect, the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, which is used as a STING inhibitor.

[0010] In another aspect, the present application provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament as a STING inhibitor.

[0011] In another aspect, the present application provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating STING-mediated diseases or disorders and related diseases or disorders.

[0012] In another aspect, the present application provides a method for preventing and / or treating a STING-mediated disease or condition and related diseases or conditions in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0013] In some embodiments, the STING-mediated disease or condition is selected from:

[0014] Tumors and / or cancers, including melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor;

[0015] Diseases or disorders of the central nervous system, peripheral nervous system, and autonomic nervous system, including but not limited to epileptic aphasia, encephalomyelitis, macular degeneration, Alpers disease, agenesis of the corpus callosum, Aicardi syndrome, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, arachnoid cysts, meningitis, Asperger syndrome, ataxia telemegaly, attention deficit hyperactivity disorder, autism, autonomic dysfunction, muscular dystrophy, benign intracranial hypertension, Binswanger disease, cerebral atrophy, gigantism, cerebral arteriosclerosis, chorea, chronic inflammatory demyelinating polyneuropathy, congenital facial palsy, corticobasal degeneration, cranial arteritis, Craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, giant cell inclusion disease, diabetic neuropathy, diffuse sclerosis, dystonia, giant cell arteritis, giant cell inclusion disease, hemifacial spasm, hereditary spastic paraplegia, multiple neuritis genetic disorders, herpes zoster, Huntington's disease, myasthenia gravis, diffuse myeloid sclerosis, Parkinson's disease, locked-in syndrome, lumbar disc disease, migraine, mitochondrial myopathy, Möbius syndrome, monosomal muscular dystrophy, motor neuron disease, multi-infarct dementia, multiple sclerosis, myoclonus, neuromyotonia, hemifacial atrophy, multifocal leukoencephalopathy, sclerosing poliomyelitis, and spinal cord injury;

[0016] STING-associated conditions, including type I interferonopathies, Aicardi-Goutières syndrome (AGS), lupus, and rheumatoid arthritis;

[0017] Autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy, irritable bowel syndrome, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis; and

[0018] Psoriatic arthritis, contact dermatitis, atopic dermatitis, vitiligo, type 1 diabetes, asthma, glomerulonephritis, periodontal disease, pars planitis, transplant rejection, neurodegenerative diseases, obesity, and hypertension.

[0019] Compound

[0020] In one aspect, the present application provides a compound of the following formula IA:

[0021] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0022] in:

[0023] L0 is selected from -NH-, -NH-C(O)-NH-, -NH-S(O)- and -NH-S(O)2-;

[0024] L C for

[0025] L1 is selected from C, S and S(O);

[0026] L2 is selected from a single bond, -CH2-, -O-, -S(O) 0-2 - and -NH-, wherein said -CH2- and -NH- are optionally replaced by R a Replace 1 to 3 times;

[0027] Ring A is selected from C 3～10 Saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic group, C 6-10 Aryl and 5-10 membered monocyclic or bicyclic heteroaryl;

[0028] Ring B is selected from C 3～6saturated or partially unsaturated monocyclic hydrocarbon group, 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl group and 5- or 6-membered heteroaryl group;

[0029] X is selected from CR a R b NR a , O, S and S(O)2;

[0030] Q is selected from CR a and N;

[0031] R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, -S(O)-C 1～6 Alkyl, -S(O)2-C 1～6 Alkyl, -S(O)-OC 1～6 Alkyl, -S(O)-NR a R b 、-S(O)2-OC 1～6 Alkyl and -S(O)2-NR a R b , wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times;

[0032] R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, -C 1～3 Alkyl-NH(C 1～3 Alkyl), -C1～3 Alkyl-N(C 1～3 Alkyl)2, -S(O)-C 1～6 Alkyl, -S(O)2-C 1～6 Alkyl, -S(O)-OC 1～6 Alkyl, -S(O)-NR a R b 、-S(O)2-OC 1～6 Alkyl, -S(O)2-NR a R b 、C 3～10 Saturated or partially unsaturated cyclic hydrocarbon group, 5-10 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl and 5-10 membered aromatic hetero groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times;

[0033] R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, -C 1～6 Alkylene-N(C 1～6 Alkyl)2, -C 1～6 Alkylene-C 3～6 Cycloalkyl, -C 1～6 Alkylene-3 to 6-membered heterocycloalkyl, -C 1～6 Alkylene-C 6-10 Aryl and -C 1～6 Alkylene-5 or 6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally replaced by R a Replace 1 to 3 times, and

[0034] wherein R3 is optionally linked to a ring atom of Ring A to form C 3～7 Saturated or partially unsaturated monocyclic hydrocarbon group, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl group, or 5 or 6 membered heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally replaced by R a Replace 1 to 3 times;

[0035] R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, C 3～10Cycloalkyl, C 7～12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered spiroheterocycloalkyl, 6-9 membered bridged heterocycloalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～6 Alkylene-C 6～10 Aryl, -C 1～6 Alkylene-5- to 10-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-C 6～10 Aryl and -C 1～6 Alkylene-C(O)-5- to 10-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, bridged heterocycloalkyl, aryl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times;

[0036] p is selected from 1, 2 and 3;

[0037] q is selected from 0, 1, 2 and 3;

[0038] R a Independently selected from H, halogen, NH2, OH, CN, C 1～6 Alkyl, -C(O)-R c 、-S(O)-R c 、-S(O)2-R c 、-C(O)-OR c 、-S(O)-OR c 、-S(O)2-OR c 、-C(O)-NHR c 、-S(O)-NHR c and -S(O)2-NHR c , wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times with halogen;

[0039] R b Independently selected from H, halogen, NH2, OH, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1～6 Alkyl and C 1～6 The alkoxy group is optionally substituted 1 to 3 times with halogen; and

[0040] R c independently selected from C optionally substituted by NH2, OH, CN and 1 to 3 halogens 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0041] In some embodiments, R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl and -S(O)2-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times.

[0042] In some embodiments, R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 1～3 Alkyl-NH(C 1～3 Alkyl), -C 1～3 Alkyl-N(C 1～3 Alkyl)2, -S(O)2-C 1～6 Alkyl, C 3～10 Saturated or partially unsaturated cyclic hydrocarbon group, 5-10 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl and 5-10 membered aromatic hetero groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times.

[0043] In some embodiments, R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, C 3～10 Cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～6 Alkylene-C 6～10 Aryl, -C 1～6 Alkylene-5- to 10-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-C 6～10 Aryl and -C 1～6 Alkylene-C(O)-5- to 10-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, aryl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times.

[0044] In some further embodiments, R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b and -NR b -C(O)-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replaced 1 to 3 times; and / or

[0045] R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 3～10 Saturated or partially unsaturated cyclic hydrocarbon group, 5-10 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl and 5-10 membered aromatic hetero groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and aromatic hetero groups are optionally replaced by R a Replaced 1 to 3 times; and / or

[0046] R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～6 Alkylene-C 6～10 Aryl, -C 1～6 Alkylene-5- to 10-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-C 6～10 Aryl and -C 1～6 Alkylene-C(O)-5- to 10-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times.

[0047] In some embodiments, L0 is -NH-.

[0048] In some embodiments, the compound of Formula IA has the structure shown in Formula IB or Formula IC:

[0049] In some of the embodiments described above, Ring B is selected from a C6 saturated or partially unsaturated monocyclic cycloalkyl, a 6-membered saturated or partially unsaturated monocyclic heterocyclyl, a phenyl group, and a 6-membered heteroaryl group.

[0050] In some embodiments, the Part of The compound of formula IA has the structure shown in formula ID or IE:

[0051] in:

[0052] represents a single bond or a double bond, provided that two adjacent Not a double bond at the same time;

[0053] Y1, Y2 and Y3 are each independently selected from CH2, CH, NH, N, O and S, wherein said CH2, CH and NH are optionally substituted 1 or 2 times by R1 as valence permits; and

[0054] Z is selected from CH2, CH, NH and N, wherein said CH2, CH and NH are optionally substituted 1 or 2 times by R1 as valence permits.

[0055] In some embodiments, the compound of Formula IA has the structure shown in Formula IF or IG:

[0056] wherein Y1, Y2, Y3 and Z are each CH; or one N among Y1, Y2, Y3 and Z and the rest are CH.

[0057] In some such embodiments, the Some selected from:

[0058] In some of the embodiments described above, X is selected from NR a , O, S and S(O)2, where:

[0059] R a Selected from H, C 1～6 Alkyl, -C(O)-R c 、-S(O)-R c and -S(O)2-R c , wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times by halogen, and

[0060] R c Selected from C optionally substituted by NH2, OH, CN and 1 to 3 halogens 1-6 Alkyl, C 2-6 Alkenyl and C2-6 Alkynyl.

[0061] In some preferred embodiments, X is selected from NR a , O, S and S(O)2, where:

[0062] R a Selected from H, C 1～3 Alkyl, -C(O)-R c 、-S(O)-R c and -S(O)2-R c , wherein the C 1～3 The alkyl group is optionally substituted 1 to 3 times by F, Cl, Br or I, and

[0063] R c Selected from C optionally substituted by NH2, OH, CN and 1 to 3 halogens 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl.

[0064] In some more preferred embodiments, X is selected from NR a , O, S and S(O)2, where:

[0065] R a Selected from H, C 1～3 Alkyl and -C(O)-R c ,and

[0066] R c Selected from C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl.

[0067] In some more preferred embodiments, X is selected from NH, N(C(O)-CH=CH2), S, and S(O)2.

[0068] In some of the above-described embodiments, Q is selected from CR a and N, where R a Selected from H, halogen, NH2, OH, CN and C 1～6 alkyl, and wherein the C 1～6 The alkyl group may be optionally substituted 1 to 3 times with halogen.

[0069] In some preferred embodiments, Q is selected from CR a and N, where R a Selected from H and C 1～3 alkyl, and wherein the C 1～3 The alkyl group may be optionally substituted 1 to 3 times with halogen.

[0070] In some more preferred embodiments, Q is selected from CH and N.

[0071] In some of the embodiments described above, R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b and -S(O)2-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times,

[0072] Preferably, R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b and -S(O)2-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times,

[0073] More preferably, R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O-5 or 6-membered heteroaryl, -C(O)-OC 1～3 Alkyl and -C(O)-NR a R b , wherein the C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times,

[0074] where R a and R b Independently selected from H and C 1～6 Alkyl, wherein the C 1～6 The alkyl group may be optionally substituted 1 to 3 times with halogen.

[0075] In some preferred embodiments, R1 is selected from H, N(R b )2, CN, OH, F, Cl, Br, C 1～3 Alkyl, C 1～3 Halogenated alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O-5 or 6-membered heteroaryl, -C(O)-OC 1～3 Alkyl and -C(O)-NR a R b , wherein the C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times,

[0076] where R a and R b Independently selected from H and C 1～3 Alkyl, preferably H, methyl and ethyl.

[0077] In some more preferred embodiments, R1 is selected from H, NH2, -NH(C 1～3 Alkyl), -N(C 1～3 Alkyl)2, CN, OH, F, Cl, Br, C 1～3 Alkyl, C 1～3 Halogenated alkyl, C 1～3 Alkoxy, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-phenyl, -C(O)-OC1～3 Alkyl, -C(O)-NH2, -C(O)-NH(C 1～3 alkyl), -C(O)-N(C 1～3 alkyl)2, wherein the C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times.

[0078] In some more preferred embodiments, R1 is selected from NH2, CN, OH, F, Cl, Br, CH3, CH2CH3, CH(CH3)CH3, CF3, methoxy, -C(O)OCH3, -C(O)-N(CH3)2, -S(O)2-CH3, cyclopropyl, Cyclopropyloxy, phenoxy and

[0079] In some more preferred embodiments, R1 is selected from NH2, CN, OH, F, Cl, Br, CH3, CH2CH3, CH(CH3)CH3, CF3, methoxy, -C(O)OCH3, -C(O)-N(CH3)2, cyclopropyl, Cyclopropyloxy, phenoxy and

[0080] In some more preferred embodiments, R1 is selected from CN, OH, F, Cl, CF3, methoxy, -C(O)OCH3, -C(O)-N(CH3)2, Cyclopropyloxy, phenoxy and

[0081] In some of the embodiments described above, the Some selected from:

[0082]

[0083] In some such embodiments, R a As defined in any embodiment above.

[0084] In some more preferred embodiments, the Some selected from:

[0085] In some such embodiments, R a As defined in any embodiment above.

[0086] In some of the embodiments described above, the compound of Formula IA has the structure shown in Formulas IH to IO:

[0087] In some such embodiments, R a As defined in any embodiment above.

[0088] In some of the embodiments described above, the Some selected from:

[0089] Additionally or alternatively, the Partially selected

[0090] In some of the embodiments described above, the ring A is selected from C 3～6 Saturated or partially unsaturated monocyclic hydrocarbon group, C 8～10 Saturated or partially unsaturated bicyclic hydrocarbon group, 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group, 8-10 membered saturated or partially unsaturated bicyclic heterocyclic group, C 6-10 aryl, 5- or 6-membered heteroaryl and 8- to 10-membered bicyclic heteroaryl.

[0091] In some preferred embodiments, the ring A is selected from C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered monocyclic heterocycloalkenyl, 8-10 membered bicyclic heterocycloalkenyl, phenyl, 5- or 6-membered heteroaryl having 1, 2, 3 or 4 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms, and 8-10 membered bicyclic heteroaryl having 1, 2, 3, 4, 5 or 6 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms.

[0092] In some preferred embodiments, the ring A is selected from:

[0093] as well as

[0094] The following structures (1)-(18):

[0095] Preferred

[0096] in:

[0097] One of the bonds identified by the letters "a" and "b" shown is connected to L0 and the other is connected to L1;

[0098] X a and X g are each independently selected from CH2, O, S and NH;

[0099] X b 、X c 、X d 、X e 、X f and X h are independently selected from CH and N; and

[0100] In the structures (1) and (2), X a 、X b 、X c and X d At least one of them is replaceable.

[0101] Additionally or alternatively, the ring A is selected from:

[0102] One of the bonds identified by the letters "a" and "b" is connected to L0, and the other is connected to L1.

[0103] In some preferred embodiments, the ring A is selected from:

[0104] In some more preferred embodiments, the ring A is selected from:

[0105] Additionally or alternatively, the ring A is preferably selected from:

[0106] One of the bonds identified by the letters "a" and "b" is connected to L0, and the other is connected to L1.

[0107] In some such embodiments, the bond shown identified by the letter "a" is connected to L0, and the bond shown identified by the letter "b" is connected to L1.

[0108] In some of the embodiments described above, R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 1～3 Alkyl-NH(C 1～3 Alkyl), -C 1～3 Alkyl-N(C 1～3 Alkyl)2, -S(O)2-C 1～6 Alkyl, C 3～6saturated or partially unsaturated cyclic hydrocarbon group, 5-6 membered saturated or partially unsaturated heterocyclic group, phenyl group and 5-6 membered aromatic hetero group,

[0109] Preferably selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 3～6 Saturated or partially unsaturated cyclic hydrocarbon groups, 5-6 membered saturated or partially unsaturated heterocyclic groups, phenyl groups and 5-6 membered aromatic hetero groups, wherein the alkyl groups, alkoxy groups, cyclic hydrocarbon groups, heterocyclic groups, phenyl groups and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times,

[0110] where R a Selected from H, halogen, NH2, OH, CN and C 1～6 alkyl; and

[0111] where R b Selected from H and C 1～6 Alkyl, wherein the C 1～6 The alkyl group may be optionally substituted 1 to 3 times with halogen.

[0112] In some preferred embodiments, R2 is selected from H, NH2, NH(C 1～3 alkyl), N(C 1～3 Alkyl)2, CN, OH, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～3 Alkyl and 5-6 membered aromatic hetero groups having 1, 2 or 3 nitrogen hetero atoms and 0 or 1 oxygen or sulfur hetero atoms, wherein the alkyl and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times,

[0113] where R a Selected from H, F, Cl, NH2, OH, CN and C 1～3 alkyl; and

[0114] where R b Selected from H and C 1～3 Alkyl, wherein the C 1～3 The alkyl group is optionally substituted 1 to 3 times by F or Cl.

[0115] Additionally or alternatively, R2 is preferably selected from C3～6 Cycloalkyl.

[0116] In some more preferred embodiments, R2 is selected from H, NH2, NH(C 1～3 alkyl), N(C 1～3 alkyl) 2, CN, OH, F, Cl, Br, C optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl and OH 1～3 Alkyl, C 1～3 Alkoxy, oxo, -C(O)-NH(C 1～3 alkyl), -C(O)-N(C 1～3 alkyl)2 and optionally 1 selected from C 1～3 The substituents of the alkyl group are pyrrole, pyrazolyl or triazolyl substituted. Additionally or alternatively, R2 is preferably selected from -C(O)-NH2, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0117] In some more preferred embodiments, R2 is selected from H, NH2, -NHCH3, CN, OH, F, Cl, methyl, ethyl, -CH2F, -CHF2, -CH2CH2F, -CH2-OH, methoxy, oxo, -C(O)-NHCH3, -C(O)-N(CH3)2 and Additionally or alternatively, R2 is preferably selected from cyclopropyl, -CH2-NH(CH3), -CH2-N(CH3)2, -S(O)2-CH3 and -C(O)-NH2.

[0118] In some embodiments, R2 is selected from -S(O)-C 1～6 Alkyl, -S(O)2-C 1～6 alkyl

[0119] In some of the embodiments described above, p is 1 or 2

[0120] In some of the embodiments described above, q is 0, 1 or 2.

[0121] In some of the embodiments described above, L1 is selected from C and S(O).

[0122] In some of the embodiments described above, R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1～3 Alkylene-OC 1～6 Alkyl, -C 1～3 Alkylene-NH-C 1～6 Alkyl, -C 1～3 Alkylene-N(C 1～6 Alkyl)2, -C 1～3 Alkylene-C3～6 Cycloalkyl, -C 1～3 Alkylene-3 to 6-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl and -C 1～3 Alkylene-5 or 6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally replaced by R a Replace 1 to 3 times,

[0123] Preferably, R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1～3 Alkylene-OC 1～6 Alkyl, -C 1～3 Alkylene-NH-C 1～6 Alkyl, -C 1～3 Alkylene-N(C 1～3 Alkyl)2, -C 1～3 Alkylene-C 3～6 Cycloalkyl and -C 1～3 Alkylene-3 to 6 membered heterocycloalkyl, wherein the alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally replaced by R a Replace 1 to 3 times,

[0124] where R a Selected from halogen, NH2, OH and CN and C 1～6 alkyl.

[0125] In some preferred embodiments, R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CH2-OC 1～6 Alkyl, -CH2-NH-C 1～6 Alkyl, -CH2-C 3～6 Cycloalkyl and -CH2-3 to 6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by R a Replace 1 to 3 times,

[0126] where R a Selected from F, Cl, NH2, OH and CN, preferably F.

[0127] In some more preferred embodiments, R3 is selected from H, CH3, -CH2CH3, -CH(CH3)CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2OCH3, -CH2NHCH3,

[0128] In other embodiments described above, R3 is linked to a ring atom of Ring A in an ortho position to L1 to form C 3～7 Saturated or partially unsaturated monocyclic hydrocarbon group, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl group, or 5 or 6 membered heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally replaced by R a Replace 1 to 3 times.

[0129] In some preferred embodiments, R3 is linked to a ring atom of Ring A in an ortho position to L1 to form C 5～6 Saturated or partially unsaturated monocyclic cycloalkyl, or 5 or 6 membered saturated or partially unsaturated monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally replaced by R a Replace 1 to 3 times.

[0130] In some more preferred embodiments, R3 is linked to a ring atom of Ring A at an ortho position to L1 to form a ring structure selected from the group consisting of: a Replace 1 to 3 times:

[0131] Preferred

[0132] in:

[0133] represents a single bond or a double bond,

[0134] The ring atoms identified by the letters "c" and "d" as shown are ring atoms of the ring A, and the double bond identified by the letter "e" as shown is connected to the N atom to which L1 and L2 are connected.

[0135] In some such embodiments, the rings A, L1, and R3 together form a structure selected from the group consisting of:

[0136] The double bond identified by the letter "e" is connected to the N atom connected to L1 and L2, and the double bond identified by the letter "f" is connected to L0.

[0137] In some of the embodiments described above, L2 is selected from a single bond, -CH2-, -O-, and S(O), wherein said -CH2- is optionally replaced by R a Replace 1 to 3 times.

[0138] In some of the embodiments described above, R4 is selected from:

[0139] R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～3 Alkylene-OC1～6 Alkyl, -C 1～3 Alkylene-NH-C 1～6 Alkyl, C 3～10 (Preferred C 3～7 )cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-C 3～7 Cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～3 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～3 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～3 Alkylene-C(O)-phenyl and -C 1～3 Alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times,

[0140] Preferred are H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～3 Alkylene-OC 1～6 Alkyl, -C 1～3 Alkylene-NH-C 1～6 Alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-C 3～7 Cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～3 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～3 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～3 Alkylene-C(O)-phenyl and -C 1～3 Alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times,

[0141] where R b Independently selected from F, Cl, Br, NH2, OH, CN, C 1-6 Alkyl and C1-6 Alkoxy, wherein the C 1～6 Alkyl and C 1～6 The alkoxy group is optionally substituted 1 to 3 times by F, Cl or Br.

[0142] In some preferred embodiments, R4 is selected from:

[0143] H, CN, C 1～6 Alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-C 3～7 Cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～3 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～3 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～3 Alkylene-C(O)-phenyl and -C 1～3 Alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times,

[0144] Preferred H, CN, C 1～6 Alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-C 3～7 Cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～3 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～3 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～3 Alkylene-C(O)-phenyl and -C 1～3 Alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times,

[0145] where R b Independently selected from F, Cl, NH2, OH, CN and C 1-3 Alkyl, wherein the C 1～3The alkyl group is optionally substituted 1 to 3 times by F or Cl.

[0146] In some more preferred embodiments, R4 is selected from H, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)CH3, -CH(CH3)CH3, -C(CH3)3, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH(CH3)CF3, -CH2CH2CH2CF3, (include ), Additionally or alternatively, R4 is selected from (include ).

[0147] In some embodiments, the application provides a compound of formula IF or IG as described above, wherein:

[0148] described Partially selected

[0149] R1 is selected from H, CN, halogen, C 1～6 Halogenated alkyl, C 1～6 Alkoxy, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -C(O)-NH(C 1～3 alkyl) and -C(O)-N(C 1～3 alkyl) 2, wherein the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally replaced by R a Replace C 1～6 Alkyl group;

[0150] p is 1 or 2;

[0151] The ring A is selected from

[0152] R2 is selected from H, NH2, CN, OH, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b , phenyl and 5-6 membered aromatic hetero groups, wherein the alkyl, alkoxy, phenyl and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times,

[0153] where R a Selected from H, halogen, OH and C1～6 alkyl; and

[0154] where R b Selected from H and C 1～6 Alkyl, wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times with halogen;

[0155] q is 0, 1, or 2;

[0156] L1 is C;

[0157] R3 is selected from H, C 1～6 Alkyl and C 3～6 Cycloalkyl;

[0158] Alternatively, R3 is linked to a ring atom of Ring A in an ortho position to L1, such that Ring A, L1 and R3 together form wherein the double bond identified by the letter "e" is connected to the N atom connected to L1 and L2, and the double bond identified by the letter "f" is connected to the NH as L0;

[0159] L2 is -O-;

[0160] R4 is selected from C 1～6 Halogenated alkyl, C 3～10 Cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-phenyl and -C 1～6 Alkylene-C(O)-5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times,

[0161] where R b independently selected from F, Cl, CN and C substituted 1 to 3 times by F or Cl 1-3 alkyl.

[0162] In some preferred embodiments, the Partially selected

[0163] In some preferred embodiments, R1 is selected from H, CN, F, Cl, C 1～3 Halogenated alkyl, C 1～3 Alkoxy, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl and -C(O)-N(C 1～3 alkyl) 2, wherein the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally replaced by C 1～3 Alkyl substitution 1 to 3 times;

[0164] In some more preferred embodiments, R1 is selected from H, CN, F, Cl, CF3, methoxy, -C(O)-N(CH3)2,

[0165] In some preferred embodiments, the ring A is selected from

[0166] In other preferred embodiments, the ring A is selected from

[0167] In some preferred embodiments, the ring A is selected from

[0168] In some preferred embodiments, R2 is selected from H, NH2, CN, OH, F, Cl, C 1～3 Alkoxy, oxo, -C(O)-NH(C 1～3 alkyl), -C(O)-N(C 1～3 alkyl)2, C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and OH 1～3 Alkyl, and optionally 1 selected from C 1～3 The substituent of the alkyl group is substituted pyrrole, pyrazolyl or triazolyl.

[0169] In some more preferred embodiments, R2 is selected from H, F, CN, OH, NH2, oxo, methoxy, methyl, ethyl, -CHF2, -CH2CH2F, -CH2-OH, -C(O)-NHCH3, -C(O)-N(CH3)2 and

[0170] In some preferred embodiments, R3 is selected from H, CH3, -CH2CH3, -CH(CH3)CH3, -CH2CH2CH3 and

[0171] In some preferred embodiments, R3 is attached to a ring atom of Ring A that is ortho to L1, such that Ring A, L1, and R3 together form

[0172] In some preferred embodiments, R3 is attached to a ring atom of Ring A that is ortho to L1, such that Ring A, L1, and R3 together form

[0173] In some preferred embodiments, R4 is selected from C 1～6 Halogenated alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-phenyl and -C 1～6 Alkylene-C(O)-5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times.

[0174] In other preferred embodiments, R4 is selected from C 1～4 Halogenated alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, -CH2-C 3～7 Cycloalkyl, -CH2-phenyl, -CH2-5 to 6-membered heteroaryl and -CH2-C(O)-3 to 7-membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkylphenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times,

[0175] where R b independently selected from F, Cl, CN, and methyl or ethyl substituted 1 to 3 times by F or Cl.

[0176] In some preferred embodiments, R4 is selected from C 1～4 Halogenated alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, -CH2-C 3～7 Cycloalkyl, -CH2-phenyl, -CH2-5 to 6-membered heteroaryl and -CH2-C(O)-3 to 7-membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally replaced by R bReplace 1 to 3 times,

[0177] where R b independently selected from F, Cl, CN, and methyl or ethyl substituted 1 to 3 times by F or Cl.

[0178] In some more preferred embodiments, R4 is selected from -CH2CF3, -CH2CH2CH2CF3, (include ),

[0179] In some more preferred embodiments, R4 is selected from -CH2CF3, -CH2CH2CH2CF3, (include ),

[0180] Additionally or alternatively, R4 is selected from (include ).

[0181] In another aspect, the present application also provides a compound shown in the following formula I:

[0182] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0183] in:

[0184] represents a single bond or a double bond;

[0185] L0 is selected from -NH-, -NH-C(O)-NH- and NH-S(O) 1-2 -;

[0186] L1 is selected from -C- and -S(O) 0-2 -;

[0187] L2 is selected from a single bond, -CH2-, -O-, -S(O) 0-2 - and -NH-, wherein said -CH2-, -NH- and -S(O) 0-2 - can be optionally replaced by R a Replace 1 to 3 times;

[0188] Ring A is a monocyclic or bicyclic ring structure, wherein the monocyclic ring is selected from a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring, and the bicyclic ring is selected from a 7-10 membered fused ring or fused heterocyclic ring formed by condensing any two independent of a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring;

[0189] Ring B is selected from a 5- to 7-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring, a 5- to 7-membered aromatic heterocyclic ring, and a 5- to 6-membered aromatic ring;

[0190] X is selected from -CH2-, -NH-, -O- and -S-, wherein said -CH2- and -NH- may be optionally replaced by R a Replace 1-2 times;

[0191] R1 is selected from H, CN, OH, halogen, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1～6 Alkoxy, -O-3 to 6-membered cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O-5 to 6-membered heteroaryl and -C(O)-OC 1～6 Alkyl, wherein the C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally replaced by R a Replace 1 to 3 times;

[0192] R2 is selected from H, N(R b )2、CN、C(O)、S(O) 0-2 , halogen, C 1～3 Alkyl and C 1～3 Alkoxy, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group may optionally be replaced by R a Replace 1 to 3 times;

[0193] R3 is selected from H, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, CH2-OC 1～6 Alkyl, CH2-NH-C 1～6 Alkyl, CH2-3 to 6-membered cycloalkyl and CH2-3 to 6-membered heterocycloalkyl, wherein the C 1～6 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl may be optionally replaced by R a Replace 1 to 3 times;

[0194] wherein R3 can further form a 5- to 7-membered ring together with the ring atoms of ring A, wherein the 5- to 7-membered ring can be optionally replaced by R a Substituted 1 to 3 times, and the 5 to 7 membered ring can be a carbocyclic ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring;

[0195] R4 is selected from H, CN, C 1～6 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-3 to 7-membered cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl and -C 1～3 Alkylene-5- to 6-membered heteroaryl, wherein the C 1～6 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally replaced by R b Replace 1 to 3 times;

[0196] p is selected from 1, 2 and 3;

[0197] q is selected from 0, 1, 2 and 3;

[0198] R a independently selected from H, F, Cl and C 1～3 alkyl;

[0199] R b Independently selected from H, F, Cl, Br, I, NH2, OH, C 1-3 Alkyl, C 1-3 Alkoxy and CN, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group may be substituted 1 to 3 times with halogen.

[0200] In another aspect, the present application also provides a compound represented by the following formula I':

[0201] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0202] in:

[0203] represents a single bond or a double bond;

[0204] X is selected from -CH2-, -NH-, -O- and -S-, wherein said -CH2- and -NH- may be optionally replaced by R a Replace 1-2 times;

[0205] Y1, Y2, Y3 are independently selected from -CH2-, -NH-, -O- and -S-, wherein the H in -CH2- and -NH- can be optionally substituted 1 or 2 times by R1 under conditions permitting by valence;

[0206] Z is selected from -CH2- and -NH-, wherein the H in said -CH2- and -NH- can be optionally substituted 1 or 2 times by R1 under conditions permitting by valence;

[0207] L1 is selected from -C- and -S(O)-;

[0208] L2 is selected from a single bond, -CH2-, -O-, -S(O)- and -NH-, wherein said -CH2- and -NH- may be optionally replaced by R a Replace 1 to 3 times;

[0209] Ring A is a monocyclic or bicyclic ring structure, wherein the monocyclic ring is selected from a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring, and the bicyclic ring is selected from a 7-10 membered fused ring or fused heterocyclic ring formed by condensing any two independent ones of a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring;

[0210] R1 is selected from H, CN, OH, halogen, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1～6 Alkoxy, -O-3 to 6-membered cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O-5 to 6-membered heteroaryl and -C(O)-OC 1～6 Alkyl, wherein the C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally replaced by R a Replace 1 to 3 times;

[0211] R2 is selected from H, F, Cl, NH2, cyano, oxo, C 1～3 Alkyl and C 1～3 Alkoxy, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group may optionally be replaced by R a Replace 1 to 3 times;

[0212] R3 is selected from H, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -CH2-OC 1～6 Alkyl, -CH2-NH-C 1～6 Alkyl, -CH2-3 to 6-membered cycloalkyl and -CH2-3 to 6-membered heterocycloalkyl, wherein the C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl may be optionally replaced by R a Replace 1 to 3 times;

[0213] Wherein R3 can further form a 5- to 7-membered ring together with the ring atoms of ring A, and the 5- to 7-membered ring can be optionally replaced by R aReplace 1 to 3 times;

[0214] R4 is selected from H, CN, C 1～6 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-3 to 7-membered cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl and -C 1～3 Alkylene-5- to 6-membered heteroaryl, wherein the C 1～6 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally replaced by R b Replace 1 to 3 times;

[0215] p is selected from 1, 2 and 3;

[0216] q is selected from 0, 1, 2 and 3;

[0217] R a Independently selected from H, F, Cl, C 1～3 Alkyl and C 1～3 alkyl halide;

[0218] R b Independently selected from H, F, Cl, Br, I, NH2, OH, C 1-3 Alkyl, C 1-3 Alkoxy and CN, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group may be substituted 1 to 3 times with halogen.

