Compound containing heterocyclic amide structure and preparation and application thereof

Abstract

The invention relates to a compound containing a heterocyclic amide structure as well as preparation and application of the compound. Specifically, the compound disclosed by the invention has a structure as shown in a formula I, and the definitions of all groups and substituent groups are described in the specification. The invention also discloses a preparation method of the compound and application of the compound in preventing and / or treating autoimmune diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to a class of compounds containing a heterocyclic amide structure, and their preparation and uses. Background Art

[0002] Autoimmune Diseases are a class of diseases induced by the breakdown of the balance of the body's immune system, which then leads to the immune system attacking the body's normal organs, tissues or cells, causing damage. Autoimmune diseases have a high incidence rate (the global incidence rate is about 5% - 8%); there are many types (according to the statistics of the American Autoimmune Related Diseases Association, more than 100 autoimmune diseases have been identified so far); they are characterized by a long course of disease, frequent relapses, and difficulty in cure. Most patients need to take medicine for life after diagnosis, which greatly affects the quality of life, and in severe cases, it even directly endangers life safety. Therefore, autoimmune diseases have been listed by the World Health Organization as the third major killer threatening human health after cardiovascular and cerebrovascular diseases and cancer.

[0003] However, the development of therapeutic drugs for autoimmune diseases is still very limited at present. Early immunosuppressants are not disease-specific and often have significant side effects; while biologic macromolecule drugs have poor stability and high costs, which also discourage many patients. Therefore, it is urgent to develop small molecule drugs specific for autoimmune diseases with new mechanisms.

[0004] Stimulator of interferon genes (STING, also known as MITA, ERIS, MPYS) is located on the endoplasmic reticulum membrane and is an important adaptor protein in the innate immune cGAS-STING pathway. After cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) recognizes the abnormally present double-stranded DNA (dsDNA) in the cytoplasm, it can catalyze adenosine triphosphate (ATP) and guanosine triphosphate (GTP) to generate cyclic guanosine monophosphate-adenosine monophosphate (2’,3’-cGAMP). Subsequently, 2’,3’-cGAMP, as a second messenger, binds to STING and causes its conformational change to the active state. Then, it is transported from the endoplasmic reticulum membrane to the Golgi apparatus, and recruits TANK binding kinase 1 (TBK1) or nuclear factor kappa-B (NF-κB), triggering a series of downstream signal cascades, and ultimately promoting the secretion of inflammatory factors such as IFNβ, TNFα, and IL-6.

[0005] However, dysregulation of the inflammatory response can lead to the occurrence of diseases, including acute inflammation caused by cytokine storms, or autoimmune or metabolic diseases caused by chronic inflammation. At present, a large number of studies have reported that STING is detected at high expression levels in patient samples of various autoimmune or inflammatory diseases; and in animal models of autoimmune or inflammatory diseases such as rheumatoid arthritis, psoriasis, acute lung injury, acute kidney injury, and acute pancreatitis, knocking out the STING expression gene or using drug treatment can effectively alleviate pathological symptoms. Therefore, the development of specific inhibitors targeting the STING pathway has broad application prospects.

[0006] Although the strategy of negatively regulating the STING pathway for the treatment of autoimmune diseases has received extensive attention, the development of STING inhibitors is still in its infancy, and the reported structural types are very limited. In 2018, Haag et al. reported in the journal Nature a nitrofurane compound C-176 obtained through phenotypic screening. This compound can covalently bind to the Cys91 residue of the STING protein to block the palmitoylation of STING and inhibit the STING pathway, and Trex1 treated with C-176 - / -Mice with reduced systemic inflammatory responses. Unfortunately, due to the species differences of STING, C-176 is only effective against murine STING and ineffective against human STING. Subsequently, through a new round of screening, the research team obtained indole urea compound H-151, which has inhibitory activity against both human and murine STING. In the same year, the team led by Wang Chen from China Pharmaceutical University reported in the journal Cell Reports that the natural product astin C isolated from Aster tataricus can act on the active pocket of STING, inhibit the recruitment process of IRF3, and also verified its in vivo efficacy in the Trex1 - / - mouse model. However, this compound has been reported to have potential toxicity risks. In 2019, Siu et al. from Merck & Co., Inc. discovered compound 18 with a tetrahydroisoquinoline skeleton. Although this compound can effectively bind to HAQ STING (competing with cGAMP for binding, IC 50 = 68 nM), it cannot effectively inhibit the production of IFNβ induced by cGAMP activation in THP1 cells (IC 50 > 30 μM). In 2020, Cravatt and his collaborative team found that BPK-25 can covalently bind to Cys91 of the STING protein and effectively inhibit the secretion of STING downstream inflammatory factors (such as IFNβ, IP-10, IL-6, TNFα, etc.) induced by cGAMP stimulation in PMBC cells. In 2021, the team led by Wang Chen reported in the journal PNAS the discovery of phenylsulfonamide compound SN-011. This compound binds to the cyclic dinucleotide pocket of the STING protein and has a higher affinity than the endogenous ligand 2’,3’-cGAMP, and can maintain STING in an inactive conformation. In the Trex1 - / - mouse model, SN-011 has good tolerance, can effectively relieve inflammation and prolong the survival period of mice. In recent years, research teams have successively discovered small molecule compounds that can target STING using strategies such as "repurposing old drugs" and "screening natural products". However, such compounds often lack good drug-likeness.

[0007]

[0008] Generally speaking, the reported structural types of STING inhibitors are scarce, and each has the disadvantages of weak activity, large side effects, and poor specificity. So far, no STING inhibitor with good drug properties has entered clinical research globally.

[0009] Therefore, based on the urgent clinical needs, small molecule STING inhibitors with novel structural skeletons and good drug properties are urgently needed to be developed. SUMMARY OF THE INVENTION

[0010] The object of the present invention is to provide a compound represented by formula I, a preparation method thereof, and its use in preventing and / or treating diseases related to high expression of STING.

[0011] In the first aspect of the present invention, there is provided a compound represented by formula I or a pharmaceutically acceptable salt thereof,

[0012]

[0013] wherein:

[0014] R1, R2, R3, R4, R5, R6, R7, R8 are each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, R a substituted or unsubstituted C1-C8 alkyl; R1 and R2, R3 and R4, R5 and R6, R7 and R8 are each independently optionally combined with the carbon atom to which they are attached to form a 3-5 membered spiro ring, fused ring or bridged ring;

[0015] A1, A2, A3, A4, A5, A6 are each independently selected from the group consisting of: C, CR9, N;

[0016] indicating that the group containing it is an unsaturated group;

[0017] Y 1 、Y 2 are each independently selected from the group consisting of: CR9, N;

[0018] Each R9 is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-, R a substituted or unsubstituted amino-(C=O)-, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-NH-, R a substituted or unsubstituted C2-C8 alkenyl-(C=O)-NH-, R a substituted or unsubstituted C1-C8 alkyl-NH-, R a substituted or unsubstituted C1-C8 alkyl-S-, 1-3 R a substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R aSubstituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a Substituted or unsubstituted C6-C10 aryl, 1-3 R a Substituted or unsubstituted 5-10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0019] Z is selected from the group consisting of: O, S, SO, SO2, N(R 10 ), CO, C(R 11 R 12 );

[0020] R 10 is selected from the group consisting of: hydrogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C3-C8 cycloalkyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-, R a substituted or unsubstituted C2-C8 alkenyl-(C=O)-, R a substituted or unsubstituted 3-8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S-(C=O)-, R a substituted or unsubstituted C1-C8 alkyl-S(=O)2-;

[0021] R 11 、R 12 each independently is selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, -OR a , amino, cyano, R a substituted or unsubstituted C1-C8 alkyl, C1-C8 alkyl-(C=O)-O-, C1-C8 alkyl-(C=O)-O-(C1-C2 alkylene)-, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl-NH-, R a substituted or unsubstituted 3-8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, R a substituted or unsubstituted C3-C8 cycloalkyl;

[0022] each R aIndependently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, C1-C8 haloalkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-, C1-C8 alkyl-(NH)-, -N(C1-C8 alkyl)2, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein each substitution independently means being substituted by one or more substituents selected from the following group: deuterium, halogen, hydroxyl, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkyl-(C=O)-, 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl.

[0023] In another preferred embodiment, selected from the group consisting of:

[0024] In another preferred embodiment, is a 9-membered heteroaryl containing 2 N's.

[0025] In another preferred embodiment, is

[0026] In another preferred embodiment, A1 is N;

[0027] A2 is N;

[0028] A3 is CH;

[0029] A4 is C;

[0030] A5 is CH;

[0031] A6 is CR9;

[0032] R9 is selected from the group consisting of: halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-, R a substituted or unsubstituted amino-(C=O)-, R aSubstituted or unsubstituted C1-C8 alkyl-(C=O)-NH-, R a Substituted or unsubstituted C2-C8 alkenyl-(C=O)-NH-, R a Substituted or unsubstituted C1-C8 alkyl-NH-, R a Substituted or unsubstituted C1-C8 alkyl-S-, 1-3 R a Substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a Substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a Substituted or unsubstituted C6-C10 aryl, 1-3 R a Substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0033] Each R a Independently selected from the group consisting of: halogen, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-.

