Imidazole-containing pentacyclic derivatives, processes for their preparation and uses thereof

Abstract

The application discloses a compound shown in formula I or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutical composition of the derivative. The compound shown in formula I or the pharmaceutical composition can be used as a TNF-alpha inhibitor for treating or preventing diseases or conditions mediated by TNF-alpha.

Description

Technical Field

[0001] This application belongs to the pharmaceutical field, and specifically relates to a pentacyclic derivative containing imidazole, a pharmaceutically acceptable salt thereof, a method for preparing the same, its use as a TNF-α inhibitor, and a pharmaceutical composition comprising the derivative. Background Technology

[0002] Tumor necrosis factor-α (TNF-α), discovered in 1975, belongs to the TNF superfamily, which includes more than 50 transmembrane proteins. Membrane-bound TNF-α (mTNF-α) is cleaved by metalloprotease TNF-converting enzyme (TACE) to produce soluble TNF-α (sTNF-α). Both forms of TNF-α are homotrimers. TNF-α signals by binding to two receptors, tumor necrosis factor-α receptor 1 (TNFR1) and tumor necrosis factor-α receptor 2 (TNFR2). The difference lies in that at physiological concentrations, sTNF activates TNFR1 but not TNFR2, while mTNF can activate both receptors.

[0003] The two receptors that bind to TNF-α have different distributions. TNFR1 is widely distributed, present on almost all cells, and mainly promotes TNF-induced inflammatory responses, while TNFR2 is mainly found on immune cells, maintaining local immune homeostasis. mTNF-α is mainly expressed on monocytes and macrophages, inducing cell-cell contact through interactions with other cell surface receptors. sTNF-α binding to TNFR1 can activate the nuclear factor NF-κB and mitogen-activated protein kinase (MAPK) inflammatory pathways or caspase cascades. TNFR2 signals through the non-canonical NF-κB pathway, and its activation is crucial for the proliferation, survival, and development of regulatory T cells (Tregs).

[0004] TNF-α is a pleiotropic cytokine involved in the inflammatory process in the body. Following infection, macrophages release TNF-α and warn other immune cells, triggering inflammation. TNF-α can induce fever, apoptosis, cachexia, and inflammation, inhibit tumorigenesis and viral replication, and respond to inflammation through cells that produce IL-1 and IL-6. TNF-α is dysregulated in autoimmune diseases such as psoriasis, rheumatoid arthritis (RA), ankylosing spondylitis, and inflammatory bowel disease (IBD). Autoimmune diseases can be treated with several TNF-α inhibitors belonging to different classical biotechnology drug classes: monoclonal antibodies (e.g., and ), or receptor fusion proteins that act as decoys competing with the TNF receptor (TNFR) (e.g. (Binding). TNF-α is also upregulated in Alzheimer's disease, cancer, asthma, and major depressive disorder.

[0005] Mounting evidence suggests that the immune system plays a crucial role in Alzheimer's disease (AD) and Parkinson's disease (PD). Abnormal activation of glial cells in patients with neurodegenerative diseases is a hallmark of AD. Modulating the neuroinflammatory response may be a therapeutic strategy for treating neurodegenerative diseases. Specifically, activating TNFR2 signaling by directly targeting TNFR2 with TNFR2 agonists or by blocking TNFR1 signaling with selective TNFR1 antagonists appears to be a promising AD treatment strategy. However, blood-brain barrier (BBB) ​​penetration of the drugs is a prerequisite for their efficacy.

[0006] Antibodies can effectively bind to and antagonize the TNF-α / TNFR interface, as demonstrated by various commercially available antibodies such as infliximab, adalimumab, golimumab, and cetuzumab (pegylated or protein-based etanercept), as well as several recent biosimilars. Biologics are more difficult to manufacture, expensive, can induce immune responses, are not orally bioavailable, cannot cross the blood-brain barrier, are effective only in a small subset of patients, and can even exacerbate disease in some. In contrast, small molecules offer oral bioavailability, are non-immunogenic, can be engineered to enter the brain, and are cost-effective to manufacture, especially for chronic indications. To date, no small-molecule TNF-α inhibitors are marketed; therefore, various companies have begun the challenge of finding small molecules that act as TNF-α inhibitors. Commonly employed strategies involve designing molecules that bind to TNF-α to antagonize its interaction with its receptor.

[0007] SAR441566, developed by UCB (Belgium) and Sanofi (France), has entered Phase I clinical trials. In preclinical mouse CIA models, it demonstrated the same therapeutic efficacy as antibody drugs. In clinical trials, SAR441566 showed good safety and tolerability, with no serious adverse events (SAEs), treatment-associated adverse events (TEAEs), or adverse events of particular concern (AESIs). Regarding efficacy, significant improvements in patient condition and the biomarker IL-17F were observed in the clinical response at week 4.

[0008] In summary, there is an urgent need to develop small molecule oral inhibitors of TNF-α to improve the existing treatment paradigm for autoimmune diseases. Summary of the Invention

[0009] According to one aspect of the invention, an object of the invention is to provide a compound of formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

[0010]

[0011] in:

[0012] For single or double bonds, when or When it is a double bond, It is a single bond;

[0013] W 1 Selected from carbon, nitrogen, oxygen, or sulfur, W 2 Selected from carbon, nitrogen, or sulfur, W 3 For carbon, W 4 W 5 W 6 W 7 W 8 W 9 and W 10 Each is independently selected from carbon or nitrogen;

[0014] Preferably, W 1 Selected from carbon, nitrogen, or oxygen, W 2 Selected from carbon or nitrogen, W 3 W 4 W 5 W 6 W 7 W 8 W 9 and W 10 It is carbon;

[0015] R 1Selected from halogens, hydroxyl groups, amino groups, cyano groups, carboxyl groups, acetyl groups, substituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 deuterated alkyl groups, substituted or unsubstituted C1-C3 haloalkyl groups, substituted or unsubstituted C1-C3 hydroxyalkyl groups, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl groups, substituted or unsubstituted C1-C3 halohydroxyalkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C1-C3 deuterated alkoxy groups, substituted or unsubstituted C1-C3 haloalkoxy groups, substituted or unsubstituted C2-C3 alkenyl groups, substituted or unsubstituted C2-C3 deuterated alkenyl groups, and substituted or unsubstituted C2-C3 haloalkenyl groups. Substituted or unsubstituted C2-C3 ynyl group, substituted or unsubstituted C2-C3 deuterated ynyl group, substituted or unsubstituted C2-C3 haloynyl group, substituted or unsubstituted C3-C5 cycloalkyl group, substituted or unsubstituted C3-C5 deuterated cycloalkyl group, substituted or unsubstituted C3-C5 halocycloalkyl group, substituted or unsubstituted 3-5 membered deuterated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 3-5 membered halocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(O)2R a9 Substituted or unsubstituted -(CH2) m10 P(O)R a10 R a11The term "substitution" refers to a substituent selectively containing 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, or 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S; or

[0016] When W 1 When it is nitrogen, R 1 and R 2 W connecting it 1 Together with carbon atoms, they form substituted or unsubstituted, saturated or unsaturated 3- to 4-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 alkyl, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl, deuterium or halogen-substituted or unsubstituted 3- to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents; or

[0017] When W 1 When it is carbon, R 1 and R 2 W connecting it 1Together with carbon atoms, they form substituted or unsubstituted, saturated or unsaturated C3-C8 cycloalkyl groups; substituted or unsubstituted, saturated or unsaturated 3-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S; substituted or unsubstituted 5-6 membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, etc. C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents; or

[0018] When W 4 When it is carbon, R 3 and W 4 W connecting it 2 and W 3 Together they form ring D, which is selected from substituted or unsubstituted, saturated or unsaturated C3-C8 cycloalkyl groups, substituted or unsubstituted, saturated or unsaturated 4-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, and substituted or unsubstituted C6-C8 cycloalkyl groups. 10 Aryl, substituted or unsubstituted, 5- to 14-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; wherein “substituted” refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl groups, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy groups, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl groups, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl groups, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl groups, deuterium or halogen-substituted or unsubstituted 3- to 5-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents;

[0019] Preferably, when W4 When it is carbon, R 3 and W 4 W connecting it 2 and W 3 Together they form ring D, wherein ring D is selected from substituted or unsubstituted saturated or unsaturated 5-6 membered heterocyclic groups containing 1 to 3 selected N or O, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected N and O; wherein “substituted” means selectively containing 1 to 2 oxo groups or C1-C3 alkyl groups;

[0020] More preferably, when W 4 When it is carbon, R 3 and W 4 W connecting it 2 and W 3 Together they form a ring D, the structure of which is selected from:

[0021]

[0022] Preferably, R 1 Selected from halogens, hydroxyl groups, amino groups, cyano groups, carboxyl groups, acetyl groups, substituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C3-C5 cycloalkyl groups, substituted or unsubstituted 4-5 membered deuterated heterocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted 4-5 membered halocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted -(CH2) groups. m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 The term "substitution" refers to the selective presence of 1 to 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, and oxo groups.

[0023] More preferably, when W 1 When it is nitrogen, R 1 and R 2 W connecting it 1 Together with carbon atoms, they form 3-4 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S;

[0024] More preferably, when W 1 When it is carbon, R 1 and R 2 W connecting it 1 Together with carbon atoms, they form C4-C5 cycloalkanes or contain one or two 4-5 membered heterocyclic groups selected from N and O;

[0025] More preferably, R 1 Selected from halogen, hydroxyl, amino, cyano, vinyl, ethynyl, cyclopropyl, or when W 1 When it is nitrogen, R 1 and R 2 W connecting it 1 Together with carbon atoms, it forms a 4-membered heterocyclic group containing one nitrogen atom, or when W... 1 When it is carbon, R 1 and R 2 W connecting it 1 Together with carbon atoms, it forms cyclobutane or contains a 4-membered heterocyclic group selected from N or O atoms;

[0026] R 2 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, oxo, thio, =NR c1 =N-OR c2 Substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 deuterated alkyl, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl, substituted or unsubstituted C1-C3 halohydroxyalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 deuterated alkoxy, substituted or unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C2-C3 alkenyl, substituted or unsubstituted C2-C3 deuterated alkenyl, substituted or unsubstituted C2-C3 haloalkenyl, substituted or unsubstituted C2-C3 ynyl, substituted or unsubstituted C2-C3 deuterated ynyl, substituted or unsubstituted C2-C3 haloynyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted C3-C5 deuterated cycloalkyl, substituted or unsubstituted C3-C5 halocycloalkyl, substituted or unsubstituted 3-5 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 3-5 membered deuterated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(O)2R a9 Substituted or unsubstituted -(CH2) m10 P(O)R a10 R a11 The term "substitution" refers to a substituent that selectively contains 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, or 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0027] Preferably, R 2 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted 4-5 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted 4-5 membered deuterated heterocyclic group containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted 4-5 membered halocyclic heterocyclic group containing 1 or 2 heteroatoms selected from N and O, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 The term "substitution" refers to the selective presence of 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, and C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen.

[0028] More preferably, R 2 Selected from hydrogen, deuterium, halogen, oxo group, thio group, methyl, ethyl, n-propyl, and isopropyl;

[0029] R 3 Selected from halogen, hydroxyl, amino, cyano, carboxyl, oxo, thio, =NR c1 =N-OR c2 Substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 deuterated alkyl, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl, substituted or unsubstituted C1-C3 halohydroxyalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 deuterated alkoxy, substituted or unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C2-C3 alkenyl, substituted or unsubstituted C2-C3 deuterated alkenyl, substituted or unsubstituted C2-C3 haloalkenyl, substituted or unsubstituted C2-C3 ynyl, substituted or unsubstituted C2-C3 deuterated ynyl, substituted or unsubstituted C2-C3 haloynyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted C3-C5 deuterated cycloalkyl, substituted or unsubstituted C3-C5 halocycloalkyl, substituted or unsubstituted 3-5 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 3-5 membered deuterated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(O)2R a9 Substituted or unsubstituted -(CH2) m10 P(O)R a10 R a11 The term "substitution" refers to a substituent that selectively contains 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, or 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0030] Preferably, R 3 Selected from halogens, hydroxyl groups, amino groups, cyano groups, carboxyl groups, oxo groups, thio groups, substituted or unsubstituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C3-C5 cycloalkyl groups, substituted or unsubstituted 4-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N and O, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 The term "substitution" refers to the selective presence of 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, and C4-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen.

[0031] More preferably, R3 Selected from oxo groups, thio groups, and halogens;

[0032] Or, R 2 and R 3 Together with the atoms connecting them, they form a ring C, wherein the ring C is selected from substituted or unsubstituted saturated or unsaturated C3-C8 cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups containing 1 to 4 heteroatoms selected from N, O, and S, or substituted or unsubstituted C6-C8 cycloalkyl groups. 10 Aryl, substituted or unsubstituted, 5- to 14-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; wherein “substituted” refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl groups, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy groups, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl groups, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl groups, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl groups, deuterium or halogen-substituted or unsubstituted 3- to 5-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents;

[0033] More preferably, R 2 and R 3 Together with the atoms that connect them, they form a ring C, wherein the ring C is selected from substituted or unsubstituted 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and O; wherein “substituted” means selectively containing 1 to 2 substituents selected from deuterium, halogen, cyano, oxo, thio, C1-C3 alkyl, and C1-C3 alkoxy.

[0034] R 4Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, acetyl, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 deuterated alkenyl, substituted or unsubstituted C1-C6 haloalkenyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl. substituted or unsubstituted C1-C6 deuterated hydroxyalkyl, substituted or unsubstituted C1-C6 halohydroxyalkyl, substituted or unsubstituted saturated or unsaturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C8 deuterated cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C8 halocycloalkyl, substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted saturated or unsaturated 3-8 membered deuterated heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted C6-C6 deuterated heterocyclic groups, substituted or unsubstituted C6-C6 deuterated heterocyclic groups, substituted or unsubstituted C1-C6 deuterated hydroxyalkyl, substituted or unsubstituted C1-C6 halohydroxyalkyl, substituted or unsubstituted C3-C6 deuterated ... 10 The aryl group, substituted or unsubstituted, comprising 5-10 heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein “substituted” refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted, C1-C3 alkoxy groups selected from hydrogen, deuterium or halogen-substituted or unsubstituted, C1-C3 hydroxyalkyl groups selected from hydrogen, deuterium or halogen-substituted or unsubstituted, C3-C8 cycloalkyl groups selected from deuterium or halogen-substituted or unsubstituted, 3-8 heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C6 heterocyclic groups selected from deuterium or halogen-substituted or unsubstituted. 10 5-10 membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, aryl, deuterium, or halogen substituted or unsubstituted; =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents;

[0035] Preferably, R 4 Selected from substituted or unsubstituted C1-C3 alkoxy groups, wherein “substituted” means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, and halogen;

[0036] Most preferably, R 4 Selected from

[0037] Ring A is selected from C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or ring A is absent;

[0038] Preferably, ring A is selected from 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, or ring A is absent;

[0039] The most preferred embodiment is ring A as follows: Or ring A does not exist;

[0040] R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C6-C 10 The aryl group, substituted or unsubstituted, comprises 5-10 membered heteroaryls containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy groups, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl groups, deuterium or halogen-substituted or unsubstituted C3-C6 cycloalkyl groups, deuterium or halogen-substituted or unsubstituted 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or deuterium or halogen-substituted or unsubstituted C6-C6 cycloalkyl groups. 10 A 5-10 membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted with aryl, deuterium, or halogen, provided that ring A is absent, R 5 It does not exist either;

[0041] Preferably, R 5 The group is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, wherein "substituted" means selectively containing 1 to 2 C1-C3 alkyl, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy, provided that ring A is absent, R 5 It does not exist either;

[0042] More preferably, R 5 It is a halogen; the condition is that R is halogenated when ring A does not exist. 5 It does not exist either;

[0043] R 6 The group is composed of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted 3-6 membered heterocyclic groups, wherein “substituted” refers to a substituent selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen substituted or unsubstituted C1-C3 alkyl, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen substituted or unsubstituted C3-C6 cycloalkyl, or deuterium or halogen substituted or unsubstituted 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0044] Preferably, R 6 The group is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, wherein "substituted" means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen substituted or unsubstituted C1-C3 alkyl, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy.