[0219] In some embodiments, Ring A is selected from pyridine, imidazole, pyridazine, oxazole, isoxazole, benzene ring, thiazole, pyrimidine, pyrazine, quinoline, isoquinoline, benzimidazole, imidazopyridine and naphthyridine, wherein Ring A is optionally substituted 1 to 3 times by R2.

[0220] In some embodiments, Ring A is selected from wherein the ring A may be optionally substituted by R2 1 to 3 times.

[0221] In some embodiments, Ring A is selected from

[0222] wherein the ring A may be optionally substituted by R2 1 to 3 times.

[0223] In some embodiments, R1 is selected from H, F, Cl, Br, CH3, CH2CH3, CH(CH3)CH3, OCH3, OH, COOCH3, wherein said R1 may be optionally replaced by R a Replace 1 to 3 times.

[0224] In some embodiments, R2 is selected from H, F, Cl, cyano, oxo, CH3.

[0225] In some embodiments, R3 is selected from H, CH3, CH2CH3, CH(CH3)CH3, CH2CH2CH3, CH2CH2CH2CH3, CH2OCH3, CH2NHCH3, The R3 may optionally be replaced by R a Replace 1 to 3 times.

[0226] In some embodiments, R4 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH2CH2CH2CH3, CH2CH(CH3)CH2CH3, CH2CH2CH(CH3)CH3, CH(CH3)CH3, C(CH3)3, CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl, methyl-cycloheptyl, methyl-phenyl, piperidine, pyridine, pyrimidine, pyrazine, pyrazole, oxetane, oxolane, hexyl oxide, azetidine, pyrrolidine, pyrrolidone, piperidone, wherein said R4 can be optionally replaced by R b Replace 1 to 3 times.

[0227] In some embodiments, R3 is further taken together with the ring atoms of ring A to form a 5-6 membered ring selected from wherein the 5- to 6-membered ring may be optionally replaced by R a Replace 1 to 3 times.

[0228] On the other hand, the present application also provides a compound shown in the following formula I":

[0229] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0230] in:

[0231] represents a single bond or a double bond;

[0232] Y1, Y2, and Y3 are independently selected from -CH2- and -NH-, wherein the H in -CH2- and -NH- can be optionally substituted 1 or 2 times by R1 under conditions permitting by valence;

[0233] Z is selected from -CH2- and -NH-, wherein the H in said -CH2- and -NH- can be optionally substituted 1 or 2 times by R1 under conditions permitting by valence;

[0234] Ring A is a monocyclic or bicyclic ring structure, wherein the monocyclic ring is selected from a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring, and the bicyclic ring is selected from a 7-10 membered fused ring or fused heterocyclic ring formed by condensing any two independent of a 4-6 membered carbocyclic ring, a 4-6 membered heterocyclic ring, a 5-6 membered aromatic heterocyclic ring and a 5-6 membered aromatic ring;

[0235] R1 is selected from H, CN, OH, halogen, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1～6 Alkoxy, -O-3 to 6-membered cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O-5 to 6-membered heteroaryl and -C(O)-OC 1～6 Alkyl, wherein the C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally replaced by R a Replace 1 to 3 times;

[0236] R2 is selected from H, F, Cl, NH2, cyano, oxo, C 1～3 Alkyl and C 1～3 Alkoxy, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group may optionally be replaced by R a Replace 1 to 3 times;

[0237] R3 is selected from H, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -CH2-OC 1～6 Alkyl, -CH2-NH-C 1～6 Alkyl, -CH2-3 to 6-membered cycloalkyl, -CH2-3 to 6-membered heterocycloalkyl, wherein the C 1～6 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl may be optionally replaced by R a Replace 1 to 3 times;

[0238] wherein R3 can further form a 5- to 7-membered ring together with the ring atoms of ring A, and the 5- to 7-membered ring can be optionally replaced by R a Replace 1 to 3 times;

[0239] R4 is selected from H, CN, C 1～6 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-3 to 7-membered cycloalkyl, -C 1～3Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl and -C 1～3 Alkylene-5- to 6-membered heteroaryl, wherein the C 1～6 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl may be optionally replaced by R b Replace 1 to 3 times;

[0240] Among them, p, q, R a 、R b Same as defined above.

[0241] In some embodiments, the present application provides the compound described above, which has a structure shown in Formula II-1 or Formula II-2:

[0242] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Ring A, R1, R2, R3, R4, and L2 are as defined above.

[0243] In some embodiments, the present application provides the compound described above, which has the structure shown in Formula II-3:

[0244] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Ring A, R1, R2, R3, R4, and L2 are as defined above.

[0245] In some embodiments, the present application provides the compound described above, which has a structure shown in Formula III-1, III-2, III-3 or III-4:

[0246] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein X a 、X b 、X c 、X d 、X e 、X f are independently selected from CH or N; R1, R2, R3, R4, L1, L2 are as defined above.

[0247] In some embodiments, the present application provides the compound described above, which has a structure shown in Formula III-5 or III-1a:

[0248] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein X a 、X b 、X c 、X d are independently selected from CH or N; R1, R2, R3, R4, L1, L2 are as defined above.

[0249] In some embodiments, the present application provides the compound described above, which has a structure shown in Formula IV-1 or IV-2:

[0250] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein X a 、X b 、X c 、X d are independently selected from CH or N; R1, R2, R3, and R4 are as defined above.

[0251] In some embodiments, the present application provides the compound described above, which has a structure shown in Formula V-1 or V-2:

[0252] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein X a 、X b 、X c 、X d are independently selected from CH or N; R1, R2, R3, and R4 are as defined above.

[0253] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0254] In some embodiments, the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0255] (include )

[0256] In other embodiments, the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0257] In other embodiments, the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0258] In other embodiments, the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0259] In other embodiments, the present application provides a compound according to the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0260] (include ),

[0261] In some embodiments, the stereoisomers of the compounds of the present invention are configurational isomers. In some embodiments, the configurational isomers are cis- / trans-isomers, also known as geometric isomers (E- / Z-isomers). In some embodiments, the configurational isomers are enantiomers. In some embodiments, the configurational isomers are diastereoisomers. In some embodiments, the compounds of the present invention are racemic.

[0262] The pharmaceutically acceptable salts of the present invention include acid addition salts and base salts. In some embodiments, the pharmaceutically acceptable salts of the compounds of the present invention are, for example, but not limited to, formate salts.

[0263] The pharmaceutically acceptable salts of the present invention can exist in unsolvated as well as solvated forms.

[0264] Pharmaceutical compositions and methods of treatment

[0265] On the other hand, the present application also provides a pharmaceutical composition comprising a compound of the present invention (including compounds of Formula IA and Formula I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0266] The compounds of the present invention, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotopically labeled compounds, or prodrugs thereof, may be used alone or in combination with at least one other therapeutic agent in therapy.

[0267] The present invention also provides a pharmaceutical composition comprising a compound of the present invention as described above or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and one or more other therapeutically active ingredients.

[0268] In another aspect, the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a drug.

[0269] In another aspect, the present application provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, which is used as a STING inhibitor.

[0270] In another aspect, the present application provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament as a STING inhibitor.

[0271] In some embodiments, the STING inhibitor or drug is used to treat and / or prevent tumors and / or cancer.

[0272] The compounds of the present invention are STING inhibitors having excellent STING receptor inhibitory activity. These STING inhibitor compounds can treat and / or prevent STING-mediated diseases or conditions and related diseases or conditions.

[0273] In one aspect, the present application provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating STING-mediated diseases or disorders and related diseases or disorders.

[0274] In another aspect, the present application provides a method for preventing and / or treating a STING-mediated disease or condition and related diseases or conditions in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0275] In some embodiments, the STING-mediated disease or condition is a tumor and / or cancer. In some embodiments, the tumor and / or cancer includes, but is not limited to, melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor.

[0276] In some embodiments, the STING-mediated disease or disorder is a disease or disorder of the central nervous system, peripheral nervous system, and autonomic nervous system. In some embodiments, the disease or disorder of the central nervous system, peripheral nervous system, and autonomic nervous system includes but is not limited to epileptic aphasia, encephalomyelitis, macular degeneration, Alpers disease, agenesis of the corpus callosum, Aicardi syndrome, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, arachnoid cysts, meningitis, Asperger syndrome, ataxia telekinesis, attention deficit hyperactivity disorder, autism, autonomic dysfunction, muscular dystrophy, benign intracranial hypertension, Binswanger disease, brain atrophy, cerebral gigantism, cerebral arteriosclerosis, chorea, chronic inflammatory demyelinating polyneuropathy, congenital facial palsy, cortical basal degeneration, cranial artery Inflammation, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, giant cell inclusion disease, diabetic neuropathy, diffuse sclerosis, dystonia, giant cell arteritis, giant cell inclusion disease, hemifacial spasm, hereditary spastic paraplegia, multiple neuritis genetic diseases, herpes zoster, Huntington's disease, myasthenia gravis, diffuse myeloid sclerosis, Parkinson's disease, locked-in syndrome, lumbar disc disease, migraine, mitochondrial myopathy, Möbius syndrome, monosomal muscular dystrophy, motor neuron disease, multi-infarct dementia, multiple sclerosis, myoclonus, neuromyotonia, hemifacial atrophy, multifocal leukoencephalopathy, sclerosing poliomyelitis, herpes zoster, spinal cord injury.

[0277] In some embodiments, the STING-mediated disease or disorder is a STING-associated disorder, including but not limited to type I interferonopathy, Aicardi-Goutières syndrome (AGS), lupus, rheumatoid arthritis.

[0278] In some embodiments, the STING-mediated disease or disorder is an autoimmune disease, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy treatment, irritable bowel syndrome, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, mucositis.

[0279] In some embodiments, the STING-mediated disease or condition and related diseases or conditions include, but are not limited to, melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor.

[0280] In some embodiments, the STING-mediated disease or condition and related diseases or conditions include, but are not limited to, encephalomyelitis, macular degeneration, Alzheimer's disease, vascular dementia, arachnoiditis, autonomic dysfunction, muscular dystrophy, cerebral atrophy, chorea, dystonia, giant cell arteritis, hemifacial spasm, herpes zoster, Huntington's disease, myasthenia gravis, Parkinson's disease, locked-in syndrome, lumbar disc disease, migraine, and multiple sclerosis.

[0281] In some embodiments, the STING-mediated diseases or conditions and related diseases or conditions include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune colitis, irritable bowel syndrome, scleroderma, and psoriasis.

[0282] In some embodiments, the STING-mediated disease or condition and related diseases or conditions include, but are not limited to, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, vitiligo, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, multiple sclerosis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune colitis, irritable bowel syndrome, scleroderma, asthma, glomerulonephritis, periodontal disease, pars planitis, transplant rejection, neurodegenerative diseases, obesity, hypertension, encephalomyelitis, macular degeneration, Alzheimer's disease, vascular dementia, arachnoiditis, autonomic dysfunction, muscular dystrophy, brain atrophy, chorea, dystonia, giant cell arteritis, hemifacial spasm, herpes zoster, Huntington's disease, myasthenia gravis, Parkinson's disease, locked-in syndrome, lumbar disc disease, migraine, and multiple sclerosis.

[0283] As used herein, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0284] As used herein, unless otherwise indicated, the terms "treat," ...

[0285] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0286] Definition and Description

[0287] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0288] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0289] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0290] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0291] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0292] Unless otherwise indicated, the term "isomer" is intended to include stereoisomers, geometric isomers, cis-trans isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0293] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0294] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0295] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0296] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0297] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0298] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0299] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0300] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0301] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0302] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0303] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0304] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0305] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0306] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0307] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0308] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0309] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0310] When a substituent's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. The substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituent does not specify the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0311] When the listed linking groups do not indicate the direction of their attachment, the direction of their attachment is arbitrary.

[0312] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines express.

[0313] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0314] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0315] As used herein, the terms "halo", "halogen" and "halogen atom" mean fluorine atom, chlorine atom, bromine atom, iodine atom, etc. Preferred halogen atoms as substituents of the aryl group of the present invention are fluorine atom and chlorine atom.

[0316] As used herein, the term "S(O) 0-2 or "-S(O) 0-2 -" means S, S(O) and S(O)2. The term "S(O) 1-2 or "-S(O) 1-2 -" means S(O) and S(O)2.

[0317] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be regarded as a group derived from an alkane by losing one hydrogen atom. 1～6 "Alkyl" is a straight or branched chain alkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl. The term "C 1～4 "Alkyl" is a straight or branched chain alkyl group having 1 to 3 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The term "C 1～3 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 3 carbons, including but not limited to methyl, ethyl, n-propyl, and isopropyl.

[0318] As used herein, the term "alkylene" refers to a linear or branched divalent group obtained by further losing one H from the "alkyl" described above. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene. The term "C 1～3 The term "alkylene" includes methylene, ethylene, propylene and isopropylene, with methylene being preferred.

[0319] As used herein, the term "haloalkyl" refers to an alkyl group (including the C 1～6 Alkyl, C1～4 Alkyl C 1～3 alkyl).

[0320] As used herein, the term “C 1～6 "Alkoxy" means a group C 1-6 Alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy. The term "C 1～4 "Alkoxy" means a group C 1-3 Alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. The term "C 1～3 "Alkoxy" means a group C 1-3 Alkyl-O- includes, but is not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0321] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, an alkenyl group has 2-6 carbon atoms ("C 2-6 alkenyl”), for example 2 to 4 carbon atoms (“C 2-4 alkenyl”), or 2 to 3 carbon atoms (“C 2-3 Examples of the alkenyl group include, for example, -CH=CH, -CHCH=CH, -C(CH)=CH, -CH-CH=CH-CH, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenyl group, the compound may be present in the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

[0322] As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 alkynyl”), for example 2 to 4 carbon atoms (“C 2-4 alkynyl”), or 2 to 3 carbon atoms (“C 2-3 The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0323] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[0324] As used herein, the term "bridge" or "bridged" means that two or more ring structures share two non-adjacent atoms with each other.

[0325] As used herein, the term "spiro" or "spiro-connected" means that two or more ring structures share 1 atom with each other.

[0326] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and / or triple bonds within the ring) monocyclic or polycyclic (e.g., bicyclic) fused hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6, 4-6, 5-6, 8-10 or 9-10) ring carbon atoms. In some embodiments, "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" are saturated or partially unsaturated hydrocarbon rings having 3-7 or 3-6 ring carbon atoms (C 3～7 or C 3～6 In some embodiments, "cycloalkyl," "hydrocarbon ring," and "cycloalkylene" are monocyclic cycloalkyl or cycloalkenyl rings having 8-10 or 9-10 ring carbon atoms (C 8～10 or C 9～10 ) bicyclic cycloalkyl or cycloalkenyl ring. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and the like. Cycloalkyl is, in some embodiments, an aromatic fused cycloalkyl, as long as the entire ring system is non-aromatic.

[0327] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6 carbon atoms. In some embodiments, "cycloalkyl" and "cycloalkylene" are groups having 3-7 or 3-6 ring carbon atoms (C 3～7 or C 3～6In some embodiments, "cycloalkyl" and "cycloalkylene" are monocyclic cycloalkyl rings having 8-10 or 9-10 ring carbon atoms (C 8～10 or C 9～10 ) is a bicyclic cycloalkyl ring.

[0328] The term "spirocycloalkyl" refers to a cyclic group formed by two or more "cycloalkyl" groups as defined above as components, with any two of the components sharing one carbon atom. For example, "C 7-12 Spirocycloalkyl" and "C 7-12 The term "spirocycloalkylene" refers to a cyclic structure containing 7 to 12 (e.g., 5-12 or 7-11) carbon atoms formed by at least two cycloalkyl rings, wherein any two of the cycloalkyl rings share only one atom.

[0329] As used herein, the term "bridged cycloalkyl" refers to a cyclic group formed by two or more "cycloalkyl" groups as defined above as components, with any two of the components sharing two carbon atoms that are not adjacent to each other. For example, "C 7-10 Bridged cycloalkyl" and "C 7-10 "Cycloalkylene" refers to a cyclic structure containing 7 to 12 (e.g., 6-10, 6-9, or 6-8) carbon atoms formed by two cycloalkyl rings sharing two non-adjacent carbon atoms.

[0330] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds within the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6. In some embodiments, "cycloalkenyl" and "cycloalkenylene" are rings having 3-7 or 3-6 ring carbon atoms (C 3～7 or C 3～6 In some embodiments, "cycloalkenyl" and "cycloalkenylene" are monocyclic cycloalkenyl rings having 8-10 or 9-10 ring carbon atoms (C 8～10 or C 9～10 ) of a bicyclic cycloalkenyl ring.

[0331] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to a saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monocyclic or bicyclic fused ring structure having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, and N in the ring. One or more ring carbon atoms in the heterocyclyl may be replaced by C(O). The S atom in the heterocyclyl may be replaced by S(O) or S(O)2. The heterocyclyl may be attached to the remainder of the molecule through any of the carbon atoms or, if present, the nitrogen atom. In some embodiments, "heterocyclyl", "heterocycle" and "heterocyclylene" are monocyclic heterocycloalkyl or heterocycloalkenyl rings with 3-7, 3-6 or 5-6 ring members (3-7, 3-6 or 5-6 ring members). In some embodiments, "heterocyclyl", "heterocycle" and "heterocyclylene" are bicyclic heterocycloalkyl or heterocycloalkenyl rings with 8-10 or 9-10 ring members (8-10 or 9-10 ring members). The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl. Heterocyclyl includes nitrogen-containing heterocyclic groups, oxygen-containing bridged ring groups and sulfur-containing heterocyclic groups. Examples that may be mentioned include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, piperidonyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.

[0332] As used herein, the term "nitrogen-containing heterocyclic group" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and at least one (e.g., 1, 2, 3 or 4) nitrogen atom in the ring, which may also optionally contain one or more (e.g., 1, 2, 3 or 4) ring members selected from N, O and S. One or more ring carbon atoms in the nitrogen-containing heterocyclic group may be replaced by C (O). The S atom in the nitrogen-containing heterocyclic group may be replaced by S (O) or S (O) 2. The nitrogen-containing heterocyclic group may be connected to the rest of the molecule by any one of the carbon atoms or a nitrogen atom. The nitrogen-containing heterocyclic group may be a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 10-membered nitrogen-containing heterocyclic group is a nitrogen-containing heterocyclic group as defined above having 3-10 ring members in the ring, including but not limited to a 3-membered nitrogen-containing heterocyclic group (such as aziridinyl), a 4-membered nitrogen-containing heterocyclic group (such as azetidinyl), a 5-membered nitrogen-containing heterocyclic group (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a 6-membered nitrogen-containing heterocyclic group (such as piperidinyl (piperidine ring), piperidinyl ketone group, morpholinyl, thiomorpholinyl, piperazinyl), a 7-membered nitrogen-containing heterocyclic group, an 8-membered bicyclic nitrogen-containing heterocyclic group, a 9-membered bicyclic nitrogen-containing heterocyclic group and a 10-membered bicyclic nitrogen-containing heterocyclic group, etc.

[0333] As used herein, the term "heterocyclyl" encompasses fused structures, and the point of connection with other groups can be on any ring in the fused structure. Therefore, the heterocyclyl of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, In some embodiments, heterocyclyl also includes heteroaryl-fused heterocyclyl or cycloalkyl, and aryl-fused heterocyclyl, as long as the entire ring system is non-aromatic. In some embodiments, heterocyclyl includes 5-6 membered monocyclic heteroaryl-fused C 5-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl-fused 5-6 membered monocyclic heterocyclyl, and benzo-fused 5-6 membered monocyclic heterocyclyl, such as pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl, imidazotetrahydropyridinyl, indolyl or indolonyl.

[0334] The term "spiroheterocycloalkyl" refers to a cyclic group formed by sharing one carbon atom with two or more "heterocycloalkyl" as defined above as components, wherein the cyclic group has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or more (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S and N in the ring. One or more ring carbon atoms in the spiroheterocycloalkyl can be replaced by C (O). The S atom in the spiroheterocyclyl can be replaced by S (O) or S (O) 2. Preferably, the spiroheterocycloalkyl is 5-12 yuan, and more preferably 5-11 (e.g. 5-10 or 7-9) yuan. According to the number of shared spiro atoms, spiroheterocycloalkyl is divided into monospiroheterocycloalkyl, dispiroheterocycloalkyl, or polyspiroheterocycloalkyl, and preferably refers to monospiroheterocycloalkyl or dispiroheterocycloalkyl, and more preferably refers to 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocycloalkyl.

[0335] As used herein, the term "bridged heterocycloalkyl" refers to a cyclic group formed by two or more "heterocycloalkyl" as defined above as components, wherein any two of the components share two non-adjacent atoms, and wherein the cyclic group has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or more (e.g., 1, 2, 3 or 4) heteroatoms selected from O, S and N in the ring. One or more ring carbon atoms in the bridged heterocycloalkyl can be replaced by C (O). The S atom in the bridged heterocyclic group can be replaced by S (O) or S (O) 2. Preferably, the bridged heterocycloalkyl is 6 to 9 yuan, and more preferably 6-8 yuan. According to the number of member rings, the bridged heterocycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocycloalkyl, and more preferably a bicyclic or tricyclic bridged heterocycloalkyl.

[0336] As used herein, the term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, including a benzo 3- to 8-membered cycloalkyl group and a benzo 3- to 8-membered heterocyclyl group.

[0337] As used herein, the term "heteroaryl" or "heteroaryl ring" refers to a heteroaromatic system having 5 to 14 ring atoms, which has 1 to 4 heteroatoms independently selected from N, O and S. One or more ring carbon atoms in the heteroaryl group can be replaced by C (O). The heteroaryl group can be benzo-fused. The heteroaryl group is preferably 5 to 10 yuan. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl group, such as, but not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl. In some embodiments, the heteroaryl group is an 8-10 yuan or 9-10 bicyclic heteroaryl group, including a 5-yuan / 5-yuan, 5-yuan / 6-yuan or 6-yuan / 6-yuan bicyclic system. Examples include, but are not limited to, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, triazolopyridinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

[0338] Unless otherwise specified, as used herein, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.

[0339] As used herein, the term "fused ring" refers to a 5-20 membered all-carbon polycyclic group, wherein each ring in the ring system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. The carbon atoms in the fused rings may be optionally replaced by heteroatoms of O, S, or N, i.e., "fused heterocycles" are also included.

[0340] The term "fused heterocycle" of the present invention refers to a 5- to 20-membered polycyclic heterocyclic group, wherein each ring in the ring system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatom, the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group.

[0341] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0342] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0343] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0344] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0345] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0346] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0347] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0348] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0349] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0350] The compounds described in the present invention are named according to their chemical structural formulas. If the compound nomenclature and chemical structural formula for the same compound do not match, the chemical structural formula shall prevail.

[0351] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0352] The solvent used in the present invention is commercially available.

[0353] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. Beneficial effects

[0354] As novel STING inhibitors, the compounds of the present invention have potent inhibitory activity against STING and can be used to prevent and / or treat STING-mediated diseases or conditions. The compounds of the present invention exhibit superior properties, including improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), and reduced resistance to drug resistance. DETAILED DESCRIPTION

[0355] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0356] Intermediate int1: 3-bromo-5-chloro-1-(triisopropylsilyl)-1H-indole

[0357] Preparation method of int1: 5-chloro-1H-indole 1a (5.00 g, 0.033 mmol) was dissolved in tetrahydrofuran (50 mL) and sodium hydride (1.45 g, 0.036 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 h. Triisopropylsilyl chloride (7.66 g, 0.039 mmol) was then added at 0°C. The reaction solution was stirred at room temperature for 1 h. After the reaction was completed, it was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (PE:EA=5:1) to obtain 5-chloro-1-(triisopropylsilyl)-1H-indole 1b (9.8 g). Compound 5-chloro-1-(triisopropylsilyl)-1H-indole 1b (2.00 g, 6.50 mmol) was dissolved in tetrahydrofuran (20 mL), and N-bromosuccinimide (1.39 g, 7.82 mmol) was added at -30°C. The reaction solution was stirred at -30°C for 40 min. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (PE:EA=10:1) to obtain compound int 1 (1.2 g). LCMS (ESI) m / z: 388.1 [M+H] + .

[0358] Intermediate int2:

[0359] Int2 preparation method:

[0360] (1) Compound 1a (25.00 g, 164.92 mmol) was dissolved in N,N-dimethylformamide (250 mL), and trifluoroacetic anhydride (36.72 g, 174.82 mmol) was added dropwise at 0°C. After stirring at room temperature for 3 hours, the mixture was poured into 1000 mL of water, the precipitate was filtered, and heated under reflux in 1000 mL of 20% NaOH overnight. After the reaction solution was cooled to room temperature, it was extracted twice with dichloromethane. The aqueous layer was acidified with hydrochloric acid, filtered, and dried in vacuo to obtain compound 2a.

[0361] (2) Compound 2a (17.00 g, 86.91 mmol) was dissolved in tetrahydrofuran (170 mL), and triethylamine (26.38 g, 260.73 mmol) and diphenylphosphoryl azide (47.84 g, 173.82 mmol) were added at 0°C. The reaction mixture was stirred at room temperature overnight. After the reaction, most of the tetrahydrofuran was removed, and methanol was added to precipitate a solid. The solid was filtered and air-dried to obtain compound 2b.

[0362] (3) Compound 2b (17.00 g, 77.06 mmol) was dissolved in tert-butanol (170 mL), and the mixture was stirred at 80°C overnight under nitrogen. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography using a mixture of petroleum ether and ethyl acetate (4:1) to obtain compound 2c.

[0363] (4) Compound 2c (9.00 g, 33.74 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (4 M, 90 mL), and the reaction mixture was stirred at room temperature for 16 h. After the reaction, the mixture was concentrated under reduced pressure to obtain compound int2. LCMS (ESI) m / z: 167.0 [M+H] + .

[0364] Intermediate int3:

[0365] Int3 preparation method:

[0366] (1) 3a (17.6 g, 108.0 mmol) was dissolved in dichloromethane (200 mL), and N,N-diisopropylethylamine (53.4 mL, 323.3 mmol) and 3b (30 g, 129.3 mmol) were added sequentially at room temperature. The reaction solution was stirred at 40°C for 16 hours. After the reaction, the reaction solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 1:1) as the eluent to obtain product 3c (15.3 g).

[0367] (2) 3c (15.0 g, 61.18 mmol) was dissolved in a mixture of dichloromethane (200 mL) and methanol (20 ml), and then hydrazine hydrate (68%) (3.063 g, 122.37 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (200 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (50 ml) and concentrated hydrochloric acid (6 ml) were added after concentration under reduced pressure at room temperature. The reaction solution was acidic, and the reaction solution was decompressed and dried to obtain the product int3 (5.3 g). 1 H NMR(400MHz,DMSO)δ4.77–4.70(m,2H).

[0368] Intermediate int4: 1-(6-aminopyridin-3-yl)ethan-1-one

[0369] Preparation of Int4: To a 250 mL sealed bottle, add 1-(6-chloropyridin-3-yl)ethan-1-one 4a (10.0 g, 64.5 mmol) and concentrated aqueous ammonia (50 mL). The mixture was stirred at 130°C for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a 5:1 ratio of PE to EA to afford compound Int4 (7 g).

[0370] Intermediate int5:

[0371] Preparation of Int5: Compound 4a (1.3 g, 8.36 mmol), compound int2 (1.4 g, 8.36 mmol), and p-toluenesulfonic acid (1.45 g, 8.36 mmol) were dissolved in N,N-dimethylformamide (15 ml) in a 100 mL sealed bottle and reacted overnight at 120°C. After cooling, the reaction solution was diluted with saturated brine (20 mL) and water (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with (0-40% ethyl acetate / petroleum ether) to obtain compound int5 (400 mg). LCMS (ESI): m / z = 391.1 (M+H) + .

[0372] Intermediate int6:

[0373] Int6 preparation method:

[0374] (1) Compound 3b (3.24 g, 10.19 mmol), compound 6a (2 g, 9.26 mmol) and triphenylphosphine (5.34 g, 10.19 mmol) were dissolved in ultra-dry tetrahydrofuran (20 mL), and a solution of di-tert-butyl azodicarboxylate (4.69 g, 10.19 mmol) in tetrahydrofuran (10 mL) was then added dropwise at 0°C. The reaction mixture was stirred at 0°C for 4 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (0-20% ethyl acetate / petroleum ether) to obtain compound 6b (1 g). 1 H NMR(400MHz, DMSO_d6)δ7.88–7.85(m,2H),7.79–7.77-4.42(m,2H),4.79–4.78(m,1H),3.06–2.96(m,4H).

[0375] (2) Compound 6b (1 g, 3.95 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (0.4 mL, 7.9 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (20 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after the extraction. After drying, the mixture was concentrated under reduced pressure at room temperature to remove most of the dichloromethane, and ethanol (20 mL) and concentrated hydrochloric acid (2 ml) were added. The reaction solution was acidic and then dried under reduced pressure to obtain compound int6 (400 mg). 1 H NMR(400MHz, DMSO_d6)δ11.13(s,2H),4.76–4.75(m,1H),3.07–2.97(m,2H),2.85–2.73(m,2H).

[0376] Intermediate int7:

[0377] Int7 preparation method:

[0378] (1) Compound 7a (4.7 g, 34.6 mmol) and compound 3b (6.2 g, 38.0 mmol) were placed in a 250 mL three-necked flask and tetrahydrofuran (60 mL) was added. The atmosphere was replaced with nitrogen three times and triphenylphosphine (9.96 g, 38 mmol) was added at 0°C. A tetrahydrofuran solution (20 mL) of DBAD (8.76 g, 38 mmol) was then added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. After the reaction was complete, 100 mL of water was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to obtain compound 7b (3.7 g). 1 H NMR(400MHz, DMSO_d6)δ7.87(s,4H),4.43–4.42(m,1H),2.25–2.13(m,2H),1.99–1.87(m,6H).

[0379] (2) Compound 7b (3.7 g, 2.53 mmol) was placed in a 100 mL single-necked flask, and dichloromethane (20 mL) and methanol (2 mL) were added dropwise. Hydrazine hydrate (0.1 mL, 68% in water) was then added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the system was filtered on a sand core funnel, the solid was washed three times with 5% ammonia water (20 mL), the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, and most of the dichloromethane was removed by vacuum concentration. Ethanol (20 mL) was then added, and concentrated hydrochloric acid was added dropwise. The resulting mixture was concentrated to give compound int7 (2.0 g). 1H NMR (400 MHz, DMSO_d6) δ 10.94 (s, 3H), 4.29 (s, 1H), 1.99–1.83 (m, 8H).

[0380] Intermediate int8:

[0381] Int8 preparation method:

[0382] (1) Compound 8a (5 g, 24.92 mmol) was dissolved in tetrahydrofuran (50 ml) in a 250 mL three-necked flask. Ethylmagnesium bromide (8.8 ml, 29.91 mmol, 3 M / L) was slowly added dropwise at 0°C. The reaction mixture was kept at 0°C for 4 h. After the reaction, the reaction mixture was quenched with saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 4:1) as the eluent to obtain compound 8b (3 g).