[0034] In another preferred embodiment, A1 is N;

[0035] A2 is N;

[0036] A3 is CH;

[0037] A4 is C;

[0038] A5 is CH;

[0039] A6 is CR9;

[0040] R9 is selected from the group consisting of: halogen, R a Substituted or unsubstituted C1-C8 alkyl, R a Substituted or unsubstituted C2-C8 alkenyl, R a Substituted or unsubstituted C2-C8 alkynyl, 1-3 R a Substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a Substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a Substituted or unsubstituted C6-C10 aryl, 1-3 R a Substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0041] Each R aIndependently selected from the following group: halogen, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy.

[0042] In another preferred embodiment, Y 1 is CR9, and R9 is selected from the following group: hydrogen, deuterium;

[0043] Y 2 is CR9, and R9 is cyano.

[0044] In another preferred embodiment, R1, R2, R3, R4, R5, R6, R7, R8 are each independently selected from the following group: hydrogen, deuterium, halogen, C1-C8 alkyl.

[0045] In another preferred embodiment, Z is C(R 11 R 12 );

[0046] R 11 、R 12 are each independently selected from the following group: hydrogen, deuterium, hydroxyl, -OR a 、R a substituted or unsubstituted C1-C8 alkyl, C1-C8 alkyl-(C=O)-O-, C1-C8 alkyl-(C=O)-O-(C1-C2 alkylene)-, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, R a substituted or unsubstituted C3-C8 cycloalkyl;

[0047] Each R a is independently selected from the following group: halogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-, and the said substitution each independently means being substituted by one or more substituents selected from the following group: deuterium, C1-C8 alkoxy.

[0048] In another preferred embodiment, Z is C(R 11 R 12 );

[0049] R 11 、R 12 are each independently selected from the following group: hydrogen, deuterium, hydroxyl, R aSubstituted or unsubstituted C1-C8 alkyl, C1-C8 alkyl-(C=O)-O-, C1-C8 alkyl-(C=O)-O-(C1-C2 alkylene)-, 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl;

[0050] Each R a Independently selected from the group consisting of: halogen, hydroxy, substituted or unsubstituted C1-C8 alkoxy, wherein each substitution independently means substituted by one or more substituents selected from the group consisting of: deuterium, C1-C8 alkoxy.

[0051] In another preferred embodiment, A1 is N;

[0052] A2 is N;

[0053] A3 is CH;

[0054] A4 is C;

[0055] A5 is CH;

[0056] A6 is CR9;

[0057] R9 is selected from the group consisting of: halogen, R a Substituted or unsubstituted C1-C8 alkyl, R a Substituted or unsubstituted C2-C8 alkenyl, R a Substituted or unsubstituted C2-C8 alkynyl, 1-3 R a Substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a Substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a Substituted or unsubstituted C6-C10 aryl, 1-3 R a Substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0058] Each R a Independently selected from the group consisting of: halogen, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy;

[0059] Z is C(R 11 R 12 );

[0060] R 11 Selected from the group consisting of: hydrogen, deuterium;

[0061] R 12 Selected from the group consisting of: 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl.

[0062] In another preferred example, A1 is N;

[0063] A2 is N;

[0064] A3 is CH;

[0065] A4 is C;

[0066] A5 is CH;

[0067] A6 is CR9;

[0068] R9 is selected from the group consisting of: halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, 1-3 R a substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a substituted or unsubstituted C6-C10 aryl, 1-3 R a substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, each R a is independently selected from the group consisting of: halogen, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy;

[0069] Z is C(R 11 R 12 );

[0070] R 11 、R 12 are each independently selected from the group consisting of: hydroxyl, R a substituted or unsubstituted C1-C8 alkyl, C1-C8 alkyl-(C=O)-O-, C1-C8 alkyl-(C=O)-O-(C1-C2 alkylene)-;

[0071] each R a is independently selected from the group consisting of: halogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-, and the substitutions are each independently defined as being substituted with one or more substituents selected from the group consisting of: deuterium, C1-C8 alkoxy.

[0072] In another preferred example, the compounds are selected from the group consisting of:

[0073]

[0074]

[0075]

[0076]

[0077]

[0078] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0079] In a third aspect of the present invention, there is provided the use of the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and / or treatment of diseases selected from the group consisting of: cancer, autoimmune diseases, neurodegenerative diseases, inflammatory diseases.

[0080] In another preferred embodiment, the disease is a STING-related disease.

[0081] In another preferred embodiment, the disease is a disease with high STING expression.

[0082] In another preferred embodiment, the cancer is selected from the group consisting of: brain cancer, head and neck cancer, leukemia and blood cancer, skin cancer, breast cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma.

[0083] In another preferred embodiment, the autoimmune disease is a STING-related autoimmune disease.

[0084] In another preferred embodiment, the autoimmune disease is an autoimmune disease with high STING expression.

[0085] In another preferred embodiment, the autoimmune disease is selected from the group consisting of: Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), retinal vasculopathy and leukoencephalopathy (RVCL), STING-associated vasculopathy with onset in infancy (SAVI), psoriasis, scleroderma, stroke, myocardial infarction, traumatic brain injury, atherosclerosis-related vascular diseases, cardiovascular diseases, small intestinal malabsorption syndrome, irritable bowel syndrome, Sjögren's syndrome, multiple sclerosis, Crohn's disease, diabetes and its complications.

[0086] In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of: amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease.

[0087] In another preferred embodiment, the inflammatory disease is selected from the group consisting of: sepsis, acute lung injury, acute pancreatitis, acute kidney injury, diabetic nephropathy, Alport syndrome, rheumatoid arthritis, osteoarthritis, non-alcoholic steatohepatitis, inflammatory bowel disease, ulcerative colitis, autoimmune colitis, hidradenitis suppurativa, uveitis, mucositis.

[0088] In another preferred embodiment, the disease is selected from the group consisting of: Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), STING-associated vasculopathy with onset in infancy (SAVI), inflammatory bowel disease, rheumatoid arthritis, psoriasis, acute lung injury, acute kidney injury, acute pancreatitis.

[0089] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed Description of the Invention

[0090] Through long-term and in-depth research, the inventors unexpectedly prepared a compound with excellent STING inhibitory activity by structural optimization. On this basis, the inventors completed the present invention.

[0091] Terms

[0092] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0093] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0094] In the present invention, "C1-C8 alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pivalyl, or similar groups. The term "C1-C6 alkyl" has a similar meaning.

[0095] In the present invention, the term "C2-C8 alkenyl" refers to a straight-chain or branched-chain alkenyl group having 2 to 8 carbon atoms and containing one double bond, including, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like. The terms "C2-C6 alkenyl" and "C3-C8 alkenyl" have similar meanings.

[0096] In the present invention, the term "C2-C8 alkynyl" refers to a straight-chain or branched-chain alkynyl group having 2 to 8 carbon atoms and containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like. The term "C2-C6 alkynyl" has a similar meaning.

[0097] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring (which can be a monocyclic, spiro or bridged ring), including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "C3-C6 cycloalkyl" has a similar meaning.

[0098] In the present invention, the term "C1-C8 alkoxy" refers to a straight-chain or branched-chain alkoxy group having 1 to 8 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. Preferably, it is C1-C6 alkoxy. The terms "C1-C6 alkoxy" and "C1-C4 alkoxy" have similar meanings.

[0099] In the present invention, the term "3-8 membered heterocyclic group" is a 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, including (but not limited to) the following groups: The term "3-6 membered heterocyclic group" has a similar meaning.

[0100] In the present invention, the terms "aromatic ring" or "aryl" have the same meaning, preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic ring group having 6 to 10 carbon atoms and containing no heteroatoms in the ring, such as phenyl, naphthyl, and the like.

[0101] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, "5- to 10-membered heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen and 1 to 9 carbon atoms. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, and the ring connected to the parent structure is the heteroaryl ring. The heteroaryl can be optionally substituted or unsubstituted. The term "5- to 6-membered heteroaryl" has a similar meaning.

[0102] In the present invention, the term "halogenated" means substituted by a halogen.

[0103] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by specific substituents. The specific substituents are the substituents described correspondingly in the foregoing or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group can have a substituent selected from a specific group at any substitutable site of the group, and the substituents can be the same or different at each position. Those skilled in the art should understand that the combinations of substituents expected in the present invention are those that are stable or chemically achievable combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino, C1-C6 alkoxy, C1-C10 sulfonyl group, etc.

[0104] In the present invention, the term 1-6 means 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "plural" means 2-6, such as 2, 3, 4, 5, or 6.

[0105] It should be understood that when a certain group is present at multiple different positions in a compound, its definitions at each position are independent of each other and can be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "each independently selected from the following group:".

[0106] Compound

[0107] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0108]

[0109] wherein each group is defined as above.

[0110] In another preferred embodiment, in the said compound, any one of R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, A4, A5, A6, Y 1 , Y 2 , Z is independently respectively the corresponding group in the specific compounds described in the present invention.