[0045] Most preferably, R 6 Selected from hydrogen, deuterium, and halogens;

[0046] L is selected from the following: C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, saturated or unsaturated C3-C... 10 Cycloalkyl, saturated or unsaturated 3-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and B, C6-C 10 Aryl, comprising 1-4 heteroatoms selected from N, O, S and B, consisting of 5-10 membered heteroaryls;

[0047] Preferably, L is selected from the following: C2-C4 alkynyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N, O, S and B, phenyl, and 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, S and B.

[0048] More preferably, L is selected from:

[0049]

[0050] R 7Selected from bonds, deuterium, halogens, amino groups, hydroxyl groups, cyano groups, carboxyl groups, oxo groups, thio groups, substituted or unsubstituted amide groups, substituted or unsubstituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 deuterated alkyl groups, substituted or unsubstituted C1-C3 haloalkyl groups, substituted or unsubstituted C1-C3 hydroxyalkyl groups, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl groups, substituted or unsubstituted C1-C3 halohydroxyalkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C1-C3 deuterated alkoxy groups, substituted or Unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C2-C3 alkenyl, substituted or unsubstituted C2-C3 deuterated alkenyl, substituted or unsubstituted C2-C3 haloalkynyl, substituted or unsubstituted C2-C3 deuterated alynyl, substituted or unsubstituted C2-C3 haloalkynyl, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted C1-C3 deuterated alkylamine, substituted or unsubstituted C1-C3 haloalkylamine, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(=O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(=O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(=O)2R a9 Substituted or unsubstituted -(CH2) m10 P(=O)R a10 R a11 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16Substituted or unsubstituted -(CH2) m15 S(=O)(=NR a17 )R a18 The term "substitution" refers to the selective presence of 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, hydrazine, cyano, carboxyl, acetyl, oxo, thio, deuterium- or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl groups, deuterium- or halogen-substituted or unsubstituted C1-C3 alkoxy groups, deuterium- or halogen-substituted or unsubstituted C2-C3 alkenyl groups, deuterium- or halogen-substituted or unsubstituted C2-C3 alkynyl groups, deuterium- or halogen-substituted or unsubstituted C3-C5 cycloalkyl groups, deuterium- or halogen-substituted or unsubstituted 3- to 3 heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or -(CH2). m10 P(=O)R a10 R a11 -(CH2) m11 (=NR a12 -(CH2) m12 (=N-OR a13 -(CH2) m8 S(=O)2NHR a8 (CH2) m6 S(=O) m7 NR a7 -(CH2) m15 S(=O)(=NR a17 )R a18 Substituents;

[0051] Preferably, R 7 Selected from bonds, deuterium, halogens, amino, hydroxyl, cyano, carboxyl, oxo, substituted or unsubstituted amide groups, substituted or unsubstituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C2-C3 alkynyl groups, substituted or unsubstituted C1-C3 alkylamine groups, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(=O) m7 NRa7 Substituted or unsubstituted -(CH2) m8 S(=O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(=O)2R a9 Substituted or unsubstituted -(CH2) m10 P(=O)R a10 R a11 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16 Substituted or unsubstituted -(CH2) m15 S(=O)(=NR a17 )R a18 The term "substitution" refers to the selective presence of 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, hydrazine, cyano, carboxyl, acetyl, oxo, deuterium- or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium- or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium- or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium- or halogen-substituted or unsubstituted C3-C5 cycloalkyl, deuterium- or halogen-substituted or unsubstituted 4- or halogen-substituted 4- or 5-membered heterocyclic groups containing 1 or 2 heteroatoms selected from N and O, and -(CH2). m10 P(=O)R a10 R a11 -(CH2) m11 (=NR a12 -(CH2) m12 (=N-OR a13 -(CH2) m8 S(=O)2NHR a8 (CH2) m6 S(=O) m7 NR a7 -(CH2) m15 S(=O)(=NR a17 )R a18 Substituents;

[0052] More preferably, R 7 Selected from key, or the following structures:

[0053]

[0054] Ring B is selected from saturated or unsaturated C3-C. 10 Cycloalkyl, saturated or unsaturated, containing 1-5 3-12 membered heterocyclic groups selected from N, O, P, S, and Si heteroatoms, C6-C 10 Aryl, saturated or unsaturated, containing 1-5 5-12 membered heteroaryl groups selected from N, O, P, S, Si heteroatoms, or without ring B;

[0055] Preferably, ring B is selected from saturated or unsaturated C3-C8 cycloalkyl groups, saturated or unsaturated 3-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, P, and S, and C6-C 10 Aryl, saturated or unsaturated 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, P, S, or ring B is absent;

[0056] More preferably, ring B is selected from the following structures or ring B does not exist:

[0057]

[0058] R 8 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, amide, cyano, carboxyl, acetyl, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted saturated or unsaturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(=O) m7 R a7 Substituted or unsubstituted -(CH2) m8 S(=O) m7 NHR a8Substituted or unsubstituted -(CH2) m9 NHS (=O) m7 R a9 Substituted or unsubstituted -(CH2) m10 P(=O)R a10 R a11 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16 The term "substitution" refers to the selective presence of 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium- or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl groups, deuterium- or halogen-substituted or unsubstituted C1-C3 alkoxy groups, deuterium- or halogen-substituted or unsubstituted C2-C3 alkenyl groups, deuterium- or halogen-substituted or unsubstituted C2-C3 alkynyl groups, deuterium- or halogen-substituted or unsubstituted C3-C5 cycloalkyl groups, and deuterium- or halogen-substituted or unsubstituted 3 heterocyclic substituents containing 1 to 3 heteroatoms selected from N, O, and S, provided that ring B is absent. 8 It does not exist either;

[0059] Preferably, R 8 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, amide, cyano, carboxyl, acetyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C3 alkoxy, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted saturated or unsaturated C3-C4 cycloalkyl, substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6S(=O) m7 R a7 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16 The term "substitution" refers to the selective presence of 1 to 3 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium- or halogen-substituted or unsubstituted C1-C3 alkoxy groups, provided that ring B is absent, R 8 It does not exist either;

[0060] More preferably, R 8 Selected from the following structures:

[0061]

[0062] n1 is an integer of 0, 1, or 2.

[0063] n2 is an integer of 0, 1, or 2.

[0064] n3 is an integer of 0, 1, 2, 3 or 4.

[0065] n4 is an integer of 0, 1, 2, 3 or 4.

[0066] n5 is an integer of 0, 1, 2 or 3.

[0067] n6 is an integer of 0, 1, 2, 3 or 4.

[0068] n7 is an integer of 0, 1, 2, 3, 4, 5, or 6.

[0069] R c1 R c2 R c3 R c4 R c5 R c6 R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R a10 Ra11 R a12 R a13 R a14 R a15 R a16 R a17 R a18 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C3 deuterated alkyl, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 deuterated alkoxy, substituted or unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl. Substituted or unsubstituted C1-C3 halohydroxyalkyl, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted C1-C3 deuterated alkylamine, substituted or unsubstituted C1-C3 haloalkylamine, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C6 deuterated cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C6 halocycloalkyl, substituted or unsubstituted saturated or unsaturated 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, S, P, substituted or unsubstituted C6-C 10 The aryl, substituted or unsubstituted 3- to 6-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, S, and P; wherein “substituted” refers to a substituent selectively containing 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 alkyl, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl, or deuterium or halogen-substituted or unsubstituted 3- to 5-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0070] Preferably, R c1 R c2 R c3 R c4 R c5 R c6 R a1 R a2 R a3 R a4 R a5 R a6 R a7 Ra8 R a9 R a10 R a11 R a12 R a13 R a14 R a15 R a16 R a17 R a18 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, S, P, substituted or unsubstituted C6-C 10 The aryl, substituted or unsubstituted 3- to 6-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, S, and P; wherein “substituted” refers to a substituent selectively containing 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 alkyl, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl, or deuterium or halogen-substituted or unsubstituted 3- to 5-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0071] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13, m14 and m15 are each an independent integer of 0, 1, 2, 3, 4, 5 or 6.

[0072] Preferably, the compound represented by Formula I, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, can be represented by the following Formula II:

[0073]

[0074] in, Ring A, Ring B, R 1 R 2 R 3 R 4 R 5 R 6 R7 R 8 W 1 W 2 W 3 W 4 W 10 The definitions of n1, n2, n3, n4, n5, n6 and n7 are the same as in Equation I.

[0075] Preferably, the compound represented by Formula I, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, can be represented by the following Formula III:

[0076]

[0077] in, Ring A, Ring B, R 1 R 2 R 3 R 4 R 5 R 7 R 8 W 1 W 2 W 3 W 4 The definitions of n1, n2, n3, n4, n6 and n7 are the same as in Equation I.

[0078] Preferably, the compound represented by Formula I or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, can be represented by the following Formulas III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9:

[0079]

[0080] Among them, rings A, B, C, D, and R 2 R 4 R 5 R 7 R 8 W 1 W 2 W 3 W 4 The definitions of n1, n2, n3, n4, n6, and n7 are the same as those in Equation I.

[0081] Preferably, the compound or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or mixture of isomers, or pharmaceutically acceptable salt thereof, or its prodrug, or its metabolite, represented by Formula I, Formula II, Formula III, III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-5, Formula III-6, Formula III-7, Formula III-8 or Formula III-9, is selected from the following compounds I-1 to I-345:

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] According to a second aspect of the invention, another object of the invention is to provide a pharmaceutical composition comprising a compound represented by formula I, II, III, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable excipient.

[0096] According to a second aspect of the invention, another object of the invention is to provide the use of compounds represented by formula I, II, III, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9, or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or mixtures of isomers thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, or said pharmaceutical compositions thereof, in the preparation of medicaments for treating autoimmune diseases and neurological diseases, wherein said medicaments for treating autoimmune diseases and neurological diseases are preferably TNF-α inhibitors.

[0097] According to a third aspect of the invention, another object of the invention is to provide a method for treating autoimmune diseases and neurological diseases, the method comprising administering to a subject in need an effective amount of a compound or isotopically labeled compound of formula I, II, III, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutical composition thereof.

[0098] Preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis; the neurological disease is selected from sarcoidosis, multiple sclerosis, neurobehçet's disease, chronic inflammatory demyelinating diseases, systemic inflammatory vasculitis, traumatic brain injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, neuropathic pain, and ischemic stroke.

[0099] According to a fourth aspect of the invention, another object of the invention is to provide a method for preparing compounds or isotopically labeled compounds of formula I, II, III, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9, or optical isomers, geometric isomers, tautomers or mixtures of isomers, pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, said method being carried out as follows:

[0100]

[0101] Compound IA-1 reacts with compound IA-2 under the action of catalyst 1 to generate compound IA-3. Compound IA-3 reacts with catalyst 1 to generate compound IA-4. Compound IA-4 reacts with compound IA-5 under the action of catalyst 2 to generate compound IA.

[0102]

[0103] Compound IA is converted into compound IB under the action of reagent 2;

[0104]

[0105] Alternatively, compound IA-4 may be converted into compound IA-6 under the action of reagent 3, and compound IA-6 and compound IA-5 may be converted into compound IB under the action of catalyst 3;

[0106]

[0107]

[0108] Compound IA-1 reacts with compound IC-1 to form compound IC-2; compound IC-2 reacts with compound IC-3 to form compound IC-4; compound IC-4 reacts with reagent 4 to form compound IC-5; compound IC-5 reacts with reagent 5 to form compound IC-6; compound IC-6 reacts with reagent 6 to form compound IC-7; and compound IC-7 and compound IA-5 react with catalyst 4 to form compound IC.

[0109]

[0110] Compound ID-1 is converted into compound ID-2 under the action of reagent 7, and compound IC-2 is converted into compound ID under the action of reagent 8;

[0111]

[0112] Compound IE-1 is reacted with reagent 9 to form compound IE-2, compound IE-2 is reacted with reagent 10 to form compound IE-3, and compound IE-3 and compound IA-5 are reacted with catalyst 3 to form compound IE.

[0113]

[0114] Compound IF-1 reacts with compound IF-2 to form compound IF-3. Compound IF-3 reacts with reagent 11 to form compound IF-4. Compound IF-4 reacts with catalyst 5 to form compound IF-5. Compound IF-5 and compound IA-5 react with catalyst 4 to form compound IF.

[0115] in, Ring A, Ring B, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 W 1 W 2 W 3 W 4 W 5 W 6 W 7 W 8 W 9 W 10 L 1 L 2 The definitions of n1, n2, n3, n4, n5, n6 and n7 are the same as in Equation I;

[0116] X 1 X 3 It is a halogen, sulfonyl ester, boric acid or borate ester; preferably chlorine, bromine, -S(=O)2CF3,

[0117] X 2 X 4 Halogens and sulfonyl esters are preferred; chlorine, bromine, and -S(=O)2CF3 are also preferred.

[0118] Y 1 It is a C1-C6 alkoxy group; preferably a C1-C2 alkoxy group;

[0119] Y 2 -Sn(C1-C6 alkyl)3; preferably -Sn(C4 alkyl)3;

[0120] Y 3 It is -S (=O) (C1-C6 alkyl) or H; preferably -S (=O) (tert-butyl);

[0121] Y 4It is -O (C1-C6 alkyl) or OH; preferably -O (tert-butyl);

[0122] Reagent 1 is LDA, LHMDS, NaHMDS, KHMDS, NaOEt, NaOMe or NaOt-Bu;

[0123] Reagent 2 and Reagent 3 are DAST, BAST, Ishikawa Reagent, SF4, Fluolead, XtalFluors or PyFluor;

[0124] Reagent 4 is a condensing agent, such as HATU, HOBt, EDCI, HOAt, BOP, PyBOP, SOCl2, MsCl, POCl3, (COCl)2 or PhPOCl2.

[0125] Reagent 5 is a reducing agent, such as BH3-THF, BH3-SMe2, BH3-Py or LAH;

[0126] Reagent 7 is a Bredereck reagent, such as DMFDMA, CH(OMe)3, CH(OEt)3, HCOOEt, tert-butyl nitrite, n-amyl nitrite, isoamyl nitrite, isopropyl nitrite, sodium nitrite, DPPA, TMSN3, and 2-chloroacetaldehyde.

[0127] Reagent 8 is methylhydrazine hydrochloride, hydroxylamine hydrochloride, or hydrazine sulfate.