[0383] (2) Compound 8b (150 mg, 0.887 mmol) and int2 (215 mg, 1.065 mmol) were added to a 50 mL sealed bottle and dissolved in acetic acid (3 ml). The mixture was reacted at 120°C for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain int8 (300 mg). LCMS (ESI): m / z = 300.1 (M+H) + .

[0384] Intermediate int9:

[0385] Int9 preparation method:

[0386] (1) Sodium hydride (1.96 g, 48.86 mmol) was dissolved in ultra-dry tetrahydrofuran (350 mL) in a 1 L three-necked reaction flask and cooled to 0°C in an ice-water bath under nitrogen protection. Raw material 9a (5.00 g, 48.86 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL) and the solution of raw material 1 was slowly added dropwise to the reaction flask using a syringe (20 minutes). After the addition was complete, the mixture was stirred at 0°C for 1 hour. Benzyl bromide (8.37 g, 48.96 mmol) was added dropwise to the reaction solution. After the addition was complete, tetrabutylammonium iodide (1.81 g, 4.90 mmol) was quickly added under nitrogen protection. The mixture was continued in an ice-water bath for 10 minutes and then stirred at room temperature for 12 hours. After the reaction was complete, the reaction was quenched with aqueous ammonium chloride (17 mL), and most of the tetrahydrofuran was concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL), washed once with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 9b (3.2 g).

[0387] (2) 9b (3.2 g, 17.11 mmol) was dissolved in dichloromethane (120 mL). Dess-Martin reagent (8.71 g, 20.54 mmol) was added under ice-water bath and stirred at 0°C for 2 hours. After the reaction was completed, the mixture was filtered and the filter cake was rinsed twice with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using (petroleum ether:ethyl acetate = 10:1) as eluent to obtain 9c (2.5 g).

[0388] (3) 9c (2.5 g, 13.14 mmol) was dissolved in ultra-dry 1,2-dichloroethane (12 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 5 mL, 27.12 mmol) was added. The mixture was stirred at 90°C overnight (16 hours) under nitrogen protection. After the reaction was completed, the cooled reaction solution was added dropwise to a sodium bicarbonate aqueous solution under stirring in an ice-water bath. After the addition was completed, the mixture was stirred at room temperature for 0.5 hours until no bubbles appeared. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate = 20:1) to obtain 9d (1.1 g).

[0389] (4) 9d (1.1 g, 5.18 mmol) was dissolved in methanol (36 mL), acetic acid (7.2 mL) and palladium carbon (1.1 g) were added, and the mixture was placed in an autoclave and replaced with hydrogen four times. The hydrogen pressure in the autoclave was adjusted to 50 psi and stirred at room temperature overnight (16 hours). After the reaction was completed, the filter cake was filtered and rinsed with methanol (10 mL). The mixture was distilled at 90°C under normal pressure to remove methanol (the top temperature dropped to 40°C). The remaining solution after cooling was diluted with anhydrous ether (50 mL), and sodium carbonate powder (11 g) was added with stirring. The mixture was stirred under nitrogen protection (without replacement) for 2 hours. The filter cake was filtered and rinsed with anhydrous ether (10 mL) three times. The anhydrous ether was distilled at 40°C under normal pressure to obtain crude product 9e.

[0390] (5) 3b (1.244 g, 7.63 mmol) was dissolved in ultra-dry toluene (42 mL) in a three-necked reaction flask. The reaction flask was moved to an ice-water bath and stirred under nitrogen replacement and protection. The crude product 9e (465 mg, 3.81 mmol) was dissolved in ultra-dry tetrahydrofuran (6 mL) and added dropwise to the reaction solution with a syringe. Triphenylphosphine (2.00 g, 7.63 mmol) was dissolved in ultra-dry tetrahydrofuran (8 mL) and added dropwise to the reaction solution with a syringe. Di-tert-butyl azodicarboxylate (DBAD, 1.755 g, 7.63 mmol) was dissolved in ultra-dry tetrahydrofuran (14 mL) and slowly added dropwise to the reaction solution with a syringe. After the addition was complete, the mixture was naturally warmed to room temperature and stirred overnight (12 hours). After the reaction was completed, water (40 mL) was added to quench the mixture, stirred for 20 minutes, and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane (40 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (petroleum ether:ethyl acetate=10:1) as the eluent to give 9f (515 mg).

[0391] (6) 9f (515 mg, 1.93 mmol) was dissolved in a mixed solvent of dichloromethane (4 mL) and anhydrous methanol (0.4 mL), cooled to 0°C in an ice-water bath under nitrogen protection, and hydrazine hydrate (98%, 197 mg, 3.86 mmol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was carried out for 2 hours. The reaction solution was filtered and the filter cake was washed twice with dichloromethane (5 mL). The aqueous phase was adjusted to pH 9-10 by adding ammonia water and extracted twice with dichloromethane (5 mL). The organic phase was concentrated under reduced pressure (temperature controlled at 20°C) to remove most of the dichloromethane. Dilute hydrochloric acid (1 mol / L, 15 mL) was added to the concentrate and stirred for 0.5 hours. The aqueous phase was separated and extracted twice with dichloromethane. The aqueous phase was lyophilized to obtain compound int9 (214 mg).

[0392] 1 H NMR(400MHz,DMSO_d6)δ11.09(br.s,3H),4.80(s,1H),2.48–2.01(m,6H).

[0393] Intermediate int10:

[0394] Int10 preparation method:

[0395] (1) 10a (5 g, 33 mmol) and silver nitrate (0.588 g, 35 mmol) were dissolved in acetonitrile (50 mL). The mixture was replaced with nitrogen three times and cooled to 0°C. Benzoyl chloride (0.487 g, 35 mmol) was slowly added dropwise to the mixture and stirred at room temperature for 0.5 h. After the reaction was completed, the reaction was quenched with aqueous solution (10 mL), ethyl acetate (30 mL) and water (30 mL) were added, stirred and allowed to stand for separation, the aqueous phase was extracted three times with ethyl acetate (15 mL), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product 10b (5.3 g) was used directly in the next step.

[0396] (2) Crude product 10b (5.3 g, 29.96 mmol) and tin dichloride (25.56 g, 134.8 mmol) were dissolved in aqueous hydrogen bromide (100 mL) and stirred at room temperature for 12 h. After the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude product 10c (5 g).

[0397] (3) 10c (5 g, 31.9 mmol) and 4a (7.8 g, 38.3 mmol) were dissolved in glacial acetic acid (100 mL). The mixture was stirred in an oil bath at 130°C for 2 h under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate = 10:1) to obtain int10 (5 g). LCMS (ESI): m / z = 286.1 (M+H) + .

[0398] Intermediate int11:

[0399] Int11 preparation method:

[0400] (1) 11a (3 g, 19.6 mmol) was dissolved in DMF (30 mL). TFAA (3 mL, 23.4 mmol) was slowly added dropwise at 0°C. The reaction temperature was maintained for 0.5 h, and then the mixture was returned to room temperature for 16 h. The mixture was concentrated in vacuo to dryness, and water (10 mL) was added and stirred at room temperature for 0.5 h. The mixture was filtered, and the resulting solid was added to 20% sodium hydroxide solution (30 mL) and heated under reflux for 8 h. After cooling to room temperature, the pH was adjusted to 3 with 3N hydrochloric acid, filtered, and washed with water to obtain 4.3 g of the product 11b.

[0401] (2) 11b (2.0 g, 10.1 mmol) and DPPA (5.6 g, 20.2 mmol) were dissolved in THF (20 mL). Triethylamine (3.0 g, 30.3 mmol) was added and stirred at room temperature for 16 h. After the reaction, the mixture was extracted with dichloromethane. The organic phases were combined to obtain the residue 11c (2.0 g), which was directly used for the next reaction.

[0402] (3) 11c (2.0 g) was dissolved in tert-butanol (20 mL) and stirred at 80°C for 16 h. After the reaction was complete, the mixture was extracted with dichloromethane, and the combined organic phases were purified by column chromatography using a mixture of petroleum ether and ethyl acetate (2:1) to afford 11d (600 mg).

[0403] (4) Dissolve 11d (600 mg) in dioxane hydrochloride solution (10 mL) and stir at room temperature for 2 h. After the reaction is complete, spin dry to obtain crude product 11e (615 mg).

[0404] (5) 11e (200 mg, 1.18 mmol) and 2-chloro-5-acetylpyridine (168 mg, 1.08 mmol) were dissolved in glacial acetic acid (2 mL) and stirred at 130°C for 4 h. After the reaction, the solvent was dried to obtain crude int11. LCMS (ESI) m / z: 288.1 [M+H] + .

[0405] Intermediate int12:

[0406] Int12 preparation method:

[0407] (1) 12a (10.0 g, 58.9 mmol) was dissolved in N,N-dimethylformamide (150 mL), and trifluoroacetic anhydride (14.86 g, 70.8 mmol) was added dropwise at ℃. After stirring at room temperature for 16 hours, the mixture was poured into 300 mL of water, the precipitate was filtered, and heated under reflux in 300 mL of 20% NaOH overnight. The reaction solution was cooled to room temperature, adjusted to pH = 3, and extracted twice with dichloromethane. The aqueous layer was acidified with hydrochloric acid, filtered, and dried in vacuo to obtain 12b (12.0 g).

[0408] (2) 12b (3.0 g, 14.08 mmol) was dissolved in tetrahydrofuran (50 mL), and triethylamine (4.28 g, 42.25 mmol) and diphenylphosphoryl azide (7.75 g, 28.17 mmol) were added at 0°C. The reaction mixture was stirred at room temperature overnight. After the reaction, the mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. Tert-butyl alcohol was added, and the mixture was concentrated under reduced pressure to remove the remaining tetrahydrofuran to obtain 12c (3 g).

[0409] (3) 12c (3 g, 12.61 mmol) was dissolved in tert-butanol (100 mL), and the mixture was stirred at 80°C overnight under nitrogen. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 12d (600 mg).

[0410] (4) 12d (500 mg, 1.76 mmol) was dissolved in TFA / DCM solution (2 / 8 mL), and the reaction mixture was stirred at room temperature for 2 h. After the reaction, the mixture was concentrated under reduced pressure to obtain 12e (600 mg).

[0411] (5) 12e (600 mg, 3.26 mmol), 4a (509 mg, 3.26 mmol), and p-toluenesulfonic acid (124 mg, 0.65 mmol) were dissolved in DMF (8 mL). The mixture was stirred at 120 °C for 2 h under nitrogen protection. After the reaction was completed, it was diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain int12 (200 mg). LCMS (ESI) m / z: 304.1 [M+H] + .

[0412] Intermediate int13:

[0413] Int13 preparation method:

[0414] (1) 13a (1.0 g, 6.57 mmol) was added portionwise to fuming HNO3 that had been cooled to 0°C. The reaction mixture was stirred at 0°C for 30 min. After the reaction, the mixture was added to ice water to quench the reaction. The product precipitated, washed with water, and air-dried. The resulting crude product 13b (1.2 g) was used directly in the next step.

[0415] (2) Crude product 13b (1.2 g, 6.09 mmol) was dissolved in acetic acid (12 mL). SnCl2.2H2O (6.6 g, 30.45 mmol) was then added to the reaction mixture. The mixture was heated to 85°C and allowed to react for 2 h. After the reaction was complete, the filtrate was filtered and concentrated under reduced pressure. The resulting crude product 13c (600 mg) was used directly in the next step.

[0416] (3) 13c (600 mg, 3.042 mmol), 4a (510 mg, 3.648 mmol), and DIEA (1.2 mL, 6.06 mmol) were dissolved in DMF (10 mL). The mixture was stirred in an oil bath at 60°C under nitrogen for 3 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative reaction to afford int13 (200 mg).

[0417] Intermediate int14:

[0418] Int14 preparation method:

[0419] (1) Compound 14a (1.0 g, 8.19 mmol, 1.0 eq) was dissolved in anhydrous ether (30 mL), and the reaction system was cooled to 0°C. LiAlH4 (466 mg, 12.3 mmol, 1.5 eq) was slowly added to the reaction solution. After the addition was complete, the reaction temperature was raised to room temperature and stirred for 18 h. After the reaction was complete, the mixture was cooled to 0°C, and 2M NaOH solution (1.0 mL) and water (1.0 mL) were added. The mixture was filtered and washed with ether (2 x 10 mL). The organic phase was dried and the resulting residue was extracted with dichloromethane and dried at 5-10°C to obtain compound 14b (0.9 g).

[0420] (2) 14b (0.8 g, 7.36 mmol, 1.2 eq), compound 3b (1.0 g, 6.13 mmol, 1.0 eq), and triphenylphosphine (1.8 g, 6.75 mmol, 1.1 eq) were dissolved in tetrahydrofuran (50 mL), and the reaction system was cooled to 0°C. DBAD (1.5 g, 6.75 mmol, 1.1 eq) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise to the reaction solution. After the addition was complete, the temperature was raised to room temperature and stirred for 6 h. After the reaction was complete, the resulting mixture was dried and extracted with ethyl acetate and water. The organic phases were combined, and the resulting residue was purified by column chromatography using a mixture of petroleum ether and ethyl acetate (3:1) as the eluent to obtain compound 14c (1.2 g).

[0421] (3) 14c (1.1 g, 4.34 mmol, 1 eq) was dissolved in (dichloromethane / methanol = 10 / 1) (10 mL), and 70% hydrazine hydrate (0.6 mL, 8.69 mmol, 2 eq) was gradually added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction, the mixture was filtered, and the filtrate was rinsed with aqueous ammonia. The mixture was extracted with dichloromethane and water. The organic phases were combined, rotary evaporated, and ethanol was added. Concentrated hydrochloric acid was added dropwise until the pH was <1, and solids precipitated. The mixture was filtered to obtain compound int14 (750 mg).

[0422] 1H NMR(400MHz, DMSO_d6)δ8.11(s,3H),4.31–4.14(m,1H),4.13–3.98(m,1H),2.24–2.12(m,1H),1.81–1.66(m,1H),1.56–1.47(m,1H).

[0423] Intermediate int15:

[0424] Int15 preparation method:

[0425] (1) Compound 15a (5 g, 35.32 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL), replaced with nitrogen three times, and stirred at -78°C for 20 min. Isopropylmagnesium bromide (2 M, 21 mL, 42.38 mmol) was slowly added dropwise to the solution. After the addition was complete, the temperature was maintained at -78°C and stirred for 2 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined and the resulting residue was purified by column chromatography, eluting with (petroleum ether:ethyl acetate = 2:1) to obtain compound 15b (2 g). LCMS (ESI) m / z: 186.0 [M+H] + .

[0426] (2) 15b (2 g, 10.77 mmol) was dissolved in dichloromethane (20.0 mL), replaced with nitrogen three times, and stirred at 0°C for 20 min. Dess-Martin reagent (5.5 g, 12.92 mmol) was slowly added dropwise to the solution. After the reaction was completed, the reaction solution was filtered, the mixture was extracted with water, and the organic phases were combined to obtain the residue, which was purified by column chromatography and eluted with (petroleum ether:ethyl acetate = 3:1) to obtain compound 15c (1.18 g). LCMS (ESI) m / z: 184.0 [M+H] + .

[0427] (3) 15c (1.18 g, 6.43 mmol) and int2 (1.3 g, 7.72 mmol) were dissolved in acetic acid (15.0 mL) and stirred at 130°C for 4 hours. After the reaction, the reaction solution was concentrated and purified by column chromatography using (petroleum ether:ethyl acetate = 4:1) to obtain compound int15 (1.12 g). LCMS (ESI) m / z: 314.1 [M+H] + .

[0428] Intermediate int16:

[0429] Int16 preparation method:

[0430] (1) Compound 16a (6 g, 58.7 mmol), compound 3b (10.5 g, 64.6 mmol), and triphenylphosphine (17 g, 64.6 mmol) were dissolved in ultra-dry tetrahydrofuran (500 mL), and di-tert-butyl azodicarboxylate (14.8 g, 64.6 mmol) was added at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 4 hours. After the reaction, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 2:1) as the eluent to obtain compound 16b (10.3 g, 70%).

[0431] (2) 16b (2 g, 8.1 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (810 mg, 16.2 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (100 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (20 ml) and concentrated hydrochloric acid (1 ml) were added after concentration under reduced pressure at room temperature. The reaction solution became acidic and was then dried under reduced pressure to obtain compound int16 (880 mg).

[0432] 1 H NMR (400MHz, CD3OD) δ4.27–4.24(m,1H),3.97–3.92(m,2H),3.52–3.46(m,2H),2.05–2.01(m,2H),1.70–1.61(m,2H).

[0433] Intermediate int17:

[0434] Int17 preparation method:

[0435] (1) Compound 17a (1.0 g, 10.745 mmol) was dissolved in dichloromethane / methanol (75 ml / 75 ml) and cooled to -78°C. Ozone was then introduced until the solution turned blue. Sodium borohydride (2.0 g, 50.05 mmol) was then added to the reaction solution, which was then warmed to room temperature and stirred for 24 h. After the reaction, the mixture was dried by rotary evaporation, and the product was dissolved in water (100 ml) and extracted with ethyl acetate. The organic phase was dried by rotary evaporation, and the resulting crude product 17b (600 mg) was used directly in the next step.

[0436] (2) The crude product 17b (600 mg, 6.185 mmol) was dissolved in THF (10 ml), and PPh3 (1.8 g, 6.80 mmol) was added to the reaction solution. The temperature was lowered to 0°C, and DBAD (1.6 g, 6.8 mmol) was dissolved in THF. 3b was added and added dropwise to the reaction solution. The reaction was stirred at room temperature for 6 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The organic phases were combined and the resulting residue was purified by column chromatography using a mixture of petroleum ether and ethyl acetate (3:1) as the eluent to obtain compound 17c (600 mg).

[0437] (3) 17c (600 mg, 2.479 mmol, 1 eq) was dissolved in (dichloromethane / methanol = 10 / 1) (10 mL), and 70% hydrazine hydrate (0.3 mL, 4.958 mmol, 2 eq) was gradually added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction, the mixture was filtered, and the filtrate was rinsed with aqueous ammonia. The mixture was extracted with dichloromethane and water. The organic phases were combined, rotary evaporated, and ethanol was added. Concentrated hydrochloric acid was added dropwise until the pH was <1, and solids precipitated. The mixture was filtered to obtain compound int17 (200 mg).

[0438] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,3H),4.79–4.76(m,1H),2.96–2.91(m,1H),2.41–2.32(m,2H),2.30–2.20(m,2H).

[0439] Intermediate int18:

[0440] Int18 preparation method:

[0441] (1) Compound 18a (5 g, 69.34 mmol) and triphenylphosphine (13 g, 79.69 mmol) were dissolved in ultra-dry tetrahydrofuran (50 mL), replaced with nitrogen three times, and 3b was added. The mixture was stirred at 0°C for 20 min. Di-tert-butyl azodicarboxylate (18.4 g, 79.89 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL) and slowly added dropwise to the solution. After the addition was complete, the reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phases were combined to obtain a residue which was purified by column chromatography using (petroleum ether:ethyl acetate = 2:1) as the eluent to obtain compound 18b (9 g).

[0442] (2) 18b (9 g, 41.43 mmol) was dissolved in a mixed solution of dichloromethane (90.0 mL) and methanol (10.0 mL), and the atmosphere was replaced with nitrogen three times. Hydrazine hydrate was slowly added dropwise to the solution at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phases were combined and concentrated. Hydrochloric acid (6 M) was added to the concentrate, and the aqueous phase was washed with dichloromethane and then lyophilized to obtain compound int18 (2 g).

[0443] 1 H NMR(400MHz,DMSO_d6)δ8.58(s,2H),5.75(d,J=4.0Hz,1H),2.08–2.01(m,1H) ,1.88–1.83(m,1H),1.68–1.53(m,1H),1.52–1.42(m,1H),1.23–0.99(m,2H).

[0444] Intermediate int19:

[0445] Int19 preparation method:

[0446] (1) Compound 3b (1.64 g, 10.08 mmol), compound 19a (1.00 g, 10.08 mmol), and triphenylphosphine (2.64 g, 10.08 mmol) were dissolved in ultra-dry tetrahydrofuran (20 mL), and diisopropyl azodicarboxylate (2.04 g, 10.02 mmol) was then added dropwise at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 16 hours. After the reaction, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 4:1) as the eluent to obtain compound 19b (2.2 g).

[0447] (2) 19b (2.2 g, 8.65 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (866 mg, 17.30 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (20 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. After concentrating under reduced pressure at room temperature, ethanol (20 ml) and concentrated hydrochloric acid (2 ml) were added. The reaction solution became acidic and was then dried under reduced pressure to obtain compound int19 (150 mg).

[0448] 1 H NMR (400MHz, DMSO_d6) δ8.93 (d, J = 4.0Hz, 2H), 8.01 (d, J = 4.0Hz, 2H), 5.42 (s, 2H).

[0449] Intermediate int20:

[0450] Int20 preparation method:

[0451] (1) Compound 3b (7.35 g, 45.05 mmol), compound 20a (5.00 g, 40.95 mmol) and triphenylphosphine (11.82 g, 45.05 mmol) were dissolved in ultra-dry tetrahydrofuran (80 mL), and a tetrahydrofuran solution of di-tert-butyl azodicarboxylate (10.4 g, 45.05 mmol) was added dropwise at 0°C. The reaction solution was allowed to warm to room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain compound 20b (22 g).

[0452] (2) 20b (11.00 g, 41.20 mmol) was dissolved in a mixture of dichloromethane (50 mL) and methanol (5 mL), and then hydrazine hydrate (68%) (4.10 g, 82.40 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (20 mL). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after the extraction. After drying, the mixture was concentrated under reduced pressure at room temperature, and ethanol (10 mL) and concentrated hydrochloric acid (2 mL) were added. The reaction solution was acidic and then dried under reduced pressure to obtain compound int20 (4.00 g).

[0453] 1 H NMR (400MHz, DMSO_d6) δ11.18 (s, 3H), 4.10 (d, J = 8.0Hz, 1H), 2.71–2.67 (m, 2H), 2.52–2.40 (m, 3H).

[0454] Intermediate int21:

[0455] Int21 preparation method:

[0456] (1) Compound 21a (2.0 g, 11.656 mmol), dimethylhydroxylamine hydrochloride (2.274 g, 23.31 mmol), and HATU (5.32 g, 13.99 mmol) were dissolved in dichloromethane (50.0 mL). DIEA (6.0 mL, 46.625 mmol) was added dropwise at room temperature under nitrogen protection. After the addition was complete, the mixture was stirred at room temperature for 18 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate = 4:1) to obtain compound 21b (1.576 g). LCMS (ESI) m / z: 215.0 [M+H] + .

[0457] (2) 21b (1.5 g, 8.157 mmol) was dissolved in tetrahydrofuran (15 mL), the reaction system was cooled to 0°C, and methylmagnesium bromide (3.0 M in THF) (5.44 mL, 16.31 mmol) was slowly added dropwise under nitrogen. After the addition was complete, the reaction temperature was raised to room temperature and stirring was continued for 3 h. After the reaction was completed, saturated ammonium chloride solution was added dropwise to quench the reaction. The mixture was extracted with dichloromethane (15 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 21c (671 mg), which was used directly in the next reaction. LCMS (ESI) m / z: 170.0 [M+H] + .

[0458] (3) 21c (200 mg, 1.07 mmol) and int2 (258 mg, 1.28 mmol) were dissolved in acetic acid (2 mL) and reacted in an oil bath at 120°C under nitrogen for 2 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove most of the acetic acid. The mixture was diluted with water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate (2:1) as the eluent to obtain compound int21 (196 mg). 1H NMR(400MHz,DMSO_d6)δ11.02(s,1H),9.28(s,1H),8.00(d,J=8.0Hz,2H),7.77(s,1H) ,7.39(d,J=12.0Hz,1H),7.11(d,J=8.0Hz,1H),6.66(s,1H),2.64(s,3H),2.45(s,3H).

[0459] Intermediate int22:

[0460] Int22 preparation method:

[0461] (1) 22a (1 g, 5.25 mmol) was dissolved in methanol (15 ml), and sodium borohydride (298 mg, 7.88 mmol) was added portionwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction, ethyl acetate and saturated brine were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (PE:EA = 4:1) to obtain 22b (1 g).

[0462] (2) 22b (800 mg, 4.166 mmol), 3b (747 mg, 4.583 mmol) and triphenylphosphine (1.2 g, 4.583 mmol) were dissolved in ultra-dry tetrahydrofuran (20 mL), and then a tetrahydrofuran solution (20 mL) of di-tert-butyl azodicarboxylate (1 g, 4.583 mmol) was added at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 22c (1 g).

[0463] (3) 22c (500 mg, 1.483 mmol) and 10% palladium on carbon (500 mg) were dissolved in methanol (5 ml), and acetic acid (0.5 ml) was added at room temperature. The reaction solution was stirred at room temperature under hydrogen protection for 3 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated under pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 4:1) as the eluent to obtain compound 22d (165 mg).

[0464] (4) 22d (800 mg, 3.235 mmol) was dissolved in dichloromethane (10 ml), and diethylaminosulfur trifluoride (625 mg, 3.882 mmol) was added at 0°C. The mixture was reacted at 0°C for 3 h. Water was slowly added dropwise to the reaction solution to quench the mixture. The mixture was extracted with dichloromethane (10 ml x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 4:1) as the eluent to give 22e (250 mg).

[0465] (5) 22e (250 mg, 1.00 mmol) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 mL), and then hydrazine hydrate (68%) (100 mg, 2.01 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and 5N ammonia water (10 mL) was added to the filtrate. The aqueous phase was extracted with dichloromethane (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at room temperature. Ethanol (5 mL) and concentrated hydrochloric acid (0.5 mL) were added. The reaction mixture became acidic and was then dried under reduced pressure to obtain compound int22 (140 mg). 1H NMR (400MHz, DMSO_d6) δ11.16(s,2H),4.75–4.70(m,1H),4.43(dd,J=8.0,4.0Hz,2H),2.66–2.53(m,1H),2.30–2.21(m,2H),2.19–2.12(m,2H).

[0466] Intermediate int23:

[0467] Int23 preparation method:

[0468] (1) 23a (10.0 g, 71.357 mmol) and 23b (21.758 g, 142.714 mmol) and sodium bicarbonate (11.989 g, 142.714 mmol) were dissolved in DMF (100.0 mL) and stirred at 100°C for 16 h under nitrogen. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (petroleum ether:ethyl acetate = 2:1) as the eluent to obtain 23c (4.52 g).

[0469] (2) 23c (1.0 g, 5.53 mmol) was dissolved in tetrahydrofuran (10 mL), and the reaction system was cooled to 0°C. LiAlH4 (1.0 M in THF, 7.7 mL, 7.7 mmol) was slowly added dropwise under nitrogen. After the addition was complete, the reaction was stirred at 0°C for 1 h. After the reaction was completed, saturated potassium sodium tartrate solution was added to quench the reaction and stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography using (petroleum ether:ethyl acetate = 1:0) to (petroleum ether:ethyl acetate = 0:1) as the eluent to obtain 23d (653 mg).

[0470] (3) 23d (1.2 g, 8.102 mmol), 3b (1.586 g, 9.723 mmol), and triphenylphosphine (3.187 g, 12.153 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction system was cooled to 0°C, and DIAD (2.1 mL, 12.153 mmol) was slowly added dropwise under nitrogen. The reaction was allowed to react at room temperature for 1 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography using (petroleum ether:ethyl acetate = 2:1) as the eluent to obtain 23e (1.4 g).

[0471] (4) 23e (220 mg, 0.750 mmol) was dissolved in a mixed solvent (DCM:MeOH = 10:1) (2 ml). After nitrogen was replaced three times, hydrazine hydrate (75 mg, 1.5 mmol) was added dropwise at room temperature and allowed to react for 2 h. After the reaction, the reaction solution was filtered and diluted with water (5 mL) and concentrated aqueous ammonia (1 mL). The mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to remove most of the solvent. Water and dichloromethane were added again, and concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was extracted twice with dichloromethane. The aqueous phase was lyophilized to obtain compound int23 (41 mg). 1 H NMR (400MHz, DMSO_d6) δ11.14(s,3H),8.43(s,1H),7.90(s,1H)7.86(t,J=60.0Hz,1H),5.04(s,2H).

[0472] Intermediate int24:

[0473] Int24 preparation method:

[0474] (1) The starting material 24a (10 g, 51.55 mmol) was dissolved in toluene (160 mL). Tetrakis(triphenylphosphine)palladium (5.96 g, 5.16 mmol) and compound 24b (22.34 g, 61.86 mmol) were added. The mixture was heated to 100°C in an oil bath under nitrogen and stirred for 4 hours. After the reaction was complete (TLC: PE / EA = 4 / 1), the resulting reaction solution, the crude compound 24c, was used directly in the next step.

[0475] (2) To the reaction flask of the mixed solution of compound 24c (180 mL, 51.55 mmol) was added aqueous hydrochloric acid solution (4 mol / L, 180 mL, 720 mmol), the temperature was raised to 60°C, and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the organic phase was separated, and the aqueous phase was extracted once with ethyl acetate (100 mL). The organic phases were combined and washed with saturated potassium fluoride aqueous solution (20 mL). After filtering to remove the tin reagent, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate = 9:1) to obtain compound 24d (2.8 g).

[0476] (3) Compound 24d (2.0 g, 12.73 mmol) and int2 (2.6 g, 12.73 mmol) were dissolved in N,N-dimethylformamide (40 mL), and N,N-diisopropylethylamine (4.9 g, 38.19 mmol) was added. The mixture was replaced with nitrogen three times, and the oil bath was heated to 60°C and stirred for 1 hour. After the reaction was completed (6-LCMS), the mixture was cooled to room temperature and diluted with water (160 mL) while stirring. The solid precipitated and was filtered. The filter cake was washed with water (40 mL). The filter cake was evaporated to dryness under reduced pressure to obtain int24 (3.1 g). LCMS (ESI) m / z: 304.0 [M+H] + .

[0477] Intermediate int25:

[0478] Int25 preparation method:

[0479] (1) Compound 25a (5.0 g, 24.22 mmol), compound 25b (17.50 g, 48.44 mmol), and Pd(PPh3)4 (280 mg, 0.24 mmol) were dissolved in anhydrous toluene (100 mL). The mixture was stirred at 110°C for 16 h. After the reaction, the solvent was evaporated to give 7.4 g of crude product 25c, which was used directly in the next reaction.

[0480] (2) 25c (crude product 7.4 g) was dissolved in dilute hydrochloric acid (2.0 M, 100 mL) and stirred at 60°C for 2 h. After the reaction was complete, the solvent was evaporated. Saturated NaHCO3 solution was added to the reaction solution until the pH was 7-8. The mixture was extracted with dichloromethane. The organic phases were combined and the resulting residue was purified by column chromatography using a mixture of petroleum ether and ethyl acetate (9:1) to give 25d (2.7 g).

[0481] (3) 25d (500 mg, 2.95 mmol) and int2 (716 mg, 3.54 mmol) were dissolved in glacial acetic acid (15 mL) and stirred at 130°C for 4 h. After the reaction, the solvent was dried and the resulting residue was purified by column chromatography using (DCM:MeOH = 30:1) as the eluent to obtain int25 (350 mg). LCMS (ESI) m / z: 300.1 [M+H] + .

[0482] Intermediate int26:

[0483] Int26 preparation method:

[0484] (1) Compound 26a (5.0 g, 31.45 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (4.6 g, 47.17 mmol, 1.5 eq), HATU (13.2 g, 34.60 mmol, 1.1 eq), and DIEA (12.2 g, 94.34 mmol, 3.0 eq) were dissolved in dichloromethane (200 mL). After the addition was complete, the reaction solution was stirred at room temperature for 16 h. After the reaction was complete, the solvent in the reaction solution was evaporated, and the resulting residue was purified by column chromatography using a mixture of petroleum ether and ethyl acetate (1:1) as the eluent to obtain 26b (4.1 g).