[0111] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or a base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salts formed by the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0112] Another preferred class of salts is the salts formed by the compounds of the present invention with bases, such as alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed by morpholine, piperazine, and lysine respectively.

[0113] It should be understood that the specific methods for preparing the compounds of formula I of the present invention are specifically described in the embodiments of the present invention, but these specific methods do not impose any limitations on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0114] Typically, the raw materials and reagents used in the compounds of the present invention can be purchased through commercial channels without special instructions.

[0115] Pharmaceutical Compositions and Administration Methods

[0116] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the said compound or its pharmaceutically acceptable salt.

[0117] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, 10 - 1000 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0118] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gelling substances which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be admixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0119] The pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.

[0120] There is no particular limitation on the administration mode of the compound or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0121] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or calcium phosphate dibasic, or with the following components: (a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerin; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retardants, e.g., paraffin wax; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0122] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released in a part of the digestive tract. Examples of embedding components that can be used are polymeric materials and wax materials. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0123] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil or mixtures of these substances.

[0124] In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0125] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar or mixtures of these substances.

[0126] Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0127] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required, if necessary.

[0128] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as drugs for preventing and / or treating autoimmune diseases).

[0129] The treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.

[0130] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is the pharmaceutically recognized effective dosage. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 50 - 1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are within the scope of the skills of a skilled physician.

[0131] Compared with the prior art, the present invention has the following main advantages:

[0132] (1) The compounds of the present invention have novel structures, excellent STING inhibitory activity (especially human STING inhibitory activity) and selectivity;

[0133] (2) The compounds of the present invention have high safety and excellent pharmacokinetic properties;

[0134] (3) The compounds of the present invention have excellent drug-forming properties.

[0135] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following embodiments are generally carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0136] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to a person skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0137] I. Part of Compound Preparation Examples

[0138] The following preparation examples exemplarily prepared some of the compounds of Formula I of the present invention, and each compound is represented by S1 to S51 respectively.

[0139] 1. Synthesis of Compound S1

[0140]

[0141] Step 1: Dissolve Compound 1a (1.83 g, 10.0 mmol) and Compound 1b (2.04 g, 12.0 mmol) in 20 mL of acetonitrile, add triethylamine (4.17 mL, 30 mmol), and react the reaction solution at the reflux temperature for about 1 hour until the raw materials are completely reacted as monitored by TLC. After the reaction solution is cooled, pour it into water, extract it 3 times with ethyl acetate, combine the organic phases, wash them with saturated brine, dry them over anhydrous sodium sulfate, filter, and concentrate. Subsequently, recrystallize with ethyl acetate - petroleum ether. After the solid completely precipitates, filter it by suction, and dry the filter cake to obtain Compound 1c (2.97 g).

[0142]

[0143] Step 2: Suspend Compound 1c (2.97 g, 9.39 mmol) in 50 mL of absolute ethanol, add 10% palladium / carbon (594 mg), and react at room temperature in a hydrogen atmosphere for about 4 hours. After the raw materials are completely reacted as monitored by TLC, filter off the palladium / carbon, wash the filter cake with an appropriate amount of ethanol, collect the filtrate, concentrate it, and dry it to obtain Compound 1d, which is directly used in the next step without further purification.

[0144]

[0145] Step 3: Dissolve compound 1d (50 mg, 0.17 mmol) and compound 1e (34 mg, 0.17 mmol) in 2 mL of N,N-dimethylformamide. Add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (91 μL, 0.52 mmol). Heat the mixture to 50 °C and react for about 6 hours until the raw materials are completely reacted as monitored by TLC. After the reaction solution is cooled, pour it into water, extract it with ethyl acetate three times, combine the organic phases, wash them with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound S1 (42 mg). 1 H NMR (700 MHz, Chloroform-d) δ 9.61 (d, J = 1.1 Hz, 1H), 8.19 (s, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.73 (s, 1H), 7.71 (dd, J = 8.9, 2.7 Hz, 1H), 7.68 (d, J = 9.5 Hz, 1H), 7.41 (dd, J = 9.5, 2.1 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 3.75 (t, J = 4.6 Hz, 4H), 3.64 (d, J = 11.7 Hz, 2H), 2.85 - 2.82 (m, 2H), 2.61 (t, J = 4.6 Hz, 4H), 2.40 - 2.36 (m, 1H), 1.98 (d, J = 12.3 Hz, 2H), 1.83 - 1.77 (m, 2H).

[0146] 2. Synthesis of compound S2

[0147]

[0148] The preparation method refers to the synthesis of compound S1. Replace compound 1e with compound 2a, and keep other experimental steps the same to obtain compound S2. 1 H NMR (400 MHz, Chloroform-d) δ 9.37 (s, 1H), 8.74 - 8.72 (m, 2H), 7.91 - 7.87 (m, 2H), 7.05 (s, 1H), 7.03 (d, J = 2.2 Hz, 1H), 3.75 (t, J = 4.6 Hz, 4H), 3.62 (d, J = 11.8 Hz, 2H), 2.84 - 2.78 (m, 2H), 2.61 (t, J = 4.6 Hz, 4H), 2.40 - 2.34 (m, 1H), 1.99 - 1.96 (m, 2H), 1.86 - 1.76 (m, 2H).

[0149] 3. Synthesis of compound S3

[0150]

[0151] The preparation method refers to the synthesis of compound S1, replace compound 1e with compound 3a, and keep other experimental steps the same to obtain compound S3. 1 H NMR(400MHz,Chloroform-d)δ10.10(s,1H),8.60(s,1H),8.15(d,J=9.5Hz,1H),7.91-7.89(m,2H),7.33(d,J=9.5Hz,1H),7.06(d,J=8.7Hz,1H),3.76(t,J=4.6Hz,4H),3.64(d,J=11.9Hz,2H),2.86-2.80(m,2H),2.62(t,J=4.6Hz,4H),2.41-2.36(m,1H),1.99(d,J=12.5Hz,2H),1.86-1.77(m,2H).

[0152] 4. Synthesis of compound S4

[0153]

[0154] The preparation method refers to the synthesis of compound S1, replace compound 1e with compound 4a, and keep other experimental steps the same to obtain compound S4. 1 H NMR(400MHz,Chloroform-d)δ9.44(br,1H),9.19(s,1H),8.07(d,J=2.6Hz,1H),7.91-7.88(m,1H),7.70(dd,J=8.9,2.6Hz,1H),7.47(dd,J=9.7,1.9Hz,1H),7.06(d,J=8.9Hz,1H),3.76(t,J=4.7Hz,4H),3.66(d,J=12.0Hz,2H),2.87-2.81(m,2H),2.63-2.60(m,4H),2.41-2.36(m,1H),1.99(d,J=12.5Hz,2H),1.86-1.76(m,2H).

[0155] 5. Synthesis of compound S5

[0156]

[0157] The preparation method refers to the synthesis of compound S1, replace compound 1e with compound 5a, and keep other experimental steps the same to obtain compound S5. 11H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.12 (d, J = 1.2 Hz, 1H), 8.75 - 8.69 (m, 2H), 8.64 (d, J = 6.2 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 7.9, 1.9 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 3.60 - 3.56 (m, 4H), 3.50 - 3.39 (m, 2H), 3.32 - 3.25 (m, 2H), 2.55 - 2.40 (m, 5H), 1.87 - 1.79 (m, 2H), 1.65 - 1.57 (m, 2H).

[0158] Synthesis of Compound S6

[0159]

[0160] The preparation method refers to the synthesis of Compound S1. Replace Compound 1e with Compound 6a, and keep other experimental steps the same to obtain Compound S6. 1 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.98 (dd, J = 6.7, 1.4 Hz, 1H), 8.76 (s, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.62 (dd, J = 7.9, 1.9 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.13 - 7.00 (m, 2H), 3.60 - 3.56 (m, 4H), 3.48 - 3.39 (m, 2H), 3.32 - 3.25 (m, 2H), 2.56 - 2.38 (m, 5H), 1.87 - 1.79 (m, 2H), 1.65 - 1.57 (m, 2H).

[0161] Synthesis of Compound S7

[0162]

[0163] The preparation method refers to the synthesis of Compound S1. Replace Compound 1e with Compound 7a, and keep other experimental steps the same to obtain Compound S7. 11H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 7.3 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.26 (s, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 8.9, 2.6 Hz, 1H), 7.57 (s, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.97 (dd, J = 7.3, 2.3 Hz, 1H), 3.76 (t, J = 4.6 Hz, 4H), 3.62 (d, J = 11.8 Hz, 2H), 2.85 - 2.79 (m, 2H), 2.62 (t, J = 4.7 Hz, 4H), 2.41 - 2.36 (m, 1H), 1.98 (d, J = 12.5 Hz, 2H), 1.85 - 1.76 (m, 2H).

[0164] 8. Synthesis of Compound S8

[0165]

[0166] Step 1: Under an argon atmosphere, dissolve Compound 8a (70 mg, 0.45 mmol) and Compound 8b (100 mg, 0.37 mmol) in 2 mL of 1,4-dioxane, add tetrakis(triphenylphosphine)palladium (43 mg, 0.04 mmol) and 2 mol / L aqueous sodium carbonate solution (0.56 mL, 1.11 mmol). Heat the reaction solution to 100 °C and react for about 1 hour until the raw materials are completely reacted as monitored by TLC. After the reaction solution is cooled, pour it into water, extract with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain Compound 8c (117 mg).