[0128] Reagent 9 is trimethyl sulfoxide or trimethyl sulfur iodide;

[0129] Reagent 10 is K2CO3, Na2CO3, K3PO 4， Cs₂CO₃ or CsF;

[0130] Reagent 11 is a TMSCN, TMS-acetylene, or vinyl reagent;

[0131] Catalyst 1 is Pd(PPh3)2Cl2 or Pd(PPh3)4, catalyst 2 is Xphos-Pd-G3 or Xphos-Pd-G4, catalyst 3 is Xphos-Pd-G3 or Xphos-Pd-G4, catalyst 4 is Xphos-Pd-G3 or Xphos-Pd-G4, and catalyst 5 is Pd2(dba)3. Detailed Implementation

[0132] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0133] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0134] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1-8" should be considered as specifically disclosing all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0135] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0136] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0137] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0138] definition

[0139] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, the isomers can be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Notre Dame University Press, Notre Dame, IN 1972). This disclosure further covers the compounds described herein as single isomers substantially free of other isomers, or mixtures of various isomers.

[0140] When listing a series of values, the intention is to cover every value within that range and every subrange. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 .

[0141] In some embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-8 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-6 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-4 carbon atoms. Therefore, exemplary aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH2-cyclohexyl moiety, etc., which may further contain one or more substituents. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propynyl), and 1-propynyl.

[0142] The term "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C"). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., a halogen, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-10 Alkyl (e.g., unsubstituted C) 1-6Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-10 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0143] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C"). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups, including pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Unless otherwise stated, each instance of an alkenyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-6 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-6 Alkenyl. In alkenyl groups, the C=C double bond without a specified stereochemistry (e.g., -CH=CHCH3 or) can be an (E)- or (Z)- double bond.

[0144] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. 2-20 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3The alkynyl group (“C2-alkynyl”) is present in some embodiments. The one or more carbon-carbon triple bonds can be internal (e.g., in the 2-butynyl group) or terminal (e.g., in the 1-butynyl group). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Unless otherwise stated, each instance of the alkynyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-6 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-6 Alkyne group.

[0145] "Cycloalkyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C"). 3-10 The cycloalkyl group comprises a non-aromatic cycloalkyl group with 3 to 8 carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3-7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 Cycloalkyl). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example C... 3-8 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C 3-10 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C10 As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the carbon ring as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a cycloalkyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C… 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0146] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C"). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3-6 Examples of cycloalkyl groups include the aforementioned C14 groups. 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0147] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the linkage of a heterocycle as defined above with one or more cycloalkyl groups is on the cycloalkyl or heterocycle, or ring systems in which a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of the heterocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group.

[0148] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0149] "Aryl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group that is optionally substituted with an aryl group. In some embodiments, the aryl group is an optionally substituted benzyl group. In some embodiments, the aryl group is a benzyl group. In some embodiments, the aryl group is an optionally substituted phenethyl group. In some embodiments, the aryl group is a phenethyl group.

[0150] "Heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linking point is on an aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have its linking point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0151] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0152] "Heteroaryl" is a subset of alkyl and heteroaryl, and refers to an alkyl group that is optionally substituted by a heteroaryl group.

[0153] "Unsaturated" or "unsaturated" refers to a group containing at least one double or triple bond. "Partially unsaturated" ring systems are also intended to cover rings with multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl). Similarly, "saturated" refers to a group that contains no double or triple bonds, i.e., all single bonds.

[0154] Unless otherwise expressly stated, atoms, portions, or groups described herein may be unsubstituted or substituted, provided that valence permits. The term "optionally substituted" refers to both substituted and unsubstituted atoms.

[0155] Unless otherwise expressly specified, the group may optionally be substituted. The term "optionally substituted" means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted," regardless of whether it is preceded by the term "optionally," means that at least one hydrogen atom present in the group (e.g., carbon or nitrogen atom) is substituted with a permissible substituent, such that the substituent, upon substitution, forms a stable compound, for example, a compound that does not spontaneously transform (e.g., through rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a “substituted” group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term “substituted” is intended to include substitution with all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all such combinations to obtain stable compounds. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. In some embodiments, the substituent is a carbon atom substituent. In some embodiments, the substituent is a nitrogen atom substituent. In some embodiments, the substituent is an oxygen atom substituent. In some embodiments, the substituent is a sulfur atom substituent.

[0156] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0157] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptahydrate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 - Salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0158] The term "tautomer" or "tautomerizing" refers to a compound in which two or more interconvertions result from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactamimide, enamine-imide, and enamine-(different enamines) tautomerization reactions.

[0159] It should also be understood that compounds with the same molecular formula but different properties, different atomic bonding sequences, or different spatial arrangements of atoms are called "isomers". Isomers with different atomic spatial arrangements are called "stereoisomers".

[0160] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are not mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and are described by the R- and S-sequence rules of Cahn and Prelog or by rotating the molecular plane of polarization, and are represented as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0161] The term "prodrug" or "prodrug derivative" refers to a compound having a cleavable group and being converted into the compound described herein by solvent decomposition or under physiological conditions, and which possesses pharmaceutical activity in vivo. Examples of such compounds include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compounds described herein, in both their acid and acid derivative forms, are active, but the acid-sensitive forms often offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (see Bundgard, H., Design of Prodrugs, pp. 7–9, 21–24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives known to those skilled in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed acid anhydrides. Simple aliphatic or aromatic esters, amides, and acid anhydrides derived from the acidic side groups of the compounds described herein are specific prodrugs. In some cases, it is necessary to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, and C7-C... of the compounds described herein are likely preferred. 12 Substituted aryl esters and C7-C 12 Arylalkyl esters.

[0162] The term “inhibition” or “inhibitor” refers to the ability of a compound to reduce, slow down, stop, or prevent the activity of a particular biological process (such as the activity of an IDO enzyme in a cell relative to its carrier).

[0163] The terms "abnormal activation" or "abnormal activity" refer to activity that deviates from normal activity. The term "increased activity" refers to activity that is higher than normal activity.

[0164] The terms “composition” and “formulation” are used interchangeably.

[0165] The term "subject" to be administered refers to a person (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged, or elderly person)). "Patient" refers to a human subject who requires treatment for a disease.

[0166] The term “administration” means the implantation, absorption, ingestion, injection, inhalation or other introduction of the compound or a combination thereof described herein into or onto a subject.

[0167] The term "treatment" refers to reversing, alleviating, delaying the onset of the disease described herein, or inhibiting its development. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the occurrence of the disease. Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0168] The “effective amount” or “therapeutic effective amount” of a compound described herein is an amount sufficient to provide therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with said condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in treating the condition. The term “therapeutic effective amount” can include amounts that improve overall treatment, reduce or avoid symptoms, signs, or causes, and / or enhance the therapeutic efficacy of another therapeutic agent.

[0169] Compounds of Formula I of this application can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of Formula I, methods well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of Formula I by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0170] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0171] Compounds of Formula I of this application can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of Formula I, methods well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of Formula I by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0172] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0173] In the following embodiments, the structures of the exemplary compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as an internal standard.

[0174] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph. Thin-layer chromatography used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as the support. Unless otherwise specified, all reactions in this invention were carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature was expressed in degrees Celsius.

[0175] Furthermore, the abbreviations used in the embodiments have the following meanings:

[0176] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; TiCl4: Titanium tetrachloride; NiCl2: Nickel dichloride; Ti(i-PrO)4: Tetraisopropyl titanate; MnO2: Manganese dioxide; KOAc: Potassium acetate; NH4Cl: Ammonium chloride; NH2OH.HCl: Hydroxylamine hydrochloride; K2CO3: Potassium carbonate; Na2CO3: Sodium carbonate; Ag2CO3: Silver carbonate; Cs2CO3: Cesium carbonate; CsF: Cesium fluoride; NaI: Sodium iodide; ZnI2: Zinc diiodide; SnCl2: Tin dichloride; KOH: Potassium hydroxide; CH3MgBr: Methylmagnesium bromide; NaH: Sodium hydride; NaBH4: Sodium borohydride; DIBAL-H: Diisobutylaluminum hydride; BH3-THF: Boranetetrahydrofuran complex; DAST: Diethylaminosulfur trifluoride; TMSCN: Trimethylcyanosilane; Bredereck's Reagent: Tert-butoxydi(dimethylamino)methane; DIB: Diacetoxyiodobenzene; CDI: Carbonyl diimidazole; CSA: Camphor sulfonic acid; Pd(OAc)2: Palladium acetate; CuI: Cuprous iodide; CuCl: Cuprous chloride; CuTC: Thiophene-2-carboxylic acid cuprous; (BOC)2O: Ditert-tert-butyl dicarbonate; PTSA: p-Toluenesulfonic acid; MsCl: Methanesulfonyl chloride; TsCl: p-Toluenesulfonyl chloride; n-BuL i: n-Butyllithium; LDA: Diisopropylaminolithium; LHMDS: Hexamethyldisilaminolithium; NaOMe: Sodium methoxide; KOt-Bu: Potassium tert-butoxide; Pd(PPh3)2Cl2: Ditriphenylphosphine dichloride palladium; Pd2(dba)3: Tridibenzylacetone dipalladium; PCy3.HBF4: Tricyclohexylphosphine tetrafluoroborate; XantPhos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene; DPPP: 1,3-bis(diphenylphosphine)propane; Xphos-Pd-G4: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) Palladium(II); BPy: bipyridine; BPD: pinacol diboronic acid; BBA: bis(boronic acid); NaOH: sodium hydroxide; NH4OH: ammonia; H2O: water; EA: ethyl acetate; PE: petroleum ether; MeOH: methanol; EtOH: ethanol; i-PrOH: isopropanol; DIPEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; Toluene: toluene; Et2O: diethyl ether; 1,4-Dioxane: 1,4-dioxane; THF: tetrahydrofuran; DCM: dichloromethane; TFA: trifluoroacetic acid; RT: room temperature.

[0177] Preparation Example:

[0178] Example I-1: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-1)

[0179]

[0180]

[0181] Step A: 2-Bromo-6-[(difluoromethyl)oxy]benzene-1-carboxaldehyde (2)

[0182] Diethyl bromodifluoromethylphosphonate (66.4 g, 248.7 mmol) was dissolved in acetonitrile (500 mL). A solution of potassium hydroxide (13.9 g, 248.7 mmol) in water (500 mL) was added with stirring at 0 °C. Then 2-bromo-6-hydroxybenzaldehyde (compound 1, 50 g, 248.7 mmol) was added. The reaction solution was stirred at 0 °C for 2 hours. The reaction solution was diluted with dichloromethane (500 mL), washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give title compound 2 (30 g, 48%).

[0183] LC-MS (m / z): 251 [M+H] + .

[0184] 1 H NMR (400MHz, CDCl3) δ.10.35 (s, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.41 (t, J = 8.0Hz, 1H), 7.26 (d, J = 8.0Hz, 1H), 6.61 (t, J = 73.6Hz, 1H).

[0185] Step B: (1E)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]methaneimine (3)

[0186] 2-Bromo-6-[(difluoromethyl)oxy]benzene-1-carboxaldehyde (compound 2, 30 g, 119.5 mmol) was dissolved in dichloromethane (400 mL), and S-tert-butylsulfinamide (17.38 g, 143.4 mmol) and cesium carbonate (46.7 g, 143.4 mmol) were added with stirring. The reaction mixture was stirred for 16 hours, filtered, and the filtrate was washed with saturated sodium chloride (400 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain title compound 3 (30 g, 71%).

[0187] LC-MS (m / z): 354 [M+H] + .

[0188] 1 H NMR (400MHz, CDCl3) δ.8.84(s,1H),7.59-7.57(m,1H),7.35-7.31(m,1H),7.26-7.24(m,1H),6.57(t,J=73.6Hz,1H),1.30(s,9H).

[0189] Step C: (3R)-3-{[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}propionate (4)

[0190] Zinc powder (5.5 g, 84.7 mmol) was added to a tetrahydrofuran solution (100 mL) of anhydrous cuprous chloride (8.42 g, 84.7 mmol) at room temperature. The mixture was stirred at 70 °C for half an hour and cooled to room temperature. A tetrahydrofuran solution (100 mL) of ethyl bromoacetate (28.3 g, 169.4 mmol) was added dropwise at room temperature. The mixture was stirred at 50 °C for half an hour. The reaction solution was filtered. At 0 °C, a tetrahydrofuran solution (50 mL) of (1E)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]methaneimine (compound 3, 30 g, 84.7 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, it was quenched with a saturated ammonium chloride solution (100 mL) and then quenched with ethyl acetate (100 x 3 mL). Extracted by 100 mL, the organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give title compound 4 (29 g, 77%).

[0191] LC-MS (m / z): 442 [M+H] + .

[0192] 1H NMR (400MHz, CDCl3) δ.7.50-7.42(m,1H),7.23-7.00(m,2H),6.62(t,J=73.2Hz,1H),5.6 8-5.55(m,1H),4.18-4.03(m,2H),3.36-2.92(m,2H),1.22(t,J=7.2Hz,3H),1.16(s,9H).

[0193] Step D: Ethyl (3R)-3-amino-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}propionate (5)

[0194] Ethyl (3R)-3-{[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}propionate (compound 4, 29 g, 65.5 mmol) was dissolved in dichloromethane (300 mL), and dioxane hydrochloride solution (4 M, 150 mL) was added with stirring at room temperature. The reaction solution was stirred for 3 hours, and the reaction solution was concentrated to give title compound 5 (28 g, 100%, crude product).

[0195] LC-MS (m / z): 338 [M+H] + .

[0196] Step E: (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propionate (6)

[0197] Potassium carbonate (26.7 g, 196.5 mmol) was added to acetonitrile (300 mL), and ethyl (3R)-3-amino-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}propionate (compound 5, 28 g, 65.5 mol, crude product) and 4-chloro-2-fluoro-1-nitrobenzene (13.7 g, 78.6 mol) were added with stirring at room temperature. The reaction solution was stirred at 80 °C for 16 hours. After returning to room temperature, the reaction solution was diluted with ethyl acetate (700 mL), the organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain title compound 6 (21.5 g, 66%).

[0198] LC-MS (m / z): 493 [M+H] + .

[0199] 1H NMR(400MHz, CDCl3)δ.8.92(d,J=8.8Hz,1H),8.08(d,J=9.2Hz,1H),7.48-7.43(m,1H),7.23–7.11(m,2H),7.11-7.04(m,1H),6.65(t, J=73.2Hz,1H),6.63-6.57(m,1H),5.87-5.77(m,1H),4.18-4.09(m,2H),3.23-3.17(m,1H),3.02-2.85(m,1H),1.22(t,J=7.2Hz,3H).

[0200] Step F: (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propionaldehyde (7)

[0201] Under nitrogen protection and at -78°C, a tetrahydrofuran solution (1M, 87mL, 87mmol) of diisobutylaluminum hydride was added to a tetrahydrofuran solution of (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propionate (compound 6, 21.5 g, 43.5 mmol) in 200 mL. The mixture was stirred at -78°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (100 mL), and extracted three times with dichloromethane (200 mL). The organic phases were combined and dried over anhydrous sulfuric acid. After filtration and concentration, column chromatography was used to give product 7 (16 g, 81%).

[0202] LC-MS (m / z): 449 [M+H] + .