[0485] (2) Compound 26b (4.0 g, 19.78 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (40 mL), and the reaction system was cooled to 0°C. MeMgBr (3.0 M in THF) (6.6 mL, 19.78 mmol, 1.0 eq) was slowly added dropwise to the reaction solution, and the mixture was stirred at 0°C for 2 h. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution under ice bath conditions, and ethyl acetate and water were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography and eluted with (petroleum ether:ethyl acetate = 5:1) to obtain compound 26c (2.5 g).

[0486] (3) 26c (500 mg, 3.18 mmol, 1 eq), int2 (1.0 g, 4.78 mmol, 1.5 eq), and DIEA (823 mg, 9.55 mmol, 3.0 eq) were dissolved in DMSO (20 mL), and the reaction mixture was stirred at 60°C for 30 min. After the reaction, ethyl acetate and water were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE / EA = 4 / 1) to obtain compound int25 (770 mg). LCMS (ESI) m / z: 304.1 [M+H] + .

[0487] Intermediate int44:

[0488] Int44 preparation method:

[0489] Raw material 44a (28.2 g, 256 mmol) was dissolved in acetonitrile (130 mL) and water (130 mL), and chromium trichloride (13.6 g, 51.2 mmol) was added, followed by stirring at 80°C for 24 hours. After the reaction was complete, most of the acetonitrile was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (200 mL), washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using (petroleum ether:ethyl acetate = 3:1) as the eluent to obtain compound 44b (8 g). Compound 44b (8 g, 62.5 mmol) was dissolved in dichloromethane (80 mL), pyridine (14.8 g, 187 mmol) was added, and benzoyl chloride (17.56 g, 125 mmol) was added under an ice-water bath. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction is completed, water is added to quench the mixture, the aqueous phase is extracted twice with dichloromethane (100 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate = 5:1) to obtain 44c (11 g). Compound 44c (11 g, 47.4 mmol) is dissolved in ultra-dry 1,2-dichloroethane (60 mL), bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 30 mL) is added, and the mixture is stirred at 50°C under nitrogen protection overnight (16 hours). After the reaction is completed, the reaction solution is added dropwise to a sodium bicarbonate aqueous solution while stirring in an ice-water bath. After the addition is complete, the mixture is stirred at room temperature for 0.5 hours until no bubbles appear. The organic phase is separated, the aqueous phase is extracted twice with dichloromethane (80 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 15:1) to give compound 44d (7.8 g). 44d (7.8 g, 30.7 mmol) was dissolved in methanol (80 mL) and water (20 mL), LiOH (13 g, 309.5 mmol) was added, and the mixture was stirred at room temperature overnight (16 hours). After the reaction was completed, water and a large amount of dichloromethane were added to extract the organic phases, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product 44e (4 g). 3b (4.78 g, 29.3 mmol) was dissolved in ultra-dry tetrahydrofuran (120 mL) in a three-necked reaction flask, nitrogen purged three times, and the reaction flask was moved to an ice-water bath and stirred. The crude product 44e (4 g, 26.6 mmol) was dissolved in ultra-dry tetrahydrofuran (20 mL) and added dropwise to the reaction solution. Then, triphenylphosphine (7.71 g, 29.3 mmol) and di-tert-butyl azodicarboxylate (DBAD, 6.75 g, 29.3 mmol) in ultra-dry tetrahydrofuran (14 mL) were added dropwise. After the addition was complete, the reaction solution was naturally warmed to room temperature and stirred overnight (12 hours). After the reaction was completed, water (100 mL) was added to quench the reaction and stirred for 20 minutes. The organic phase was separated and the aqueous phase was extracted three times with dichloromethane (200 mL). The combined organic phases were dried, filtered, and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 5:1) to obtain compound 44f (2.1 g). 44f (450 mg, 1.53 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and anhydrous methanol (1 mL). The mixture was cooled to 0°C in an ice-water bath under nitrogen protection. Hydrazine hydrate (98%, 153 mg, 3.05 mmol) was added dropwise. After the addition was complete, the mixture was naturally warmed to room temperature and reacted for 2 hours. The reaction solution was filtered, and the filter cake was washed twice with dichloromethane (5 mL). Dilute hydrochloric acid (1 mol / L, 15 mL) was added to the filtrate and stirred for 0.5 hours. The aqueous phase was separated and lyophilized to obtain compound int44 (280 mg, 63.97%). 1 H NMR(400MHz,DMSO_d6)δ10.91(br.s,2H),4.33–4.27(m,1H),2.62–2.54(m,1H ),2.45–2.30(m,1H),2.13–1.91(m,3H),1.77–1.68(m,2H),1.57–1.48(m,3H).

[0490] Intermediate int27

[0491] Int27 preparation method:

[0492] (1) Compound 27a (6 g, 19.4 mmol), Zn(CN)2 (2.73 g, 23.2 mmol) and t-Buxphos Pd G3 (307 mg, 0.39 mmol) were dissolved in THF (50 mL) and water (10 mL). The mixture was stirred at 70°C for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and then added with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed twice with water, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain compound 27b (2.5 g, yield: 50.1%). LCMS (ESI) m / z: 258.2 [M+H] + .

[0493] (2) Compound 27b (2.5 g, 9.69 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (4 M, 30 mL), and the reaction mixture was stirred at room temperature for 16 h. After the reaction, the mixture was concentrated under reduced pressure to obtain compound 27c (1.5 g). LCMS (ESI) m / z: 158.2 [M+H] + .

[0494] (3) Compound 27c (1 g, 5.2 mmol), 1-(6-chloropyridin-3-yl)ethane-1-one (800 mg, 5.2 mmol), and p-toluenesulfonic acid (200 mg, 1.04 mmol) were dissolved in DMF (8 mL). The mixture was stirred at 60°C for 2 h under nitrogen protection. After the reaction, water (15 mL) and ethyl acetate (15 mL) were added to dilute the mixture. The mixture was extracted with ethyl acetate (15 mL x 3) three times. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain int27 (250 mg). LCMS (ESI) m / z: 277.2 [M+H] + .

[0495] Intermediate int28

[0496] Int28 preparation method:

[0497] (1) Compound 28a (1.0 g, 6.66 mmol) was dissolved in tetrahydrofuran (10.0 mL), and compound 3b (1.30 g, 7.99 mmol) and triphenylphosphine (2.62 g, 9.99 mmol) were added. The reaction mixture was purged with nitrogen three times, and the temperature of the reaction system was lowered to 0°C. Diisopropyl azodicarboxylate (2.0 mL, 9.99 mmol) was added dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 6 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate (10.0 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography using (petroleum ether:ethyl acetate = 4:1) as the eluent to obtain compound 28b (1.127 g).

[0498] (2) 28b (1.0 g, 3.816 mmol) was dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (10 ml). After nitrogen replacement three times, hydrazine hydrate (382 mg, 7.633 mmol) was added dropwise at room temperature. The reaction solution was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, and concentrated ammonia (1 ml) and water (10 ml) were added to the filtrate. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. Water (20 ml) was added to the filtrate, and concentrated hydrochloric acid was added to adjust the pH to acidic. The aqueous phase was extracted with dichloromethane and freeze-dried to obtain int28 (1.0 g). 1 H NMR (400MHz, DMSO_d6) δ3.93 (d, J = 6.4Hz, 2H), 2.02–2.00 (m, 2H), 1.88–1.73 (m, 4H), 1.27–1.18 (m, 2H).

[0499] Intermediate int29

[0500] Int29 preparation method:

[0501] (1) Compound 29a (15.0 g, 98.50 mmol) was dissolved in ultra-dry dichloromethane (380 mL), and then m-CPBA (51.0 g, 295.50 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 16 hours. After the reaction, the reaction solution was washed with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (DCM:MeOH=10:1) as the eluent to obtain compound 29b (9.0 g, yield: 54.3%). LCMS (ESI) m / z: 169.1 [M+H] + .

[0502] (2) 29b (8.0 g, 47.46 mmol) was dissolved in acetic anhydride (100 mL), and the reaction mixture was stirred at 150°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using (PE:EA = 10:1) as the eluent to afford 29c (5.8 g, yield: 48.3%). LCMS (ESI) m / z: 253.1 [M+H] + .

[0503] (3) 29c (5.8 g, 22.96 mmol) and potassium carbonate (9.5 g, 68.88 mmol) were dissolved in methanol (100 mL) and water (20 mL), and the reaction mixture was stirred at 80°C for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using (DCM:MeOH = 15:1) as the eluent to obtain 29d (2.4 g, yield: 62.1%). LCMS (ESI) m / z: 169.1 [M+H] + .

[0504] (4) 29d (1.0 g, 5.93 mmol) was dissolved in ultra-dry tetrahydrofuran (100 mL), and trimethylsilyldiazomethane (4.5 mL, 8.90 mmol) was added. The mixture was stirred at 50°C overnight under nitrogen protection. After monitoring for incomplete reaction, trimethylsilyldiazomethane (4.5 mL, 8.90 mmol) was added twice, and the mixture was stirred at 50°C under nitrogen protection for another 2 days. After the reaction was completed, the reaction solution was diluted with saturated brine and extracted three times with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain 29e (570 mg, yield: 52.8%). LCMS (ESI) m / z: 183.1 [M+H]+ .

[0505] (5) 29e (470 mg, 2.57 mmol) was dissolved in ultra-dry DMF (5 mL), and TFAA (0.4 mL, 2.72 mmol) was added at 0°C. The mixture was stirred at room temperature under nitrogen for 16 h. After the reaction was completed, the reaction solution was quenched with water to precipitate a brown solid, which was filtered to obtain 29f (1.7 g, crude product).

[0506] (6) 29f (1.7 g, crude) was dissolved in 20% NaOH (10 mL). The mixture was stirred at 100°C for 16 hours under nitrogen. After the reaction, concentrated hydrochloric acid was added to adjust the pH to 3. A brown solid precipitated, which was filtered and dried under vacuum to obtain 29g (380 mg). LCMS (ESI) m / z: 225.0 [MH] + .

[0507] (7) 29g (380mg, 1.68mmol) was dissolved in ultra-dry tetrahydrofuran (5mL), and DPPA (0.7mL, 3.36mmol) and triethylamine (0.7mL, 5.04mmol) were added. The mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, methanol was added, and a brown solid was precipitated. The residue obtained after filtration and spin drying was 29h (420mg, crude product). LCMS (ESI) m / z: 249.9 [MH] + .

[0508] 29h (420 mg, crude) was dissolved in tert-butanol (5 mL). The mixture was stirred at 80°C under nitrogen for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using a PE:EA (4:1) eluent to afford 29i (190 mg). LCMS (ESI) m / z: 298.1 [M+H] + , 1 H NMR (400MHz, DMSO_d6) δ11.26(s,1H),9.28(s,1H),8.27(s,1H),7.26(s,1H),3.93(s,3H),1.48(s,9H).

[0509] (8) 29i (190 mg, 0.64 mmol) was dissolved in 4 M dioxane hydrochloride (4 mL). The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the residue was dried to obtain int29 (150 mg). LCMS (ESI) m / z: 198.1 [M+H] + .

[0510] Intermediate int30

[0511] Int30 preparation method:

[0512] (1) 30a (1.0 g, 4.80 mmol), DMAP (59 mg, 0.48 mmol) and TEA (1.3 mL, 9.60 mmol) were dissolved in ultra-dry DMF (10 mL), and then (Boc)2O (3.1 g, 14.40 mmol) was added at 0°C. The reaction solution was naturally warmed to room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 10:1) as the eluent to obtain 30b (1.6 g). LCMS (ESI): m / z = 471.0 [M+64] +

[0513] (2) 30b (1.6 g, 3.92 mmol), 30c (1.7 g, 4.70 mmol), and Pd(PPh3)4 (453 mg, 0.39 mmol) were dissolved in ultra-dry toluene (16 mL) and stirred at 80°C under nitrogen for 16 h. After the reaction, 30d was obtained and used directly in the next reaction.

[0514] (3) 4M HCl (20.0 mL) was added to the reaction solution obtained in the previous step and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 4:1) as the eluent to obtain 30e (1.2 g). LCMS (ESI): m / z = 435.1 [M+64] +

[0515] (4) 30e (1.0 g, 2.69 mmol) was dissolved in 2M HCl / EA (15.0 mL) and stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to give 30f (500 mg). LCMS (ESI): m / z = 172.1 [M+1] +

[0516] (5) 30f (500 mg, 2.91 mmol) and 30g (1.7 g, 8.73 mmol) were dissolved in ethanol (12 mL), and a 48% aqueous hydrobromic acid solution (1.3 mL) was added. The mixture was stirred at 80°C under nitrogen for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to give 30h (500 mg, crude product). LCMS (ESI): m / z = 178.1 [M+1] +

[0517] (6) 30h (500 mg, crude) was dissolved in phosphorus oxychloride (10 mL). The mixture was stirred at 120°C for 16 hours under nitrogen. After the reaction was completed, it was concentrated under reduced pressure. The concentrate was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound int30 (200 mg). LCMS (ESI): m / z = 196.0 [M+1] +

[0518] Intermediate int31

[0519] Preparation method of Int31

[0520] (1) Compound 31a (1 g, 9.1 mmol), compound 3b (1.8 g, 11 mmol), and triphenylphosphine (2.6 g, 10 mmol) were dissolved in ultra-dry tetrahydrofuran (10 mL), and di-tert-butyl azodicarboxylate (2.3 g, 10 mmol) was added at 0°C. The reaction solution was naturally warmed to room temperature and stirred for 4 hours. After the reaction, the reaction solution was diluted with saturated brine, extracted three times with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (PE:EA = 1:1) to obtain mixture 31b (2 g). 1 H NMR(400MHz, DMSO_d6)δ8.52(dd,J=4.0,1.2Hz,1H),7.90–7.88(m,1H),7.86(s,4H),7.70(d,J=8.0Hz,1H),7.41-7.38(m,1H),5.24(s,2H).

[0521] (2) Compound 31b (1 g, 3.9 mmol) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 ml), and then hydrazine hydrate (68%) (394 mg, 7.9 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (50 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at room temperature. Ethanol (10 ml) and concentrated hydrochloric acid (1 ml) were added. The reaction solution became acidic, and purified water (100 ml) was added again. The solution was extracted twice with dichloromethane (50 ml). The aqueous phase was lyophilized to obtain compound int31 (350 mg). 1 H NMR (400MHz, DMSO_d6) δ8.78(d,J=4.0Hz,1H),8.28(t,J=8.0Hz,1H),7.84(d,J=8.0Hz,1H),7.78–7.75(m,1H),5.37(s,2H).

[0522] Intermediate int32

[0523] Preparation method of Int32

[0524] (1) Compound 32a (5 g, 49.4 mmol), compound 32b (10.6 g, 49.4 mmol), and cesium carbonate (32 g, 98.9 mmol) were dissolved in ultra-dry acetonitrile (50 mL). The reaction mixture was stirred at 90°C for 4 hours. After the reaction was completed, the reaction mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was added with water and extracted with dichloromethane three times (50 mL x 3). The organic phase was concentrated under reduced pressure to obtain compound 32c (4 g).

[0525] (2) 32c (4 g, 24.2 mmol), 3b (4.35 g, 26.6 mmol), and triphenylphosphine (7 g, 26.6 mmol) were dissolved in ultra-dry tetrahydrofuran (40 mL), and di-tert-butyl azodicarboxylate (6.1 g, 26.6 mmol) was added at 0°C. The reaction mixture was stirred at 0°C until it reached room temperature for 4 hours. After the reaction, the reaction mixture was diluted with water (100 mL) and extracted three times with dichloromethane (100 mL x 3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using (PE:EA = 1:1) as the eluent to obtain the mixture 32d (2.5 g). 1H NMR(400MHz,DMSO_d6)δ7.87–7.84(m,4H),6.28–5.95(m,1H),4.35–4.16(m,1H ),2.93–2.64(m,4H),2.38–2.36(m,2H),1.98–1.88(m,2H),1.75–1.64(m,2H).

[0526] (3) 32d (2 g, 3.9 mmol) was dissolved in a mixture of dichloromethane (20 mL) and methanol (2 ml), and then hydrazine hydrate (68%) (618 mg, 12.33 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (50 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (10 ml) and concentrated hydrochloric acid (1 ml) were added after concentration under reduced pressure at room temperature. The reaction solution became acidic and was extracted again with purified water (100 ml) and dichloromethane (100 ml) twice. The aqueous phase was freeze-dried to obtain int32 (300 mg).

[0527] Intermediate int33

[0528] Preparation method of Int33

[0529] (1) Compound 33a (2.3 g, 22.66 mmol), 33b (4 g, 20.6 mmol) and cesium carbonate (13.4 g, 41.2 mmol) were dissolved in ultra-dry acetonitrile (30 mL). The reaction mixture was stirred at 90°C until it reached room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was added with water and extracted with dichloromethane three times (50 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 33c (800 mg).

[0530] (2) 33c (500 mg, 3.44 mmol), 3b (618 mg, 3.79 mmol) and triphenylphosphine (994 mg, 3.79 mmol) were dissolved in ultra-dry tetrahydrofuran (5 mL), and then di-tert-butyl azodicarboxylate (873 mg, 3.79 mmol) was added at 0°C. The reaction solution was stirred at 0°C until it reached room temperature for 4 hours. The reaction was completed by dotting the plate. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with dichloromethane. After adding water to the filtrate, it was extracted with dichloromethane three times (50 mL x 3) and dried over anhydrous sodium sulfate to obtain crude product 33d (2 g).

[0531] (3) The crude product 33d (2 g) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 ml), and then hydrazine hydrate (68%) (375 mg, 6.16 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered and the filtrate was rinsed with 5N ammonia water (50 ml). The aqueous phase was extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate after extraction. After drying, ethanol (10 ml) and concentrated hydrochloric acid (1 ml) were added after concentration under reduced pressure at room temperature. The reaction solution became acidic and was extracted again with purified water (100 ml) and dichloromethane (100 ml) twice. The aqueous phase was freeze-dried to obtain int33 (600 mg). LCMS (ESI) m / z: 163.2 [M+H] + .

[0532] Intermediate int34

[0533] Preparation method of Int34

[0534] (1) The starting material 34a (800 mg, 3.58 mmol) was dissolved in toluene (12 mL), and tetrakis(triphenylphosphine)palladium (413 mg, 0.358 mmol) and 34b (1.55 g, 4.3 mmol) were added. The mixture was heated to 80°C in an oil bath under nitrogen and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the resulting reaction solution, the crude product 34c, was used directly in the next step.

[0535] (2) Aqueous hydrochloric acid solution (4 mol / L, 10 mL, 40 mmol) was added to the reaction flask containing the mixed solution of 34c, and the reaction solution was stirred at 60°C for 2 hours. After the reaction was completed, it was cooled to room temperature, the organic phase was separated, and the aqueous phase was extracted once with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 9:1) to obtain int34 (300 mg). LCMS (ESI) m / z: 187.0 [M+H] + .

[0536] Intermediate int35

[0537] Preparation method of Int35

[0538] (1) The starting material 35a (5 g, 25.13 mmol) was dissolved in toluene (80 mL), and the catalysts tetrakis(triphenylphosphine)palladium (2.91 g, 2.51 mmol) and 35b (18.15 g, 50.25 mmol) were added. The reaction mixture was heated to 100°C in an oil bath under nitrogen and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the resulting reaction mixture, the crude product 35c, was used directly in the next step.

[0539] (2) Aqueous hydrochloric acid (4 mol / L, 90 mL, 360 mmol) was added to the reaction flask containing the mixed solution of 35c (140 mL). The reaction flask was placed in an oil bath at 60°C and stirred rapidly for 2 hours. After the reaction was completed, it was cooled to room temperature and extracted with dichloromethane (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (0-10% petroleum ether:ethyl acetate) as the eluent to obtain 35d (2 g). LCMS (ESI) m / z: 163.1 [M+H] + .

[0540] (3) 35d (1.2 g, 7.41 mmol), CuCl2 (1.18 g, 8.89 mmol), and isoamyl nitrite (1.04 g, 8.89 mmol) were dissolved in ACN (25 mL). The mixture was stirred at 65°C overnight under nitrogen protection. After the reaction was completed, it was diluted with water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (0-30% ethyl acetate: petroleum ether) to obtain int35 (1.2 g, yield: 84.08%). LCMS (ESI) m / z: 182.1 [M+H] + .

[0541] Intermediate int36

[0542] Preparation method of Int36

[0543] (1) Fuming nitric acid was added to a 100 mL three-necked flask and the temperature was lowered to 0°C. Compound 36a (1 g, 6.98 mmol) was added portionwise, and the reaction mixture was stirred at 0°C for 30 min. After the reaction, the mixture was added to ice water to quench the reaction. The product precipitated and was filtered. The filter cake was washed twice with water and concentrated under reduced pressure to remove water, yielding crude product 36b (0.6 g).

[0544] (2) The crude product 36b (0.6 g, 3.19 mmol) was dissolved in a 40% aqueous HBr solution (6 mL). Then, SnCl2.2H2O (1.435 g, 6.38 mmol) was added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at room temperature for 16 hours. After the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product 36c (400 mg) was used directly in the next step. LCMS (ESI) m / z: 159.1 [M+H] + .

[0545] (3) 36c (400 mg, 2.53 mmol), 1-(6-chloropyridin-3-yl)ethan-1-one (328 mg, 2.1 mmol), and p-toluenesulfonic acid monohydrate (398 mg, 2.1 mmol) were dissolved in DMF (8 mL). The mixture was stirred in an oil bath at 90 °C under nitrogen for 4 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain int36 (100 mg). LCMS (ESI) m / z: 278.2 [M+H] + .

[0546] Intermediate int37

[0547] Preparation method of Int37

[0548] (1) 37a (4 g, 2.04 mmol) was dissolved in DMF (30 mL), and Zn(CN)2 (7.16 g, 6.12 mmol) and Pd(PPh3)4 (2.35 g, 0.204 mmol) were added. The reaction mixture was kept at 100°C under nitrogen for 16 h. The reaction solution was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 x 3 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (0%-30%) as the eluent to obtain 37b (2.2 g). LCMS: m / z = 144.1 [M+H] + .

[0549] (2) 37b (2.0 g, 1.40 mmol) was added to a mixed solution of DMF (10 mL) and fuming HNO3 (2 mL) at 0°C. The mixture was stirred at 0°C for 0.5 h. Then, an ice-water mixture (10 mL) was added and stirred at 0°C for 0.5 h. After the reaction was completed, the mixture was filtered and dried to obtain the crude product 37c (3.5 g), which was directly used for the next step.

[0550] (3) 37c (1 g, 2.3 mmol) and SnCl2 (6 g, 26.6 mmol) were dissolved in aqueous hydrobromic acid (20 mL) and stirred at 0°C for 2 h. After the reaction was complete, the mixture was filtered and dried to obtain a red solid, 37d (600 mg). LCMS: m / z = 159.0 [M+H] + .

[0551] (4) 37d (600 mg, 3.79 mmol) was dissolved in DMSO (6 mL), and 37e (592 mg, 3.79 mmol) and triethylamine (1.2 g, 11.37 mmol) were added. The mixture was stirred at 60°C for 3 h. After the reaction was completed, the mixture was extracted with water (200 mL) and ethyl acetate (150 x 3 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (0%-50%) as the eluent. The obtained light yellow solid was int37 (200 mg). LCMS (ESI) m / z: 279.0 [M+H] + .

[0552] Intermediate int38

[0553] Preparation method of Int38

[0554] (1) Compound 38a (6 g, 19.4 mmol), Zn(CN)2 (2.73 g, 23.2 mmol), and t-Buxphos Pd G3 (307 mg, 0.39 mmol) were dissolved in THF (50 mL) and water (10 mL). The mixture was stirred at 70°C for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with water, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using (ethyl acetate:petroleum ether = 1:1) as the eluent to give 38b (2.5 g, 50.1%). LCMS (ESI) m / z: 258.2 [M+H] + .

[0555] (2) 38b (2.5 g, 9.69 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (4 M, 30 mL), and the reaction mixture was stirred at room temperature for 16 h. After the reaction, the mixture was concentrated under reduced pressure to obtain 38c (1.5 g). LCMS (ESI) m / z: 158.2 [M+H] + .

[0556] (3) 38c (300 mg, 1.55 mmol), 38d (243 mg, 1.55 mmol), and TEA (315 mg, 3.11 mmol) were dissolved in DMSO (4 mL). The mixture was stirred at 60°C under nitrogen for 2 h. After the reaction, water was added, filtered, and dried to obtain int38 (200 mg). LCMS (ESI) m / z: 278.1 [M+H] + .

[0557] Intermediate int39

[0558] Preparation method of Int39

[0559] (1) 39a (1 g, 4.34 mmol) was dissolved in ultra-dry dimethyl sulfoxide (10 mL), and trifluoroacetic anhydride (0.6 mL, 4.60 mmol) was added at 0°C. The mixture was stirred at room temperature under nitrogen for 16 h. After the reaction was completed, the reaction solution was quenched with water to precipitate a brown solid, which was filtered to obtain 39b (1.7 g, crude product).

[0560] (2) 39b (1.7 g, crude) was dissolved in sodium hydroxide solution (20%, 10 mL). The mixture was stirred at 100°C for 16 hours under nitrogen. After the reaction, concentrated hydrochloric acid was added to adjust the pH to 3. A brown solid precipitated, which was filtered and dried to give 39c (640 mg). LCMS (ESI) m / z: 273.9 [MH] + .

[0561] (3) 39c (640 mg, 2.33 mmol) was dissolved in ultra-dry tetrahydrofuran (7 mL), and diphenylphosphoryl azide (1.0 mL, 4.66 mmol) and triethylamine (1.0 mL, 6.99 mmol) were added. The mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent (do not concentrate to dryness), and methanol was added to precipitate a brown solid. The residue obtained after filtration and spin drying was 39d (680 mg). LCMS (ESI) m / z: 298.8 [MH] + .

[0562] (4) 39d (680 mg, crude) was dissolved in tert-butanol (10 mL). The mixture was stirred at 80°C for 16 hours under nitrogen. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using (PE:EA = 4:1) as the eluent to obtain 39e (450 mg). LCMS (ESI) m / z: 290.9 [M-55] +

[0563] (5) 39e (430 mg, 1.24 mmol) was dissolved in tetrahydrofuran (6 mL) and water (1.5 mL), and zinc cyanide (176 mg, 1.50 mmol) and t-BuXPhosPdG3 (20 mg, 0.025 mmol) were added at room temperature. The mixture was stirred at 70 °C under nitrogen for 16 hours. After the reaction, the reaction solution was filtered, diluted with water (20 mL), and extracted with dichloromethane three times (20 mL x 3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using (PE:EA=3:1) as the eluent to obtain 39f (300 mg). LCMS (ESI) m / z: 348.2 [M+18+39] + , 1 H NMR (400MHz, DMSO_d6) δ11.54(s,1H),9.39(s,1H),8.10(s,1H),7.94(s,1H),7.80(s,1H),1.49(s,9H).

[0564] (6) 39f (200 mg, 0.69 mmol) was dissolved in 4 M HCl / EA (4 mL). The mixture was stirred at room temperature for 16 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain int39 (160 mg). LCMS (ESI) m / z: 192.1 [M+H] + .

[0565] Intermediate int40

[0566] Preparation method of Int40

[0567] (1) Under nitrogen protection, POCl3 (4.55 g, 29.7 mmol, 1.1 eq) was added dropwise to N,N-dimethylformamide (40 mL) at 0°C, stirred at 0°C for 0.5 h, and then stirred at room temperature for 1 h. The reaction system was cooled to 0°C and added dropwise to a solution of reactant 40a (5 g, 27 mmol, 1 eq) in N,N-dimethylformamide (50 mL), stirred at 0°C for 0.5 h, and then stirred at room temperature for 15 h. After the reaction was completed, ice water was added to quench the reaction, the pH was adjusted to 10 with NaOH solution, filtered, and the filter cake was rinsed with water to obtain compound 40b (2.71 g, yield: 47.1%). LCMS (ESI) m / z: 214.0 [M+H] + .

[0568] (2) 40b (2 g, 9.4 mmol, 1 eq) and 2-methyl-2-butene (1.31 g, 18.8 mmol, 2 eq) were dissolved in a mixed solution of acetonitrile (30 mL) and tert-butanol (30 mL). An aqueous solution (50 mL) of NaClO2 (8.4 g, 94 mmol, 10 eq) and NaH2PO4 (13 g, 94 mmol, 10 eq) was added at 0°C. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (petroleum ether:ethyl acetate = 3:1) as the eluent to obtain 40c (1.5 g, yield: 69.7%). LCMS (ESI) m / z: 228.0 [MH] -

[0569] (3) 40c (1.0 g, 4.36 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and triethylamine (1.32 g, 13.1 mmol) and diphenylphosphoryl azide (2.4 g, 8.73 mmol) were added at 0°C. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the solution was concentrated under reduced pressure to remove most of the tetrahydrofuran, and methanol was added to precipitate a solid. The solid was filtered and dried to obtain 40d (700 mg, yield: 63.6%). LCMS (ESI) m / z: 253.0 [MH] -

[0570] (4) 40d (700 mg, 2.75 mmol) was dissolved in tert-butanol (7 mL), and the mixture was stirred at 80°C overnight under nitrogen. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using (petroleum ether:ethyl acetate = 4:1) as the eluent to obtain 40e (550 mg, yield: 66%). LCMS (ESI) m / z: 245.0 [M-55] +

[0571] (5) 40e (550 mg, 1.83 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (4 M, 2 mL), and the reaction mixture was stirred at room temperature for 16 h. After the reaction, the mixture was concentrated under reduced pressure to obtain the crude product int40 (400 mg). LCMS (ESI) m / z: 201.0 [M+H] + .

[0572] Intermediate int41

[0573] Preparation method of Int41

[0574] (1) The starting material 41a (1 g, 4.85 mmol) was dissolved in anhydrous toluene (15 mL). The catalyst tetrakis(triphenylphosphine)palladium (560 mg, 0.484 mmol) and 41b (2.2 g, 6.09 mmol) were added. The mixture was heated to 110°C in an oil bath under nitrogen and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the resulting reaction solution, the crude product 41c, was used directly in the next step.

[0575] (2) Aqueous hydrochloric acid (4 mol / L, 10 mL, 40 mmol) was added to the reaction flask containing the mixed solution of 41c and stirred rapidly at room temperature for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, the organic phase was separated, and the aqueous phase was extracted once with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether: ethyl acetate = 9:1) to obtain compound int41 (200 mg, 24.3%). LCMS (ESI) m / z: 170.1 [M+H] + .

[0576] Intermediate int42

[0577] Preparation method of Int42

[0578] (1) Compound 42a (1.0 g, 5.376 mmol) was dissolved in THF (10 ml). Under nitrogen, the reaction mixture was cooled to -45°C and DIBAL-H (7.0 ml, 10.752 mmol) was added. The reaction mixture was stirred at -45°C for 4 h. After the reaction was completed, 1 M HCl (20 ml) was added to the reaction mixture and stirred for 5 minutes. DCM (20 ml x 3) was then added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain product 42b (600 mg). LCMS (ESI) m / z: 159.1 [M+H] + .

[0579] (2) 42b (600 mg, 3.797 mmol) was dissolved in DCM (5 ml). The reaction solution was protected with nitrogen and cooled to 0°C. DMP (1.93 g, 4.556 mmol) was then added and the temperature was slowly raised to room temperature for 4 h. After the reaction was completed, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-20%) to obtain product 42c (450 mg). 1H NMR (400MHz, CDCl3) δ10.03(s,1H),8.70(s,1H),2.69(s,3H).