[0167]

[0168] Step 2: Dissolve Compound 8c (115 mg, 0.38 mmol) in a 33 mL mixed solution of tetrahydrofuran - water (v / v = 2:1), add lithium hydroxide monohydrate (48 mg, 1.15 mmol). Heat the reaction solution to 85 °C and react for about 4 hours until the raw materials are completely reacted as monitored by TLC. Concentrate under reduced pressure to remove the organic solvent, dissolve the residue in excess water, filter to remove insoluble substances, gradually add 3 mol / L hydrochloric acid solution dropwise to the filtrate to adjust the pH to 5 - 6. After the solid fully precipitates, filter by suction, wash the filter cake with water several times, collect, and dry to obtain Compound 8d (71 mg).

[0169]

[0170] Step 3: Dissolve compound 8d (57 mg, 0.21 mmol) and compound 1d (60 mg, 0.21 mmol) in 2 mL of N,N-dimethylformamide. Add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (159 mg, 0.42 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.63 mmol). Heat the reaction mixture to 50 °C and stir overnight until the reaction of the starting materials is complete as monitored by TLC. After the reaction mixture is cooled, pour it into water and extract with ethyl acetate three times. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound S8 (38 mg). 1 H NMR(400MHz,Chloroform-d)δ8.58-8.55(m,2H),8.28(s,1H),7.87(d,J=2.6Hz,1H),7.74(dd,J=8.9,2.7Hz,1H),7.67-7.64(m,2H),7.59(s,1H),7.48-7.45(m,2H),7.22(dd,J=7.2,2.1Hz,1H),7.03(d,J=8.9Hz,1H),3.75(t,J=4.6Hz,4H),3.62(d,J=11.9Hz,2H),2.84-2.78(m,2H),2.62-2.60(m,4H),2.40-2.34(m,1H),1.99-1.96(m,2H),1.85-1.75(m,2H).

[0171] 9. Synthesis of compound S9

[0172]

[0173] Step 1: Dissolve compound 1a (200 mg, 1.10 mmol) and compound 9a (170 mg, 1.31 mmol) in 4 mL of acetonitrile. Add triethylamine (0.46 mL, 3.29 mmol). Reflux the reaction mixture for about 1 hour until the reaction of the starting materials is complete as monitored by TLC. After the reaction mixture is cooled, concentrate it and purify by column chromatography to obtain compound 9b (293 mg).

[0174]

[0175] Step 2: Dissolve compound 9b (290 mg, 1.05 mmol) in 1 mL of pyridine. Add acetic anhydride (0.49 mL, 5.27 mmol). React the reaction mixture at room temperature for about 1 hour until the reaction of the starting materials is complete as monitored by TLC. Concentrate the reaction mixture under reduced pressure to remove the solvent and purify by column chromatography to obtain compound 9c (334 mg).

[0176]

[0177] Step 3: Suspend compound 9c (330 mg, 1.04 mmol) in 5 mL of absolute ethanol, add 10% palladium / carbon (99 mg), and react at room temperature under a hydrogen atmosphere for about 4 hours. After monitoring the reaction of the starting material by TLC until it is complete, filter off the palladium / carbon, wash the filter cake with an appropriate amount of ethanol, collect the filtrate, concentrate it, and dry it to obtain compound 9d. Without further purification, it is directly used for the next step.

[0178]

[0179] Step 4: The preparation method refers to the synthesis of compound S7. Replace compound 1d with compound 9d, and keep the other experimental steps the same to obtain compound S9. 1 H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 7.3, 0.8 Hz, 1H), 8.39 (dd, J = 2.4, 0.8 Hz, 1H), 8.27 (s, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 8.9, 2.7 Hz, 1H), 7.59 (s, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.96 (dd, J = 7.3, 2.3 Hz, 1H), 3.95 (s, 2H), 3.28 - 3.22 (m, 2H), 3.14 - 3.08 (m, 2H), 2.10 (s, 3H), 1.83 - 1.77 (m, 2H), 1.62 - 1.60 (m, 2H).

[0180] 10. Synthesis of compound S10

[0181]

[0182] Step 1: Dissolve compound S9 (39 mg, 0.08 mmol) in 2 mL of a mixed solution of tetrahydrofuran - water (v / v = 1:1), add lithium hydroxide monohydrate (11 mg, 0.25 mmol), and react the reaction solution at room temperature for about 3 hours until the reaction of the starting material is monitored by TLC to be complete. Dropwise add 3 mol / L hydrochloric acid solution to the reaction solution to adjust the pH to 5 - 6, extract with ethyl acetate 3 times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound S10 (28 mg). 11H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.91 (d, J = 7.3 Hz, 1H), 8.79 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.10 - 8.10 (m, 1H), 7.88 - 7.85 (m, 1H), 7.24 - 7.20 (m, 2H), 4.60 (t, J = 5.5 Hz, 1H), 3.23 - 3.15 (m, 4H), 3.03 - 2.97 (m, 2H), 1.70 - 1.63 (m, 2H), 1.39 - 1.34 (m, 2H), 0.93 (s, 3H).

[0183] 11. Synthesis of Compound S11

[0184]

[0185] Step 1: The preparation method refers to the synthesis of Compound S9 (Step 4). Replace Compound 7a with Compound 11a (Synthesis reference: ACS Med. Chem. Lett. 2015, 6: 814 - 818.), and keep other experimental steps the same to obtain Compound 11b.

[0186]

[0187] Step 2: The preparation method refers to the synthesis of Compound S10. Replace Compound S9 with Compound 11b, and keep other experimental steps the same to obtain Compound S11. 1 1H NMR (400 MHz, Chloroform-d) δ 8.33 - 8.31 (m, 1H), 8.20 - 8.19 (m, 1H), 7.80 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 8.9, 2.7 Hz, 1H), 7.39 (s, 1H), 7.05 (d, J = 8.9 Hz, 1H), 6.88 (dd, J = 7.3, 2.3 Hz, 1H), 3.49 - 3.47 (m, 3H), 3.32 - 3.26 (m, 2H), 3.11 - 3.05 (m, 2H), 2.75 (s, 3H), 1.81 - 1.74 (m, 2H), 1.56 - 1.51 (m, 2H), 1.05 (s, 3H).

[0188] 12. Synthesis of Compound S12

[0189]

[0190] The preparation method refers to the synthesis of Compound S1. Replace Compound 1b and 1e with Compound 12a and 7a respectively, and keep other experimental steps the same to obtain Compound S12. 11H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 7.3 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.26 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 8.9, 2.7 Hz, 1H), 7.52 (s, 1H), 7.08 (d, J = 8.9 Hz, 1H), 6.96 (dd, J = 7.4, 2.4 Hz, 1H), 3.43 (s, 3H), 3.35 - 3.31 (m, 4H), 3.23 - 3.16 (m, 2H), 2.26 (s, 1H), 1.88 - 1.77 (m, 4H).

[0191] Synthesis of Compound S13

[0192]

[0193] Step 1: Dissolve compound 13a (200 mg, 0.85 mmol) in 2 mL of toluene, add acetic anhydride (0.12 mL, 1.27 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol), heat to 100 °C and react overnight until the raw materials are completely reacted as monitored by TLC. After the reaction solution is cooled, it is concentrated and purified by column chromatography to obtain compound 13b (165 mg).

[0194]

[0195] Step 2: Dissolve compound 13b (154 mg, 0.56 mmol) in 3 mL of anhydrous methanol, add 10% palladium hydroxide / carbon (46 mg), react at room temperature in a hydrogen atmosphere for about 6 hours. After the raw materials are completely reacted as monitored by TLC, palladium hydroxide / carbon is filtered off, the filter cake is washed with an appropriate amount of methanol, the filtrate is collected and concentrated, and then dried under vacuum to obtain compound 13c, which is directly used in the subsequent reaction without further purification.

[0196]

[0197] Steps 3 - 5: The preparation method refers to the synthesis of compound S12. Replace compound 12a with compound 13c, and the other experimental steps are the same to obtain compound S13. 11H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 7.3 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 7.88 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 7.3, 2.3 Hz, 1H), 3.79 (s, 2H), 3.38 - 3.35 (s, 5H), 3.05 (t, J = 11.7 Hz, 2H), 2.43 (d, J = 13.8 Hz, 2H), 2.10 (s, 3H), 1.95 - 1.87 (m, 2H).

[0198] Synthesis of Compound S14

[0199]

[0200] The preparation method refers to the synthesis of Compound S13. In Step 1, isobutyryl chloride is used to replace acetic anhydride, and other experimental steps are the same to obtain Compound S14. 1 1H NMR (400 MHz, Chloroform-d) δ 8.46 - 8.44 (m, 1H), 8.40 - 8.39 (m, 1H), 8.27 (s, 1H), 7.87 (d, J = 2.6 Hz, 1H), 7.75 (dd, J = 8.9, 2.6 Hz, 1H), 7.59 (s, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.97 (dd, J = 7.4, 2.3 Hz, 1H), 3.77 (s, 2H), 3.39 - 3.37 (m, 5H), 3.06 - 3.00 (m, 2H), 2.63 - 2.56 (m, 1H), 2.43 (d, J = 13.8 Hz, 2H), 1.96 - 1.88 (m, 2H), 1.20 (d, J = 7.0 Hz, 6H).