[0203] 1 H NMR(400MHz, CDCl3)δ.9.81(s,1H),8.84(d,J=9.2Hz,1H),8.08(d,J=9.2Hz,1H),7.49-7.43(m,1H),7.22-7.14(m,2H), 7.13-7.06(m,1H),6.67(t,J=73.2Hz,1H),6.65-6.60(m,1H),5.97-5.88(m,1H),3.56-3.41(m,1H),3.22-2.93(m,1H).

[0204] Step G: (4R)-4-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (8)

[0205] (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propanal (compound 7, 16 g, 35.5 mmol) was dissolved in dichloromethane (300 mL). Trimethylcyanosilane (4.2 g, 42.6 mmol), zinc iodide (1.13 g, 3.55 mmol), and triethylamine (1 mL, 7.1 mmol) were added with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (500 mL). The organic phase was washed with saturated ammonium chloride solution (200 mL) and water (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give title compound 8 (18 g, 92%, crude product).

[0206] LC-MS (m / z): 548 [M+H] + .

[0207] Step H: (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (9)

[0208] (4R)-4-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (compound 8, 18 g, 32.79 mmol) was dissolved in ethanol (100 mL), and stannous chloride (31.2 g, 163.95 mmol) was added with stirring at room temperature. The reaction solution was stirred at 80 °C for 16 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate (200 mL). Saturated sodium carbonate solution was added to adjust the pH of the system to 10. The mixture was filtered, and the filtrate was washed with saturated sodium chloride (100 mL). The organic phase was concentrated, and the mixture was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain title compound 9 (4.4 g, 31%).

[0209] LC-MS (m / z): 429 [M+H] + .

[0210] Step I: (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (10)

[0211] (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (compound 9, 1 g, 2.33 mmol) was dissolved in tetrahydrofuran solution (30 mL), and manganese dioxide (870 mg, 10 mmol) was added at room temperature. The reaction solution was stirred at 50 °C for 16 hours. After filtration, the reaction solution was concentrated under vacuum to obtain crude compound 10 (950 mg, 95%).

[0212] LC-MS (m / z): 427 [M+H] + .

[0213] Step J:(1R)-1-{2-acetyl-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (11)

[0214] Compound (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (compound 10, 950 mg, 2.22 mmol) was dissolved in toluene (20 mL). Ditriphenylphosphine palladium dichloride (155.84 mg, 0.222 mmol) and tributyl(1-ethoxyenyl)tin (801.42 mg, 2.22 mmol) were added at room temperature. The reaction mixture was heated to 105 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was then quenched with an aqueous potassium fluoride solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was dissolved in tetrahydrofuran (50 mL), and p-toluenesulfonic acid (200 mg) and water (5 mL) were added. The mixture was stirred at 45 °C for 5 hours. The reaction solution was poured into ice water, alkalized with sodium bicarbonate aqueous solution (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the title compound 11 (720 mg, 83%).

[0215] LC-MS (m / z): 391 [M+H] + .

[0216] Step K: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one(12)

[0217] (1R)-1-{2-acetyl-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (compound 11, 720 mg, 1.84 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of diisopropylaminolithium (2 M, 0.92 mL, 1.84 mmol) was added at -70 °C, followed by stirring at -70 °C for 2 hours. The reaction mixture was then quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the title compound 12 (220 mg, 30%).

[0218] LC-MS (m / z): 391 [M+H] + .

[0219] Step L: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one(13)

[0220] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 12, 220 mg, 0.56 mmol), pinacol diboronate (285 mg, 1.12 mmol), and potassium acetate (110 mg, 1.12 mmol) were dissolved in 1,4 In dioxane (10 mL), the reaction solution was protected with nitrogen. Tris(dibenzylacetone)dipalladium (34 mg, 0.04 mmol) and tricyclohexylphosphine tetrafluoroborate (14.72 mg, 0.04 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 13 (180 mg, 66%).

[0221] LC-MS (m / z): 483 [M+H] + .

[0222] Step M: (cyclobutylidene)[(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amine (16)

[0223] Tetraisopropyl titanate (289 g, 1.02 mol) was added to a tetrahydrofuran solution (1 L) of cyclobutanone (52 g, 713 mmol) and tert-butylsulfinamide (82 g, 679 mmol). The reaction mixture was protected with nitrogen and stirred at 60 °C for 16 hours. The reaction mixture was then diluted with ethyl acetate (1 L) and quenched with saturated sodium bicarbonate solution (1 L). After filtration, the organic phase was separated, washed once with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1-1 / 1) to obtain the title compound 16 (52 g, 44%).

[0224] LC-MS (m / z): 174 [M+H] + .

[0225] 1 H NMR (400MHz, CDCl3) δ.3.59-3.22(m,2H),3.21-3.03(m,2H),2.12(t,J=8.0Hz,2H),1.24(s,9H).

[0226] Step N: 5-Bromo-2-({[(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}cyclobutyl)pyrimidine (17)

[0227] Butyllithium (2.5 M, 106 mL, 265 mmol) was added dropwise to tetrahydrofuran (1.2 L) containing 5-bromo-2-iodopyrimidine (75.5 g, 265 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min under nitrogen protection. Then, a tetrahydrofuran (300 mL) solution of (cyclobutylidene)[(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amine (compound 16, 46 g, 265 mmol) was added at -78 °C. After the reaction was complete, the mixture was quenched in ice water (1 L) and extracted with ethyl acetate (1 L x 3). The organic phases were combined, washed once with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 6 / 1-3 / 1) to obtain the title compound 17 (30 g, 34%).

[0228] LC-MS (m / z): 332 [M+H] + .

[0229] 1 H NMR (400MHz, CDCl3) δ = 8.77 (s, 2H), 4.78 (s, IH), 2.88-2.78 (m, IH), 2.73-2.55 (m, 2H), 2.54-2.43 (m, IH), 2.14-1.92 (m, 2H), 1.24 (s, 9H).

[0230] Step O: 5-Bromo-2-({[(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}cyclobutyl)pyrimidine (18)

[0231] Concentrated hydrochloric acid (12M, 30mL) was added to methanol (300mL) containing 5-bromo-2-({[(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}cyclobutyl)pyrimidine (compound 17, 30g, 90.3mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and then directly concentrated under vacuum to obtain crude compound 18 (25g, 100%).

[0232] LC-MS (m / z): 228 [M+H] + .

[0233] 1 H NMR (400MHz, MeOD-d4) δ = 9.02 (s, 2H), 2.84-2.82 (m, 2H), 2.81-2.78 (m, 2H), 2.60-2.27 (m, 2H).

[0234] Step P: {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (19)

[0235] 5-Bromo-2-({[(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}cyclobutyl)pyrimidine (compound 18, 25 g, 90.3 mmol) was added to a solution of di-tert-butyl dicarbonate (23.6 g, 108.2 mmol) and triethylamine (12 g, 108.2 mmol) in tetrahydrofuran (300 mL) at room temperature. The reaction mixture was stirred at room temperature for half an hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 6 / 1-3 / 1) to obtain title compound 19 (25 g, 84%).

[0236] LC-MS (m / z): 328 [M+H] + .

[0237] 1 H NMR (400MHz, CDCl3) δ = 8.78 (s, 2H), 5.80-5.63 (m, 1H), 2.76-2.67 (m, 2H), 2.66-2.53 (m, 2H), 2.21-2.04 (m, 2H), 1.43 (s, 9H).

[0238] Step Q: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (14)

[0239] The following were added: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccinate-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 32.8 mg, 0.10 mmol), and potassium carbonate (27.6 mg). The compound 14 (25 mg, 0.20 mmol) was dissolved in a mixture of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 14 (25 mg, 41%).

[0240] LC-MS (m / z): 604 [M+H] + .

[0241] Step R:(1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-1)

[0242] A 1,4-dioxane solution (4 M, 4 mL) of hydrochloric acid was added to a 1,4-dioxane (2 mL) of [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxylidene-3,10-diazapentane[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 14, 25 mg, 0.041 mmol)] at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-1 (5 mg, 24.2%).

[0243] LC-MS (m / z): 504 [M+H] + .

[0244] 1 H NMR (400MHz, MeOD-d4) δ.8.74(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2. 0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3. 18-3.15(m,1H),2.80-2.65(m,2H),2.28-2.18(m,4H),1.88-1.80(m,2H).

[0245] The following examples follow the synthetic method steps of Example I-1, where M, N, O, and P are selected to synthesize the corresponding brominated products and to prepare the products by coupling reactions with compound 13 from Example I-1:

[0246]

[0247]

[0248]

[0249]

[0250] The NMR data of the compounds prepared in the above examples are as follows:

[0251]

[0252]

[0253]

[0254]

[0255] Example I-81: (1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[2-(hydroxycyclobutyl)pyrimidin-5-yl]-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-81)

[0256]

[0257] Step A: 1-(5-bromopyrimidin-2-yl)cyclobut-1-ol (20)

[0258] Butyllithium (2.5 M, 4 mL, 10 mmol) was added dropwise to anhydrous tetrahydrofuran (50 mL) containing 5-bromo-2-iodopyrimidine (2.85 g, 10 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min under nitrogen protection. Then, a tetrahydrofuran (20 mL) solution containing cyclobutanone (700 mg, 10 mmol) was added at -78 °C. After the reaction was complete, the mixture was quenched in a saturated ammonium chloride aqueous solution (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed once with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1-3 / 1) to obtain the title compound 20 (1.15 g, 50%).

[0259] LC-MS (m / z): 229 [M+H] + .

[0260] 1 H NMR (400MHz, MeOD-d4) δ = 8.80 (s, 2H), 2.57 (dddd, J = 11.2, 5.2, 4.4, 2.5Hz, 2H), 2.32-2.23 (m, 2H), 1.93-1.76 (m, 2H).

[0261] Step B: (1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[2-(hydroxycyclobutyl)pyrimidin-5-yl]-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-81)

[0262] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 1-(5-bromopyrimidin-2-yl)cyclobut-1-ol (compound 20, 22.9 mg, 0.10 mmol) and potassium carbonate (27. 6 mg (0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-81 (15 mg, 29%).

[0263] LC-MS (m / z): 505 [M+H] + .

[0264] 1 H NMR(400MHz,MeOD-d4)δ.8.75(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2. 0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3. 18-3.15(m,1H),2.80-2.66(m,2H),2.36-2.22(m,4H),1.99-1.89(m,2H).

[0265] The following examples illustrate the synthesis of the corresponding brominated derivatives by selecting appropriate starting materials and reacting them with compound 13 from Examples I-81 via a coupling reaction, following step A of the synthetic method in Examples I-81:

[0266]

[0267]

[0268]

[0269] The NMR data of the compounds prepared in the above examples are as follows:

[0270]

[0271]

[0272] Example I-121: (1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[2-(1,4-oxazacyclohexyl-4-yl)pyrimidin-5-yl]-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-121)

[0273]

[0274] Step A: 5-Bromo-2-(1,4-oxazacyclohexyl-4-yl)pyrimidine (22)

[0275] Potassium carbonate (11 g, 78.80 mmol) was added to acetonitrile (50 mL) containing 5-bromo-2-chloropyrimidine (3 g, 15.50 mmol) and morpholine (4.1 mL, 47 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated and diluted with water (30 mL). It was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1-2 / 1) to obtain the title compound 22 (3.2 g, 84%).

[0276] LC-MS (m / z): 246 [M+H] + .

[0277] 1 H NMR (400MHz, CDCl3) δ = 8.3 (s, 2H), 3.74 (br s, 8H).

[0278] Step B: ((1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[2-(1,4-oxazacyclohexyl-4-yl)pyrimidin-5-yl]-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-121)

[0279] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromo-2-(1,4-oxazacyclohexyl-4-yl)pyrimidine (compound 22, 24.3 mg, 0.10 mmol) and potassium carbonate (2 7.6 mg (0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-121 (10 mg, 19%).

[0280] LC-MS (m / z): 520 [M+H] + .

[0281] 1 H NMR(400MHz,MeOD-d4)δ.8.61(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd, J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3.79-3.70(m,8H),3.18-3.13(m,1H),2.82-2.65(m,2H).

[0282] The following examples illustrate the synthesis of the corresponding brominated derivatives by selecting appropriate starting materials and reacting them with compound 13 from Examples I-121 via a coupling reaction, following step A of the synthetic method in Examples I-121:

[0283]

[0284]

[0285]

[0286] The NMR data of the compounds prepared in the above embodiments are as follows:

[0287]

[0288]

[0289] Example I-161: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[(7S)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (I-161)

[0290]

[0291] Step A: 3-Bromo-7-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-7-ol (24)

[0292] Magnesium methyl bromide (3M, 14 mL, 42.5 mmol) was added dropwise at 0 °C to a tetrahydrofuran solution (50 mL) of 3-bromo-6,7-dihydro-5H-cyclopentano[1,2-b]pyridin-7-one (compound 23, 3 g, 14.15 mmol). The reaction mixture was stirred at 0 °C for 4 hours. After the reaction was completed, the mixture was quenched with ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 1 / 2) to obtain the title compound 24 (1 g, 32%).

[0293] LC-MS (m / z): 228 [M+H] + .

[0294] 1 H NMR (400MHz, CDCl3) δ=8.51-8.46(m,1H),7.73-7.67(m,1H),3.06-2.93(m,1H),2.88-2.75(m,1H),2.37-2.19(m,2H),1.58(s,3H).

[0295] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[(7S)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (I-161)

[0296] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 3-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-7-ol (compound 24, 22.7 mg, 0.10 mmol) and carbon Potassium sulfate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was separated by preparative chromatography and then chiralized again to obtain the title compound I-161 (4 mg, 8%).

[0297] LC-MS (m / z): 504 [M+H] + .

[0298] 1H NMR(400MHz,MeOD-d4)δ.8.53(d,J=2.0Hz,1H),7.97-7.95(m,2H),7.81(d,J=2.0Hz,1H),7.80 -7.78(m,1H),7.74(dd,J=8.0,2.0Hz,1H),7.31-7.27(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70- 6.67(m,1H),3.89-3.85(m,1H),3.79-3.70(m,8H),3.18-3.13(m,1H),2.87-2.64(m,4H),2.24-2.10(m,2H),1.61(s,3H).

[0299] Example I-162: (1R,11R)-7-[(7S)-7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-162)

[0300]

[0301] Step A: 3-Bromo-7-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-7-amine (26)

[0302] Diphenyl azidophosphate (1.19 g, 4.2 mmol) was added to 3-bromo-6,7-dihydro-5H-cyclopenta[1,2-b] at room temperature.

[0303] The reaction mixture of pyridin-7-one (compound 25, 1 g, 3.9 mmol) and triethylamine (474 ​​g, 4.2 mmol) in a toluene solution (50 mL) was stirred at 110 °C for 3 hours. After the reaction was complete, 20% sodium hydroxide solution (50 mL) and tetrahydrofuran (50 mL) were added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 8 / 1) to obtain the title compound 26 (221 mg, 25%).

[0304] LC-MS (m / z): 227 [M+H] + .

[0305] 1 H NMR (400MHz, DMSO-d6) δ=8.51-8.36(m,1H),7.93-7.80(m,1H),2.95-2.83(m,1H),2.83-2.70(m,1H),2.22(s,2H),2.07-1.91(m,2H),1.28(s,3H).

[0306] Step B: (1R,11R)-7-[(7S)-7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-162)

[0307] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosero-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 3-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[1,2-b]pyridine-7-amine (compound 26, 22.6 mg, 0.10 mmol) and carbon Potassium sulfate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was separated by preparative chromatography and then chirally prepared again to obtain the title compound I-162 (3 mg, 6%).