[0580] (3) 42c (450 mg, 2.884 mmol) was dissolved in THF (5.0 ml). The reaction solution was protected with nitrogen and cooled to 0°C. EtMgBr (1.92 ml, 5.769 mmol) was then added and the temperature was slowly raised to room temperature for 2 h. After the reaction, water (10 ml) was added to the reaction solution, followed by extraction with ethyl acetate (10 ml x 3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) to obtain product 42d (300 mg). 1 H NMR (400MHz, DMSO-d6) δ8.37 (s, 1H), 5.57 (d, J = 4.8Hz, 1H), 4.58-4.54 (m, 1H ),2.57(s,3H),1.83–1.75(m,1H),1.71–1.60(m,1H),0.86(t,J=7.2Hz,3H).

[0581] (4) 42d (300 mg, 1.612 mmol) was dissolved in DCM (5 ml). The reaction solution was protected with nitrogen and cooled to 0°C. DMP (1.36 g, 3.225 mmol) was then added and the temperature was slowly raised to room temperature for 4 h. After the reaction was completed, the insoluble matter was filtered off and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain the product int42 (200 mg). LCMS (ESI) m / z: 185.1 [M+H] + .

[0582] Intermediate int43

[0583] Preparation method of Int43

[0584] (1) Compound 43a (1.0 g, 3.76 mmol) was dissolved in THF (10 ml). The reaction solution was cooled to -40°C under nitrogen protection, and DIBAL-H (5.0 ml, 7.52 mmol) was added. The reaction solution was stirred at -40°C for 4 h. After the reaction was completed, 1 M HCl (20 ml) was added to the reaction solution, stirred for 5 minutes, and then extracted with DCM (20 ml x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-10%) to obtain product 43b (500 mg).1 H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.99(s,1H).

[0585] (2) 43b (500 mg, 2.11 mmol) was dissolved in DCM (5 ml), and then TEA.3HF (680 mg, 4.22 mmol) and XtalFluor (725 mg, 3.165 mmol) were added. The mixture was heated to 40°C under nitrogen and allowed to react for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated sodium bicarbonate (10 ml) was added, and the mixture was stirred for 5 min. DCM (20 ml x 3) was then added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane) to obtain product 43c (200 mg). 1 H NMR (400MHz, CDCl3) δ8.55 (s, 1H), 6.75 (t, J = 53.2Hz, 1H).

[0586] (3) 43c (200 mg, 0.826 mmol) was dissolved in anhydrous toluene (5.0 ml), and then 43d (0.23 ml, 0.661 mmol) and Pd(PPh3)4 (95 mg, 0.0826 mmol) were added. The reaction solution was protected with nitrogen and heated to 110°C for 16 h. After the reaction was completed, water (10 ml) was added to the reaction solution and stirred for 5 min. Ethyl acetate (10 ml x 3) was added for extraction. The organic phase was distilled under reduced pressure to obtain a crude product, which was dissolved in THF. 4 M HCl (5 ml) was added, and the solution was heated to 60°C and stirred for 2 h. After the reaction, water (10 ml) was added to the reaction solution, and then ethyl acetate (10 ml x 3) was added for extraction. Saturated KF (10 ml) was added to the organic phase and stirred for 30 minutes. The solid was filtered off and the filtrate was separated. The obtained organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to give the product int43 (100 mg). 1 H NMR (400MHz, CDCl3) δ9.12 (s, 1H), 6.94 (t, J = 53.2Hz, 1H), 2.75 (s, 3H).

[0587] Intermediate int45

[0588] Preparation method of Int45

[0589] (1) 45a (4.0 g, 18.691 mmol) was dissolved in ultra-dry tetrahydrofuran (40 mL), and trifluoroacetic anhydride (4.16 g, 19.813 mmol) was then added dropwise at 0°C. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with water (100 mL) and stirred for half an hour to precipitate a white solid. The mixture was filtered, the solids obtained were combined, and 20% aqueous sodium hydroxide solution (50 mL) was added. The reaction solution was reacted at 105°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated hydrochloric acid (30 mL) was added in batches at 0°C to adjust the pH to 6, and a white solid precipitated. The mixture was filtered, and the solids obtained were combined to obtain 45b (3.2 g). 1 H NMR (400MHz, DMSO_d6) δ12.22(s,1H),12.15(s,1H),8.19(d,J=6.8Hz,1H),8.07(d,J=2.8Hz,1H),7.48(d,J=9.2Hz,1H).

[0590] (2) 45b (3.2 g, 12.403 mmol) was dissolved in ultra-dry tetrahydrofuran (300 mL), and then DPPA (6.8 g, 24.806 mmol) and triethylamine (3.7 g, 37.209 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the mixture was quenched with methanol (200 mL). After stirring for half an hour, a white solid precipitated. The mixture was filtered and the solid obtained was combined to obtain 45c (2.2 g). LCMS (ESI) m / z: 280.9 [M+H] -

[0591] (3) 45c (2.2 g, 7.829 mmol) was dissolved in tert-butanol (200 mL), and the reaction mixture was stirred at 80°C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 5:1) as the eluent to obtain 45d (2.1 g). LCMS (ESI) m / z: 331.0 [M+H] + .

[0592] (4) 45d (1 g, 3.037 mmol), zinc cyanide (428 mg, 3.645 mmol), and t-Buxphos Pd G3 (48 mg, 0.060 mmol) were dissolved in tetrahydrofuran (8 mL) and purified water (2 mL), and the reaction mixture was stirred at 70°C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was filtered, and the combined organic phases were diluted with water (100 mL) and extracted three times with dichloromethane (100 mL x 3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using (PE:EA = 4:1) as the eluent to obtain 45e (900 mg). 1 H NMR (400MHz, DMSO_d6) δ11.39(s,1H),9.42(s,1H),8.34(d,J=6.0Hz,1H),7.59(s,1H),7.36(d,J=10.4Hz,1H),1.50(s,9H).

[0593] (5) 45e (200 mg, 0.726 mmol) was dissolved in a hydrochloric acid and ethyl acetate solution (5 mL, 4 M), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain int45 (140 mg). LCMS (ESI) m / z: 176.2 [M+H] + .

[0594] Intermediate int46

[0595] Preparation method of Int46

[0596] (1) Anhydrous magnesium sulfate (20.4 g, 170 mmol) was added to DCE (200 mL), followed by concentrated H2SO4 (2.3 mL, 42.6 mmol). The mixture was stirred at room temperature for 15 min, and compound 46a (10 g, 42.6 mmol) and tert-butyl alcohol (20 mL, 213 mmol) were added. The reaction mixture was reacted at room temperature for 16 h. The mixture was added with water (1000 mL) and dichloromethane (1000 x 2 mL), extracted, and washed with saturated brine (1000 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using petroleum ether / ethyl acetate (0%-20%) as the eluent to obtain product 46b (4.5 g). LCMS: m / z = 293.9 [M+H] + .

[0597] (2) Compound 46b (10 g, 34.18 mmol) was dissolved in toluene (150 mL). Tetrakis(triphenylphosphine)palladium (3.9 g, 3.418 mmol) and 46c (24.7 g, 68.36 mmol) were added as catalysts. The reaction mixture was heated to 110°C in an oil bath under nitrogen and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the resulting reaction solution, the crude product 46d, was used directly in the next step.

[0598] (3) Aqueous hydrochloric acid (4 mol / L, 90 mL, 360 mmol) was added to the reaction flask containing the mixed solution of 46d (150 mL, 34.18 mmol), and the reaction solution was rapidly stirred in an oil bath at 60°C for 2 hours. After the reaction was completed, it was cooled to room temperature, the organic phase was separated, and the aqueous phase was extracted three times with dichloromethane (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (ethyl acetate / petroleum ether = 0% to 20%) to obtain 46e (3.5 g). LCMS (ESI) m / z: 256.1 [M+H] + .

[0599] (4) 46e (2 g, 3.79 mmol) was dissolved in DMSO (20 mL), and int2 (1.6 g, 9.39 mmol) and DIEA (2.0 g, 15.64 mmol) were added. The reaction solution was stirred at 25°C for 4 h. After the reaction was completed, water (100 mL) was added to the mixture, and the precipitated solid was filtered. The filter cake was washed twice with water to obtain a light yellow solid, which was the product 46f (2.5 g). LCMS (ESI) m / z: 386.0 [M+H] + .

[0600] (5) 46f (2 g, 5.18 mmol) was dissolved in dichloromethane (16 mL), trifluoroacetic acid (4 mL) was added, and the reaction solution was stirred at 30°C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the product 46g (2.5 g). LCMS (ESI) m / z: 330.0 [M+H] + .

[0601] (6) Compound 46g (500 mg, 1.5 mmol) was added to DMF (5 mL), followed by the addition of methylamine hydrochloride (112 mg, 1.65 mmol), HATU (688 g, 1.8 mmol), and DIEA (581 mg, 4.5 mmol). The reaction mixture was allowed to react at room temperature for 4 h. Water (100 mL) and dichloromethane (100 x 2 mL) were added to the mixture for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using ethyl acetate / petroleum ether (0%-40%) as the eluent to obtain the product, int46 (240 mg), as a white solid. LCMS: m / z = 343.0 [M+H] + .

[0602] Intermediate int47

[0603] Int47 preparation method:

[0604] (1) The raw material 47a (500 mg, 4.94 mmol) was dissolved in acetonitrile (25 mL), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.15 g, 4.94 mmol) and cesium carbonate (3.22 g, 9.89 mmol) were added. The mixture was heated to 85°C in an oil bath under nitrogen and stirred for 2 hours. After the reaction was complete, the reaction solution was filtered to remove the solids, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in dichloromethane (25 mL), and after ultrasonic dissolution for 3 minutes, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 47b (900 mg). 1 H NMR(400MHz, DMSO_d6)δ4.55(d,J=4.0Hz,1H),3.50–3.38(m,1H),3.10(q,J=10.4H z,2H),2.86–2.74(m,2H),2.41–2.31(m,2H),1.72–1.62(m,2H),1.39–1.35(m,2H).

[0605] (2) In a three-necked reaction flask, 47b (300 mg, 1.64 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL), and 3b (294 mg, 1.80 mmol) and triphenylphosphine (516 mg, 1.96 mmol) were added. Under nitrogen protection, the reaction solution was placed in an ice-water bath and stirred for 10 minutes. Di-tert-butyl azodicarboxylate (453 mg, 1.96 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL), and the solution was slowly added dropwise to the above reaction flask. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (petroleum ether:ethyl acetate = 9:1) to obtain 47c (757 mg). 1 H NMR(400MHz,DMSO_d6)δ7.87(s,4H),4.27–4.21(m,1H),3.19(q,J=10.4Hz ,2H),2.96–2.88(m,2H),2.47(s,2H),1.9–1.92(m,2H),1.76–1.67(m,2H).

[0606] 47c (757 mg, 1.64 mmol) was dissolved in a mixed solvent of dichloromethane (7 mL) and methanol (0.7 mL). Hydrazine hydrate (98%, 164 mg, 3.28 mmol) was added dropwise and allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed twice with dichloromethane (5 mL) and then with dilute ammonia (5 mol / L, 5 mL). The resulting filtrate was stirred for 10 minutes, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (to remove ammonia). The residue was dissolved in dichloromethane (20 mL), and dilute hydrochloric acid (1 mol / L, 10 mL) was added to the above solution and stirred for 1 hour. The aqueous phase was separated and lyophilized to obtain int47 (268 mg). 1 H NMR (400MHz, CD3OD) δ4.56–4.48(m,1H),4.33(q,J=9.2Hz,2H),3.65–3.57(m,4H),2.45–2.37(m,2H),2.29–2.21(m,2H).

[0607] Example 1

[0608] Synthesis route:

[0609] (1) Synthesis of compound C001-1a: Int3 (900 mg, 5.96 mmol) and compound int4 (810 mg, 5.96 mmol) were dissolved in acetonitrile (5 mL), and p-toluenesulfonic acid (203.8 mg, 1.19 mmol) was added. The mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The resulting residue was purified by silica gel chromatography and eluted with (petroleum ether: ethyl acetate = 1:1) to obtain product C001-1a (400 mg). 1 H NMR (400MHz, DMSO) δ10.96(s,1H),9.06(s,1H),8.38(d,J=36.0Hz,2H),7.90(s,1H),7.80(d,J=8.0Hz,2H ),7.37(d,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),4.74(d,J=8.0Hz,2H),2.22(s,3H).

[0610] (2) Synthesis of compound C001-1b: C001-1a (100 mg, 0.43 mmol), compound int1 (151 mg, 0.39 mmol), t-BuBrettPhos (19 mg, 0.043 mmol), Pd2(dba)3 (37 mg, 0.043 mmol) and potassium phosphate (166 mg, 0.78 mmol) were dissolved in tert-butanol (5 mL). The mixture was stirred at 120°C for 5 h under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and then added with water. The mixture was extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography and eluted with (petroleum ether: ethyl acetate = 3:1) to obtain product C001-1b (120 mg). LCMS (ESI) m / z: 539.6 [M+H] + .

[0611] (5) Synthesis of Compound C001: C001-1b (160 mg, 0.30 mmol) was dissolved in tetrahydrofuran (2 mL), and cesium fluoride (137 mg, 0.90 mmol) was added. The reaction solution was stirred at room temperature for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative analysis to obtain Compound C001 (5.95 mg). LCMS (ESI) m / z: 383.1 [M+H] + . 1H NMR (400MHz, DMSO) δ10.96(s,1H),9.06(s,1H),8.42(s,1H),8.34(s,0.7H),7.90(s,1H),7.80(d,J=8.0Hz ,2H),7.37(d,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),4.75-4.73(m,2H),2.22(s,3H).

[0612] Example 2:

[0613] Synthesis route:

[0614] Compound int 5 (100 mg, 0.35 mmol) and compound int 6 (51 mg, 0.70 mmol) were dissolved in acetonitrile (2 mL)

[0615] To the reaction mixture, p-toluenesulfonic acid (11.98 mg, 0.07 mmol) was added. The mixture was stirred at 90°C under nitrogen for 4 hours. After the reaction, the reaction solution was concentrated. The resulting residue was purified by reverse phase preparative method to obtain the final product C002 (5.07 mg). LCMS (ESI): m / z = 391.1 (M+H)+. 1 H NMR (400MHz, DMSO_d6) δ10.94(s,1H),9.03(s,1H),8.42(d,J=4.0Hz,1H),7.90(s,1H),7.84–7.75(m,2H),7.36(d,J=12. 0Hz,1H),7.09(d,J=8.0Hz,1H),6.82(d,J=12.0Hz,1H),4.74(s,1H),3.07–2.93(m,2H),2.81–2.69(m,2H),2.20(s,3H).

[0616] Example 3:

[0617] Synthesis route:

[0618] (1) Compound C003-3a (5.0 g, 27.3 mmol) was placed in a 100 mL single-necked bottle, methylamine hydrochloride (3.6 g, 54.6 mmol) was added, and then acetonitrile (50 mL) and potassium carbonate (11.3 g, 81.9 mmol) were added at 0°C. After nitrogen displacement three times, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, 100 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether).

[0619] Compound C003-3b (3.0 g) was obtained. LCMS (ESI): m / z = 195.1 (M+H) + .

[0620] (2) Compound C003-3b (3 g, 15.4 mmol) was placed in a 100 mL single-necked flask, methanol (40 mL) was added, and then palladium carbon (300 mg, 1.5 mmol) was added. After hydrogen substitution twice, the reaction solution was stirred under a hydrogen balloon at room temperature for 2 hours. After the reaction was completed, the system was filtered on a fritted funnel filled with diatomaceous earth, and the solid was washed three times with methanol (50 mL). The organic phases were combined and concentrated in vacuo to obtain compound C003-3c (3.0 g). LCMS (ESI): m / z = 165.1 (M+H)+.

[0621] (3) Compound C003-3c (3.0 g, 18.3 mmol) was dissolved in methanol (30 mL), and cyanogen bromide (2.9 g, 27.4 mmol) was added. The mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, silica gel was added and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10-50% ethyl acetate / petroleum ether) to obtain compound C003-3d (2.0 g). LCMS (ESI): m / z = 190.3 (M+H) + .

[0622] (4) Compound C003-3d (900 mg, 4.8 mmol) was dissolved in acetonitrile (40 mL), and compound int3 (657 mg, 5.7 mmol) and p-toluenesulfonic acid monohydrate (181 mg, 0.9 mmol) were added respectively. After nitrogen replacement three times, the temperature was raised to 90°C and stirred for 4 hours. After the reaction was completed, it was cooled to room temperature, quenched with 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10-40% ethyl acetate / petroleum ether) to obtain compound C003-3e (800 mg). LCMS (ESI): m / z = 287.2 (M+H) + .

[0623] (5) Compound C003-3e (200 mg, 0.7 mmol) and compound int1 (541 g, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL), and potassium phosphate (445 mg, 2.1 mmol), t-BuBrettPhos (102 mg, 0.21 mmol) and tris(dibenzylideneacetone)dipalladium (128 mg, 0.14 mmol) were added. After nitrogen substitution, the reaction mixture was stirred at 120°C for 10 hours. After the reaction was completed, the system was cooled to room temperature, 50 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (20-40% ethyl acetate / petroleum ether) to obtain compound C003-3f (100 mg). LCMS (ESI): m / z = 592.3 (M+H) +

[0624] (6) Compound C003-3f (100 mg, 0.17 mmol) was dissolved in acetonitrile (2 mL). Triethylamine trihydrogen fluoride (1 mL) was added to the system under ice-cooling conditions. After the addition, the temperature was raised to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was purified by reverse phase preparative chromatography to obtain compound C003 (10 mg). LCMS (ESI): m / z = 436.2 (M+H) + .1H NMR (400MHz, DMSO) δ12.53(s,1H),11.62(s,1H),7.77(d,J=12.0Hz,2H),7.62(s,2H),7.52 (d,J=12.0Hz,2H),7.20(d,J=8.0Hz,1H),4.77(q,J=8.0Hz,2H),3.82(s,3H),2.27(s,3H).

[0625] Example 4:

[0626] Synthesis route:

[0627] (1) Compound C004-4a (25 g, 222.9 mmol) was dissolved in dichloromethane (250 mL), and then N,N-dimethylformamide dimethyl acetal (32 mL, 240.7 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solid was dried and dissolved in ethanol. Cyanoacetamide (60.55 g, 719.9 mmol), piperidine (10 ml) and N,N-dimethylformamide (200 ml) were added. The reaction solution was reacted at 80°C overnight. After the reaction solution was cooled, it was filtered and rinsed with water and cold ethanol to obtain compound C004-4b (28.6 g). LCMS (ESI): m / z = 207.2 (M+H) + .

[0628] (2) Compound C004-4b (28.6 g, 138.7 mmol) was dissolved in concentrated hydrochloric acid (500 mL) and stirred at 100°C for 6 hours. After the reaction was complete, the mixture was filtered and rinsed with water and ethanol, and the solid was collected and dried to obtain compound C004-4c (28.21 g). LCMS (ESI): m / z = 208.2 (M+H) + .

[0629] (3) Compound C004-4c (1 g, 4.82 mmol) was heated to 320°C for 1 hour to obtain a crude compound C004-4d (610 mg). LCMS (ESI): m / z = 164.1 (M+H) + ,

[0630] (4) Compound C004-4d (1 g, 6.12 mmol) and phosphorus oxychloride (2 ml, 23.9 mmol) were dissolved in acetonitrile (10 ml), and the reaction mixture was reacted at 90°C for 2 hours. After the reaction, the reaction mixture was neutralized with ammonia water, and the organic phase was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the organic phase was spin-dried. The concentrate was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to obtain compound C004-4e (300 mg). LCMS (ESI): m / z = 182.2 (M+H) +,

[0631] (5) Compound C004-4e (100 mg, 0.55 mmol), compound int 2 (92 mg, 0.55 mmol), and p-toluenesulfonic acid (94.8 mg, 0.55 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction solution was stirred at 120°C for 16 h. After the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel plate chromatography, and the concentrate was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to obtain compound C004-4f (90 mg). LCMS (ESI): m / z = 312.1 (M+H) + ,

[0632] (6) Compound C004-4f (90 mg, 0.28 mmol), compound int 3 (89 mg, 0.77 mmol), and p-toluenesulfonic acid (22 mg, 0.12 mmol) were dissolved in acetonitrile (2 mL), and the reaction mixture was stirred at 90°C for 4 h. After the reaction, the reaction mixture was concentrated, and the resulting residue was purified by reverse phase preparative analysis to obtain the final compound (9.68 mg). LCMS (ESI): m / z = 409.1 (M+H) + . 1 H NMR (400MHz, DMSO_d6) δ10.92(s,1H),9.10(s,1H),8.00(s,1H),7.87–7.84(m,2H),7.36(d,J=8.0Hz,1H),7.10(d,J=4. 0Hz,1H),6.71(d,J=8.0Hz,1H),4.70(q,J=12.0Hz,2H),2.78(t,J=8.0Hz,2H),2.70(t,J=8.0Hz,2H),1.86–1.83(m,2H).

[0633] Example 5:

[0634] Synthesis route:

[0635] Compound int 5 (200 mg, 0.7 mmol) and compound int 7 (128 mg, 0.84 mmol) were dissolved in acetonitrile (2 mL). p-Toluenesulfonic acid (27 mg, 0.14 mmol) was added. After addition, the temperature was raised to 90°C and stirred for 4 hours. After completion of the reaction, the final product C005 (10 mg) was obtained by reverse phase preparative purification. LCMS (ESI): m / z = 419.2 (M+H) +.1H NMR(400MHz,DMSO_d6)δ11.12(s,1H),8.34–8.28(m,1H),7.95-7.93(m,1H),7.86(s,1H),7.73(s,1H), 7.49–7.39(m,1H),7.13–7.10(m,1H),6.89(s,1H),4.36–4.29(m,1H),2.18(s,3H),2.07–1.84(m,8H).

[0636] Example 6:

[0637] Synthesis route:

[0638] (1) Compound C006-6a (1.0 g, 7.17 mmol, 1 eq), compound int2 (1.6 g, 7.88 mmol, 1.1 eq), and p-toluenesulfonic acid hydrate (1.5 g, 7.88 mmol, 1.1 eq) were dissolved in N,N-dimethylformamide (25.0 mL) and stirred at 120°C for 5 h. After the reaction, the solvent was dried, the reactants were extracted with ethyl acetate and washed with water, the organic phases were combined, and the resulting residue was purified by column chromatography. The concentrate was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to obtain compound C006-6b (1.5 g). LCMS (ESI): m / z = 270.0 (M+H)+,

[0639] (2) Compound C006-6b (400 mg, 1.48 mmol, 1 eq) was dissolved in ultra-dry tetrahydrofuran (3.0 mL), the atmosphere was replaced with nitrogen, and the mixture was stirred at 0°C for 20 min. Methylmagnesium bromide (4.44 mL, 4.44 mmol, 3 eq) was slowly added dropwise to the solution. After the addition was complete, the temperature was raised to 45°C and stirred for 16 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined to obtain a residue which was purified by column chromatography and eluted with (petroleum ether:ethyl acetate = 2:1) to obtain compound C006-6c (250 mg). LCMS (ESI): m / z = 287.0 (M+H) + .

[0640] (3) Compound C006-6c (200 mg, 0.70 mmol, 1 eq), compound int3 (127 mg, 0.84 mmol, 1.2 eq), and p-toluenesulfonic acid hydrate (26 mg, 0.14 mmol, 0.2 eq) were dissolved in acetonitrile (5.0 mL) and stirred at 90°C for 4 h. After the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the resulting residues were purified by reverse phase preparative chromatography to obtain the final product C006 (33.48 mg). LCMS (ESI): m / z = 383.9 (M+H) + . 1 H NMR(400MHz, DMSO_d6)δ11.07(s,1H),9.38(s,1H),8.04(d,J=4.0Hz,1H),7.84(s,1H),7.77(d,J=12.0Hz,1H),7.39(d, J=12.0Hz,1H),7.18(d,J=8.0Hz,1H),7.13(d,J=4.0Hz,1H),7.11(d,J=4.0Hz,1H),4.84(q,J=8.0Hz,2H),2.38(s,3H).

[0641] Example 7:

[0642] Synthesis route:

[0643] (1) Compound C007-7a (4.5 g, 37.8 mmol) was placed in a 100 mL single-necked bottle, tetrahydrofuran (40 mL) was added, and the atmosphere was replaced with nitrogen three times. MeMgBr (1 M in THF, 114 mmol, 114 mL) was added dropwise at 0°C. The reaction temperature was controlled at 0°C-5°C for 2 hours. After the reaction was completed, 100 mL of ice water was poured into the reaction solution to quench it. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to obtain compound C007-7b (3.5 g). LCMS (ESI): m / z = 137.1 (M+H) + .

[0644] (2) Compound C007-7b (1.1 g, 8.3 mmol) and compound int 3 (800 mg, 6.96 mmol) were placed in a 100 mL single-necked flask, acetonitrile (40 mL) was added, and then p-toluenesulfonic acid (265 mg, 1.39 mmol) was added. After nitrogen displacement twice, the reaction solution was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, silica gel was added, and the concentrate was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to obtain compound C007-7c (300 mg). LCMS (ESI): m / z = 234.1 (M+H) + .

[0645] (3) Compound C007-7c (260 mg, 1.2 mmol) and compound int 1 (516 mg, 1.34 mmol) were dissolved in tert-butanol (5 mL), and potassium phosphate (710 mg, 3.35 mmol), t-BuBreetPhos (108 mg, 0.22 mmol) and tris(dibenzylideneacetone)dipalladium (102 mg, 0.11 mmol) were added. After nitrogen substitution, the mixture was stirred at 120°C for 10 hours. After the reaction was completed, the system was cooled to room temperature, 50 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10-30% ethyl acetate / petroleum ether) to obtain compound C007-7d (200 mg). LCMS (ESI): m / z = 539.2 (M+H) + .

[0646] (4) Compound C007-7d (150 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL). CsF (127 mg, 0.84 mmol) was added to the system under ice bath conditions. After addition, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the final product C007 (10 mg) was obtained by reverse phase preparative purification. LCMS (ESI): m / z = 383.1 (M+H) + . 1 H NMR(400MHz, DMSO_d6)δ11.19(s,1H),8.18(s,1H),8.15(d,J=4.0Hz,1H),7.64(d,J=8.0Hz,1H), 7.47(d,J=4.0Hz,1H),7.42-7.40(m,2H),7.13-7.08(m,2H),4.76(q,J=8.0Hz,2H),2.25(s,3H).

[0647] Example 8:

[0648] Synthesis route:

[0649] (1) Compound C008-8a (4.0 g, 31.2 mmol, 1.1 eq), compound 3b (4.6 g, 28.4 mmol, 1.0 eq) and triphenylphosphine (8.2 g, 31.2 mmol, 1.1 eq) were added to tetrahydrofuran (100 mL) and the reaction system was cooled to 0°C. DBAD (7.2 g, 31.2 mmol, 1.1 eq) was dissolved in tetrahydrofuran (100 mL) and slowly added dropwise to the reaction solution. After the addition was complete, the temperature was raised to room temperature and stirred for 6 h. After the reaction was completed, the mixture was dried and extracted with dichloromethane and water. The organic phases were combined and the resulting residue was purified by column chromatography using (petroleum ether:ethyl acetate = 3:1) as the eluent to obtain compound C008-8b (4.2 g). LCMS (ESI): m / z = 273.1 (M+H) + . 1 H NMR (400MHz, DMSO_d6) δ7.87 (s, 4H), 4.22 (t, J = 8.0Hz, 2H), 2.58–2.52 (m, 2H), 1.93–1.86 (m, 2H).

[0650] (2) Compound C008-8b (1 g, 3.66 mmol, 1 eq) was dissolved in (dichloromethane / methanol = 10 / 1) (10 mL), and 68% hydrazine hydrate (0.5 mL, 7.32 mmol, 2 eq) was gradually added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction, the mixture was filtered, and the filtrate was washed with aqueous ammonia. The mixture was extracted with dichloromethane and water. The organic phases were combined, rotary evaporated, and ethanol was added. Concentrated hydrochloric acid was added dropwise to acidify the mixture, and a solid precipitated. The mixture was filtered to obtain compound C008-8c (500 mg). 1 H NMR (400MHz, DMSO_d6) δ11.14 (s, 2H), 4.09 (t, J = 8.0Hz, 2H), 2.41–2.28 (m, 2H), 1.87–1.80 (m, 2H).

[0651] (3) Compound C008-8c (100 mg, 0.56 mmol, 1 eq), compound int 5 (191 mg, 0.67 mmol, 1.2 eq), and p-toluenesulfonic acid hydrate (21 mg, 0.11 mmol, 0.2 eq) were dissolved in acetonitrile (3.0 mL) and stirred at 90°C for 4 h. After the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the resulting residues were purified by preparative analysis to obtain the final product C008 (9.30 mg). LCMS (ESI): m / z = 411.1 (M+H) + .1 H NMR (400MHz, DMSO_d6) δ10.93(s,1H),8.99(s,1H),8.40(d,J=2.0Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.0Hz,1H),7.80(s,1H),7. 36(d,J=8.0Hz,1H),7.10-7.07(m,1H),6.81(d,J=8.0Hz,1H),4.15(t,J=8.0Hz,2H),2.39–2.32(m,2H),2.17(s,3H),1.92–1.85(m,2H).

[0652] Example 9:

[0653] Synthesis route:

[0654] (1) Compound 3c (4 g, 15.43 mmol) was dissolved in a mixture of dichloromethane (40 mL) and methanol (4 mL), and then hydrazine hydrate (68%) (1.5 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the precipitate was filtered, and the filtrate was added with 5N aqueous ammonia (100 mL) and stirred, then allowed to stand for separation. The aqueous phase was extracted three times with dichloromethane (50 mL), and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was concentrated under reduced pressure at room temperature, and then ethanol (20 mL) and concentrated hydrochloric acid (2 mL) were added. The reaction mixture became acidic and was concentrated under reduced pressure to obtain int3·HCl (2 g). 1 H NMR (400MHz, DMSO_d6) δ4.31 (d, J = 8.0Hz, 2H), 2.82–2.74 (m, 2H).

[0655] (2) Int5 (200 mg, 0.70 mmol) and int3·HCl (101.65 mg, 1.05 mmol) were dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid (18 mg, 0.14 mmol) was added. The mixture was stirred at 90°C for 4 hours under nitrogen. After the reaction, the reaction solution was concentrated. The resulting residue was purified by reverse phase preparative analysis to obtain compound C009 (38.91 mg). LCMS (ESI) m / z: 397.0 [M+H] + ; 1H NMR (400MHz, DMSO_d6) δ10.94(s,1H),9.01(s,1H),8.42(d,J=4.0Hz,1H),7.90(d,J=4.0Hz,1H),7.84(dd,J=8.0,2.0Hz,1H),7.79(d,J=4 .0Hz,1H),7.37(d,J=8.0Hz,1H),7.09(dd,J=4.0,4.0Hz,1H),6.80(d,J=8.0Hz,1H),4.3(d,J=8.0Hz,2H),2.75–2.67(m,2H),2.16(s,3H).

[0656] Example 10:

[0657] Synthesis route:

[0658] (1) Int5 (220 mg, 0.708 mmol) and int7 (135 mg, 0.849 mmol) were dissolved in ACN (5 mL), p-toluenesulfonic acid hydrate (26 mg, 0.141 mmol) was added, and the mixture was stirred at 60°C for 4 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase preparative analysis to obtain compound C010 (22.75 mg). LCMS (ESI) m / z: 416.2 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ8.49(d,J=4.0Hz,1H),8.20(d,J=4.0Hz,1H),7.49(s,1H),7.36–7.35(m,2H ),7.10(dd,J=2.0Hz,8.0Hz,1H),4.79–4.76(m,1H),2.99–2.90(m,2H),2.82–2.69(m,2H),2.2(s, 3H).