[0201] Synthesis of Compound S15

[0202]

[0203] Step 1: Dissolve compound 15a (358 mg, 1.48 mmol) and compound 12c (450 mg, 1.48 mmol) in 5 mL of N,N-dimethylformamide. Add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (846 mg, 2.23 mmol) and N,N-diisopropylethylamine (0.78 mL, 4.45 mmol). Heat the mixture to 50 °C and react for about 4 hours until the raw materials are completely reacted as monitored by TLC. After the reaction solution is cooled, pour it into water, extract it with ethyl acetate three times, combine the organic phases, wash them with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound 15b (625 mg).

[0204]

[0205] Step 2: Under an argon atmosphere, dissolve compound 15b (50 mg, 0.10 mmol) and compound 8a (24 mg, 0.15 mmol) in 1.5 mL of 1,4-dioxane. Add tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) and 2 mol / L aqueous sodium carbonate solution (0.15 mL, 0.31 mmol). Heat the reaction solution to 100 °C for reaction until the raw materials are completely reacted as monitored by TLC. After the reaction solution is cooled, pour it into water, extract it with ethyl acetate three times, combine the organic phases, wash them with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound S15 (36 mg). 1 H NMR (400 MHz, Chloroform-d) δ8.59 - 8.54 (m, 2H), 8.28 (s, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 8.9, 2.7 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.55 (s, 1H), 7.49 - 7.46 (m, 2H), 7.23 (dd, J = 7.1, 2.2 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 3.43 (s, 3H), 3.36 - 3.31 (m, 4H), 3.22 - 3.16 (m, 2H), 2.26 (s, 1H), 1.88 - 1.78 (m, 4H).

[0206] 16. Synthesis of Compound S16

[0207]

[0208] The preparation method refers to the synthesis of compound S15 (Step 2), replace compound 8a with compound 16a, and keep other experimental steps the same to obtain compound S16. 11H NMR (400 MHz, Chloroform-d) δ 8.63 - 8.61 (m, 2H), 8.32 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.77 - 7.71 (m, 3H), 7.64 (s, 1H), 7.28 - 7.25 (m, 1H), 7.09 (d, J = 8.9 Hz, 1H), 3.43 (s, 3H), 3.35 - 3.31 (m, 4H), 3.22 - 3.15 (m, 2H), 2.28 (s, 1H), 1.87 - 1.78 (m, 4H).

[0209] Synthesis of Compound S17

[0210]

[0211] The preparation method refers to the synthesis of Compound S15 (Step 2). Replace Compound 8a with Compound 17a, and keep other experimental steps the same to obtain Compound S17. 1 1H NMR (400 MHz, Chloroform-d) δ 8.57 - 8.55 (m, 1H), 8.53 - 8.52 (m, 1H), 8.32 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.75 - 7.72 (m, 2H), 7.71 - 7.67 (m, 2H), 7.22 - 7.13 (m, 4H), 3.43 (s, 3H), 3.35 - 3.31 (m, 4H), 3.27 - 3.21 (m, 2H), 1.91 - 1.78 (m, 4H).

[0212] Synthesis of Compound S18

[0213]

[0214] The preparation method refers to the synthesis of Compound S15 (Step 2). Replace Compound 8a with Compound 18a, and keep other experimental steps the same to obtain Compound S18. 1 1H NMR (400 MHz, Chloroform-d) δ 8.59 - 8.56 (m, 2H), 8.31 (s, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.75 - 7.73 (m, 3H), 7.68 (s, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.22 (dd, J = 7.2, 2.1 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 3.43 (s, 3H), 3.34 - 3.30 (m, 4H), 3.2 - 3.16 (m, 2H), 2.27 (s, 1H), 1.88 - 1.77 (m, 4H).

[0215] Synthesis of Compound S19

[0216]

[0217] The preparation method refers to the synthesis of Compound S15 (Step 2). Replace Compound 8a with Compound 19a, and keep other experimental steps the same to obtain Compound S19. 1 H NMR(400MHz,Chloroform-d)δ8.48 - 8.46(m,2H),8.37(s,1H),8.30(s,1H),7.89(d,J=2.6Hz,1H),7.77(dd,J=8.9,2.6Hz,1H),7.64 - 7.61(m,2H),7.18(dd,J=7.1,2.2Hz,1H),7.01(d,J=8.9Hz,1H),6.99 - 6.95(m,2H),3.85(s,3H),3.41(s,3H),3.28 - 3.24(m,4H),3.18 - 3.11(m,2H),1.84 - 1.74(m,4H).

[0218] Synthesis of Compound S20

[0219]

[0220] The preparation method refers to the synthesis of Compound S15 (Step 2). Replace Compound 8a with Compound 20a, and keep other experimental steps the same to obtain Compound S20. 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.96(d,J=7.3Hz,1H),8.80(s,1H),8.54(t,J=1.5Hz,1H),8.20 - 8.14(m,3H),7.91 - 7.87(m,2H),7.60 - 7.56(m,1H),7.23(d,J=9.0Hz,1H),4.44(s,1H),3.21 - 3.19(m,4H),3.12 - 3.06(m,2H),1.83 - 1.75(m,2H),1.55(d,J=13.0Hz,2H).

[0221] Synthesis of Compound S21

[0222]

[0223] The preparation method refers to the synthesis of Compound S15 (Step 2). Replace Compound 8a with Compound 21a, and keep other experimental steps the same to obtain Compound S21. 11H NMR (400 MHz, Chloroform-d) δ 8.63 - 8.60 (m, 2H), 8.35 (s, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.76 - 7.71 (m, 3H), 7.61 - 7.53 (m, 2H), 7.21 (dd, J = 7.2, 2.2 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 3.43 (s, 3H), 3.35 - 3.31 (m, 4H), 3.24 - 3.18 (m, 2H), 2.28 (s, 1H), 1.88 - 1.80 (m, 4H).

[0224] Synthesis of Compound S22

[0225]

[0226] The preparation method refers to the synthesis of Compound S15 (Step 2), replace Compound 8a with Compound 22a, and keep other experimental steps the same to obtain Compound S22. 1 1H NMR (400 MHz, Chloroform-d) δ 8.60 - 8.57 (m, 1H), 8.48 - 8.47 (m, 1H), 8.30 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 8.9, 2.6 Hz, 1H), 7.57 (s, 1H), 7.09 - 7.04 (m, 2H), 6.86 - 6.79 (m, 2H), 3.43 (s, 3H), 3.34 - 3.31 (m, 4H), 3.22 - 3.15 (m, 2H), 2.25 (s, 1H), 1.87 - 1.77 (m, 4H).

[0227] Synthesis of Compound S23

[0228]

[0229] The preparation method refers to the synthesis of Compound S15 (Step 2), replace Compound 8a with Compound 23a, and keep other experimental steps the same to obtain Compound S23. 11H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J = 2.3 Hz, 1H), 8.68 - 8.66 (m, 2H), 8.33 (s, 1H), 8.21 (dd, J = 8.0, 2.3 Hz, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.72 (dd, J = 8.9, 2.6 Hz, 1H), 7.57 (s, 1H), 7.27 - 7.25 (m, 1H), 7.09 (d, J = 8.9 Hz, 1H), 3.43 (s, 3H), 3.36 - 3.31 (m, 4H), 3.23 - 3.17 (m, 2H), 2.25 (s, 1H), 1.88 - 1.78 (m, 4H).

[0230] Synthesis of Compound S24

[0231]

[0232] The preparation method refers to the synthesis of Compound S15 (Step 2), replacing Compound 8a with Compound 24a, and keeping other experimental steps the same, to obtain Compound S24. 1 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.31 (s, 1H), 8.93 - 8.91 (m, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.58 - 8.54 (m, 1H), 8.20 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 9.0, 2.6 Hz, 1H), 7.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.23 (d, J = 9.1 Hz, 1H), 3.31 (s, 3H), 3.21 - 3.19 (m, 4H), 3.12 - 3.06 (m, 2H), 1.83 - 1.75 (m, 2H), 1.56 (d, J = 12.8 Hz, 2H).

[0233] Synthesis of Compound S25

[0234]

[0235] The preparation method refers to the synthesis of Compound S15 (Step 2), replacing Compound 8a with Compound 25a, and keeping other experimental steps the same, to obtain Compound S25. 11H NMR (400 MHz, Chloroform-d) δ 8.52 - 8.50 (m, 1H), 8.46 - 8.45 (m, 1H), 8.25 (s, 1H), 7.99 (d, J = 0.7 Hz, 1H), 7.95 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 8.9, 2.6 Hz, 1H), 7.60 (s, 1H), 7.11 (dd, J = 7.2, 2.0 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 4.77 (q, J = 8.3 Hz, 2H), 3.43 (s, 3H), 3.35 - 3.31 (m, 4H), 3.23 - 3.16 (m, 2H), 2.27 (s, 1H), 1.88 - 1.77 (m, 4H).