[0308] LC-MS (m / z): 503 [M+H] + .

[0309] 1H NMR(400MHz,MeOD-d4)δ.8.48(d,J=2.0Hz,1H),7.96-7.94(m,2H),7.80 -7.78(m,1H),7.74(dd,J=8.0,2.0Hz,1H),7.71(d,J=3.2Hz,1H),7.31-7.27(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz, 1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3.79-3.70(m,8H),3.18-3.13(m,1H),2.87-2.64(m,4H),2.24-2.10(m,2H),1.57(s,3H).

[0310] The following examples refer to step A of the synthesis method in Examples I-161 and I-162, selecting appropriate starting materials to synthesize the corresponding brominated products and preparing them by coupling reaction with compound 13 in Example I-161:

[0311]

[0312] The NMR data of the compounds prepared in the above embodiments are as follows:

[0313]

[0314]

[0315] Example I-171: (1R,11R)-13-[(difluoromethyl)oxy]-7-{6-[dimethyl(oxoyne)-λ5-methphospho]pyridin-3-yl}-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-171)

[0316]

[0317] Step A: 5-Bromo-2-[dimethyl(oxylidene)-λ5-methylphospho]pyridine (28)

[0318] Dimethyl(oxomyl)-λ5-methylphosphine (compound 27, 1.68 g, 21.6 mmol) was added to 1,4-dioxane (50 mL) of 2,5-dibromopyridine (4.6 g, 19.6 mmol) and triethylamine (3.3 mL, 23.5 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 28 (2.5 g, 55%).

[0319] LC-MS (m / z): 234 [M+H] + .

[0320] 1 H NMR (400MHz, CDCl3) δ = 8.44 (d, J = 2.0Hz, 1H), 7.65 (dd, J = 8.4, 2.0Hz, 1H), 7.48 (d, J = 8.4Hz, 1H), 1.95 (s, 3H), 1.93 (s, 3H).

[0321] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-7-{6-[dimethyl(oxoyne)-λ5-methphospho]pyridin-3-yl}-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-171)

[0322] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromo-2-[dimethyl(oxylidene)-λ5-methylphosphono]pyridine (compound 28, 23.3 mg, 0.10 mmol) and potassium carbonate (2 7.6 mg (0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-171 (15 mg, 29%).

[0323] LC-MS (m / z): 510 [M+H] + .

[0324] 1 H NMR(400MHz,MeOD-d4)δ.8.72(d,J=2.0Hz,1H),7.94(d,J=8.0Hz,1H),7.89(dd ,J=8.0,2.0Hz,1H),7.75-7.71(m,3H),7.53(d,J=8.0Hz,1H),7.32-7.27(m,1H ),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89 -3.85(m,1H),3.18-3.13(m,1H),2.82-2.65(m,2H),1.95(s,3H),1.92(s,3H).

[0325] Example I-172: (1R,11R)-13-[(difluoromethyl)oxy]-7-[6-({[dimethyl(oxylidene)-λ5-methphospho]methyl}oxy)pyridin-3-yl]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-172)

[0326]

[0327] Step A: 5-Bromo-2-({[dimethyl(oxoyne)-λ5-methylphospho]methyl}oxy)pyridine (30)

[0328] (Chloromethyl)dimethyl(oxylidene)-λ5-methylphosphine (compound 29, 1.05 g, 8.27 mmol) was added to N,N-dimethylformamide (15 mL) containing 5-bromo-2-hydroxypyridine (2.3 g, 13.22 mmol) and potassium carbonate (5.48 g, 39.66 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 30 (327 mg, 15%).

[0329] LC-MS (m / z): 266 [M+H] + .

[0330] 1 H NMR (400MHz, CDCl3) δ = 8.20 (s, 1H), 7.73-7.67 (m, 1H), 6.77-6.72 (s, 1H), 4.65 (d, J = 6.0Hz, 2H), 1.59 (s, 3H), 1.63 (s, 3H).

[0331] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-7-[6-({[dimethyl(oxylidene)-λ5-methphospho]methyl}oxy)pyridin-3-yl]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-172)

[0332] The following were added: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromo-2-({[dimethyl(oxylidene)-λ5-methphospho]methyl}oxy)pyridine (compound 30, 26.5 mg, 0.10 mmol) and carbon Potassium phosphate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-172 (10 mg, 18%).

[0333] LC-MS (m / z): 540 [M+H] + .

[0334] 1 H NMR(400MHz,MeOD-d4)δ.8.26(d,J=2.0Hz,1H),7.94(d,J=8.0Hz,1H),7.91-7.88( m,2H),7.75-7.72(m,2H),7.53(d,J=8.0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8. 0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),4.40(d,J=12.0Hz,1H),3 .89-3.85(m,1H),3.18-3.13(m,1H),2.82-2.65(m,2H),1.49(s,3H),1.46(s,3H).

[0335] Example I-173: (1R,11R)-13-[(difluoromethyl)oxy]-7-(6-{[dimethyl(oxoyne)-λ5-methphospho]methyl}pyridin-3-yl)-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-173)

[0336]

[0337] Step A: 5-Bromo-2-{[dimethyl(oxoyne)-λ5-methylphospho]methyl}pyridine (31)

[0338] Lithium bis(trimethylsilylamino)ene (1 M, 19.4 mL, 19.4 mmol) was added to tetrahydrofuran (50 mL) of dimethyl(oxylidene)-λ5-methylphosphine (compound 27, 1.51 g, 19.4 mmol) at room temperature, followed by the addition of 5-bromo-2-(chloromethyl)pyridine (4 g, 19.4 mmol). The reaction mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 31 (388 mg, 8%).

[0339] LC-MS (m / z): 248 [M+H] + .

[0340] 1 H NMR (400MHz, CDCl3) δ = 8.60 (d, J = 2.4Hz, 1H), 7.83-7.78 (m, 1H), 7.31-7.27 (m, 1H), 3.35 (d, J = 14.8Hz, 2H), 1.54 (s, 3H), 1.51 (s, 3H).

[0341] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-7-(6-{[dimethyl(oxylidene)-λ5-methphospho]methyl}pyridin-3-yl)-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-173)

[0342] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromo-2-{[dimethyl(oxylidene)-λ5-methylphospho]methyl}pyridine (compound 31, 26.5 mg, 0.10 mmol) and potassium carbonate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-173 (10 mg, 18%).

[0343] LC-MS (m / z): 524 [M+H] + .

[0344] 1 H NMR(400MHz,MeOD-d4)δ.8.75(d,J=2.0Hz,1H),7.94(d,J=8.0Hz,1H),7.89(dd,J=8.0,2.0Hz,1H) ,7.80(d,J=2.0Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.70(dd,J=8.0,2.0Hz,1H),7.39(d,J=8.0Hz, 1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.8 9-3.85(m,1H),3.49-3.46(m,2H),3.18-3.13(m,1H),2.82-2.65(m,2H),1.51(s,3H),1.48(s,3H).

[0345] The following examples follow the synthetic method steps A of Examples I-171, I-172, and I-173, selecting appropriate starting materials to synthesize the corresponding brominated products and preparing them by coupling reaction with compound 13 from Example I-171:

[0346]

[0347]

[0348] The NMR data of the compounds prepared in the above embodiments are as follows:

[0349]

[0350] Example I-181: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[6-(methyldioxane-λ6-thio)pyridin-3-yl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-181)

[0351]

[0352] Step A: 5-Bromo-2-(methyldioxane-λ6-thio)pyridine (33)

[0353] Potassium peroxymonosulfate complex salt (4.15 g, 6.76 mmol) was added to a mixed solution of 5-bromo-2-methylthiopyridine (compound 32, 600 mg, 2.94 mmol) in isopropanol (40 mL) and water (20 mL) at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum and diluted with ethyl acetate (100 mL). It was washed twice with water (50 mL) and once with saturated sodium chloride solution (50 mL). The solution was dried with anhydrous sodium sulfate and then concentrated under vacuum to obtain crude compound 33 (690 mg, 100%).

[0354] LC-MS (m / z): 236 [M+H] + .

[0355] 1 H NMR (400MHz, CDCl3) δ = 8.76 (d, J = 2.0Hz, 1H), 8.08 (dd, J = 8.4, 2.2Hz, 1H), 7.95 (d, J = 8.0Hz, 1H), 3.20 (s, 3H).

[0356] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[6-(methyldioxane-λ6-thio)pyridin-3-yl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-181)

[0357] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromo-2-(methyldioxane-λ6-thio)pyridine (compound 33, 23.6 mg, 0.10 mmol) and potassium carbonate (2 7.6 mg (0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-181 (3 mg, 6%).

[0358] LC-MS (m / z): 512 [M+H] + .

[0359] 1 H NMR(400MHz,MeOD-d4)δ.8.59(d,J=2.0Hz,1H),8.11(dd,J=8.0,2.0Hz,1H) ,7.95-7.90(m,3H),7.82-7.80(m,1H),7.74(dd,J=8.0,2.0Hz,1H),7.31-7. 27(m,1H),7.20(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.70-6.67(m ,1H),3.89-3.85(m,1H),3.32(s,3H),3.18-3.13(m,1H),2.82-2.63(m,2H).

[0360] Example I-182: (1R,11R)-7-{6-[(R)-nitro(methyl)(oxynyl)-λ6-thio]pyridin-3-yl}-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-182)

[0361]

[0362] Step A: (R)-(5-bromopyridin-2-yl)(methyl)(oxoyl)-λ6-thionimine (34)

[0363] Diacetoxyiodobenzene (15.8 g, 49 mmol) was added to 5-bromo-2-methylthiopyridine (compound 32) at room temperature.

[0364] The reaction mixture was stirred in a methanol (100 mL) solution containing 5 g (24.5 mmol) and ammonium acetate (5.7 g, 73.5 mmol) at room temperature for 16 hours. After the reaction was completed, the crude compound was concentrated under vacuum. The residue was purified by silica gel column chromatography (EA / PE = 1 / 1) and chiral preparative chromatography was used to obtain the title compound 34 (2 g, 35%).

[0365] LC-MS (m / z): 235 [M+H] + .

[0366] 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (d, J = 2.4Hz, 1H), 8.37 (dd, J = 8.4, 2.4Hz, 1H), 8.01 (d, J = 8.4Hz, 1H), 4.54 (s, 1H), 3.17 (s, 3H).

[0367] Step B: (1R,11R)-7-{6-[(R)-aza-yl(methyl)(oxoyl)-λ6-thio]pyridin-3-yl}-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-182)

[0368] The following compounds were prepared: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), (R)-(5-bromopyridin-2-yl)(methyl)(oxoyl)-λ6-thionimine (compound 34, 23.5 mg, 0.10 mmol) and carbon Potassium sulfate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-182 (5 mg, 10%).

[0369] LC-MS (m / z): 511 [M+H] + .

[0370] 1 H NMR(400MHz,MeOD-d4)δ.8.56(d,J=2.0Hz,1H),8.00-7.96(m,2H),7.95-7.90(m,2H),7.84-7.83(m,1H),7.74(dd,J=8.0,2.0Hz,1H),7.32-7.27(m ,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1 H),3.89-3.85(m,1H),3.71(s,3H),3.18-3.13(m,1H),2.82-2.62(m,2H).

[0371] Example I-183: 5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyridine-2-sulfonamide (I-183)

[0372]

[0373] Step A: 5-Bromopyridine-2-sulfonamide (36)

[0374] Ammonia water (25%, 25 mL) was added to a dichloromethane (10 mL) solution of 5-bromopyridine-2-sulfonyl chloride (compound 35, 750 mg, 2.92 mmol) at room temperature. The reaction solution was stirred at 70 °C for 16 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain crude compound 36 (320 mg, 46%).

[0375] LC-MS (m / z): 237 [M+H] + .

[0376] 1 H NMR (400MHz, DMSO-d6) δ = 8.86 (d, J = 2.0Hz, 1H), 8.34 (dd, J = 8.4, 2.4Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.43-7.36 (m, 3H).

[0377] Step B: 5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyridine-2-sulfonamide (I-183)

[0378] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromopyridine-2-sulfonamide (compound 36, 23.6 mg, 0.10 mmol) and potassium carbonate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The temperature was raised to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-183 (4 mg, 8%).

[0379] LC-MS (m / z): 513 [M+H] + .

[0380] 1 H NMR(400MHz,MeOD-d4)δ.8.76(d,J=2.0Hz,1H),8.15(dd,J=8.0,2.0Hz,1H),8. 10(d,J=8.0Hz,1H),7.95-7.91(m,2H),7.82(d,J=2.0Hz,1H),7.74(dd,J=8.0,2 .0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H ),6.70-6.67(m,1H),3.89-3.85(m,1H),3.18-3.13(m,1H),2.82-2.65(m,2H)).

[0381] The following examples follow the synthetic method steps A of Examples I-181, I-182, and I-183, selecting appropriate starting materials to synthesize the corresponding brominated products and preparing them by coupling reaction with compound 13 from Example I-181:

[0382]

[0383] The NMR data of the compounds prepared in the above embodiments are as follows:

[0384]

[0385]

[0386] Example I-191: {5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyridin-2-yl}methanehydroxyline (I-191)

[0387]

[0388] Step A: (5-bromopyridin-2-yl)methanehydroxyline (38)

[0389] 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.17 g, 100 mmol) was added to hydroxylamine hydrochloride (6.95 g, 100 mmol), 1-hydroxybenzotriazole (13.51 g, 100 mmol), and triethylamine (30.3 g, 1 mmol) at room temperature.

[0390] 300 mmol), 5-bromopyridine-2-carboxylic acid (compound 37, 20.2 g, 100 mmol) was reacted in N,N-dimethylformamide (100 mL) solution. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, it was diluted with water (1 L) and then dissolved in dichloromethane (500 mL).

[0391] Extracted three times (mL x 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound.

[0392] The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give title compound 38 (10.85 g, 50%).

[0393] LC-MS (m / z): 217 [M+H] + .

[0394] 1 H NMR (400MHz, MeOH-d4) δ = 8.61 (d, J = 2.0Hz, 1H), 8.04 (dd, J = 8.0, 2.0Hz, 1H), 8.00 (d, J = 8.0Hz, 1H).

[0395] Step B: {5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyridin-2-yl}methanehydroxyline (I-191)

[0396] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosero-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), (5-bromopyridin-2-yl)methanehydroxylamine (compound 38, 21.7 mg, 0.10 mmol), and potassium carbonate (27.6 mg, 0.10 mmol) were added. The compound I-191 (2 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-191 (2 mg, 4%).

[0397] LC-MS (m / z): 493 [M+H] + .

[0398] 1 H NMR(400MHz,MeOD-d4)δ.9.03(d,J=2.0Hz,1H),8.08(dd,J=8.0,2.0Hz,1H),8 .03(d,J=8.0Hz,1H),7.95-7.90(m,2H),7.84-7.82(m,1H),7.74(dd,J=8.0,2. 0Hz,1H),7.31-7.28(m,1H),7.20(dd,J=8.0,2.0Hz,1H),6.99(t,J=57.6Hz,1H ),6.70-6.67(m,1H),3.89-3.85(m,1H),3.18-3.13(m,1H),2.80-2.61(m,2H).