[0659] Example 11:

[0660] Synthesis route:

[0661] (1) In a three-necked reaction flask, C011-1a (19 g, 141.66 mmol) was dissolved in dichloromethane (380 mL), and boron trifluoride ether solution (23.2 mL, 184.16 mmol) was dissolved in dichloromethane (95 mL) as standby solution a. The solution was placed in a constant pressure dropping funnel. Ethyl diazoacetate C011-11b (21 g, 184.16 mmol) was dissolved in dichloromethane (95 mL) as standby solution b. The solution was placed in another constant pressure dropping funnel. After nitrogen substitution, the reaction system was cooled to -10°C. After stirring for 15 minutes, standby solution a was added dropwise. After the addition was complete, the temperature was maintained at -10°C and stirred for 10 minutes. Standby solution b was added dropwise. After the addition was complete, the temperature was maintained at -10°C and stirred for 1 hour. The ice-salt bath was removed and the mixture was naturally warmed to room temperature. After the reaction was complete, the reaction was quenched with aqueous potassium carbonate solution (30 wt%, 190 mL). The organic phase was separated, washed once with saturated brine, dried and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product C011-11c (30 g) which was directly used in the next step.

[0662] (2) In a 1 L reaction flask, the crude product C011-11c (30 g, 141.66 mmol) was added to a hydrochloric acid solution (3 mol / L, 285 mL). The reaction system was stirred, heated to 100°C, and refluxed for 4 hours. After the reaction was completed, it was cooled to room temperature and extracted twice with dichloromethane (100 mL). The combined organic phases were dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound C011-11d (6.96 g).

[0663] (3) C011-11d (6.96 g, 46.97 mmol) was dissolved in anhydrous methanol (70 mL) and cooled to 0°C under nitrogen protection. Sodium borohydride (2.13 g, 56.36 mmol) was added in several portions. After the addition, the ice bath was not removed and the reaction solution was naturally warmed to room temperature. After the reaction was completed, the reaction was quenched with saturated brine (70 mL) and the methanol was concentrated under reduced pressure. The product was extracted three times with ethyl acetate (70 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound C011-11e (4.96 g).

[0664] (4) Di-tert-butyl azodicarboxylate (DBAD, 8.1 g, 35.16 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) as a standby solution a. C011-11e (4.8 g, 31.96 mmol), compound 3b (5.74 g, 35.16 mmol) and triphenylphosphine (9.23 g, 35.16 mmol) were dissolved in anhydrous toluene (177 mL), cooled to 0°C under nitrogen protection, stirred, and standby solution a was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature. After the reaction was completed, water (100 mL) was added, and the mixture was extracted three times with dichloromethane (100 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound C011-11f (2.246 g).

[0665] (5) C011-11f (2.246 g, 7.61 mmol) was dissolved in a mixed solvent of dichloromethane (22 mL) and anhydrous methanol (2.2 mL). The mixture was cooled to 0°C in an ice-water bath under nitrogen protection. Hydrazine hydrate (98%, 771 mg, 15.1 mmol) was added dropwise. After completion of the addition, the mixture was naturally warmed to room temperature and reacted for 2 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane (20 mL) and then with ammonia water (20 mL) twice. The aqueous phase was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature. Anhydrous ethanol (10 mL) was added for dissolution, and the mixture was adjusted to acidity (pH = 3) with concentrated hydrochloric acid. The mixture was concentrated to dryness under reduced pressure to obtain compound C011-11g.

[0666] (6) C011-11g (315 mg, 1.1 mmol), int5 (142 mg, 0.7 mmol), and p-toluenesulfonic acid monohydrate (27 mg, 0.14 mmol) were dissolved in acetonitrile (4.8 mL) and stirred at 90°C for 4 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. Compound C011 (23 mg) was obtained by reverse phase preparative analysis and purification. LCMS (ESI) m / z: 433.3 [M+H] + ; 1H NMR(400MHz, DMSO_d6)δ10.94(s,1H),8.99(s,1H),8.40(d,J=2.0Hz,1H),7.91(s,1H),7.84–7.78(m,2H),7.37(d,J=8.4Hz,1H),7.09(dd,J=8.0 ,2.0Hz,1H),6.81(d,J=8.0Hz,1H),4.37–4.31(m,1H),2.20(s,3H),2.1 9–1.92(m,9H),1.87–1.74(m,2H),1.70–1.60(m,1H),1.55–1.43(m,1H).

[0667] Example 12 and Example 13:

[0668] Synthesis route: Compound C011 was separated into compound C012 and compound C013 by chiral SFC.

[0669] System: Waters SFC 150; Column: Column size: 250*25mm 10m; Mobile phase A: supercritical CO2; Mobile phase B: MEOH (+0.1% 7.0mol / l ammonia in MEOH); A:B=70:30; Wavelength: 214nm; Flow rate: 100ml / min; Column temperature: room temperature; Back pressure: 100bar; Injection: 1mL; Cycle time: 5.1 minutes; Solvent: Methanol: redistilled grade, Supercritical CO2: food grade; Preparation of sample solution: Dissolve the sample in approximately 30mL MeOH.

[0670] Example 14:

[0671] Synthesis route:

[0672] (1) C004-4f (100 mg, 0.32 mmol), int6 (78 mg, 0.64 mmol), and p-toluenesulfonic acid (12 mg, 0.06 mmol) were dissolved in acetonitrile (2 mL), and the reaction mixture was stirred at 90°C for 4 h. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase preparative analysis to obtain compound C014 (11.56 mg). LCMS (ESI) m / z: 417.2 [M+H] + ; 1H NMR(400MHz,DMSO_d6)δ10.91(s,1H),9.07(s,1H),8.00(s,1H),7.92–7.82(m,2H),7.36(d,J=8.0Hz,1H),7.09 (dd,J=12.0,4.0Hz,1H),6.71(d,J=8.0Hz,1H),4.70(m,1H),2.99(m,2H),2.79–2.66(m,6H),1.89–1.79(m,2H).

[0673] Example 15:

[0674] Synthesis route:

[0675] Int6 (200 mg, 0.667 mmol) and Int8 (98 mg, 0.801 mmol) were dissolved in acetonitrile (4 mL), followed by the addition of p-toluenesulfonic acid (22.9 mg, 0.133 mmol). The mixture was stirred at 70°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was concentrated. The resulting residue was purified by preparative analysis to yield Compound C015 (29.95 mg). 1 H NMR(400MHz, DMSO_d6)δ10.96(s,1H),9.05(s,1H),8.41(s,1H),7.92(s,1H),7.85–7.79(m,2H),7.36(d,J=12.0Hz,1H),7.09(d,J=2 .0,1H),7.08(d,J=2.0Hz,1H),6.83(d,J=8.0Hz,1H),4.76–4.74(m,1H),3.01–2.98(m,2H),2.77–2.64(m,4H),1.07(t,J=8.0Hz,3H).

[0676] Example 16 and Example 17:

[0677] Synthesis route:

[0678] (1) Under nitrogen protection, C016-16a (5 g, 24.99 mmol, 1 eq) was dissolved in tetrahydrofuran (20 ml), cooled to 0°C, and ethylmagnesium bromide solution (19 ml, 37.49 mmol, 2 M, 1.5 eq) was added dropwise. The temperature was then raised to 45°C and stirred for 16 h. After the reaction, the reaction solution was quenched with saturated ammonium chloride, and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by combining the organic phases was purified by column chromatography (PE:AE = 4:1) to obtain C016-16b (2.5 g, 54, 48%). LCMS (ESI) m / z: 184.1 [M+H] + .

[0679] (2) C016-16b (1 g, 5.46 mmol, 1 eq.) and int2 (1.3 g, 6.56 mmol, 1.2 eq.) were dissolved in acetic acid and stirred at 130°C for 4 h. After the reaction, the reaction solution was concentrated under reduced pressure and the pH was adjusted to a weak alkaline state by dropwise addition of aqueous ammonia. The residue was purified by column chromatography using a PE:AE = 3:1 eluent to obtain C016-16b (650 mg). LCMS (ESI) m / z: 314.1 [M+H] + .

[0680] (3) C016-16b (400 mg, 1.28 mmol, 1 eq), int6 (334 mg, 1.91 mmol, 1.5 eq), and p-toluenesulfonic acid (49 mg, 0.26 mmol, 0.2 eq.) were dissolved in N,N-dimethylformamide (3 mL). Under nitrogen, the temperature was raised to 120°C and stirred for 4 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using a PE:AE = 3:1 eluent to obtain the product. 100 mg of the product was separated by SFC to obtain compound C016 (7.1 mg) and compound C017 (55.91 mg).

[0681] SFC separation method: System: Waters SFC 150; Column: Column dimensions: 250*25mm 10m; Mobile phase A: supercritical CO2, Mobile phase B: MEOH (+0.1% 7.0mol / l ammonia in MEOH); A:B: 80:20; Wavelength: 214nm; Flow rate: 100ml / min; Column temperature: room temperature; Back pressure: 100bar; Injection: 3mL; Cycle time: 4.1 minutes; Solvent: Methanol: redistilled grade, Supercritical CO2: food grade; Preparation of sample solution: Dissolve the sample in approximately 20mL of MeOH.

[0682] C016&C017:LCMS(ESI)m / z:419.2[M+H] + ; 1 H NMR(400MHz,CD3OD)δ8.27(d,J=2.2Hz,1H),7.69(dd,J=8.8,2.0Hz,1H),7.51(s,1 H),7.44(d,J=2.0Hz,1H),7.34(d,J=8.4Hz,1H),7.09(dd,J=8.0,2.0Hz,1H),6.63( d,J=8.0Hz,1H),4.66–4.59(m,1H),2.92-2.85(m,2H),2.71–2.51(m,2H),2.53(t,J =8.0Hz,2H),1.55–1.45(m,2H),0.92(t,J=8.0Hz,3H). / LCMS(ESI)m / z:419.3[M+H] + ; 1 H NMR (400MHz, CD3OD) δ8.27(d,J=4.0Hz,1H),7.79(dd,J=8.0,2.0Hz,1H),7.51(s,1H),7.43(d,J=2.0Hz,1H),7.34(d,J=8.0Hz,1H),7.09(dd,J=8.0,2. 0Hz,1H),6.63(d,J=8.0Hz,1H),4.76–4.69(m,1H),2.97-2.88(m,2H),2.77 –2.69(m,2H),1.63–1.53(m,2H),1.55–1.45(m,2H),0.97(t,J=8.0Hz,3H).

[0683] Example 18:

[0684] Synthesis route:

[0685] (1) 2-Chloro-1-methyl-1H-imidazole (10 g, 85.8 mmol) was added to THF (50 mL), the system was cooled to -70°C, and n-butyllithium (36 mL, 2.5 mmol / L in THF) was added dropwise. The mixture was stirred at -70°C for 1 h, and DMF (6.58 g, 90.1 mmol) was added dropwise. After the addition was complete, the reaction mixture was naturally warmed to room temperature and stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain C018-18b (7 g).

[0686] (2) C018-18b (7 g, 48.6 mmol) was dissolved in THF (70 mL). The system was cooled to -70°C and methylmagnesium bromide (19.4 mL, 3 mmol / L in THF) was added dropwise. The mixture was stirred at -70°C for 2 h. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C018-18c (3 g).

[0687] (3) C018-18c (3 g, 18.57 mmol) was dissolved in DCM (50 mL), and DMP (8.35 g, 19.69 mmol) was added and stirred at room temperature for 2 h. After the reaction, the dichloromethane phase was washed with water, and the organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain C018-18d (1.05 g).

[0688] (4) C018-18d (500 mg, 3.16 mmol) was dissolved in p-xylene (10 mL), and int2 (703 mg, 3.48 mmol) and p-toluenesulfonic acid (19 mg, 0.32 mmol) were added. The mixture was stirred at 150°C for 16 h. After the reaction, methanol was added and the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 9:1) to obtain C018-18e (300 mg).

[0689] (5) C018-18e (200 mg, 0.69 mmol) was dissolved in acetonitrile (5 mL), and int6 (94 mg, 0.76 mmol) and p-toluenesulfonic acid monohydrate (26 mg, 0.14 mmol) were added and stirred at 60°C for 4 h. After the reaction, compound C018 (9.01 mg) was obtained by reverse phase preparative purification. LCMS (ESI) m / z: 394.2 [M+H] + ; 1 H NMR(400MHz,DMSO_d6)δ10.85(s,1H),8.22(s,1H),8.12(s,1H),7.77(s,1H),7.70(s,1H),7.34(d,J=12.0Hz,1H),7.12 (s,1H),7.06(dd,J=8.4,2.0Hz,1H),4.75–4.73(m,1H),3.74(s,3H),3.01–2.98(m,2H),2.82–2.77(m,2H),2.12(s,3H).

[0690] Example 19:

[0691] Synthesis route:

[0692] (1) 4-Chloro-3-nitroacetophenone (10 g, 50.1 mmol) and methylamine hydrochloride (5.07 g, 75.2 mmol) were added to acetonitrile (150 mL), and potassium carbonate (27.7 g, 200.4 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water and extracted three times with ethyl acetate (50 mL), and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain C019-19b (8.5 g).

[0693] (2) C019-19b (8.5 g, 43.81 mmol) was dissolved in methanol (120 mL), and then Raney nickel was added to the solution. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered and the filtrate was dried to obtain C019-19c (5.6 g, 70.98%). LCMS (ESI) m / z: 165.2 [M+H] + .

[0694] (3) C019-19c (5.6 g, 34.1 mmol) and cyanogen bromide (5.43 g, 51.2 mmol) were dissolved in methanol (100 mL). The mixture was stirred at room temperature for 1 h. After the reaction was completed, it was diluted with water and extracted three times with ethyl acetate (100 mL). The organic phases were combined and washed twice with saturated brine. The organic phases were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain C019-19d (3.1 g). LCMS (ESI) m / z: 190.1 [M+H] + .

[0695] (4) C019-19d (2 g, 10.5 mmol), int1 (4.89 g, 12.6 mmol), t-BuBrettphos (1.026 g, 2.12 mmol), Pd2(dba)3 (968 mg, 1.05 mmol), and potassium phosphate (6.73 g, 31.7 mmol) were dissolved in dioxane (50 mL). The mixture was stirred at 120 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and then added with water (50 mL). It was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C019-19f (1.0 g). LCMS (ESI) m / z: 495.3 [M+H] + .

[0696] (5) C019-19f (1 g, 2.02 mmol) was dissolved in a mixture of triethylamine hydrofluoride (5 mL) and acetonitrile (10 mL) and stirred at room temperature for 1 h. After the reaction, the mixture was filtered and purified by reverse phase preparative purification to obtain C019-19g (180 mg, 26.3%). LCMS (ESI) m / z: 339.2 [M+H] + .

[0697] (6) C019-19g (120 mg, 0.355 mmol), int6 (66 mg, 0.533 mmol), and p-toluenesulfonic acid monohydrate (14 mg, 0.071 mmol) were dissolved in acetonitrile (2 mL). The mixture was stirred at 90°C for 5 h. After the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative purification to obtain compound C019 (13.81 mg). LCMS (ESI) m / z: 444.3 [M+H] + ; 1 H NMR(400MHz,DMSO_d6)δ11.01(s,1H),8.65(s,1H),8.14(s,1H),7.95(s,1H),7.87(s,1H),7.59(s,1H),7.39(d,J=8.0Hz,2H),7.2 7(d,J=8.0Hz,1H),7.10(dd,J=8.0,2.0Hz,1H),4.81–4.71(m,1H),3.75(s,3H),3.03-2.98(m,2H),2.82–2.75(m,2H),2.27(s,3H).

[0698] Example 20:

[0699] Synthesis route:

[0700] (1) 3-Amino-6-cyanopyridine (4.5 g, 37.8 mmol) was added to THF (40 mL), the system was cooled to 0°C, and methylmagnesium bromide (114 mL, 1 mmol / L in THF) was added dropwise. The mixture was stirred at 0°C for 2 h. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate (50 mL), and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA=10:1) to give C020-20b (3.5 g, 68.06%). LCMS (ESI) m / z: 137.4 [M+H] + .

[0701] (2) C020-20b (670 mg, 4.92 mmol), int6 (909 mg, 7.39 mmol) and p-toluenesulfonic acid monohydrate (187 mg, 0.99 mmol) were dissolved in acetonitrile (10 mL). Stirred at 90 ° C for 4 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), and then added with water (30 mL). It was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed twice with saturated brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to give C020-20c (200 mg). LCMS (ESI) m / z: 242.3 [M+H] + .

[0702] (3) C020-20c (108 mg, 0.448 mmol), C019-19e (207 mg, 0.54 mmol), t-BuBrettphos (43 mg, 0.089 mmol), Pd2(dba)3 (41 mg, 0.049 mmol), and potassium phosphate (285 mg, 1.34 mmol) were dissolved in tert-butanol (5 mL). The mixture was stirred at 120 ° C for 5 h under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and then added with water (20 mL). It was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C020-20d (100 mg). LCMS (ESI) m / z: 547.4 [M+H] + .

[0703] (4) C020-20d (80 mg, 0.15 mmol) was dissolved in a mixture of triethylamine hydrofluoride (1 mL) and acetonitrile (2 mL) and stirred at room temperature for 1 h. After the reaction, the mixture was filtered and purified by reverse phase preparative purification to obtain compound C020 (19.95 mg). LCMS (ESI) m / z: 391.2 [M+H] + ; 1 H NMR(400MHz, DMSO_d6)δ11.20(s,1H),8.17–8.13(m,2H),7.66(d,J=8.0Hz,1H),7.47–7.40(m, 3H),7.14–7.09(m,2H),4.76–4.74(m,1H),3.04–2.97(m,2H),2.81-2.73(m,2H),2.22(s,3H).

[0704] Example 21:

[0705] Synthesis route:

[0706] (1) 3-Fluoro-4-nitroacetophenone (5 g, 27.3 mmol) and methylamine hydrochloride (2.77 g, 41.0 mmol) were added to acetonitrile (100 mL), and potassium carbonate (15.1 g, 109.21 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, it was diluted with water and extracted three times with ethyl acetate (50 mL). The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain C021-21b (5 g, 94.32%).

[0707] (2) C021-21b (5 g, 25.77 mmol) was dissolved in methanol (60 mL), and then Raney nickel was added to the solution. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered and the filtrate was dried to obtain C021-21c (4.2 g).

[0708] (3) C021-21c (3.5 g, 21.34 mmol) was dissolved in THF (50 mL), and triethylamine (4.3 g, 42.68 mmol) and CDI (10.38 g, 64.02 mmol) were added. The mixture was stirred at 60°C for 3 h. After the reaction was completed, ethyl acetate (50 mL) was added for dilution, and water (80 mL) was added. The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain C021-21d (1.9 g).

[0709] (4) C021-21d (1.9 g, 10 mmol) was dissolved in POCl3 (50 mL). The mixture was stirred at 100 ° C for 15 h under nitrogen protection. The reaction solution was cooled to room temperature, phosphorus oxychloride was dried, diluted with ethyl acetate (50 mL), and then water (50 mL) was added. It was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to give C021-21e (900 mg). LCMS (ESI) m / z: 209.1 [M+H] + .

[0710] (5) C021-21e (340 mg, 1.63 mmol) was dissolved in p-xylene (10 mL), and int2 (363 mg, 1.80 mmol) and p-toluenesulfonic acid monohydrate (31 mg, 0.16 mmol) were added and stirred at 150°C for 16 h. After the reaction, methanol was added and the mixture was purified by silica gel column chromatography using a ratio of dichloromethane to methanol (9:1) to give C021-21f (300 mg). LCMS (ESI) m / z: 339.0 [M+H] + .

[0711] (6) C021-21f (270 mg, 0.797 mmol), int6 (108 mg, 0.88 mmol), and p-toluenesulfonic acid (30 mg, 0.16 mmol) were dissolved in acetonitrile (5 mL). The mixture was stirred at 90°C for 5 h. After the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative chromatography to obtain compound C021 (25.89 mg). LCMS (ESI) m / z: 444.4 [M+H] + ; 1H NMR(400MHz,DMSO_d6)δ11.02(s,1H),8.68(s,1H),8.15(s,1H),7.93(s,1H),7.86(s,1H),7.55(s,1H),7.39(d,J=8.0Hz,2H),7 .26(d,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),4.79–4.77(m,1H),3.77(s,3H),3.05-3.02(m,2H),2.80–2.74(m,2H),2.29(s,3H).

[0712] Example 22:

[0713] Synthesis route:

[0714] (1) Dissolve 4a (234 mg, 1.50 mmol) and int2 (366 mg, 1.80 mmol) in glacial acetic acid (5.8 mL). Stir the mixture at 130°C for 2 h. After the reaction, concentrate to dryness under reduced pressure. The resulting residue is crude product C022-22b, which can be used directly in the next step.

[0715] (2) C022-22b (423 mg, 1.50 mmol), int9 (214 mg, 1.23 mmol), and p-toluenesulfonic acid (47 mg, 0.247 mmol) were dissolved in acetonitrile (6 mL). The reaction mixture was reacted at 60°C for 12 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, dissolved in DMF, and purified by preparative analysis to obtain compound C022 (13.29 mg).

[0716] 1 H NMR (400MHz, CD3OD) δ8.31(d,J=2.0Hz,1H),7.84(dd,J=8.8,2.4Hz,1H),7.53(s,1H),7.45(d,J=2.0Hz,1H),7.36(d,J=8.4 Hz,1H),7.11(dd,J=8.4,2.0Hz,1H),6.65(d,J=8.8Hz,1H),4.84(s,1H),2.44–2.34(m,3H),2.20(s,3H),2.17–2.10(m,3H).

[0717] Example 23:

[0718] Synthesis route

[0719] (1) Int10 (2 g, 7.00 mmol), Int6 (1.68 g, 10.5 mmol), and p-toluenesulfonic acid (241.1 mg, 1.40 mmol) were added to acetonitrile (20 ml). The mixture was stirred in an oil bath at 60°C under nitrogen for 12 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by TLC using a mixture of petroleum ether and ethyl acetate (4:1) to obtain compound C023 (18.31 mg).

[0720] 1 H NMR (400MHz, CD3OD) δ8.24(d,J=2.0Hz,1H),7.79(dd,J=8.0,2.0Hz,1H),7.39(s,1H),7.32(d,J=8.0Hz,1H),7.06(t,J=8.0 Hz,1H),6.96(d,J=4.0Hz,1H),6.51(d,J=8.0Hz,1H),4.76-4.67(m,1H),2.98–2.87(m,2H),2.78–2.66(m,2H),2.19(s,3H).

[0721] Example 24:

[0722] Synthesis route

[0723] (1) Crude int11 (200 mg), int6 (172 mg, 0.55 mmol), and p-toluenesulfonic acid hydrate (26 mg, 0.10 mmol) were dissolved in acetonitrile (2.5 mL) and stirred at 90°C for 4 h. After the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined to obtain the residue, which was purified by preparative analysis to yield C024 (12.39 mg).

[0724] 1 H NMR (400MHz, DMSO_d6) δ10.90(s,1H),9.00(s,1H),8.41(d,J=2.0Hz,1H),7.87(d,J=2.0Hz,1H),7.82(dd,J=8.0Hz,2.0Hz,1H),7.67(dd,J=12 .0Hz,8.0Hz,1H),7.35(dd,J=12.0Hz,6.0Hz,1H),6.80(d,J=8.0Hz,1H),4.74–4.72(m,1H),3.04-2.95(m,2H),2.81–2.73(m,2H),2.19(s,3H).

[0725] Example 25:

[0726] Synthesis route

[0727] (1) C025-25a (500 mg, 3.19 mmol, 1 eq), int2 (980 mg, 4.79 mmol, 1.5 eq), Pd2(dba)3 (290 mg, 0.319 mmol, 0.1 eq), tBuBretterPhos (310 mg, 0.638 mmol, 0.2 eq), and K3PO4 (2.03 g, 9.57 mmol, 3 eq) were dissolved in tert-butanol (40 mL), the atmosphere was replaced with nitrogen, and the mixture was stirred at 120°C for 2 h. After the reaction, the solvent was dried and the resulting residue was purified by column chromatography using (petroleum ether:ethyl acetate = 1:1) as the eluent to obtain C025-25b (213 mg, 23.3%).

[0728] (2) C025-25b (213 mg, 0.743 mmol, 1 eq), int6 (138 mg, 1.121 mmol, 1.5 eq), and p-toluenesulfonic acid hydrate (29 mg, 0.152 mmol, 0.2 eq) were dissolved in acetonitrile (5.0 mL) and stirred at 90°C for 4 h. After the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the resulting residue was purified by thin-layer chromatography to afford C025 (18.8 mg).

[0729] 1 H NMR (400MHz, DMSO_d6) δ11.02(s,1H),9.85(s,1H),8.72(s,2H),7.95(d,J=2.0Hz,1H),7.86(d,J=2.0Hz,1H),7. 36(d,J=8.4Hz,1H),7.08(dd,J=8.4,2.0Hz,1H),4.76(s,1H),3.01–2.78(m,2H),2.51–2.50(m,2H),2.21(s,3H).

[0730] Example 26:

[0731] Synthesis route

[0732] (1) Compound C026-26a (800 mg, 5.14 mmol, 1 eq) and int2 (1.25 g, 6.17 mmol, 1.2 eq) were dissolved in glacial acetic acid (15 mL) and stirred at 130°C for 2 h. After the reaction, the reaction solution was evaporated to dryness, and the resulting residue was purified by column chromatography (DCM / MeOH = 50 / 1) to obtain crude product C026-26b (900 mg).

[0733] (2) C026-26b (900 mg, 3.16 mmol, 1 eq), int14 (603 mg, 3.79 mmol, 1.2 eq), and p-toluenesulfonic acid hydrate (120 mg, 0.63 mmol, 0.2 eq) were dissolved in acetonitrile (12.0 mL) and stirred at 90°C for 4 h. After the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined and the resulting residues were purified by preparative analysis to obtain C026. Chiral preparations were then performed to obtain C026-A (23.4 mg, 1.9%) and C026-B (23.2 mg, 1.9%).

[0734] C026: 1 H NMR(400MHz, DMSO_d6)δ10.94(s,1H),9.00(s,1H),8.42(d,J=2.0Hz,1H),7.94–7.77(m,3H),7.36(d,J=8.4Hz,1H),7.09(dd,J=8.4,2.0H z,1H),6.81(d,J=8.8Hz,1H),4.26–4.16(m,1H),4.14–4.03(m,1H),2.18(s,3H),2.15–2.10(m,1H),1.73–1.61(m,1H),1.46–1.34(m,1H).

[0735] Example 27:

[0736] Synthesis route

[0737] (1) 6-Chloronicotinic acid (26.5 g, 162.49 mmol) was added to dichloromethane (500 mL), followed by dimethylhydroxylamine hydrochloride (18.1 g, 178.74 mmol), HATU (70.4 g, 178.74 mmol), and DIEA (94 mL, 487.46 mmol). The mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was extracted with water and dichloromethane, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with (PE:EA=4:1) to obtain C027-27b (28 g).

[0738] (2) C027-27b (4 g, 20 mmol) was dissolved in THF (50 mL), the system was cooled to 0°C, and isopropylmagnesium bromide (30 mL, 1 mmol / L in THF) was added dropwise. The mixture was stirred at room temperature for 16 h. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C027-27c (1.5 g).

[0739] (3) C027-27c (500 mg, 2.76 mmol) and int2 (506 mg, 3.04 mmol) were dissolved in acetic acid (8 mL). The mixture was stirred at 100°C for 2 h under nitrogen. After the reaction, the acetic acid was dried, diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C027-27d (300 mg).

[0740] (4) C027-27d (300 mg, 0.96 mmol) was dissolved in acetonitrile (5 mL), and int6 (142 mg, 1.16 mmol) and p-toluenesulfonic acid (37 mg, 1.93 mmol) were added. The mixture was stirred at 90°C for 4 h. After the reaction, the mixture was filtered and purified by reverse phase chromatography to obtain compound C027 (15.19 mg).

[0741] 1 H NMR(400MHz,DMSO_d6)δ10.96(s,1H),9.01(s,1H),8.17–8.12(m,1H),7.87(d, J=2.0Hz,1H),7.78(s,1H),7.56(d,J=7.2Hz,1H),7.37(d,J=8.4Hz,1H),7.09(d d,J=8.4,2.0Hz,1H),6.80(d,J=8.8Hz,1H),4.82–4.63(m,1H),3.12–2.93(m,2 H),2.80–2.66(m,2H),2.13–2.10(m,1H),0.97–0.92(m,2H),0.66–0.63(m,2H).

[0742] Example 28:

[0743] Synthesis route

[0744] (1) In a 50 mL sealed bottle, compound C028-28a (100 mg, 0.642 mmol), compound int2 (154 mg, 0.770 mmol), Pd2(dba)3 (58 mg, 0.064 mmol), cesium carbonate (418 mg, 1.284 mmol), and t-Bubrettphos (62 mg, 0.128 mmol) dissolved in dioxane (4 mL) were added and reacted at 100°C for 2 hours. After cooling, the reaction solution was washed with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain C028-28b (200 mg).

[0745] (2) C028-28b (100 mg, 0.35 mmol) and int6 (51 mg, 0.42 mmol) were dissolved in acetonitrile (2 mL), and p-toluenesulfonic acid (11.98 mg, 0.07 mmol) was added. The mixture was stirred at 90°C under nitrogen for 4 hours. After the reaction, the reaction solution was concentrated. The resulting residue was purified by preparative analysis to obtain compound C028 (37.42 mg).

[0746] 1 H NMR(400MHz, DMSO_d6)δ10.85(s,1H),8.90(s,1H),8.15(d,J=8.0Hz,1H),7.91(s,1H),7.83(s,1H)7.35(d,J=8.0Hz, 1H),7.09–7.06(m,2H),6.88(d,J=4.0Hz,1H),4.83–4.79(m,1H),3.07–2.98(m,2H),2.83–2.74(m,2H),2.19(s,3H).

[0747] Example 29:

[0748] Synthesis route

[0749] (1) C029-29a (800 mg, 5.14 mmol), int2 (1.246 g, 6.17 mmol), t-BuBrettphos (499 mg, 1.03 mmol), Pd2(dba)3 (470 mg, 0.514 mmol) and potassium phosphate (3.27 g, 15.4 mmol) were dissolved in tert-butanol (15 mL). The mixture was stirred at 120 ° C for 5 h under nitrogen protection. After the reaction was completed, it was diluted with ethyl acetate, and then water was added. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography and eluted with (ethyl acetate: petroleum ether = 1:1) to obtain C029-29b (300 mg).

[0750] (2) C029-29b (200 mg, 0.70 mmol) was dissolved in acetonitrile (5 mL), and int6 (95 mg, 0.77 mmol) and p-toluenesulfonic acid (27 mg, 0.14 mmol) were added. The mixture was stirred at 90°C for 4 h. After the reaction, the mixture was filtered and purified by reverse phase chromatography to obtain compound C029 (24.73 mg).

[0751] 1 H NMR (400MHz, DMSO_d6) δ10.87(s,1H),8.88(s,1H),7.93(d,J=2.0Hz,1H),7.86(d,J=2.0Hz,1H),7.56–7.50(m,1H),7.35(d,J =8.4Hz,1H),7.14–7.06(m,2H),6.85(d,J=8.0Hz,1H),4.83–4.79(m,1H),3.08–3.01(m,2H),2.81–2.76(m,2H),2.31(s,3H).