[0236] Synthesis of Compound S26

[0237]

[0238] Procedure: Under an argon atmosphere, mix Compound 15b (20 mg, 0.04 mmol), Compound 26a (16 mg, 0.06 mmol), palladium acetate (1 mg, 0.004 mmol), n-butylbis(1-adamantyl)phosphine (3 mg, 0.008 mmol), and copper(I) oxide (6 mg, 4 mmol) in 0.5 mL of cyclopentyl methyl ether. Add 1.5 mol / L aqueous cesium carbonate solution (0.08 mL, 0.12 mmol). Heat the reaction mixture to 120 °C in a microwave reactor and react for 5 hours. Monitor the reaction by TLC until the starting materials are completely consumed. After cooling, pour the reaction mixture into water, extract with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain Compound S26 (8 mg). 1 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.74 (s, 1H), 8.46 (dd, J = 6.6, 0.6 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 7.9, 2.3 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.10 - 6.98 (m, 2H), 4.39 (s, 1H), 3.58 - 3.53 (m, 2H), 3.44 - 3.38 (m, 4H), 3.24 (s, 3H), 2.16 - 2.10 (m, 6H), 2.00 - 1.85 (m, 4H).

[0239] Synthesis of Compound S27

[0240]

[0241] Step 1: Under an argon atmosphere, mix compound 8b (500 mg, 1.89 mmol), trimethylsilylacetylene (0.29 mL, 2.04 mmol), bis(triphenylphosphine)palladium dichloride (26 mg, 0.04 mmol), and copper(I) iodide (7 mg, 0.04 mmol) in 4 mL of triethylamine, and react at room temperature for about 2 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Pour the reaction solution into water, extract it with ethyl acetate three times, combine the organic phases, wash them with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound 27a (326 mg).

[0242] Step 2: Dissolve compound 27a (320 mg, 1.12 mmol) in 3 mL of tetrahydrofuran, then add a tetrahydrofuran solution of 1.0 mol / L tetrabutylammonium fluoride (2.23 mL, 2.23 mmol), and react at room temperature for about 2 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Pour the reaction solution into water, extract it with ethyl acetate three times, combine the organic phases, wash them with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound 27b (280 mg).

[0243] Step 3: Dissolve compound 27b (280 mg, 1.31 mmol) in 4 mL of a tetrahydrofuran-water (v / v = 2:1) mixed solution, add lithium hydroxide monohydrate (165 mg, 3.92 mmol), and react at room temperature for about 3 hours until the raw materials are completely reacted as monitored by TLC. Concentrate under reduced pressure to remove the organic solvent, add 3 mol / L hydrochloric acid solution dropwise to the residue to adjust the pH to 5 - 6. After the solid precipitates fully, filter it, wash the filter cake with water several times, collect it, and dry it to obtain compound 27c (253 mg).

[0244] Step 4: Refer to the synthesis method of compound 15b, replace compound 15a with compound 27c, and keep other experimental steps the same to obtain compound S27. 1 H NMR(400MHz,Chloroform-d)δ8.53-8.49(m,1H),8.45(dd,J=7.1,1.0Hz,1H),8.29(s,1H),7.90(d,J=2.6Hz,1H),7.73(dd,J=8.9,2.7Hz,1H),7.64(s,1H),7.10(d,J=8.9Hz,1H),6.99(dd,J=7.2,1.9Hz,1H),3.43(s,3H),3.34-3.31(m,5H),3.24-3.18(m,2H),1.89-1.77(m,4H).

[0245] 28. Synthesis of Compound S28

[0246]

[0247] Procedure: Mix compound S27 (30 mg, 0.07 mmol), diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (56 mg, 0.14 mmol), copper(I) iodide (13 mg, 0.07 mmol), 2,2'-bipyridine (11 mg, 0.07 mmol) and potassium carbonate (10 mg, 0.07 mmol) in 2 mL of N,N-dimethylformamide, heat to 60 °C and react for about 3 hours until the raw materials are completely reacted as monitored by TLC. After the reaction solution is cooled, pour it into water, extract with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and purify by column chromatography to obtain compound S28 (26 mg). 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (br, 1H), 8.53 (dd, J = 7.2, 1.1 Hz, 1H), 8.33 (s, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 8.9, 2.6 Hz, 1H), 7.57 (s, 1H), 7.12 (d, J = 8.9 Hz, 1H), 7.03 (dd, J = 7.1, 1.9 Hz, 1H), 3.43 (s, 3H), 3.36 - 3.33 (m, 2H), 3.31 (s, 2H), 3.26 - 3.19 (m, 2H), 2.25 (s, 1H), 1.89 - 1.78 (m, 4H).

[0248] 29. Synthesis of Compound S29

[0249]

[0250] Steps 1 - 2: The preparation method of compound 29b refers to the synthesis of compound 8d. Replace compound 8a with compound 16a, and keep other experimental steps the same to obtain compound 29b.

[0251]

[0252] Steps 3 - 5: The preparation method of compound S29 refers to the synthesis of compound S1. Replace compound 1b and 1e with compound 29c and 29b respectively, and keep other experimental steps the same to obtain compound S29. 11H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.97 (dd, J = 7.3, 0.9 Hz, 1H), 8.81 (s, 1H), 8.58 (dd, J = 2.2, 0.9 Hz, 1H), 8.15 (d, J = 2.6 Hz, 1H), 8.11 - 8.03 (m, 2H), 7.91 - 7.87 (m, 3H), 7.54 (dd, J = 7.3, 2.2 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.32 (s, 1H), 3.14 - 3.11 (m, 4H), 1.70 - 1.62 (m, 4H), 1.20 (s, 3H).

[0253] 30. Synthesis of Compound S30

[0254]

[0255] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 30a, and keep other experimental steps the same to obtain Compound S30. 1 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.81 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.93 - 7.90 (m, 3H), 7.56 - 7.53 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.04 (s, 1H), 3.36 - 3.33 (m, 2H), 3.09 - 3.03 (m, 2H), 1.91 - 1.80 (m, 4H).

[0256] 31. Synthesis of Compound S31

[0257]

[0258] The preparation method refers to the synthesis of Compounds S9 - 10. Replace Compounds 9a and 7a with Compounds 31a and 29b respectively, and keep other experimental steps the same to obtain Compound S31. 11H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.81 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 2.6 Hz, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.92 - 7.87 (m, 3H), 7.55 (dd, J = 7.2, 2.1 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.64 (t, J = 5.8 Hz, 1H), 4.20 (s, 1H), 3.26 - 3.12 (m, 4H), 3.12 - 3.06 (m, 2H), 1.83 - 1.76 (m, 2H), 1.52 - 1.49 (m, 2H).

[0259] 32. Synthesis of Compound S32

[0260]

[0261] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 32a, and keep other experimental steps the same to obtain Compound S32. 1 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.97 (dd, J = 7.3, 0.9 Hz, 1H), 8.81 (s, 1H), 8.58 - 8.57 (m, 1H), 8.16 (d, J = 2.6 Hz, 1H), 8.09 - 8.06 (m, 2H), 7.92 - 7.87 (m, 3H), 7.54 (dd, J = 7.3, 2.2 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.40 (s, 1H), 3.59 - 3.57 (m, 2H), 3.49 - 3.47 (m, 2H), 3.29 (s, 2H), 3.27 (s, 3H), 3.23 - 3.20 (m, 2H), 3.12 - 3.06 (m, 2H), 1.84 - 1.77 (m, 2H), 1.55 (d, J = 12.9 Hz, 2H).

[0262] 33. Synthesis of Compound S33

[0263]

[0264] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 33a, and keep other experimental steps the same to obtain Compound S33. 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.73 - 8.66 (m, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.72 - 7.56 (m, 4H), 7.02 (d, J = 7.9 Hz, 1H), 4.57 (s, 1H), 4.52 (s, 2H), 3.58 - 3.37 (m, 6H), 3.29 (s, 3H), 2.01 - 1.81 (m, 4H).

[0265] 34. Synthesis of Compound S34

[0266]

[0267] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 34a, and keep other experimental steps the same to obtain Compound S34. 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.74 - 8.65 (m, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.72 - 7.58 (m, 4H), 7.02 (d, J = 7.9 Hz, 1H), 4.40 (s, 1H), 3.57 - 3.52 (m, 2H), 3.45 (s, 2H), 3.43 - 3.38 (m, 2H), 1.99 - 1.83 (m, 4H).

[0268] 35. Synthesis of Compound S35

[0269]

[0270] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 35a, and keep other experimental steps the same to obtain Compound S35. 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.74 - 8.66 (m, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.70 - 7.65 (m, 2H), 7.65 - 7.59 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 3.81 - 3.67 (m, 2H), 2.98 (dd, J = 12.5, 3.1 Hz, 2H), 2.61 (dd, J = 12.4, 3.0 Hz, 2H), 1.16 (d, J = 5.4 Hz, 6H).