[0399] Example I-192: (1R,11R)-13-[(difluoromethyl)oxy]-7-[6-(5,5-dimethyl-1,4,2-dioxazacyclopenten-3-yl)pyridin-3-yl]-1-hydroxy-3,10-diazapentane[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-192)

[0400]

[0401] Step A: 5-Bromo-2-(5,5-dimethyl-1,4,2-dioxazacyclopenten-3-yl)pyridine (39)

[0402] (5-Bromopyridin-2-yl)methanehydroxyline (compound 38, 2.17 g, 10 mmol) was added to a solution of camphor sulfonic acid (2.32 g, 10 mmol) and 2,2-dimethoxypropane (3.12 g, 30 mmol) in anhydrous dichloromethane (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solution was diluted with saturated sodium carbonate solution (100 mL), and extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain the title compound 39 (1.1 g).

[0403] g, 43%.

[0404] LC-MS (m / z): 257 [M+H] + .

[0405] 1 H NMR (400MHz, CDCl3) δ = 8.51-8.49 (m, 1H), 7.87-7.85 (m, 2H), 1.64 (s, 6H).

[0406] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-7-[6-(5,5-dimethyl-1,4,2-dioxazopenten-3-yl)pyridin-3-yl]-1-hydroxy-3,10-diazapentane[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-192)

[0407] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromo-2-(5,5-dimethyl-1,4,2-dioxazapentan-3-yl)pyridine (compound 39, 25.6 mg, 0.10 mmol) Potassium carbonate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-192 (5 mg, 10%).

[0408] LC-MS (m / z): 533 [M+H] + .

[0409] 1 H NMR(400MHz,MeOD-d4)δ.8.93(d,J=2.0Hz,1H),7.97(dd,J=8.0,2.0Hz,1H),7. 95-7.89(m,3H),7.85-7.83(m,1H),7.74(dd,J=8.0,2.0Hz,1H),7.31-7.28(m,1 H),7.20(dd,J=8.0,2.0Hz,1H),6.99(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.8 9-3.85(m,1H),3.18-3.13(m,1H),2.80-2.61(m,2H),1.67(s,3H),1.62(s,3H).

[0410] Example I-193: (1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[6-(5-oxoylidene-1,4,2-dioxazacyclopenten-3-yl)pyridin-3-yl]-2,9-diazapentane[9.8.1.03,8.02,10.014,19]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-193)

[0411]

[0412] Step A: 3-(5-bromopyridin-2-yl)-1,4,2-dioxazacyclopenten-5-one (40)

[0413] (5-Bromopyridin-2-yl)methanehydroxyline (compound 38, 2.17 g, 10 mmol) was added to a solution of triethylamine (2.02 g, 20 mmol) and N,N-carbazyldiimidazole (1.62 g, 10 mmol) in anhydrous dichloromethane (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solution was diluted with saturated ammonium chloride (100 mL) and extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain the title compound 40 (1.2 g, 49%).

[0414] LC-MS (m / z): 243 [M+H] + .

[0415] 1 H NMR (400MHz, CDCl3) δ=8.50-8.48(m,1H),7.90–7.85(m,2H).

[0416] Step B: (1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[6-(5-oxoylidene-1,4,2-dioxazacyclopenten-3-yl)pyridin-3-yl]-2,9-diazapentane[9.8.1.03,8.02,10.014,19]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-193)

[0417] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 3-(5-bromopyridin-2-yl)-1,4,2-dioxazapentan-5-one (compound 40, 24.2 mg, 0.10 mmol) and carbon Potassium phosphate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-193 (7 mg, 14%).

[0418] LC-MS (m / z): 519 [M+H] + .

[0419] 1 H NMR(400MHz,MeOD-d4)δ.8.94(d,J=2.0Hz,1H),7.99(dd,J=8.0,2.0Hz,1H),7.95-7.90(m,3H),7.85-7.83(m,1H),7.74(dd,J=8.0,2.0Hz,1H),7. 32-7.28(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.99(t,J=57.6Hz,1H),6.7 0-6.67(m,1H),3.89-3.85(m,1H),3.18-3.13(m,1H),2.80-2.61(m,2H).

[0420] Example I-194: (1R,11R)-7-{6-[amino(nitro)methyl]pyridin-3-yl}-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-194)

[0421]

[0422] Step A: (5-bromopyridin-2-yl)formamidin (42)

[0423] Sodium methoxide (540 mg, 10 mmol) was added to a methanol (100 mL) solution of 5-bromo-2-cyanopyridine (compound 41, 9.15 g, 50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. Then, ammonium chloride (2.67 g, ...) was added again.

[0424] 50 mmol), stirred at 70 °C for 3 hours, concentrated after the reaction was complete, diluted with ethanol (100 mL), refluxed and stirred for 1 hour, cooled and filtered, and the filtrate was concentrated to obtain crude compound 42 (7.2 g, 72%).

[0425] LC-MS (m / z): 200 [M+H] + .

[0426] 1 H NMR (400MHz, MeOD-d4) δ = 8.51 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.0, 2.4Hz, 1H), 7.68 (d, J = 8.0Hz, 1H).

[0427] Step B: (1R,11R)-7-{6-[amino(aza-dimethyl)methyl]pyridin-3-yl}-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-194)

[0428] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), (5-bromopyridin-2-yl)formamidin (compound 42, 20.0 mg, 0.10 mmol), and potassium carbonate (27.6 mg) 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The temperature was raised to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-194 (1 mg, 2%).

[0429] LC-MS (m / z): 476 [M+H] + .

[0430] 1 H NMR(400MHz,MeOD-d4)δ.8.83(d,J=2.0Hz,1H),7.96-7.89(m,2H),7.84-7.82 (m,1H),7.81(dd,J=8.0,2.0Hz,1H),7.77(d,J=8.0Hz,1H),7.74(dd,J=8.0,2. 0Hz,1H),7.31-7.28(m,1H),7.20(dd,J=8.0,2.0Hz,1H),6.99(t,J=57.6Hz,1H ),6.70-6.67(m,1H),3.89-3.85(m,1H),3.18-3.14(m,1H),2.80-2.62(m,2H).

[0431] Example I-195: (1R,11R)-13-[(difluoromethyl)oxy]-7-[6-(5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-3-yl]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-195)

[0432]

[0433] Step A: 5-Bromo-2-(4,4-dimethyl-4,5-dihydro-3H-imidazol-2-yl)pyridine (43)

[0434] Phosphorus pentasulfide (444 mg, 1 mmol) was added to 5-bromo-2-cyanopyridine (compound 41, 549 mg) at room temperature.

[0435] The reaction mixture was microwaved at 100°C for 1 hour in a solution of 3 mmol of 2-methylprop-1,2-diamine (5 mL). After the reaction was complete, the mixture was diluted with 10 mL of water and extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 43 (190 mg, 25%).

[0436] LC-MS (m / z): 254 [M+H] + .

[0437] 1 H NMR (400MHz, MeOD-d4) δ = 8.60 (d, J = 2.0Hz, 1H), 7.84 (dd, J = 8.0, 2.0Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 1.41 (s, 6H).

[0438] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-7-[6-(5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-3-yl]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-195)

[0439] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 5-bromo-2-(4,4-dimethyl-4,5-dihydro-3H-imidazol-2-yl)pyridine (compound 43, 25.4 mg, 0.10 mmol) Potassium carbonate (27.6 mg, 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-195 (4 mg, 8%).

[0440] LC-MS (m / z): 530 [M+H] + .

[0441] 1 H NMR(400MHz,MeOD-d4)δ.8.69(d,J=2.0Hz,1H),7.95-7.90(m,2H),7.88(dd,J=8.0,2 .0Hz,1H),7.84-7.81(m,2H),7.74(dd,J=8.0,2.0Hz,1H),7.31-7.28(m,1H),7.20(d d,J=8.0,2.0Hz,1H),6.99(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3 .71(d,J=14.0Hz,2H),3.18-3.13(m,1H),2.80-2.61(m,2H),1.41(d,J=20.4Hz,6H).

[0442] The following examples follow the synthetic method steps A of Examples I-191, I-192, I-193, I-194, and I-195, selecting appropriate starting materials to synthesize the corresponding brominated products and preparing them by coupling reaction with compound 13 from Example I-191:

[0443]

[0444]

[0445] The NMR data of the compounds prepared in the above embodiments are as follows:

[0446]

[0447]

[0448] Example I-211: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(1-methylpyrazol-4-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-211)

[0449]

[0450] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 4-iodo-1-methylpyrazole (compound 44, 20.8 mg, 0.10 mmol) and potassium carbonate (27.6 mg, 0.10 mmol) were added. 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-211 (15 mg, 30%).

[0451] LC-MS (m / z): 437 [M+H] + .

[0452] 1H NMR(400MHz,MeOD-d4)δ.9.63(d,J=1.6Hz,1H),8.04(d,J=1.6Hz,1H),7.98(dd,J=8 .0,2.0Hz,1H),7.85(d,J=8.0Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.71(d,J=2.0Hz ,1H),7.31-7.28(m,1H),7.20(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.71- 6.67(m,1H),3.92(s,3H),3.89-3.85(m,1H),3.18-3.13(m,1H),2.80-2.61(m,2H).

[0453] The following examples illustrate the preparation of compounds 13 from Examples I-211 by coupling appropriate starting material halogenated derivatives or trifluoromethanesulfonates with compound 13 from Examples I-211 using the synthetic method described in Examples I-211:

[0454]

[0455]

[0456] The NMR data of the compounds prepared in the above embodiments are as follows:

[0457]

[0458]

[0459] Example I-221: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[(3-methyloxacyclobut-3-yl)ethynyl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (I-221)

[0460]

[0461] Step A: 3-(3-methyloxetane-3-yl)prop-2-ynyleneic acid (46)

[0462] Butyllithium (1M, 1mL, 1mmol) was added dropwise to a tetrahydrofuran (8mL) solution of 3-ethynyl-3-methyloxetane (compound 45, 960mg, 10mmol) at -70°C. The reaction mixture was stirred at -70°C for half an hour, and then dry ice (200mg) was added. After the reaction was complete, the mixture was diluted with saturated ammonium chloride aqueous solution (10mL), and extracted three times with ethyl acetate (20mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 46 (500mg, 35%).

[0463] LC-MS (m / z): 141 [M+H] + .

[0464] 1 H NMR (400MHz, MeOD-d4) δ = 3.96-3.92 (m, 2H), 3.81-3.77 (m, 2H), 1.31 (s, 3H).

[0465] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[(3-methyloxetane-3-yl)ethynyl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (I-221)

[0466] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 3-(3-methyloxacyclobut-3-yl)prop-2-alkynic acid (compound 4) 6,14.1 mg (0.10 mmol), 2,2-bipyridine (9.6 mg, 0.06 mmol), sodium carbonate (10.6 mg, 0.10 mmol), silver carbonate (27.5 mg, 0.10 mmol), and nickel dichloride (3.9 mg, 0.03 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was protected with nitrogen and heated to 80 °C with stirring for 16 hours. The reaction solution was filtered, and the title compound I-221 (1 mg, 2%) was obtained directly by chromatographic separation and purification.

[0467] LC-MS (m / z): 451 [M+H]+ .

[0468] 1 H NMR(400MHz,MeOD-d4)δ.7.82(d,J=2.0Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.62(d,J=2.0Hz,1H),7.59(dd,J=8.0,2.0Hz,1H),7.31-7.28(m,1H ),7.20(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.71-6.67(m,1H ),3.97-3.80(m,5H),3.18-3.13(m,1H),2.80-2.61(m,2H),1.31(s,3H).

[0469]

[0470] Example I-225: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[(3-methyloxacyclobut-3-yl)ethynyl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (I-225)

[0471] Step A: (1R,11R)-5-[4-bromo-3-(hydroxymethyl)phenyl]-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]teico-3(8),4,6,9,14(15),16,18-heptaen-13-one(48)

[0472] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 96.4 mg, 0.20 mmol), (2-bromo-5-iodophenyl)methanol (compound 47, 62.6 mg, 0.20 mmol), and potassium carbonate (55.2 mg) 0.40 mmol) was dissolved in a mixed solution of 1,4-dioxane (16 mL) and water (4 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (35.4 mg, 0.04 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by thin-layer chromatography to obtain the title compound 48 (50 mg, 46%).

[0473] LC-MS (m / z): 541 [M+H] + .

[0474] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-[(3-methyloxetane-3-yl)ethynyl]-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (I-225)

[0475] The following compounds were added: (1R,11R)-5-[4-bromo-3-(hydroxymethyl)phenyl]-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccinic acid (2-di(8),4,6,9,14(15),16,18-heptaen-13-one (compound 48, 50 mg, 0.09 mmol), diboronic acid (14.7 mg, 0.18 mmol), and methanesulfonic acid (2-di( ... Cyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (35.4 mg, 0.04 mmol) and sodium acetate (17.6 mg, 0.27 mmol) were dissolved in tetrahydrofuran (5 mL). The reaction solution was protected with nitrogen and heated to 70 °C with stirring for 2 hours. The reaction solution was filtered and the title compound I-225 (2 mg, 18%) was obtained directly by chromatographic separation and purification.

[0476] LC-MS (m / z): 489 [M+H] + .

[0477] 1 H NMR(400MHz,MeOD-d4)δ.7.90(dd,J=8.0,2.0Hz,1H),7.87(d,J=8.0Hz,1H),7.75-7.72(m,2H),7.69-7.68(m,1H),7.46-7.38(m,2H),7.31-7.28(m ,1H),7.20(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.71-6.67(m,1 H),5.23(s,2H),3.97-3.80(m,5H),3.18-3.13(m,1H),2.80-2.61(m,2H).

[0478] Example I-228: (1R,11R)-5-{2-[(2S)-azacyclobut-2-yl]pyrimidin-5-yl}-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-228)

[0479]

[0480] Step A: 4-(5-bromopyrimidin-2-yl)azacyclobut-2-one (50)

[0481] Chlorosulfonyl isocyanate (2.32 g, 16 mmol) was added to 5-bromo-2-vinylpyrimidine (compound 49) at 0 °C.

[0482] The reaction mixture was heated from 0°C to room temperature and stirred at room temperature for 16 hours in 20 mL of ether (2.96 g, 16 mmol). The reaction mixture was diluted with 100 mL of dichloromethane, quenched with 50 mL of sodium sulfite solution and 50 mL of disodium hydrogen phosphate solution, and the pH was adjusted to 6 to 8 with sodium hydroxide solution. Dichloromethane (100 mL) was added again for extraction. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 50 (1.3 g, 36%).

[0483] LC-MS (m / z): 228 [M+H] + .

[0484] 1 H NMR (400MHz, MeOD-d4) δ = 8.61 (s, 2H), 5.17-5.07 (m, 1H), 3.12-3.02 (m, 2H).

[0485] Step B: 2-(azacyclobut-2-yl)-5-bromopyrimidine (51)

[0486] Boranetetrahydrofuran complex (1M, 11.4 mmol, 11.4 mmol) was added at 0 °C with 2-(azacyclobutane-2-

[0487] In a tetrahydrofuran (10 mL) solution of 5-bromopyrimidine (compound 50, 1.3 g, 5.7 mmol), the reaction solution was heated from 0 °C to room temperature and stirred at room temperature for 16 hours. The reaction solution was quenched with methanol (2 mL), diluted with saturated ammonium chloride solution (20 mL), and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 51 (300 mg, 24%).

[0488] LC-MS (m / z): 214 [M+H] + .