[0752] Example 31:

[0753] Synthesis route

[0754] (1) Int5 (400 mg, 1.39 mmol, 1 eq), O-benzylhydroxylamine (267 mg, 1.67 mmol, 1.2 eq), and p-toluenesulfonic acid hydrate (48 mg, 0.279 mmol, 0.2 eq) were dissolved in acetonitrile (3.0 mL) and stirred at 90°C for 4 h. After the reaction, the reaction solution was filtered, washed with acetonitrile, and the organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative analysis to obtain compound C031 (17.02 mg).

[0755] 1H NMR(400MHz, DMSO_d6)δ10.94(s,1H),9.00(s,1H),8.39(d,J=4.0Hz,1H),7.90(d,J=4.0Hz,1H),7.80–7.7 8(m,2H),7.40–7.35(m,6H),7.08(dd,J=8.0,2.0Hz,1H),6.80(d,J=8.0Hz,1H),5.16(s,2H),2.19(s,3H).

[0756] Example 32:

[0757] Synthesis route

[0758] Int12 (220 mg, 0.40 mmol) was dissolved in acetonitrile (5 mL), and int6 (58 mg, 0.475 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol) were added and stirred at 90°C for 4 h. After the reaction, the mixture was filtered and purified by reverse phase to obtain compound C032 (22.71 mg).

[0759] 1 H NMR(400MHz, DMSO_d6)δ10.99(s,1H),9.11(s,1H),8.43(d,J=2.0Hz,1H),7.96–7.92(m,3H),7.82(d,J=2.0Hz,1H), 7.35(d,J=12.0Hz,1H),6.84(d,J=8.8Hz,1H),4.75–7.72(m,1H),3.04–2.97(m,2H),2.78–2.73(m,2H),2.20(s,3H).

[0760] Example 33:

[0761] Synthesis route

[0762] Int13 (100 mg, 0.348 mmol), int6 (50 mg, 0.418 mmol), and PTSA (15 mg, 0.05 mmol) were added sequentially to acetonitrile (5 mL). The mixture was stirred in a 60°C oil bath under nitrogen for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative chromatography to yield compound C033 (2.7 mg).

[0763] 1H NMR (400MHz, DMSO_d6) δ11.64(s,1H),9.37(s,1H),8.37(s,1H),8.23(s,2H),7.99(d,J=4.0Hz,1H),7.91(d ,J=8.0Hz,1H),6.88(d,J=8.0Hz,1H),4.77–4.75(m,1H),3.02-2.95(m,2H),2.84–2.71(m,2H),2.20(s,3H).

[0764] Example 34:

[0765] Synthesis route

[0766] (1) C034-34a (100 mg, 0.528 mmol), int2 (212 mg, 1.05 mmol), and DIEA (0.1 mL, 1.05 mmol) were dissolved in DMSO (10 mL). The mixture was stirred in an oil bath at 90°C for 3 h under nitrogen. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate (1:1) as the eluent to obtain C034-34b (50 mg).

[0767] (2) C034-34b (50 mg, 0.156 mmol), int6 (30 mg, 0.372 mmol), and PTSA (12 mg, 0.062 mmol) were added sequentially to acetonitrile (5 mL). The mixture was stirred in an oil bath at 60°C under nitrogen for 4 h. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative chromatography to obtain compound C034 (2.7 mg).

[0768] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.43(s,1H),8.27(d,J=4.0Hz,1H),7.97(d,J=4.0Hz,1H),7.65(d,J=4.0Hz,1H),7. 49(s,1H),7.39(d,J=8.0Hz,1H),7.12–7.04(m,1H),4.76–4.74(m,1H),3.06–2.95(m,2H),2.78–2.73(m,2H),2.18(s,3H).

[0769] Example 35:

[0770] Synthesis route

[0771] Int24 (2.17 g, 7.14 mmol), int6 (1.37 g, 8.57 mmol) and p-toluenesulfonic acid (272 mg, 1.43 mmol) were dissolved in acetonitrile (39 mL). The reaction solution was reacted at 80°C for 2 hours. After the reaction was completed, it was cooled to room temperature and filtered. The filter cake was transferred to a 250 mL single-necked reaction flask, ethyl acetate (100 mL) and water (40 mL) were added, and concentrated ammonia (0.1 mL) was added dropwise with stirring. After the organic layer was dissolved and cleared, the organic phase was separated, and the aqueous phase was extracted once with ethyl acetate (20 mL). The organic phases were combined, dried, filtered, and concentrated, and then purified by high-performance liquid chromatography preparative analysis to obtain compound C035 (698.80 mg).

[0772] 1 H NMR (400MHz, DMSO_d6) δ11.04(s,1H),8.91(s,1H),8.22(s,1H),7.86(d,J=2.4Hz,1H),7.82(d,J=2.0Hz,1H),7.73(dd,J=12.8,2. 0Hz,1H),7.37(d,J=8.8Hz,1H),7.08(dd,J=8.4,2.0Hz,1H),4.79–4.72(m,1H),3.03–2.99(m,2H),2.79–2.74(m,2H),2.20(s,3H).

[0773] Example 36:

[0774] Synthesis route

[0775] (1) Compound C036-36a (500 mg, 3.19 mmol) and int2 (649 mg, 3.19 mmol) were dissolved in N,N-dimethylformamide (15 mL) and triethylamine (970 mg, 9.58 mmol) was added. The mixture was stirred at 120°C for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and slurried with ethyl acetate to obtain C036-36b, which was used directly in the next step.

[0776] (2) C036-36b (100 mg, 0.34 mmol), int6 (108 mg, 0.68 mmol), and p-toluenesulfonic acid (13 mg, 0.068 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was reacted at 90°C for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative analysis to obtain compound C036 (2.2 mg). 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.58(s,1H),8.57(d,J=4.0Hz,1H),8.25(d,J=4.0Hz,1H),7.90(dd,J=36.0,2.1Hz,2H),7.3 9(d,J=8.0Hz,1H),7.12(dd,J=8.0,2.0Hz,1H),4.80(s,1H),3.02(dt,J=20.0,7.5Hz,2H),2.80(tt,J=12,7.2Hz,2H),2.23(s,3H).

[0777] Example 37:

[0778] Synthesis route

[0779] Int21 (138 mg, 0.461 mmol) and Int6 (68 mg, 0.554 mmol) were dissolved in ACN (2 mL), and p-toluenesulfonic acid hydrate (15 mg, 0.092 mmol) was added. The mixture was stirred at 90°C under nitrogen for 4 h. After completion of the reaction, the mixture was filtered, and the filter cake was washed with acetonitrile. The organic phases were combined, and the resulting residue was purified by reverse phase preparative analysis to yield compound C037 (25.53 mg).

[0780] 1 H NMR(400MHz, DMSO_d6)δ10.97(s,1H),8.93(s,1H),7.91(s,1H),7.76(s,1H),7.48(s,1H),7.38(d,J=8.8Hz,1H),7.11–7.08( m,1H),6.66(s,1H),6.65(d,J=8.4Hz,1H),4.74–4.72(m,1H),3.09–2.95(m,2H),2.77–2.31(m,2H),2.46(s,1H),2.15(s,1H).

[0781] Example 38:

[0782] Synthesis route

[0783] Compounds int25 (150 mg, 0.50 mmol), int6 (80 mg, 0.55 mmol), and p-toluenesulfonic acid hydrate (19 mg, 0.10 mmol) were dissolved in acetonitrile (5.0 mL) and stirred at 90°C for 4 h. After completion of the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined to obtain a residue which was purified by preparative analysis to afford C038 (18.69 mg).

[0784] 1 H NMR (400MHz, DMSO_d6) δ10.92(s,1H),8.79(s,1H),8.39(s,1H),8.07(s,1H),7.84(d,J=2.0Hz,1H),7.76(d,J=2.0Hz,1H),7.36(d ,J=8.6Hz,1H),7.09–7.07(m,1H),6.63(s,1H),4.81–4.62(m,1H),3.04–2.93(m,2H),2.82–2.68(m,2H),2.26(s,3H),2.17(s,3H).

[0785] Example 39:

[0786] Synthesis route

[0787] Int26 (200 mg, 0.66 mmol, 1 eq), int6 (126 mg, 0.79 mmol, 1.2 eq) and p-toluenesulfonic acid hydrate (25 mg, 0.13 mmol, 0.2 eq) were dissolved in DMF (5.0 mL) and stirred at 120°C for 4 h. After the reaction, the reaction solution was dried and the resulting residue was purified by column chromatography (PE / EA = 4 / 1) to give C039 (70 mg).

[0788] 1 H NMR (400MHz, DMSO_d6) δ11.05(s,1H),9.34(s,1H),7.81–7.75(m,3H),7.39(d,J=8.4Hz,1H),7.11(dd,J=8.4,2. 0Hz,1H),6.70(d,J=8.0Hz,1H),4.79–4.70(m,1H),3.03–2.96(m,2H),2.80–2.73(m,2H),2.18(d,J=2.4Hz,3H).

[0789] Example 40:

[0790] Synthesis route

[0791] Int15 (400 mg, 1.27 mmol), int6 (187 mg, 1.52 mmol) and p-toluenesulfonic acid hydrate (48 mg, 0.25 mmol) were dissolved in acetonitrile (5.0 mL) and stirred at 90°C for 4 hours. After the reaction, the reaction solution was concentrated and extracted with dichloromethane. The combined organic phases were purified by column chromatography using (petroleum ether:ethyl acetate = 4:1) as the eluent to obtain compounds C040-a (45 mg) and C40-b (40 mg).

[0792] C040-a: 1 H NMR (400MHz, CD3OD) δ8.07(d,J=4.0Hz,1H),7.50–7.49(m,2H),7.44(d,J=4.0Hz,1H),7.33(d,J=12.0Hz,1H),7.09(dd,J =8.0,4.0Hz,1H),6.64(d,J=12.0Hz,1H),4.62–4.60(m,1H),2.93–2.78(m,3H),2.71–2.59(m,2H),1.13(d,J=8.0Hz,6H).

[0793] C40-b: 1 H NMR (400MHz, CD3OD) δ8.10–8.06(m,1H),7.59(dd,J=8.0,2.0Hz,1H),7.49(s,1H),7.42(d,J=4.0Hz,1H),7.34(d,J=8.0Hz,1H),7.09(dd,J =8.0,2.0Hz,1H),6.62(d,J=8.0Hz,1H),4.75–4.64(m,1H),3.42–3.28(m,1H),3.02–2.86(m,2H),2.79–2.62(m,2H),1.23(d,J=8.0Hz,6H).

[0794] Example 41:

[0795] Synthesis route

[0796] Int5 (500 mg, 1.74 mmol) and int16 (300 mg, 2.5 mmol) were dissolved in acetonitrile (5 mL), followed by the addition of p-toluenesulfonic acid (50 mg, 0.26 mmol). The mixture was stirred at 90°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was concentrated. The resulting residue was purified by reverse phase preparative analysis to yield compound C041 (13.16 mg).

[0797] 1 H NMR (400MHz, DMSO_d6) δ10.94(s,1H),8.99(s,1H),8.40(d,J=4.0Hz,1H),7.90(d,J=4.0Hz,1H),7.86–7.77(m,2H),7.36(d,J=8.0Hz,1H),7.09(dd,J =8.0,2.0Hz,1H),6.81(d,J=8.0Hz,1H),4.33–4.28(m,1H),3.87–3.78(m, 2H),3.48–3.42(m,2H),2.18(s,3H),1.99-1.96(m,2H),1.65–1.56(m,2H).

[0798] Example 42:

[0799] Synthesis route

[0800] (1) 6-Hydroxynicotinic acid (5 g, 35.94 mmol) was added to water (10 mL) and methanol (70 mL), followed by the addition of iodomethane (21 mL, 359.43 mmol). The mixture was stirred at 100°C for 16 h. After the reaction, the mixture was extracted with water (200 mL) and dichloromethane (100 mL x 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using PE:EA = 4:1 as the eluent to obtain C042-42b (2.1 g).

[0801] (2) C042-42b (5.1 g, 33.3 mmol) was added to acetonitrile (100 mL), followed by dimethylhydroxylamine hydrochloride (3.9 g, 39.9 mmol), T3P (32 g, 49.9 mmol, 50% in DMF), and pyridine (7.9 g, 99.9 mmol). The mixture was stirred at room temperature for 16 h. After the reaction, the mixture was extracted with water (200 mL) and dichloromethane (100 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 8:1) as the eluent to obtain C042-42c (1.9 g).

[0802] (3) C042-42c (1.5 g, 7.65 mmol) was dissolved in THF (15 mL), the system was cooled to 0°C, and methylmagnesium bromide (4 mL, 3 mmol / L in THF) was added dropwise. The mixture was stirred at room temperature for 16 h. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride (5 mL), diluted with water (50 mL), and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and eluted with ethyl acetate to obtain C042-42d (490 mg).

[0803] (4) C042-42d (420 mg, 2.78 mmol) was added to DMF (10 mL), followed by the addition of NCS (371 mg, 2.78 mmol). The mixture was stirred at 50°C for 2 h. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using (PE:EA = 2:1) as the eluent to obtain C042-42e (360 mg).

[0804] (5) C042-42e (270 mg, 1.45 mmol), int2 (244 mg, 1.21 mmol), t-BuBrettphos (117 mg, 0.24 mmol), Pd2(dba)3 (111 mg, 0.12 mmol) and potassium phosphate (769 mg, 3.63 mmol) were dissolved in tert-butanol (5 mL). The mixture was stirred at 120°C for 5 h under nitrogen. After the reaction, ethyl acetate (30 mL) was added for dilution. Water (30 mL) was then added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using (ethyl acetate: petroleum ether = 1:1) as the eluent to obtain compound C042-42f (330 mg).

[0805] (6) C042-42f (170 mg, 0.54 mmol) was dissolved in acetonitrile (5 mL), and int6 (73 mg, 0.59 mmol) and p-toluenesulfonic acid (21 mg, 0.11 mmol) were added. The mixture was stirred at 90°C for 4 h. After the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by HPLC to obtain compound C042 (11.1 mg). 1H NMR(400MHz,DMSO_d6)δ11.20(s,1H),7.42–7.40(m,3H),7.30(s,1H),7.11(d,J=6.8Hz,1H),6.2 4–6.19(m,2H),4.76(br.s,1H),3.50(s,3H),3.05–2.95(m,2H),2.77–2.66(m,2H),2.13(s,3H).

[0806] Example 43:

[0807] Synthesis route

[0808] Int22 (89 mg, 0.755 mmol) and int5 (180 mg, 0.629 mmol) were dissolved in acetonitrile (2 mL), followed by the addition of p-toluenesulfonic acid (10 mg, 0.063 mmol). The mixture was stirred at 70°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was concentrated. The resulting residue was purified by preparative analysis to yield compound C043 (13.67 mg).

[0809] 1 H NMR (400MHz, CD3OD) δ8.27(d,J=2.0Hz,1H),7.80(dd,J=8.0,2.0Hz,1H),7.50(s,1H),7.42(d,J=2.0Hz,1H),7.33(d,J=8.0Hz,1H),7.08(dd, J=4.0,4.0Hz,1H),6.62(d,J=8.0Hz,1H),4.82–4.77(m,1H),4.43(dd,J=8.0,4.0Hz,2H),2.66–2.57(m,1H),2.39–2.24(m,4H),2.17(s,3H).

[0810] Example 44:

[0811] Synthesis route

[0812] Int17 (183 mg, 0.645 mmol), int5 (114 mg, 0.774 mmol), and PTSA (25 mg, 0.129 mmol) were added sequentially to acetonitrile (5 mL). The mixture was stirred in a 60°C oil bath under nitrogen for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by reverse preparative method to yield compound C044 (2.1 mg).

[0813] 1 H NMR (400MHz, CDCl3) δ8.36(d,J=4.0Hz,1H),8.14(s,1H),7.79(dd,J=8.0,2.0Hz,1H),7.40(d,J=12.0Hz,2H),7.33(d,J=8.0Hz,1H),7.20(dd,J =8.0,4.0Hz,1H),6.73(s,1H),6.47(d,J=8.0Hz,1H),5.12–4.81(m,1H) ,3.21–3.16(m,1H),2.76–2.69(m,2H),2.68–2.61(m,2H),2.20(s,3H).

[0814] Example 45:

[0815] Synthesis route

[0816] Compound int18 (100 mg, 3.03 mmol) and compound int5 (566 mg, 3.64 mmol) were dissolved in acetic acid (5.0 mL) and stirred at 130° C. for 4 hours. After the reaction, the reaction solution was concentrated to obtain compound C045 (600 mg).

[0817] 1 H NMR (400MHz, CD3OD) δ8.26(s,1H),7.80(dd,J=8.0,2.0Hz,1H),7.49(s,1H),7.42(s,1H),7.33(d,J=8.0Hz,1H),7.09(d,J= 8.0Hz,1H),6.62(d,J=8.0Hz,1H),4.74–4.69(m,1H),2.32–2.26(m,2H),2.18(s,3H),2.16–2.08(m,2H),1.79–1.62(m,2H).

[0818] Example 46:

[0819] Step 1:

[0820] Dissolve sodium hydride (1.72 g, 43.1 mmol) in ultra-dry tetrahydrofuran (350 mL) in a 1 L three-necked reaction flask and cool to 0°C in an ice-water bath under nitrogen. Dissolve C046-1 (5.00 g, 43.1 mmol) in ultra-dry tetrahydrofuran (50 mL) and slowly add dropwise to the reaction flask (approximately 20 minutes). After the addition is complete, stir the reaction solution at 0°C for 1 hour. Add benzyl bromide (7.37 g, 43.1 mmol) dropwise to the reaction solution. After the addition is complete, quickly add tetrabutylammonium iodide (1.59 g, 4.31 mmol) under nitrogen. Continue the ice-water bath for 10 minutes, then stir at room temperature for 12 hours. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution (17 mL), and the mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The residue was dissolved in dichloromethane (200 mL), washed once with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate (3:1) to obtain compound C046-2 (4.3 g, 48.43%) as a colorless liquid.

[0821] 1 H NMR(400MHz,DMSO_d6)δ7.35–7.24(m,5H),4.60–4.58(m,1H),4.49(s,2H),3.38–3.25(m,2H), 2.25–2.21(m,1H),1.96–1.93(m,1H),1.77–1.75(m,1H),1.68–1.64(m,1H),1.13–0.98(m,4H).

[0822] Step 2:

[0823] Compound C046-2 (4.3 g, 20.87 mmol) was dissolved in dichloromethane (120 mL). Dess-Martin reagent (10.62 g, 25.04 mmol) was added under ice-water bath and stirred at 0°C for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filter cake was rinsed twice with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate (10:1) to obtain compound C046-3 (3.8 g, 90.09%) as a colorless liquid.

[0824] 1 H NMR(400MHz,DMSO_d6)δ7.36–7.25(m,5H),4.50–4.43(m,2H),3.93–3.89(m,1H),2.64–2 .60(m,1H),2.45–2.40(m,1H),2.31–2.19(m,2H),1.91–1.85(m,3H),1.71–1.62(m,1H).

[0825] Step 3:

[0826] Compound C046-3 (3.8 g, 18.62 mmol) was dissolved in anhydrous 1,2-dichloroethane (12 mL). Bis(2-methoxyethyl)aminosulfur trifluoride (BAST, 5 mL, 27.12 mmol) was added and stirred at 90°C under nitrogen overnight (16 hours). After the reaction was completed, the mixture was cooled to room temperature and slowly added dropwise to a saturated aqueous sodium bicarbonate solution cooled to 0°C. After the addition was complete, the mixture was stirred at room temperature for 0.5 hours until no bubbles appeared. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate (20:1) to obtain compound C046-4 (2.7 g, 64%) as a colorless liquid.

[0827] 1 H NMR(400MHz, DMSO_d6)δ7.38–7.25(m,5H),4.56–4.46(m,2H),3.58–3.53(m,1H),2.44–2.31(m,1H),2.00–1.69(m,5H),0.88-0.82(m,2H).

[0828] Step 4:

[0829] Compound C046-4 (2.7 g, 11.94 mmol) was dissolved in methanol (36 mL), acetic acid (7.2 mL) and 10% wet palladium on carbon (1.1 g) were added, and the mixture was placed in an autoclave and replaced with hydrogen four times. The hydrogen pressure in the autoclave was adjusted to 50 psi and stirred at room temperature overnight (16 hours). After the reaction was completed, the reaction solution was filtered and the filter cake was rinsed with methanol (10 mL). The methanol was distilled at 90°C under normal pressure to remove the methanol (the top temperature dropped to 40°C). The remaining solution after cooling was diluted with anhydrous ether (50 mL), and sodium carbonate powder (11 g) was added with stirring. The mixture was stirred for 2 hours under nitrogen protection (without replacement). The mixture was filtered and the filter cake was rinsed with anhydrous ether (10 mL) three times. The anhydrous ether was distilled at 40°C under normal pressure to remove the anhydrous ether to obtain crude compound C046-5 (1.5 g).

[0830] 1 H NMR(400MHz,DMSO_d6)δ4.95(br.s,1H),3.68–3.61(m,6H),2.30–2.19(m,1H) ,1.98–1.83(m,2H),1.80–1.59(m,3H),1.44–1.33(m,1H),1.31–1.16(m,1H).

[0831] Step 5:

[0832] Compound C046-6 (3.6 g, 22.05 mmol) was dissolved in anhydrous toluene (50 mL) in a three-necked reaction flask. Under nitrogen purge and protection, a solution of crude compound C046-5 (1.5 g, 11.025 mmol) in anhydrous tetrahydrofuran (15 mL), a solution of triphenylphosphine (5.78 g, 22.05 mmol) in anhydrous tetrahydrofuran (60 mL), and a solution of di-tert-butyl azodicarboxylate (DBAD, 5.07 g, 22.05 mmol) in anhydrous tetrahydrofuran (50 mL) were added dropwise at 0°C. After the addition was complete, the reaction solution was naturally warmed to room temperature and stirred overnight (12 hours). After completion of the reaction, water (40 mL) was added to quench the reaction and stirred for 20 minutes. The organic phase was then separated and the aqueous phase was extracted three times with dichloromethane (40 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (10:1) to give compound C046-7 (515 mg, yield 16.14%) as a white solid.

[0833] 1 H NMR(400MHz, DMSO_d6)δ7.86(s,4H),4.35–4.28(m,1H),2.18–1.82(m,4H),1.64–1.56(m,1H),1.44–1.34(m,3H).

[0834] Step 6:

[0835] Compound C046-7 (515 mg, 1.83 mmol) was dissolved in a mixed solvent of dichloromethane (4 mL) and methanol (0.4 mL). The mixture was cooled to 0°C in an ice-water bath under nitrogen. Hydrazine hydrate (98%, 183.21 mg, 3.66 mmol) was added dropwise. After completion of the addition, the mixture was naturally warmed to room temperature and reacted for 2 hours. The reaction solution was filtered, and the filter cake was washed twice with dichloromethane (5 mL). Dilute hydrochloric acid (1 mol / L, 15 mL) was added to the filtrate and stirred for 0.5 hours. The aqueous phase was separated and lyophilized to obtain compound C046-8 (192 mg, 59.47%).

[0836] 1 H NMR(400MHz, DMSO_d6)δ11.2(br.s,3H),4.34–4.28(m,1H),2.07–1.77(m,6H),1.55–1.38(m,2H).

[0837] Step 7:

[0838] Compound C046-9 (400 mg, 2.571 mmol) and compound C046-10 (626 mg, 3.085 mmol) were dissolved in glacial acetic acid (10 mL). The mixture was stirred at 130°C for 2 hours. After completion of the reaction, the product was concentrated to dryness under reduced pressure. The resulting residue was crude compound C046-11, which was used directly in the next step.

[0839] LCMS (ESI) m / z: 286.0 [M+H] + .

[0840] Step 8:

[0841] Compound C046-11 (436 mg, 1.525 mmol), compound C046-8 (192 mg, 1.27 mmol), and p-toluenesulfonic acid (48 mg, 0.254 mmol) were dissolved in acetonitrile (6 mL). The reaction mixture was allowed to react at 60°C for 12 hours. After completion of the reaction, the product was concentrated to dryness under reduced pressure, dissolved in DMF, and purified by preparative analysis to yield compound C046 (3.85 mg) as a white solid.

[0842] LCMS (ESI) m / z: 419.0 [M+H] + .

[0843] Example 47:

[0844] Synthesis route

[0845] Compound int5 (600 mg, 2.10 mmol), C047-47a (400 mg, 2.26 mmol), and p-toluenesulfonic acid hydrate (72 mg, 0.42 mmol) were dissolved in acetonitrile (10.0 mL) and stirred at 70°C for 4 h. After completion of the reaction, the reaction solution was concentrated, and the resulting residue was purified by preparative analysis to afford C047 (24.10 mg).

[0846] 1 H NMR(400MHz, DMSO_d6)δ10.94(s,1H),9.01(s,1H),8.39(d,J=2.4Hz,1H),7.90(s,1H),7.79–7.76(m,2H),7.48–7.44(m,2 H),7.36(d,J=8.4Hz,1H),7.22–7.18(m,2H),7.08(dd,J=8.4,2.0Hz,1H),6.80(d,J=8.8Hz,1H),5.14(s,2H),2.18(s,3H).

[0847] Example 48:

[0848] Synthesis route

[0849] Compounds int5 (194 mg, 0.68 mmol) and int19 (130 mg, 0.81 mmol) were dissolved in acetonitrile (3 mL), followed by the addition of p-toluenesulfonic acid (27 mg, 0.14 mmol). The mixture was stirred at 60°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was concentrated. The resulting residue was purified by reverse phase preparative analysis to yield compound C048 (30.19 mg).

[0850] 1 H NMR (400MHz, DMSO_d6) δ10.94(s,1H),9.01(s,1H),8.56(d,J=4.0Hz,2H),8.39(d,J=2.0Hz,1H),8.18(s,0.36H),7.89(d,J=4 .0Hz,1H),7.78–7.75(m,2H),7.38–7.35(m,3H),7.08(dd,J=8.0,4.0Hz,1H),6.79(d,J=8.0Hz,1H),5.22(s,2H),2.26(s,3H).

[0851] Example 49:

[0852] Synthesis route

[0853] Int5 (260 mg, 0.640 mmol) and int23 (154 mg, 0.770 mmol) were dissolved in ACN (2 mL), and p-toluenesulfonic acid hydrate (25 mg, 0.130 mmol) was added. The mixture was stirred at 90°C under nitrogen for 4 h. After completion of the reaction, the reaction mixture was filtered and washed with acetonitrile. The organic phases were combined to obtain the residue, which was then purified by preparative analysis to yield compound C049 (44.15 mg).

[0854] 1 H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.01(s,1H),8.41(s,1H),8.29(s,1H),7.94–7.65( m,5H),7.37(d,J=12.0Hz,1H),7.10(d,J=2.0Hz,1H),6.82(d,J=8.0Hz,1H),5.06(s,2H).

[0855] Example 50:

[0856] Synthesis route

[0857] (1) Compound C050-50a (100 mg, 0.613 mmol, 1 eq) and compound int2 (148 mg, 0.735 mmol, 1.2 eq) were dissolved in dimethyl sulfoxide (2 mL), and DIEA (0.2 mL, 1.225 mmol, 2.0 eq) was added and stirred at 90°C for 4 h. After completion of the reaction, the mixture was extracted with dichloromethane and water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain compound C050-50b (143 mg).

[0858] (2) C050-50b (143 mg, 0.461 mmol, 1 eq), compound int6 (68 mg, 0.553 mmol, 1.2 eq), and p-toluenesulfonic acid hydrate (15.8 mg, 0.092 mmol, 0.2 eq) were dissolved in acetonitrile (3.0 mL) and stirred at 60°C for 4 h. After the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined, the resulting residues were purified by reverse phase preparative analysis, and compound C050 (41.59 mg) was obtained.

[0859] 1 H NMR(400MHz, DMSO_d6)δ11.36(s,1H),8.54(s,1H),8.25(s,1H),7.81(d,J=4.0Hz,1H),7.67–7.64(m,1H),7.45–7.43(m,2H),7.24 (s,1H),7.13(dd,J=8.0,4.0Hz,1H),6.57(d,J=8.0Hz,1H),4.75–4.67(m,1H),3.00–2.97(m,2H),2.75–2.70(m,2H),2.16(s,3H).

[0860] Example 51:

[0861] Synthesis route

[0862] Compound int5 (310 mg, 1.10 mmol) and compound int20 (227 mg, 1.32 mmol) were dissolved in acetonitrile (5 mL), followed by the addition of p-toluenesulfonic acid (42 mg, 0.22 mmol). The mixture was stirred at 60°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was concentrated. The resulting residue was purified by HPLC to yield compound C051 (32.93 mg).

[0863] 1 H NMR (400MHz, CD3OD) δ8.28(d,J=4.0Hz,1H),7.81(dd,J=8.0,4.0Hz,1H),7.50(s,1H),7.42(s,1H),7.33(d,J=8.0Hz,1H),7 .09(dd,J=8.0,4.0Hz,1H),6.63(d,J=8.0Hz,1H),4.18(d,J=8.0Hz,2H),2.72–2.51(m,3H),2.49–2.35(m,2H),2.18(s,3H).

[0864] Example 52:

[0865] Synthesis route

[0866] Int5 (220 mg, 0.77 mmol), int44 (140 mg, 0.85 mmol), and p-toluenesulfonic acid (30 mg, 0.15 mmol) were dissolved in acetonitrile (6 mL). The reaction mixture was incubated at 60°C for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by HPLC to yield compound C052 (57.06 mg).

[0867] 1 H NMR(400MHz,DMSO_d6)δ10.94(s,1H),9.02(s,1H),8.40(d,J=2.0Hz,1H),7.9 2(d,J=2.0Hz,1H),7.83–7.81(m,2H),7.37(d,J=8.4Hz,1H),7.09(dd,J=8.4, 2.0Hz,1H),6.83(d,J=8.8Hz,1H),4.36–4.31(m,1H),2.64–2.51(m,1H),2.47 –2.30(m,1H),2.16(s,3H),2.13–1.93(m,3H),1.82–1.73(m,2H),1.58(s,3H).

[0868] Example 53:

[0869] Synthesis route

[0870] Int26 (100 mg, 0.33 mmol), int7 (60 mg, 0.39 mmol), and p-toluenesulfonic acid hydrate (12 mg, 0.06 mmol) were dissolved in DMF (2.0 mL) and stirred at 120°C for 4 h. After completion of the reaction, the reaction mixture was filtered and purified by HPLC to obtain C053 (24.34 mg). 1 H NMR (400MHz, CD3OD) δ7.75–7.70(m,1H),7.66(s,1H),7.55(s,1H),7.32(d,J=8.0Hz,1H),7.09(dd, J=8.0,2.0Hz,1H),6.53(d,J=8.0Hz,1H),4.33(br.s,1H),2.22(d,J=4.0Hz,3H),2.08–1.88(m,8H).

[0871] Example 54:

[0872] Synthesis route

[0873] Int21 (250 mg, 0.84 mmol), int7 (127 mg, 0.84 mmol), and p-toluenesulfonic acid hydrate (32 mg, 0.17 mmol) were dissolved in DMF (5.0 mL) and stirred at 120°C for 4 h. After the reaction, the reaction solution was directly purified by HPLC to obtain C054 (40 mg).

[0874] 1 H NMR (400MHz, CD3OD) δ7.55(s,1H),7.43(s,1H),7.38–7.31(m,2H),7.08(d,J=8.8Hz,1H),6.42(d ,J=9.2Hz,1H),4.30(br.s,1H),2.45(d,J=2.0Hz,3H),2.17(d,J=2.0Hz,3H),2.10–1.76(m,8H).