[0271] 36. Synthesis of Compound S36

[0272]

[0273] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 36a, and keep other experimental steps the same to obtain Compound S36. 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.70 (dd, J = 6.7, 0.6 Hz, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.70 - 7.56 (m, 4H), 7.03 (d, J = 8.0 Hz, 1H), 3.64 - 3.61 (m, 4H), 2.82 - 2.77 (m, 4H).

[0274] 37. Synthesis of Compound S37

[0275]

[0276] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 37a, and keep other experimental steps the same to obtain Compound S37. 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.70 (dd, J = 6.7, 0.6 Hz, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.70 - 7.59 (m, 4H), 7.02 (d, J = 8.0 Hz, 1H), 3.77 - 3.45 (m, 4H), 2.21 - 2.03 (m, 4H).

[0277] 38. Synthesis of Compound S38

[0278]

[0279] The preparation method refers to the synthesis of compound S29. Replace compound 29c with compound 38a, and keep other experimental steps the same to obtain compound S38. 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.76(s,1H),8.70(dd,J=6.7,0.6Hz,1H),8.03(d,J=1.2Hz,1H),7.92(d,J=2.3Hz,1H),7.80-7.74(m,2H),7.70-7.58(m,4H),7.02(d,J=8.0Hz,1H),4.29(s,1H),3.60-3.40(m,4H),2.01-1.71(m,4H).

[0280] 39. Synthesis of compound S39

[0281]

[0282] The preparation method refers to the synthesis of compound S29. Replace compound 29c with compound 39a, and keep other experimental steps the same to obtain compound S39. 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.76(s,1H),8.70(dd,J=6.7,0.6Hz,1H),8.03(d,J=1.4Hz,1H),7.93(d,J=2.2Hz,1H),7.81-7.74(m,2H),7.70-7.54(m,4H),6.96(d,J=7.7Hz,1H),5.26(s,1H),4.11-3.68(m,3H),2.47-2.17(m,2H),2.03-1.68(m,2H),1.20(d,J=5.9Hz,3H).

[0283] 40. Synthesis of compound S40

[0284]

[0285] The preparation method refers to the synthesis of compound S29. Replace compound 29c with compound 40a, and keep other experimental steps the same to obtain compound S40. 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.71 - 8.63 (m, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.84 - 7.71 (m, 2H), 7.69 - 7.58 (m, 4H), 7.03 (d, J = 7.9 Hz, 1H), 5.38 (s, 1H), 3.80 - 3.46 (m, 3H), 3.10 (dd, J = 12.5, 3.5 Hz, 1H), 2.53 - 2.23 (m, 2H), 1.97 - 1.92 (m, 1H), 1.00 (d, J = 5.8 Hz, 3H).

[0286] 41. Synthesis of Compound S41

[0287]

[0288] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 41a, and keep other experimental steps the same to obtain Compound S41. 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.73 - 8.68 (m, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.71 - 7.58 (m, 4H), 7.00 (d, J = 7.9 Hz, 1H), 5.61 (s, 1H), 3.85 (d, J = 12.4 Hz, 1H), 3.68 - 3.44 (m, 3H), 2.33 - 2.28 (m, 1H), 2.06 - 2.01 (m, 1H), 1.00 (d, J = 19.9 Hz, 6H).

[0289] 42. Synthesis of Compound S42

[0290]

[0291] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 42a, and keep other experimental steps the same to obtain Compound S42. 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.73 - 8.65 (m, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.70 - 7.58 (m, 4H), 6.98 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H), 4.32 - 3.92 (m, 2H), 3.83 - 3.72 (m, 2H), 2.44 - 2.39 (m, 1H), 2.14 - 2.09 (m, 1H).

[0292] Synthesis of Compound S43

[0293]

[0294] For the preparation method, refer to the synthesis of Compound S29. Replace Compound 29c with Compound 43a, and keep other experimental steps the same to obtain Compound S43. 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.73 - 8.64 (m, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.82 - 7.53 (m, 6H), 6.91 (d, J = 7.5 Hz, 1H), 5.19 (s, 1H), 4.07 - 3.98 (m, 2H), 2.38 - 2.33 (m, 2H), 1.88 - 1.82 (m, 2H), 1.20 (d, J = 5.8 Hz, 6H).

[0295] Synthesis of Compound S44

[0296]

[0297] For the preparation method, refer to the synthesis of Compound S31. Replace Compound 31a with Compound 44a, and keep other experimental steps the same to obtain Compound S44. 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.75 - 8.66 (m, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.71 - 7.58 (m, 4H), 7.02 (d, J = 7.9 Hz, 1H), 4.63 (t, J = 6.5 Hz, 1H), 3.69 - 3.41 (m, 6H), 2.31 - 1.86 (m, 4H).

[0298] Synthesis of Compound S45

[0299]

[0300] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 45a, and keep other experimental steps the same to obtain Compound S45. 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.76(s,1H),8.74-8.61(m,1H),8.03(d,J=1.4Hz,1H),7.92(d,J=2.3Hz,1H),7.81-7.73(m,2H),7.71-7.55(m,4H),7.01(d,J=7.9Hz,1H),3.15(t,J=4.7Hz,4H),2.83-2.72(m,4H),2.32(s,3H).

[0301] Synthesis of Compound S46

[0302]

[0303] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 46a, and keep other experimental steps the same to obtain Compound S46. 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.76(s,1H),8.74-8.67(m,1H),8.03(d,J=1.2Hz,1H),7.92(d,J=2.3Hz,1H),7.81-7.72(m,2H),7.72-7.57(m,4H),7.01(d,J=7.9Hz,1H),3.31-3.11(m,4H),2.81(dd,J=5.6,4.1Hz,2H),2.67-2.45(m,3H),0.78-0.46(m,4H).

[0304] Synthesis of Compound S47

[0305]

[0306] The preparation method refers to the synthesis of Compound S29. Replace Compound 29c with Compound 47a, and keep other experimental steps the same to obtain Compound S47. 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.75 - 8.66 (m, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.72 - 7.56 (m, 4H), 7.01 (d, J = 7.9 Hz, 1H), 3.34 - 3.10 (m, 8H), 2.87 (s, 3H).

[0307] Synthesis of Compound S48

[0308]

[0309] Steps 1 - 3: For the preparation method of compound 48d, refer to the synthesis of compound S29. Replace compound 29c with compound 48a, and keep other experimental steps the same to obtain compound 48d.

[0310]

[0311] Step 4: Dissolve compound 48d (60 mg, 0.10 mmol) in 2 mL of dichloromethane, add 0.5 mL of trifluoroacetic acid, and react at room temperature for about 2 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Concentrate under reduced pressure to remove the organic solvent to obtain compound 48e, which is directly used in the next step without further purification.

[0312]

[0313] Step 5: Dissolve compound 48e (calculated as 0.10 mmol) in 2 mL of dichloromethane, add N,N - diisopropylethylamine (88 μL, 0.51 mmol) and acryloyl chloride (12 μL, 0.15 mmol), and react at room temperature for about 3 hours until the raw materials are completely reacted as monitored by TLC. Concentrate under reduced pressure to remove the organic solvent, and purify by column chromatography to obtain compound S48 (36 mg). 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.76 (s, 1H), 8.72 - 8.65 (m, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.70 - 7.58 (m, 4H), 7.01 (d, J = 7.9 Hz, 1H), 6.47 (t, J = 17.0 Hz, 1H), 6.06 - 5.88 (m, 2H), 3.83 - 3.59 (m, 4H), 3.25 - 3.18 (m, 4H).

[0314] Synthesis of Compound S49

[0315]

[0316] The preparation method refers to the synthesis of compound S48. Replace acryloyl chloride with 4-chlorocarbonylmorpholine, and keep other experimental steps the same to obtain compound S49. 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.76(s,1H),8.72-8.65(m,1H),8.03(d,J=1.2Hz,1H),7.92(d,J=2.3Hz,1H),7.81-7.74(m,2H),7.72-7.58(m,4H),7.01(d,J=7.9Hz,1H),3.65-3.44(m,8H),3.26-3.02(m,8H).

[0317] 50. Synthesis of compound S50

[0318]

[0319] The preparation method refers to the synthesis of compound S30. Replace compound 1a with compound 50a, and keep other experimental steps the same to obtain compound S50. 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.76(s,1H),8.75-8.65(m,1H),8.38(d,J=2.0Hz,1H),8.03(d,J=1.4Hz,1H),7.82-7.72(m,2H),7.71-7.62(m,3H),7.55(dd,J=8.7,1.9Hz,1H),6.81(d,J=8.7Hz,1H),4.99(s,1H),3.76-3.67(m,4H),2.32-3.26(m,2H),2.07-2.01(m,2H).

[0320] 51. Synthesis of compound S51

[0321]

[0322] Step 1: The preparation method refers to the synthesis of compound 15b. Replace compound 12c with compound 30c, and keep other experimental steps the same to obtain compound 51a.