[0489] 1 H NMR (400MHz, MeOD-d4) δ = 8.60 (s, 2H), 4.83-4.76 (m, 1H), 3.25-3.10 (m, 2H), 2.35-2.15 (m, 2H).

[0490] Step C: (1R,11R)-5-{2-[(2S)-azacyclobut-2-yl]pyrimidin-5-yl}-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-228)

[0491] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 2-(azacyclobut-2-yl)-5-bromopyrimidine (compound 51, 21.4 mg, 0.10 mmol) and potassium carbonate (27.6 mg) 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The temperature was raised to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography and chiral separation to obtain the title compound I-228 (2 mg, 4%).

[0492] LC-MS (m / z): 490 [M+H] + .

[0493] 1 H NMR(400MHz,MeOD-d4)δ.9.04(s,2H),8.03-8.00(m,2H),7.88(d,J=2.0Hz,1H),7.74(dd,J=8.0,2.4Hz,1H),7.32-7.28(m,1H),7.21(dd,J=8.0,2. 0Hz,1H),6.98(t,J=57.6Hz,1H),6.71-6.67(m,1H),4.86-4.79(m,1H),3. 89-3.85(m,1H),3.22-3.13(m,3H),2.80-2.61(m,2H),2.34-2.22(m,2H).

[0494] Example I-229: (1R,11R)-5-{2-[(2S)-hexahydropyridin-2-yl]pyrimidin-5-yl}-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-229)

[0495]

[0496] Step A: {[5-(5-bromopyrimidin-2-yl)-5-oxoylidenepentyl]amino}methane-2-methylpropyl-2-yl ester (53)

[0497] 5-Bromo-2-iodopyrimidine (compound 52, 2.85 mmol) was added dropwise to n-butyllithium (1 M, 11 mL, 11 mmol) at -78 °C.

[0498] The reaction mixture was stirred in 50 mL of ether (1.99 g, 10 mmol) at -78 °C for half an hour. Then, 2-oxoylidenehexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (1.99 g, 10 mmol) was added. After the reaction was complete, the mixture was diluted with 10 mL of saturated ammonium chloride aqueous solution and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 53 (2.8 g, 72%).

[0499] LC-MS (m / z): 358 [M+H] + .

[0500] Step B: 5-Bromo-2-(3,4,5,6-Tetrahydropyridin-2-yl)pyrimidine (54)

[0501] The {[5-(5-bromopyrimidin-2-yl)-5-oxoylidenepentyl]amino}methane-2-methylpropyl-2-yl ester (compound 53,

[0502] The mixture was stirred in a solution of 2.8 g (7.2 mmol) of trifluoroacetic acid (20 mL) at room temperature for 2 hours. After the reaction was complete, the mixture was directly concentrated under vacuum to obtain crude compound 54 (1.7 g, 99%).

[0503] LC-MS (m / z): 240 [M+H] + .

[0504] 1 H NMR (400MHz, MeOD-d4) δ = 8.60 (s, 2H), 4.44-4.39 (m, 1H), 3.12-3.02 (m, 2H), 2.19-2.02 (m, 2H), 1.78-1.61 (m, 4H).

[0505] Step C: 5-Bromo-2-(hexahydropyridin-2-yl)pyrimidine (55)

[0506] Sodium borohydride (242 mg, 7.1 mmol) was added at 0 °C to a tetrahydrofuran (10 mL) solution of 5-bromo-2-(3,4,5,6-tetrahydropyridin-2-yl)pyrimidine (compound 54, 1.7 g, 7.1 mmol). The reaction mixture was heated from 0 °C to room temperature and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), extracted three times with ethyl acetate (50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound 55 (1 g, 60%).

[0507] LC-MS (m / z): 242 [M+H] + .

[0508] 1 H NMR (400MHz, MeOD-d4) δ = 9.20 (s, 2H), 3.62-3.51 (m, 2H), 2.94-2.90 (m, 2H), 1.96-1.88 (m, 2H), 1.83-1.74 (m, 2H).

[0509] Step D: (1R,11R)-5-{2-[(2S)-hexahydropyridin-2-yl]pyrimidin-5-yl}-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-229)

[0510] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 2-(azacyclobut-2-yl)-5-bromopyrimidine (compound 55, 24.2 mg, 0.10 mmol) and potassium carbonate (27.6 mg) 0.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The temperature was raised to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography and chiral separation to obtain the title compound I-229 (3 mg, 6%).

[0511] LC-MS (m / z): 518 [M+H] + .

[0512] 1 H NMR(400MHz,MeOD-d4)δ.9.06(s,2H),8.04-8.01(m,2H),7.87(d,J=2.0Hz,1H ),7.74(dd,J=8.0,2.4Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2.0Hz,1H), 6.98(t,J=57.6Hz,1H),6.71-6.67(m,1H),4.31-4.26(m,1H),3.89-3.85(m,1H ),3.15-3.05(m,3H),2.80-2.61(m,2H),2.11-1.99(m,2H),1.76-1.66(m,4H).

[0513] Example I-231: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-231)

[0514]

[0515] Step A: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one(56)

[0516] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosero-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 12,780 mg, 2 mmol) was dissolved in dichloromethane (10 mL), and diethylaminosulfur trifluoride (322 mg, 2 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was then quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The title compound 56 (50 mg, 6%) was obtained by separation and purification by silica gel column chromatography (PE / EA = 1 / 1).

[0517] LC-MS (m / z): 393 [M+H] + .

[0518] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one(57)

[0519] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosero-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 56, 50 mg, 0.12 mmol), pinacol diboronate (61 mg, 0.24 mmol), and potassium acetate (23.5 mg, 0.24 mmol) were dissolved in 1,4 In dioxane (5 mL), the reaction solution was protected with nitrogen. Tris(dibenzylacetone)dipalladium (17 mg, 0.02 mmol) and tricyclohexylphosphine tetrafluoroborate (7.36 mg, 0.02 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 57 (25 mg, 43%).

[0520] LC-MS (m / z): 485 [M+H] + .

[0521] Step C: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (58)

[0522] The following compounds were added: (1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccinate-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 57, 25 mg, 0.05 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 19.7 mg, 0.06 mmol), and potassium carbonate (13.8 mg). The compound 58 (12 mg, 0.10 mmol) was dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg, 0.01 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 58 (12 mg, 39%).

[0523] LC-MS (m / z): 606 [M+H] + .

[0524] Step D: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-231)

[0525] A 1,4-dioxane solution (4 M, 4 mL) of hydrochloric acid was added to a 1,4-dioxane (2 mL) of [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxonyl-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 58, 12 mg, 0.02 mmol) in 1,4-dioxane. The reaction mixture was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-231 (2 mg, 21%).

[0526] LC-MS (m / z): 506 [M+H]+ .

[0527] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.04-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.73(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd, J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.81-3.49(m,2H),2.82-2.58(m,2H),2.30-2.21(m,4H),1.88-1.81(m,2H).

[0528] The following examples illustrate the preparation of compounds 57 from Examples I-231 by coupling the corresponding brominated derivatives, methanesulfonates, or alkynates with compounds 57 from Examples I-231, following the synthetic method described in Examples I-231:

[0529]

[0530]

[0531]

[0532] The NMR data of the compounds prepared in the above embodiments are as follows:

[0533]

[0534]

[0535] Example I-281: (1R,11R,12R)-5-[2-(aminocyclobutyl)pyrimidin-5-yl]-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.014,19.02,10]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I- 281), (1R,11R,12S)-5-[2-(aminocyclobutyl)pyrimidin-5-yl]-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.014,19.02,10]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-282)

[0536]

[0537] Step A: (1R)-7-chloro-1-{6-[(difluoromethyl)oxy]-2-[(1Z)-1-ethoxypropyl-1-enyl]phenyl}-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (59)

[0538] Compound (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (compound 10, 2.14 g, 5 mmol) was dissolved in N,N-dimethylformamide (20 mL). Palladium acetate (112 mg, 0.5 mmol), 1,3-bis(diphenylphosphine)propane (206 mg, 0.5 mmol), potassium carbonate (1.38 g, 10 mmol), and (1Z)-1-ethoxyprop-1-ene (860 mg, 10 mmol) were added at room temperature. The reaction mixture was heated to 130 °C and stirred under nitrogen protection for 3 hours. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 59 (1.2 g, 55%).

[0539] LC-MS (m / z): 433 [M+H] + .

[0540] Step B: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one(60)

[0541] (1R)-7-chloro-1-{6-[(difluoromethyl)oxy]-2-[(1Z)-1-ethoxypropyl-1-enyl]phenyl}-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (compound 59, 1.2 g, 2.77 mmol) was dissolved in dichloromethane (20 mL), titanium tetrachloride (1.57 g, 8.31 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was then quenched with saturated sodium bicarbonate aqueous solution (20 mL), filtered, and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the title compound 60 (420 mg, 37.5%).

[0542] LC-MS (m / z): 405 [M+H] + .

[0543] Step C: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-19-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one(61)

[0544] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]teico-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 60, 420 mg, 1.03 mmol), pinacol diboronate (570 mg, 2.24 mmol), and potassium acetate (220 mg, 2.24 mmol) were dissolved in... In 1,4-dioxane (10 mL), the reaction solution was protected with nitrogen. Tris(dibenzylacetone)dipalladium (68 mg, 0.08 mmol) and tricyclohexylphosphine tetrafluoroborate (29.5 mg, 0.08 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 61 (150 mg, 29%).

[0545] LC-MS (m / z): 497 [M+H] + .

[0546] Step D: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (62)

[0547] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosero-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 61, 150 mg, 0.3 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 118.2 mg, 0.3 mmol) and potassium carbonate (82.8 mg, 0.6 mmol) were dissolved in 1 In a mixed solution of 10 mL of 4-dioxane and 2 mL of water, the reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (40.3 mg, 0.05 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 62 (38 mg, 21%).

[0548] LC-MS (m / z): 618 [M+H] + .

[0549] Step E: (1R,11R,12R)-5-[2-(aminocyclobutyl)pyrimidin-5-yl]-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.014,19.02,10]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-28) 1), (1R,11R,12S)-5-[2-(aminocyclobutyl)pyrimidin-5-yl]-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.014,19.02,10]eicosuccin-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-282)

[0550] A 1,4-dioxane solution (4 M, 4 mL) of hydrochloric acid was added to a 1,4-dioxane (2 mL) of [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxonyl-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 62, 38 mg, 0.06 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by chiral preparative chromatography to obtain the title compounds I-281 (2 mg, 6%) and I-282 (2 mg, 6%).

[0551] LC-MS (m / z): 518 [M+H] + (I-281); LC-MS (m / z): 518 [M+H] + (I-282)

[0552] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.04-8.00(m,2H),7.91(d,J=2.8Hz,1 H),7.67(dd,J=8.0,2.0Hz,1H),7.32-7.26(m,1H),7.20(dd,J=8.0,2.0Hz,1 H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.73-3.63(m,1H),2.78-2.52 (m,2H),2.28-2.18(m,4H),1.88-1.80(m,2H),1.16(d,J=8.0Hz,3H).(I-281)

[0553] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.05-7.99(m,2H),7.91(d,J=3.2Hz,1 H),7.65(dd,J=8.0,2.0Hz,1H),7.31-7.26(m,1H),7.21(dd,J=8.0,2.0Hz,1 H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.72-3.65(m,2H),2.82-2.50 (m,2H),2.30-2.18(m,4H),1.89-1.81(m,2H),1.24(d,J=8.0Hz,3H).(I-282)

[0554] The following examples illustrate the preparation of compounds 60 from Example I-281 using the synthetic method of Example I-231:

[0555]

[0556]

[0557] Example I-285: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(dichloromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-285)

[0558]

[0559] Step A: (1R,11R)-5-chloro-18-[(dichloromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one(64)

[0560] (1R)-7-chloro-1-{6-[(difluoromethyl)oxy]-2-(1-ethoxyvinyl)phenyl}-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (compound 63, 836 mg, 2 mmol) was dissolved in dichloromethane (20 mL), titanium tetrachloride (2.26 g, 12 mmol) was added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction solution was then quenched with saturated sodium bicarbonate aqueous solution (20 mL), filtered, and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the title compound 64 (400 mg, 47%).

[0561] LC-MS (m / z): 423 [M+H] + .

[0562] Step B: (1R,11R)-13-[(dichloromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaen-18-one(65)

[0563] (1R,11R)-5-chloro-18-[(dichloromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 63, 400 mg, 0.95 mmol), pinacol diboronate (570 mg, 2.24 mmol), and potassium acetate (220 mg, 2.24 mmol) were dissolved in 1,4 In dioxane (10 mL), the reaction solution was protected with nitrogen. Tris(dibenzylacetone)dipalladium (68 mg, 0.08 mmol) and tricyclohexylphosphine tetrafluoroborate (29.5 mg, 0.08 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 65 (110 mg, 22%).

[0564] LC-MS (m / z): 515 [M+H] + .

[0565] Step C: [({5-[(1R,11R)-13-[(dichloromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (66)

[0566] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-12-methyl-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicoseno-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 65, 110 mg, 0.21 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 82.7 mg, 0.21 mmol) and potassium carbonate (58.0 mg, 0.42 mmol) were dissolved in... In a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), the reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (24.2 mg, 0.03 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 66 (25 mg, 19%).

[0567] LC-MS (m / z): 636 [M+H] + .

[0568] Step D: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(dichloromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-285)

[0569] A 1,4-dioxane solution (4 M, 4 mL) in hydrochloric acid was added to a 1,4-dioxane (2 mL) solution of [({5-[(1R,11R)-13-[(dichloromethyl)oxy]-1-hydroxy-18-oxylidene-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 66, 25 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by chiral preparative chromatography to obtain the title compound I-285 (3 mg, 14%).

[0570] LC-MS (m / z): 536 [M+H] + .

[0571] 1 H NMR(400MHz,MeOD-d4)δ.8.74(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.73(dd,J=8.0,2.0Hz,1H),7.44(s,1H),7.32-7.27(m,1H),7 .14(dd,J=8.0,2.0Hz,1H),6.70-6.65(m,1H),3.89-3.85(m,1H),3.17 -3.12(m,1H),2.83-2.65(m,2H),2.27-2.18(m,4H),1.90-1.82(m,2H).

[0572] Example I-286: 1-{5-[(1R,11R,18E)-13-[(difluoromethyl)oxy]-1,18-difluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16,18-octaen-7-yl]pyrimidin-2-yl}cyclobut-1-amine (I-286)

[0573]

[0574] Step A: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11,13-difluoro-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,12,14(15),16,18-octaene(67); (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11,13,13-trifluoro-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(19),15,17-heptaene(68)

[0575] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosero-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 12,780 mg, 2 mmol) was dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (6.4 g, 40 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 40 h. The reaction solution was then quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The title compounds 67 (250 mg, 32%) and 68 (100 mg, 12%) were separated by silica gel column chromatography (PE / EA = 1 / 1) and purified by preparative chromatographic analysis.

[0576] LC-MS (m / z): 395 [M+H] + (Compound 67); LC-MS (m / z): 415 [M+H] + (Compound 68);

[0577] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-1,18-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16,18-octaene(69)

[0578] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11,13-difluoro-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,12,14(15),16,18-octaene (compound 67, 250 mg, 0.63 mmol), pinacol diboronate (315 mg, 1.24 mmol), and potassium acetate (150.6 mg, 1.24 mmol) were dissolved in 1 In 4-dioxane (5 mL), the reaction solution was protected with nitrogen. Tris(dibenzylacetone)dipalladium (85.5 mg, 0.1 mmol) and tricyclohexylphosphine tetrafluoroborate (36.8 mg, 0.1 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 69 (120 mg, 39%).