[0875] Example 55:

[0876] Synthesis route

[0877] (1) In a 250 mL single-necked reaction flask, C055-a (4.50 g, 24.38 mmol) was dissolved in toluene (72 mL). The catalyst, tetrakis(triphenylphosphine)palladium (2.54 g, 2.44 mmol) and C055-b (15.3 mL, 48.76 mmol), were added. The mixture was heated to 110°C in an oil bath under nitrogen and stirred for 16 hours. After the reaction was complete (TLC showed no starting material), the mixture was concentrated under reduced pressure to obtain crude C055-c, which was used directly in the next step.

[0878] (2) Aqueous hydrochloric acid (2 mol / L, 60 mL, 120 mmol) was added to a single-necked bottle containing the crude product C055-c (7.0 g, 24.38 mmol) and stirred in an oil bath at 60°C for 2 hours. After the reaction was completed, the product was cooled to room temperature and extracted twice with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate (1:1) as the eluent to obtain C055-d (2.6 g). 1 H NMR(400MHz,DMSO_d6)δ9.08(s,2H),2.59(s,6H).

[0879] (3) C055-d (2.6 g, 15.46 mmol) was dissolved in anhydrous dichloromethane (42 mL), and m-chloroperbenzoic acid (3.5 g, 20.28 mmol) was added in batches under stirring in an ice-water bath. After the addition, stirring in an ice-water bath was continued for 2 hours. After the reaction was completed, sodium bicarbonate aqueous solution was added dropwise under an ice-water bath to neutralize to pH = 7-8, and sodium bisulfite aqueous solution was added dropwise to consume the excess m-chloroperbenzoic acid. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography and eluted with (dichloromethane: methanol = 9:1) to obtain C055-e (1.6 g). LCMS (ESI) m / z: 185.0 [M+H] + .

[0880] (4) C055-e (1.0 g, 5.43 mmol) was dissolved in 1,4-dioxane (24 mL), int2 (919 mg, 4.52 mmol) and N,N-diisopropylethylamine (1.75 g, 13.57 mmol) were added, and stirred at 60°C for 2 hours. After the reaction was completed (7-LCMS), the reaction solution was concentrated to dryness under reduced pressure, slurried with ethyl acetate (10 mL), and filtered to obtain compound C055-f. LCMS (ESI) m / z: 287.0 [M+H] + .

[0881] (5) C055-f (200 mg, 0.698 mmol), int7 (158 mg, 0.837 mmol) and p-toluenesulfonic acid monohydrate (27 mg, 0.140 mmol) were dissolved in acetonitrile (4.6 mL). The reaction mixture was reacted at 60°C for 4 hours. After the reaction was completed, the mixture was filtered and the filter cake was dissolved in DMF and purified by HPLC to obtain compound C055 (107.85 mg). LCMS (ESI) m / z: 420.3 [M+H] + .

[0882] Example 56:

[0883] Synthesis route

[0884] (1) Compound C056-56a (500 mg, 3.19 mmol) and compound C056-56b (649 mg, 3.19 mmol) were dissolved in N,N-dimethylformamide (15 mL), and triethylamine (970 mg, 9.58 mmol) was added. The mixture was stirred at 120°C for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and slurried with ethyl acetate. The resulting product C056-56c was used directly in the next step (450 mg).

[0885] (2) C056-56c (217 mg, 0.757 mmol), int7 (163 mg, 0.869 mmol), and p-toluenesulfonic acid (30 mg, 0.158 mmol) were dissolved in acetonitrile (4 mL). The reaction mixture was reacted at 60°C for 4 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, dissolved in DMF, and purified by HPLC to obtain compound C056 (33.78 mg).

[0886] 1 H NMR (400MHz, CD3OD) δ8.53(s,1H),8.11(s,1H),7.74(s,1H),7.59(s,1H),7.34(d,J= 8.0Hz,1H),7.11(d,J=8.0Hz,1H),4.40–4.37(m,1H),2.25(s,3H),2.08–1.95(m,8H).

[0887] Example 57:

[0888] Synthesis route

[0889] C038 (100 mg, 0.33 mmol), int7 (60 mg, 0.40 mmol), and p-toluenesulfonic acid hydrate (13 mg, 0.07 mmol) were dissolved in acetonitrile (3.0 mL) and stirred at 60°C for 4 hours. After completion of the reaction, the reaction solution was filtered and washed with acetonitrile. The organic phases were combined to obtain the residue, which was purified by preparative analysis to yield compound C057 (20.23 mg).

[0890] 1 H NMR(400MHz,DMSO_d6)δ10.91(s,1H),8.75(s,1H),8.05(s,1H),7.84(s,1H),7.76(s,1H),7.36(d,J=8.0H z,1H),7.08(d,J=8.0Hz,1H),6.62(s,1H),4.30–4.28(m,1H),2.26(s,3H),2.16(s,3H),1.99–1.87(m,8H).

[0891] Example 58:

[0892] Synthesis route

[0893] (1) Compound C058-a (5.0 g, 37.0 mmol) and silver nitrate (6.9 g, 40.70 mmol) were dissolved in ACN (50 mL). Benzoyl chloride (4.7 ml, 40.698 mmol) was added dropwise at 0°C under nitrogen protection, and the reaction solution was stirred at 0°C for 0.5 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and the resulting residue was purified by column chromatography using (petroleum ether:ethyl acetate = 2:1) as the eluent to obtain compound C058-b (4.0 g, yield: 60.02%). LCMS (ESI) m / z: 181.1 [M+H] + .

[0894] (2) Compound C058-b (1.5 g, 8.327 mmol) and tin dichloride dihydrate (7.894 g, 41.634 mmol) were dissolved in acetic acid (15 mL), the nitrogen atmosphere was replaced, and the mixture was reacted at 80°C for 2 h under nitrogen protection. After the reaction, the reaction solution was cooled to 0°C and a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH value to a weak alkaline state (pH = 8). The mixture was then extracted with DCM (50 mL x 5), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was directly dried to obtain crude product C058-c (915 mg). LCMS (ESI) m / z: 151.1 [M+H] + .

[0895] (3) C058-c (800 mg, 5.333 mmol) and 1-(6-chloropyridin-3-yl)ethan-1-one (200 mg, 5.333 mmol) were dissolved in acetic acid (8 mL), replaced with nitrogen, and reacted at 100°C for 4 h. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate (50 mL x 5), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and the solvent was dried to obtain crude product C058-d (200 mg). LCMS (ESI) m / z: 270.1 [M+H] + .

[0896] (4) C058-d...

Claims

1. A compound of the following formula IA: or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, in: L0 is selected from -NH-, -NH-C(O)-NH-, -NH-S(O)- and -NH-S(O)2-; L C for L1 is selected from C, S and S(O); L2 is selected from a single bond, -CH2-, -O-, -S(O) 0-2 - and -NH-, wherein said -CH2- and -NH- are optionally replaced by R a Replace 1 to 3 times; Ring A is selected from C 3～10 Saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic group, C 6-10 Aryl and 5-10 membered monocyclic or bicyclic heteroaryl; Ring B is selected from C 3～6 saturated or partially unsaturated monocyclic hydrocarbon group, 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl group and 5- or 6-membered heteroaryl group; X is selected from CR a R b , NR a , O, S and S(O)2; Q is selected from CR a and N; R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, -S(O)-C 1～6 Alkyl, -S(O)2-C 1～6 Alkyl, -S(O)-OC 1～6 Alkyl, -S(O)-NR a R b 、-S(O)2-OC 1～6 Alkyl and -S(O)2-NR a R b , wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times; R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, -C 1～3 Alkyl-NH(C 1～3 Alkyl), -C 1～3 Alkyl-N(C 1～3 Alkyl)2, -S(O)-C 1～6 Alkyl, -S(O)2-C 1～6 Alkyl, -S(O)-OC 1～6 Alkyl, -S(O)-NR a R b 、-S(O)2-OC 1～6 Alkyl, -S(O)2-NR a R b 、C 3～10 Saturated or partially unsaturated cyclic hydrocarbon group, 5-10 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl and 5-10 membered aromatic hetero groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times; R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, -C 1～6 Alkylene-N(C 1～6 Alkyl)2, -C 1～6 Alkylene-C 3～6 Cycloalkyl, -C 1～6 Alkylene-3 to 6-membered heterocycloalkyl, -C 1～6 Alkylene-C 6-10 Aryl and -C 1～6 Alkylene-5 or 6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally replaced by R a Replace 1 to 3 times, and wherein R3 is optionally linked to a ring atom of Ring A to form C 3～7 Saturated or partially unsaturated monocyclic hydrocarbon group, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl group, or 5 or 6 membered heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally replaced by R a Replace 1 to 3 times; R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, C 3～10 Cycloalkyl, C 7～12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered spiroheterocycloalkyl, 6-9 membered bridged heterocycloalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～6 Alkylene-C 6～10 Aryl, -C 1～6 Alkylene-5- to 10-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-C 6～10 Aryl and -C 1～6 Alkylene-C(O)-5- to 10-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, bridged heterocycloalkyl, aryl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times; p is selected from 1, 2 and 3; q is selected from 0, 1, 2 and 3; R a Independently selected from H, halogen, NH2, OH, CN, C 1～6 Alkyl, -C(O)-R c 、-S(O)-R c 、-S(O)2-R c 、-C(O)-OR c 、-S(O)-OR c 、-S(O)2-OR c 、-C(O)-NHR c 、-S(O)-NHR c and -S(O)2-NHR c , wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times with halogen; R b Independently selected from H, halogen, NH2, OH, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1～6 Alkyl and C 1～6 The alkoxy group is optionally substituted 1 to 3 times with halogen; and R c independently selected from C optionally substituted by NH2, OH, CN and 1 to 3 halogens 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

2. The compound according to claim 1, wherein: R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl and -S(O)2-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replaced 1 to 3 times; and / or R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 1～3 Alkyl-NH(C 1～3 Alkyl), -C 1～3 Alkyl-N(C 1～3 Alkyl)2, -S(O)2-C 1～6 Alkyl, C 3～10 Saturated or partially unsaturated cyclic hydrocarbon group, 5-10 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl and 5-10 membered aromatic hetero groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and aromatic hetero groups are optionally replaced by R a Replaced 1 to 3 times; and / or R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, C 3～10 Cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～6 Alkylene-C 6～10 Aryl, -C 1～6 Alkylene-5- to 10-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-C 6～10 Aryl and -C 1～6 Alkylene-C(O)-5- to 10-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, aryl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times.

3. The compound according to claim 1 or 2, wherein: R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b and -NR b -C(O)-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replaced 1 to 3 times; and / or R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 3～10 Saturated or partially unsaturated cyclic hydrocarbon group, 5-10 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl and 5-10 membered aromatic hetero groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and aromatic hetero groups are optionally replaced by R a Replaced 1 to 3 times; and / or R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～6 Alkylene-OC 1～6 Alkyl, -C 1～6 Alkylene-NH-C 1～6 Alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 6～10 Aryl, 5-10 membered heteroaryl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～6 Alkylene-C 6～10 Aryl, -C 1～6 Alkylene-5- to 10-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-C 6～10 Aryl and -C 1～6 Alkylene-C(O)-5- to 10-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times.

4. The compound according to any one of claims 1 to 3, wherein L0 is -NH-.

5. The compound according to any one of claims 1 to 4, wherein the compound has a structure shown in Formula IB or Formula IC:

6. The compound according to any one of claims 1 to 5, wherein: Ring B is selected from a C6 saturated or partially unsaturated monocyclic hydrocarbon group, a 6-membered saturated or partially unsaturated monocyclic heterocyclic group, a phenyl group and a 6-membered heteroaryl group.

7. The compound according to any one of claims 1 to 6, wherein the Part of The compound has a structure shown in Formula ID or IE: in: represents a single bond or a double bond, provided that two adjacent Not a double bond at the same time; Y1, Y2 and Y3 are each independently selected from CH2, CH, NH, N, O and S, wherein said CH2, CH and NH are optionally substituted 1 or 2 times by R1 as valence permits; and Z is selected from CH2, CH, NH and N, wherein said CH2, CH and NH are optionally substituted 1 or 2 times by R1 as valence permits.

8. The compound according to any one of claims 1 to 7, wherein the compound has a structure shown in Formula IF or IG: wherein Y1, Y2, Y3 and Z are each CH; or one N among Y1, Y2, Y3 and Z and the rest are CH.

9. The compound according to claim 8, wherein Some selected from:

10. The compound according to any one of claims 1 to 9, wherein: X is selected from NR a , O, S and S(O)2, R a Selected from H, C 1～6 Alkyl, -C(O)-R c 、-S(O)-R c and -S(O)2-R c , wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times by halogen, and R c Selected from C optionally substituted by NH2, OH, CN and 1 to 3 halogens 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl; Preferably, X is selected from NR a , O, S and S(O)2, R a Selected from H, C 1～3 Alkyl, -C(O)-R c 、-S(O)-R c and -S(O)2-R c , wherein the C 1～3 The alkyl group is optionally substituted 1 to 3 times by F, Cl, Br or I, and R c Selected from C optionally substituted by NH2, OH, CN and 1 to 3 halogens 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl; More preferably, X is selected from NR a , O, S and S(O)2, R a Selected from H, C 1～3 Alkyl and -C(O)-R c ,and R c Selected from C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl; More preferably, X is selected from NH, N(C(O)-CH=CH2), S and S(O)2.

11. The compound according to any one of claims 1 to 10, wherein: Q is selected from CR a and N, and R a Selected from H, halogen, NH2, OH, CN and C 1～6 Alkyl, wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times with halogen; Preferably, Q is selected from CR a and N, and R a Selected from H and C 1～3 Alkyl, wherein the C 1～3 The alkyl group is optionally substituted 1 to 3 times with halogen; More preferably, Q is selected from CH and N.

12. The compound according to any one of claims 1 to 11, wherein: R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b and -S(O)2-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times, Preferably, R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -OC 6-10 Aryl, -O-5- to 10-membered heteroaryl, -C(O)-OC 1～6 Alkyl, -C(O)-NR a R b and -S(O)2-C 1～6 Alkyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times, More preferably, R1 is selected from H, N(R b )2、CN、OH、halogen、C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O-5 or 6-membered heteroaryl, -C(O)-OC 1～3 Alkyl and -C(O)-NR a R b , wherein the C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times, where R a and R b Independently selected from H and C 1～6 Alkyl, wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times with halogen; More preferably, R1 is selected from H, N(R b )2, CN, OH, F, Cl, Br, C 1～3 Alkyl, C 1～3 Halogenated alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -OC 3～6 Cycloalkyl, -O-3 to 6-membered heterocycloalkyl, -O-phenyl, -O-5 or 6-membered heteroaryl, -C(O)-OC 1～3 Alkyl and -C(O)-NR a R b , wherein the C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times, where R a and R b Independently selected from H and C 1～3 Alkyl, preferably H, methyl and ethyl; More preferably, R1 is selected from H, NH2, -NH(C 1～3 Alkyl), -N(C 1～3 Alkyl)2, CN, OH, F, Cl, Br, C 1～3 Alkyl, C 1～3 Halogenated alkyl, C 1～3 Alkoxy, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -OC 3～6 Cycloalkyl, -O-phenyl, -C(O)-OC 1～3 Alkyl, -C(O)-NH2, -C(O)-NH(C 1～3 alkyl), -C(O)-N(C 1～3 alkyl)2, wherein the C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally replaced by R a Replace 1 to 3 times; More preferably, R1 is selected from NH2, CN, OH, F, Cl, Br, CH3, CH2CH3, CH(CH3)CH3, CF3, methoxy, -C(O)OCH3, -C(O)-N(CH3)2, -S(O)2-CH3, cyclopropyl, Cyclopropyloxy, phenoxy and More preferably, R1 is selected from NH2, CN, OH, F, Cl, Br, CH3, CH2CH3, CH(CH3)CH3, CF3, methoxy, -C(O)OCH3, -C(O)-N(CH3)2, cyclopropyl, Cyclopropyloxy, phenoxy and More preferably, R1 is selected from CN, OH, F, Cl, CF3, methoxy, -C(O)OCH3, -C(O)-N(CH3)2, Cyclopropyloxy, phenoxy and 13. The compound according to any one of claims 8 to 12, wherein the Some selected from: Selected from where R a As defined in claim 1, preferably in claim 10.

14. The compound according to claim 13, wherein the compound has a structure shown in Formula IH to 10: where R a As defined in claim 1, preferably in claim 8.

15. The compound according to claim 13, wherein Some selected from:

16. A compound according to any one of claims 1 to 15, wherein: The ring A is selected from C 3～6 Saturated or partially unsaturated monocyclic hydrocarbon group, C 8～10 Saturated or partially unsaturated bicyclic hydrocarbon group, 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group, 8-10 membered saturated or partially unsaturated bicyclic heterocyclic group, C 6-10 Aryl, 5- or 6-membered heteroaryl, and 8- to 10-membered bicyclic heteroaryl; Preferably, the ring A is selected from C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered monocyclic heterocycloalkenyl, 8-10 membered bicyclic heterocycloalkenyl, phenyl, 5- or 6-membered heteroaryl having 1, 2, 3 or 4 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms (e.g., pyridine, imidazole, pyridazine, oxazole, isoxazole, thiazole, pyrimidine, pyrazine), and 8-10 membered bicyclic heteroaryl having 1, 2, 3, 4, 5 or 6 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms (e.g., quinoline, isoquinoline, benzimidazole, imidazopyridine and naphthyridine).

17. The compound according to claim 16, wherein the ring A is selected from: as well as The following structures (1)-(18): Preferred in: One of the keys identified by the letters "a" and "b" shown is connected to L0 and the other is connected to L1; X a and X g are each independently selected from CH2, O, S and NH; X b 、X c 、X d 、X e 、X f and X h are independently selected from CH and N; and In the structures (1) and (2), X a 、X b 、X c and X d At least one of them is replaceable.

18. The compound according to claim 17, wherein the ring A is selected from: Selected from:

19. The compound of claim 17 or 18, wherein the bond shown identified by the letter "a" is connected to L0, and the bond shown identified by the letter "b" is connected to L1.

20. The compound according to any one of claims 1 to 19, wherein: R2 is selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 1～3 Alkyl-NH(C 1～3 Alkyl), -C 1～3 Alkyl-N(C 1～3 Alkyl)2, -S(O)2-C 1～6 Alkyl, C 3～6 saturated or partially unsaturated cyclic hydrocarbon group, 5-6 membered saturated or partially unsaturated heterocyclic group, phenyl group and 5-6 membered aromatic hetero group, Preferably selected from H, N(R b )2、CN、OH、halogen、C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～6 Alkyl, C 3～6 Saturated or partially unsaturated cyclic hydrocarbon groups, 5-6 membered saturated or partially unsaturated heterocyclic groups, phenyl groups and 5-6 membered aromatic hetero groups, wherein the alkyl groups, alkoxy groups, cyclic hydrocarbon groups, heterocyclic groups, phenyl groups and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times, where R a Selected from H, halogen, NH2, OH, CN and C 1～6 alkyl; and where R b Selected from H and C 1～6 Alkyl, wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times with halogen; Preferably, R2 is selected from H, NH2, NH(C 1～3 alkyl), N(C 1～3 Alkyl)2, CN, OH, halogen, C 1～3 Alkyl, C 1～3 Alkoxy, oxo, -C(O)-NR a R b 、-NR b -C(O)-C 1～3 Alkyl, C 3～6 Cycloalkyl and 5-6 membered aromatic hetero groups having 1, 2 or 3 nitrogen hetero atoms and 0 or 1 oxygen or sulfur hetero atoms, wherein the alkyl and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times, where R a Selected from H, F, Cl, NH2, OH, CN and C 1～3 alkyl; and where R b Selected from H and C 1～3 Alkyl, wherein the C 1～3 The alkyl group is optionally substituted 1 to 3 times with F or Cl; More preferably, R2 is selected from H, NH2, NH(C 1～3 alkyl), N(C 1～3 alkyl) 2, CN, OH, F, Cl, Br, C optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl and OH 1～3 Alkyl, C 1～3 Alkoxy, oxo, -C(O)-NH2, -C(O)-NH(C 1～3 alkyl), -C(O)-N(C 1～3 alkyl) 2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and optionally 1 selected from C 1～3 pyrrole, pyrazolyl or triazolyl substituted by the alkyl group; More preferably, R2 is selected from H, NH2, -NHCH3, -N(CH3)2, CN, OH, F, Cl, methyl, ethyl, -CH2F, -CHF2, -CH2CH2F, -CH2-OH, methoxy, oxo, cyclopropyl, -CH2-NH(CH3), -CH2-N(CH3)2, -S(O)2-CH3, -C(O)-NH2, -C(O)-NHCH3, -C(O)-N(CH3)2 and 21. A compound according to any one of claims 1 to 20, wherein: p is 1 or 2; and / or q is 0, 1, or 2.

22. The compound according to any one of claims 1 to 21, wherein L1 is selected from C and S(O).

23. A compound according to any one of claims 1 to 22, wherein: R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1～3 Alkylene-OC 1～6 Alkyl, -C 1～3 Alkylene-NH-C 1～6 Alkyl, -C 1～3 Alkylene-N(C 1～6 Alkyl)2, -C 1～3 Alkylene-C 3～6 Cycloalkyl, -C 1～3 Alkylene-3 to 6-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl and -C 1～3 Alkylene-5 or 6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally replaced by R a Replace 1 to 3 times, Preferably, R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1～3 Alkylene-OC 1～6 Alkyl, -C 1～3 Alkylene-NH-C 1～6 Alkyl, -C 1～3 Alkylene-N(C 1～3 Alkyl)2, -C 1～3 Alkylene-C 3～6 Cycloalkyl and -C 1～3 Alkylene-3 to 6 membered heterocycloalkyl, wherein the alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally replaced by R a Replace 1 to 3 times, where R a Selected from halogen, NH2, OH and CN and C 1～6 alkyl; More preferably, R3 is selected from H, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CH2-OC 1～6 Alkyl, -CH2-NH-C 1～6 Alkyl, -CH2-C 3～6 Cycloalkyl and -CH2-3 to 6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally replaced by R a Replace 1 to 3 times, where R a Selected from F, Cl, NH2, OH and CN, preferably F; More preferably, R3 is selected from H, CH3, -CH2CH3, -CH(CH3)CH3, -CH2CH2CH3, -CH2CH2CH2CH3, <h2 style=";text-align:left;direction:ltr">-CH2OCH3,-CH2NHCH3,<h2 style=";text-align:left;direction:ltr"> 24. A compound according to any one of claims 1 to 22, wherein: R3 is connected to a ring atom of ring A at an ortho position to L1 to form C 3～7 Saturated or partially unsaturated monocyclic hydrocarbon group, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic group, phenyl group, or 5 or 6 membered heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally replaced by R a Replace 1 to 3 times, Preferably, R3 is linked to a ring atom of Ring A in an ortho position to L1 to form C 5～6 Saturated or partially unsaturated monocyclic cycloalkyl, or 5 or 6 membered saturated or partially unsaturated monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally replaced by R a Replace 1 to 3 times, More preferably, R3 is linked to the ring atom of ring A at the ortho position of L1 to form a ring structure selected from the group consisting of a Replace 1 to 3 times: in: represents a single bond or a double bond, The ring atoms identified by the letters "c" and "d" as shown are the ring atoms of the ring A, and the double bond identified by the letter "e" as shown is connected to the N atom connected to L1 and L2; More preferably, the ring A, L1 and R3 together form a structure selected from the following: The double bond identified by the letter "e" is connected to the N atom connected to L1 and L2, and the double bond identified by the letter "f" is connected to L0.

25. according to the compound described in any one of claim 1 to 24, wherein L2 is selected from single bond, -CH2-, -O- and S(O), wherein said -CH2- is optionally replaced by R a Replace 1 to 3 times.

26. A compound according to any one of claims 1 to 25, wherein: R4 is selected from H, CN, OH, NH2, halogen, C 1～6 Alkyl, -C 1～3 Alkylene-OC 1～6 Alkyl, -C 1～3 Alkylene-NH-C 1～6 Alkyl, C 3～10 (Preferred C 3～7 )cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-C 3～7 Cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～3 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～3 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～3 Alkylene-C(O)-phenyl and -C 1～3 Alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally replaced by R at each occurrence. b Replace 1 to 3 times, where R b Independently selected from F, Cl, Br, NH2, OH, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1～6 Alkyl and C 1～6 The alkoxy group is optionally substituted 1 to 3 times by F, Cl or Br; Preferably, R4 is selected from H, CN, C 1～6 Alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1～3 Alkylene-C 3～7 Cycloalkyl, -C 1～3 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～3 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～3 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～3 Alkylene-C(O)-phenyl and -C 1～3 Alkylene-C(O)-5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times, where R b Independently selected from F, Cl, NH2, OH, CN and C 1-3 Alkyl, wherein the C 1～3 The alkyl group is optionally substituted 1 to 3 times with F or Cl; More preferably, R4 is selected from H, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)CH3, -CH(CH3)CH3, -C(CH3)3, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH(CH3)CF3, -CH2CH2CH2CF3, (include )、 (include )。 27. A compound according to any one of claims 8 to 26, wherein: described Partially selected R1 is selected from H, CN, halogen, C 1～6 Halogenated alkyl, C 1～6 Alkoxy, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -C(O)-NH(C 1～3 alkyl) and -C(O)-N(C 1～3 alkyl) 2, wherein the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally replaced by R a Replace C 1～6 Alkyl group; p is 1 or 2; The ring A is selected from R2 is selected from H, NH2, CN, OH, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, oxo, -C(O)-NR a R b , phenyl and 5-6 membered aromatic hetero groups, wherein the alkyl, alkoxy, phenyl and aromatic hetero groups are optionally replaced by R a Replace 1 to 3 times, where R a Selected from H, halogen, OH and C 1～6 alkyl; and where R b Selected from H and C 1～6 Alkyl, wherein the C 1～6 The alkyl group is optionally substituted 1 to 3 times with halogen; q is 0, 1, or 2; L1 is C; R3 is selected from H, C 1～6 Alkyl and C 3～6 Cycloalkyl; Alternatively, R3 is linked to a ring atom of Ring A in an ortho position to L1, such that Ring A, L1 and R3 together form wherein the double bond identified by the letter "e" is connected to the N atom connected to L1 and L2, and the double bond identified by the letter "f" is connected to the NH as L0; L2 is -O-; R4 is selected from C 1～6 Halogenated alkyl, C 3～10 (Preferred C 3～7 )cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, -C 1～6 Alkylene-C 3～7 Cycloalkyl, -C 1～6 Alkylene-3 to 7-membered heterocycloalkyl, -C 1～3 Alkylene-phenyl, -C 1～3 Alkylene-5- to 6-membered heteroaryl, -C 1～6 Alkylene-C(O)-C 3～7 Cycloalkyl, -C 1～6 Alkylene-C(O)-3 to 7 membered heterocycloalkyl, -C 1～6 Alkylene-C(O)-phenyl and -C 1～6 Alkylene-C(O)-5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkyl, phenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times, where R b independently selected from F, Cl, CN and C substituted 1 to 3 times by F or Cl 1-3 alkyl.

28. The compound according to claim 27, wherein Partially selected 29. The compound according to claim 25 or 26, wherein: R1 is selected from H, CN, F, Cl, C 1～3 Halogenated alkyl, C 1～3 Alkoxy, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl and -C(O)-N(C 1～3 alkyl) 2, wherein the 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally replaced by C 1～3 Alkyl substitution 1 to 3 times; Preferably, R1 is selected from H, CN, F, Cl, CF3, methoxy, -C(O)-N(CH3)2, 30. The compound according to any one of claims 27 to 29, wherein the ring A is selected from 31. A compound according to any one of claims 27 to 30, wherein: R2 is selected from H, NH2, CN, OH, F, Cl, C 1～3 Alkoxy, oxo, -C(O)-NH(C 1～3 alkyl), -C(O)-N(C 1～3 alkyl)2, C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and OH 1～3 Alkyl, and optionally 1 selected from C 1～3 The alkyl group is substituted with a pyrrole, pyrazolyl or triazolyl group, More preferably, R2 is selected from H, F, CN, OH, NH2, oxo, methoxy, methyl, ethyl, -CHF2, -CH2CH2F, -CH2-OH, -C(O)-NHCH3, -C(O)-N(CH3)2 and 32. The compound according to any one of claims 27 to 31, wherein: R3 is selected from H, CH3, -CH2CH3, -CH(CH3)CH3, -CH2CH2CH3 and or R3 is linked to a ring atom of Ring A in the ortho position to L1, so that Ring A, L1 and R3 together form 33. A compound according to any one of claims 27 to 32, wherein: R4 is selected from C 1～4 Halogenated alkyl, C 3～7 Cycloalkyl, 3-7 membered heterocycloalkyl, 7-11 membered spiroheterocycloalkyl, -CH2-C 3～7 Cycloalkyl, -CH2-phenyl, -CH2-5 to 6-membered heteroaryl and -CH2-C(O)-3 to 7-membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, spiroheterocycloalkylphenyl and heteroaryl are optionally replaced by R b Replace 1 to 3 times, where R b independently selected from F, Cl, CN, and methyl or ethyl substituted 1 to 3 times by F or Cl; Preferably, R4 is selected from -CH2CF3, -CH2CH2CH2CF3, (include )、 (include )； More preferably, R4 is selected from -CH2CF3, -CH2CH2CH2CF3, (include )、 (include )。 34. The compound of claim 1, wherein the compound is selected from: (include ), 35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

36. Use of the compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition according to claim 33, in the preparation of a medicament as a STING inhibitor.

37. Use of the compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition according to claim 33, in the preparation of a medicament for preventing and / or treating STING-mediated diseases or conditions and related diseases or conditions.

38. The use according to claim 37, wherein the STING-mediated disease or condition is selected from: Tumors and / or cancers, including melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor; Diseases or disorders of the central nervous system, peripheral nervous system, and autonomic nervous system, including but not limited to epileptic aphasia, encephalomyelitis, macular degeneration, Alpers disease, agenesis of the corpus callosum, Aicardi syndrome, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, arachnoid cysts, meningitis, Asperger syndrome, ataxia telemegaly, attention deficit hyperactivity disorder, autism, autonomic dysfunction, muscular dystrophy, benign intracranial hypertension, Binswanger disease, cerebral atrophy, gigantism, cerebral arteriosclerosis, chorea, chronic inflammatory demyelinating polyneuropathy, congenital facial palsy, corticobasal degeneration, cranial arteritis, Craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, giant cell inclusion disease, diabetic neuropathy, diffuse sclerosis, dystonia, giant cell arteritis, giant cell inclusion disease, hemifacial spasm, hereditary spastic paraplegia, multiple neuritis genetic disorders, herpes zoster, Huntington's disease, myasthenia gravis, diffuse myeloid sclerosis, Parkinson's disease, locked-in syndrome, lumbar disc disease, migraine, mitochondrial myopathy, Möbius syndrome, monosomal muscular dystrophy, motor neuron disease, multi-infarct dementia, multiple sclerosis, myoclonus, neuromyotonia, hemifacial atrophy, multifocal leukoencephalopathy, sclerosing poliomyelitis, and spinal cord injury; STING-associated conditions, including type I interferonopathies, Aicardi-Goutières syndrome (AGS), lupus, and rheumatoid arthritis; Autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), inflammatory bowel disease (IBD), ulcerative colitis (UC), autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy, irritable bowel syndrome, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis; and Psoriatic arthritis, contact dermatitis, atopic dermatitis, vitiligo, type 1 diabetes, asthma, glomerulonephritis, periodontal disease, pars planitis, transplant rejection, neurodegenerative diseases, obesity, and hypertension.

Images