[0323]

[0324] Step 2: The preparation method refers to the synthesis of compound S26. Replace compound 15b with compound 51a, and keep other experimental steps the same to obtain compound S51. 11H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.74 (s, 1H), 8.46 (dd, J = 6.6, 0.6 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 7.9, 2.3 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.07 (dd, J = 6.6, 1.5 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 4.99 (s, 1H), 3.66 - 3.45 (m, 4H), 2.26 - 2.21 (m, 2H), 2.14 (br, 6H), 2.00 - 1.94 (m, 2H).

[0325] II. Evaluation of the inhibitory activity of the compound on the STING signaling pathway in human monocytes (THP1)

[0326] Experimental principle: MSA-2 is a small molecule STING agonist of acyclic dinucleotide (Science, 2020, 369(6506)), and has good agonist activity in human and murine cells. MSA-2 specifically binds to the homodimer of STING protein in the endoplasmic reticulum, causing conformational changes and polymerization of the protein, and then inducing the translocation of STING protein from the endoplasmic reticulum to the Golgi apparatus, activating the downstream signaling pathway. STING protein recruits TBK1 and IRF3 proteins in the Golgi apparatus. TBK1 recruited to the STING polymer is activated by autophosphorylation, and then phosphorylates STING and IRF3 proteins. The phosphorylated IRF3 protein forms a homodimer, enters the nucleus through the nuclear pore to play a transcriptional regulatory role, and promotes the expression of type I interferon genes and other pro-inflammatory cytokines. Therefore, by detecting the effect of the compound on the expression level of interferon-stimulated gene reporter luciferase induced by MSA-2-stimulated THP1-Dual cells, it can be indirectly judged whether the compound is a STING inhibitor.

[0327] Experimental method: THP1-Dual cells grow in suspension in the medium. The compound test starts with 1×10 6 cells / mL. At the same time, add serum-free medium containing MSA-2 agonist (final concentration of MSA-2 is 20 μmol / L) and the corresponding test concentration of the compound (the compound is dissolved in DMSO, IC 50 Test concentrations: 45, 15, 5, 1.67, 0.556, 0.185, 0.0617, 0.0206 μM) to treat the cells, so that MSA-2 enters the cells to activate the STING signaling pathway. The blank control group only adds an equal amount of DMSO, and the negative control group only adds MSA-2 stimulation. After co-incubation for 24 hours, collect the cell supernatant and detect the expression level of reporter luciferase.

[0328] The method for detecting luciferase is as follows: Take 20 μL of cell supernatant, add 50 μL of luciferin substrate InvivoGen Quanti-Luc in the dark, and immediately measure the fluorescence absorption. The inhibition rate of the STING signaling pathway after MSA-2 stimulation is calculated based on the fluorescence absorption value: (Lum 给药组 -Lum 空白组 ) / (Lum 阴性组 -Lum 空白组 )*100%. Determination of IC 50 value: Set 8 concentration gradients for each compound, obtain the inhibition rates at different concentrations through experiments, and then calculate the IC 50 value of the compound in graphpad software.

[0329] The experimental results are shown in Table 1, where A: IC 50 ≤100 nM, B: 100 nM < IC 50 ≤500 nM, C: 500 nM < IC 50 ≤5 μM, D: IC 50 > 5 μM.

[0330] Table 1

[0331]

[0332]

[0333] III. Pharmacokinetic (PK) property study of compound S16

[0334] Experimental method: Six SPF-grade male ICR mice, 4 - 6 weeks old, weighing 18 - 22 g, were divided into two groups. Compound S16 was administered by gavage and tail vein injection respectively. The doses for intravenous injection and gavage were 1 mg / kg and 3 mg / kg respectively. For the intravenous injection group, blood samples of about 0.05 mL were collected from the cheek at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration; for the gavage group, blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The concentration of S16 in mouse plasma samples was determined by LC-MS / MS method, and the pharmacokinetic parameters were calculated using WinNolin software.

[0335] Experimental results: As shown in Table 2.

[0336] Table 2. Pharmacokinetic parameters of compound S16 in mice

[0337]

[0338] All documents mentioned in this invention are cited herein by reference as if each individual document was cited by reference. In addition, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, R a substituted or unsubstituted C1-C8 alkyl; R1 and R2, R3 and R4, R5 and R6, R7 and R8 each independently optionally form a 3- to 5-membered spiro ring, fused ring, or bridged ring with the carbon atom to which they are attached; A1, A2, A3, A4, A5, A6 are each independently selected from the group consisting of: C, CR9, N; means that the group containing it is an unsaturated group; Y 1 、Y 2 each independently selected from the group consisting of: CR9, N; Each R9 is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-, R a substituted or unsubstituted amino-(C=O)-, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-NH-, R a substituted or unsubstituted C2-C8 alkenyl-(C=O)-NH-, R a substituted or unsubstituted C1-C8 alkyl-NH-, R a substituted or unsubstituted C1-C8 alkyl-S-, 1-3 R a substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a substituted or unsubstituted C6-C10 aryl, 1-3 R a substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; Z is selected from the group consisting of: O, S, SO, SO2, N(R 10 ), CO, C(R 11 R 12 ); R 10 selected from the group consisting of hydrogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C3-C8 cycloalkyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-, R a substituted or unsubstituted C2-C8 alkenyl-(C=O)-, R a substituted or unsubstituted 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S-(C=O)-, R a substituted or unsubstituted C1-C8 alkyl-S(=O)2-; R 11 and R 12 are each independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, -OR a , amino, cyano, R a -substituted or unsubstituted C1-C8 alkyl, C1-C8 alkyl-(C=O)-O-, C1-C8 alkyl-(C=O)-O-(C1-C2 alkylene)-, R a -substituted or unsubstituted C1-C8 alkoxy, R a -substituted or unsubstituted C1-C8 alkyl-NH-, R a -substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, R a -substituted or unsubstituted C3-C8 cycloalkyl; Each R a is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, C1-C8 haloalkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-, C1-C8 alkyl-(NH)-, -N(C1-C8 alkyl)2, substituted or unsubstituted 3-8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein each substitution independently means being substituted by one or more substituents selected from the group consisting of: deuterium, halogen, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkyl-(C=O)-, 3-8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A1 is N; A2 is N; A3 is CH; A4 is C; A5 is CH; A6 is CR9; R9 is selected from the group consisting of: halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-, R a substituted or unsubstituted amino-(C=O)-, R a substituted or unsubstituted C1-C8 alkyl-(C=O)-NH-, R a substituted or unsubstituted C2-C8 alkenyl-(C=O)-NH-, R a substituted or unsubstituted C1-C8 alkyl-NH-, R a substituted or unsubstituted C1-C8 alkyl-S-, 1-3 R a substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a substituted or unsubstituted C6-C10 aryl, 1-3 R a substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; Each R a is independently selected from the group consisting of: halogen, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Y 1 is CR9, where R9 is selected from the group consisting of: hydrogen, deuterium; Y 2 is CR9, where R9 is a cyano group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R6, R7, R8 are each independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C8 alkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Z is C(R 11 R 12 )); R 11 and R 12 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, -OR a and R a substituted or unsubstituted C1-C8 alkyl, C1-C8 alkyl-(C=O)-O-, C1-C8 alkyl-(C=O)-O-(C1-C2 alkylene)-, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, R a substituted or unsubstituted C3-C8 cycloalkyl; Each R a is independently selected from the group consisting of: halogen, hydroxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-, wherein each substitution independently means being substituted by one or more substituents selected from the group consisting of deuterium, C1-C8 alkoxy.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, A1 is N; A2 is N; A3 is CH; A4 is C; A5 is CH; A6 is CR9; R9 is selected from the group consisting of: halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, 1-3 R a substituted or unsubstituted 3-8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a substituted or unsubstituted C6-C10 aryl, 1-3 R a substituted or unsubstituted 5-10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; Each R a is independently selected from the group consisting of: halogen, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy; Z is C(R 11 R 12 )); R 11 selected from the group consisting of hydrogen and deuterium; R 12 selected from the group consisting of a 3- to 8-membered heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O or S, and a C3-C8 cycloalkyl group.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, A1 is N; A2 is N; A3 is CH; A4 is C; A5 is CH; A6 is CR9; R9 is selected from the group consisting of: halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, 1-3 R a substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, 1-3 R a substituted or unsubstituted C3-C8 cycloalkyl, 1-3 R a substituted or unsubstituted C6-C10 aryl, 1-3 R a substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, each R a is independently selected from the group consisting of: halogen, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy; Z is C(R 11 R 12 )); R 11 、R 12 each independently selected from the group consisting of: hydroxy, R a substituted or unsubstituted C1-C8 alkyl, C1-C8 alkyl-(C=O)-O-, C1-C8 alkyl-(C=O)-O-(C1-C2 alkylene)-; Each R a is independently selected from the group consisting of: halogen, hydroxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl-(C=O)-, C1-C8 alkyl-(C=O)-O-, C1-C8 alkoxy-(C=O)-, where each substitution independently means being substituted by one or more substituents selected from the group consisting of deuterium, C1-C8 alkoxy.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein The compound is selected from the group consisting of:

9. A pharmaceutical composition, characterized in that, Comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, For the preparation of a medicament for preventing and / or treating diseases selected from the group consisting of: cancer, autoimmune diseases, neurodegenerative diseases, inflammatory diseases.

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