[0579] LC-MS (m / z): 487 [M+H] + .

[0580] Step C: [({5-[(1R,11R,18E)-13-[(difluoromethyl)oxy]-1,18-difluoro-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16,18-octaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (70)

[0581] The compounds (1R,11R)-13-[(difluoromethyl)oxy]-1,18-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccinate-2(3),4(5),6,8,12(13),14,16,18-octaene (compound 69, 120 mg, 0.24 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 58.8 mg, 0.24 mmol) and potassium carbonate (68 mg) were added. The compound (2,4-dioxane, 0.50 mmol) was dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg, 0.03 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 70 (52 mg, 36%).

[0582] LC-MS (m / z): 608 [M+H] + .

[0583] Step D: 1-{5-[(1R,11R,18E)-13-[(difluoromethyl)oxy]-1,18-difluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16,18-octaen-7-yl]pyrimidin-2-yl}cyclobut-1-amine (I-286)

[0584] A 1,4-dioxane solution (4 M, 4 mL) of hydrochloric acid was added to a 1,4-dioxane (2 mL) solution of [({5-[(1R,11R,18E)-13-[(difluoromethyl)oxy]-1,18-difluoro-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16,18-octaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 70, 52 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-286 (15 mg, 37%).

[0585] LC-MS (m / z): 508 [M+H] + .

[0586] 1 H NMR(400MHz,MeOD-d4)δ.8.74(s,2H),8.05-7.99(m,2H),7.94(d,J=2.4Hz,1H),7.52(dd,J=8.0,2.0Hz,1H),7.18-7.13(m,1H),7.11(dd,J=8.0,2.0H z,1H),6.98(t,J=57.6Hz,1H),5.69(d,J=19.6Hz,1H),5.11-5.04(m,1H),3 .19-3.07(m,1H),2.83-2.75(m,1H),2.27-2.18(m,4H),1.90-1.80(m,2H).

[0587] Example I-287: 1-{5-[(1R,11R)-13-[(difluoromethyl)oxy]-1,18,18-trifluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobut-1-amine (I-287)

[0588]

[0589] Step A: (1R,11R)-13-[(difluoromethyl)oxy]-1,18,18-trifluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(5),6,8,12(13),14,16-heptaene(71)

[0590] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11,13,13-trifluoro-2,9-diazapentacyclo[9.8.1.03,8.02,10.014,19]eicosuccin-3(4),5,7,9,14(19),15,17-heptaene (compound 68, 100 mg, 0.24 mmol), pinacol diboronate (122 mg, 0.48 mmol), and potassium acetate (58.3 mg, 0.48 mmol) were dissolved in 1, In 4-dioxane (5 mL), the reaction solution was protected with nitrogen. Tris(dibenzylacetone)dipalladium (42.5 mg, 0.05 mmol) and tricyclohexylphosphine tetrafluoroborate (18.4 mg, 0.05 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 71 (42 mg, 34%).

[0591] LC-MS (m / z): 507 [M+H] + .

[0592] Step B: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1,18,18-trifluoro-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (72)

[0593] The compounds (1R,11R)-13-[(difluoromethyl)oxy]-1,18-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccinate-2(3),4(5),6,8,12(13),14,16,18-octaene (compound 71, 42 mg, 0.08 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 19.6 mg, 0.08 mmol) and potassium carbonate (23 mg) were added. The compound 72 (12 mg, 0.16 mmol) was dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg, 0.01 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 72 (12 mg, 24%).

[0594] LC-MS (m / z): 628 [M+H] + .

[0595] Step C: 1-{5-[(1R,11R)-13-[(difluoromethyl)oxy]-1,18,18-trifluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobut-1-amine (I-287)

[0596] A 1,4-dioxane solution (4 M, 4 mL) of hydrochloric acid was added to a 1,4-dioxane (2 mL) solution of [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1,18,18-trifluoro-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicosuccinate-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 72, 12 mg, 0.02 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-287 (1 mg, 9%).

[0597] LC-MS (m / z): 528 [M+H] + .

[0598] 1 H NMR(400MHz,MeOD-d4)δ.8.72(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.33-7.27(m,2H),7.12(dd,J=8.0,2.0Hz, 1H),6.98(t,J=57.6Hz,1H),6.23-6.19(m,1H),3.52-3.15(m,2H),2.82-2.62(m,2H),2.28-2.18(m,4H),1.88-1.80(m,2H).

[0599] Example I-288: (1R,12R)-16-[2-(aminocyclobutyl)pyrimidin-5-yl]-10-[(difluoromethyl)oxy]-4,13,20-triazahexane[10.9.1.01,4.06,11.013,21.014,19]tetradosuccinate-6(7),8,10,14(19),15,17,20-heptaen-5-one (I-288)

[0600]

[0601] Step A: (1R)-3-[(E)-[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]azine]-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (73)

[0602] (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (compound 10, 4.27 g, 10.0 mmol), (R)-tert-butylsulfinamide (1.21 g, 10.0 mmol) and tetraisopropyl titanate (5.68 g, 20.0 mmol) were dissolved in tetrahydrofuran (50 mL). The reaction solution was protected with nitrogen and stirred at 60 °C for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain title compound 73 (3.71 g, 70%).

[0603] LC-MS (m / z): 530 [M+H] + .

[0604] Step B: [(1R,3S)-3-{[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl]acetic acid-2-methylpropyl-2-yl ester (74)

[0605] Ethyl bromoacetate (2.94 g, 17.50 mmol), zinc powder (4.55 g, 70 mmol), and cuprous chloride (688.5 mg, 7.0 mmol) were dissolved in tetrahydrofuran (30 mL). The reaction mixture was protected with nitrogen and stirred at 60 °C for half an hour. After cooling to 0 °C, (1R)-3-[(E)-[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]azine]-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl]}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (compound 73, 3.71 g, 7.0 mmol) was reacted with stirring at 0 °C for 1 hour. The reaction solution was filtered, the filtrate was diluted with ethyl acetate (100 mL), washed with dilute hydrochloric acid (100 mL) and saturated sodium bicarbonate solution (100 mL), concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to give title compound 74 (2.7 g, 60%).

[0606] LC-MS (m / z): 646 [M+H] + .

[0607] Step C: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one(75)

[0608] A 1,4-dioxane solution (4 M, 40 mL) of hydrochloric acid was added to a 1,4-dioxane (40 mL) solution of [(1R,3S)-3-{[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl]acetic acid-2-methylpropyl-2-yl ester (compound 74, 2.7 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound 75 (2 g, 98%).

[0609] LC-MS (m / z): 486 [M+H] + .

[0610] Step D: (1'R,3'S)-1'-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[1,2-a]imidazolium]-4-one (76)

[0611] Methanesulfonyl chloride (563 mg, 4.9 mmol) was added to (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.012,17.02,10.04,9]eicosuccin-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (compound 75, 2 The reaction mixture was prepared in acetonitrile (30 mL) containing sodium bicarbonate (2.07 g, 24.6 mmol) and 4.1 mmol (4.1 mmol) under nitrogen protection and stirred at 80 °C for 2 hours. The filtrate was diluted with ethyl acetate (120 mL), washed with saturated sodium bicarbonate (100 mL), concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to give the title compound 76 (1.38 g, 72%).

[0612] LC-MS (m / z): 468 [M+H] + .

[0613] Step E: (1'R,3'R)-1'-{6-bromo-2-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[2,1-b]imidazole](77)

[0614] A borane tetrahydrofuran complex (4.4 mL, 4.4 mmol) was added to a tetrahydrofuran (30 mL) solution of (1'R,3'S)-1'-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[1,2-a]imidazolium]-4-one (compound 76, 1.39 g, 2.94 mmol). The reaction mixture was protected with nitrogen and stirred at 0 °C for 1 hour. The mixture was quenched with methanol (5 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (100 mL), concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 77 (720 mg, 54%).

[0615] LC-MS (m / z): 454 [M+H] + .

[0616] Step F: (1R,12R)-16-chloro-10-[(difluoromethyl)oxy]-4,13,20-triazahexacyclo[10.9.1.01,4.014,19.013,21.06,11]tetracodone-6(7),8,10,14(15),16,18,20-heptaen-5-one(78)

[0617] (1'R,3'R)-1'-{6-bromo-2-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[2,1-b]imidazole] (compound 77, 720 mg, 1.58 mmol), palladium acetate (35.8 mg, 0.16 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (89.2 mg, 0.16 mmol), and potassium carbonate (658 mg, 4.77 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was stirred at 110 °C for 16 hours under a carbon monoxide pressure of 5 atm. After concentration, the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain title compound 78 (330 mg, 52%).

[0618] LC-MS (m / z): 402 [M+H] + .

[0619] Step G: [({5-[(1R,12R)-10-[(difluoromethyl)oxy]-5-oxoylide-4,13,20-triazahexane[10.9.1.01,4.06,11.014,19.013,21]tetradosuccinate-6(7),8,10,14(19),15,17,20-heptaen-16-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (79)

[0620] The ester of [({5-[(1R,12R)-10-[(difluoromethyl)oxy]-5-oxoylide-4,13,20-triazahexane[10.9.1.01,4.06,11.014,19.013,21] dodecyl-6(7),8,10,14(19),15,17,20-heptaen-16-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester ( Compound 78 (330 mg, 0.82 mmol), pinacol diboronate (417 mg, 1.64 mmol), and potassium acetate (161 mg, 1.64 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-) was added with stirring at room temperature. Biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added. The reaction solution was purged three times with dry nitrogen and microwaved at 130 °C for 1 hour. Then, 5-bromo-2-(5,5-dimethyl-1,4,2-dioxazacyclopenten-3-yl)pyridine (compound 39, 268 mg, 0.82 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol), potassium carbonate (226.3 mg, 1.64 mmol), and water (1 mL) were added. The reaction solution was kept under nitrogen protection and stirred at 110 °C for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound 79 (32 mg, 6%).

[0621] LC-MS (m / z): 615 [M+H] + .

[0622] Step H: (1R,12R)-16-[2-(aminocyclobutyl)pyrimidin-5-yl]-10-[(difluoromethyl)oxy]-4,13,20-triazahexane[10.9.1.01,4.06,11.013,21.014,19]tetra-6(7),8,10,14(19),15,17,20-heptaen-5-one (I-288)

[0623] A 1,4-dioxane solution (4 M, 4 mL) of hydrochloric acid was added to a 1,4-dioxane (2 mL) of [({5-[(1R,12R)-10-[(difluoromethyl)oxy]-5-oxonyl-4,13,20-triazahexane[10.9.1.01,4.06,11.014,19.013,21]tetano-6(7),8,10,14(19),15,17,20-heptaen-16-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 79, 32 mg, 0.128 mmol)] at room temperature. The reaction solution was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-288 (8 mg, 12%).

[0624] LC-MS (m / z): 504 [M+H] + .

[0625] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.05-7.99(m,2H),7.93(d,J=2.4Hz,1H),7.47(dd,J=8.0,2.0Hz,1H),7.33-7.27(m,1H),7.21(dd, J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),5.06-5.04(m,1H),3.94-3.73(m,2H),2.69-2.39(m,4H),2.26-2.20(m,4H),1.88-1.80(m,2H).

[0626] The following examples illustrate the preparation of compounds by coupling the corresponding brominated derivatives described above with compound 78 from Examples I-288, following the synthetic method of Examples I-288:

[0627]

[0628]

[0629] The NMR data of the compounds prepared in the above embodiments are as follows:

[0630]

[0631]

[0632] Example I-291: (1R,13R)-19-[2-(aminocyclobutyl)pyrimidin-5-yl]-5,5-difluoro-13-hydroxy-15,22-diaza-4,6-dioxahexane[11.9.1.03,7.02,10.014,22.016,21]tetradecano-2(3),7(8),9,14(15),16(21),17,19-heptaen-11-one (I-291)

[0633]

[0634] Step A: 5-Bromo-2,2-difluorobenzo[d][1,3]dioxacyclopentene-4-carboxaldehyde (81)

[0635] 5-Bromo-2,2-difluorobenzo[d][1,3]dioxane (compound 80, 237 g, 1 mol) was dissolved in dry tetrahydrofuran (2 L). Diisopropylaminolithium (2 M, 500 mL, 1 mol) was added dropwise with stirring at -78 °C. The mixture was stirred at -78 °C for 1 hour, followed by the addition of N,N-dimethylformamide (87.6 g, 1.2 mol). The reaction mixture was stirred at -78 °C for another 1 hour, and then quenched with saturated ammonium chloride solution (1 L). The mixture was extracted with ethyl acetate (1 L x 3), and the organic phases were combined, washed with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the title compound 81 (206.7 g, 78%).

[0636] LC-MS (m / z): 265 [M+H] + .

[0637] 1 H NMR (400MHz, CDCl3) δ.10.31 (s, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.21 (d, J = 8.4Hz, 1H).

[0638] Step B: (1E)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]methaneimine (82)

[0639] Compound 82 was prepared by using compound 81 as a raw material instead of compound 2, following step B of Example I-1.

[0640] LC-MS (m / z): 368 [M+H] + .

[0641] Step C: (3R)-3-{[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)propionate (83)

[0642] Compound 83 was prepared by using compound 82 as a raw material instead of compound 3, following step C of Example I-1.

[0643] LC-MS (m / z): 456 [M+H] + .

[0644] Step D: Ethyl (3R)-3-amino-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)propionate (84)

[0645] Compound 84 was prepared by using compound 83 as a raw material instead of compound 4, following step D of Example I-1.

[0646] LC-MS (m / z): 352 [M+H] + .

[0647] Step E: (3R)-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-3-[(5-chloro-2-nitrophenyl)amino]propionate (85)

[0648] Compound 85 was prepared by using compound 84 as a raw material instead of compound 5, following step E of Example I-1.

[0649] LC-MS (m / z): 507 [M+H] + .

[0650] Step F: (3R)-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-3-[(5-chloro-2-nitrophenyl)amino]propionaldehyde (86)

[0651] Compound 86 was prepared by using compound 85 as a raw material instead of compound 6, following step F of Example I-1.

[0652] LC-MS (m / z): 463 [M+H] + .

[0653] Step G: (4R)-4-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (87)

[0654] Compound 87 was prepared by using compound 86 as a raw material instead of compound 7, following step G of Example I-1.

[0655] LC-MS (m / z): 562 [M+H] + .

[0656] Step H: (1R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (88)

[0657] Compound 88 was prepared by using compound 87 as a raw material instead of compound 8, following step H of Example I-1.

[0658] LC-MS (m / z): 443 [M+H] + .

[0659] Step I: (1R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (89)

[0660] Compound 89 was prepared by using compound 88 as a raw material instead of compound 9, following step I of Example I-1.

[0661] LC-MS (m / z): 441 [M+H] + .

[0662] Step J:(1R)-1-(5-acetyl-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (90)

[0663] Compound 90 was prepared by using compound 89 as a raw material instead of compound 10, following step J of Example I-1.

[0664] LC-MS (m / z): 405 [M+H] + .

[0665] Step K: (1R,13R)-17-chloro-9,9-difluoro-1-hydroxy-14,21-diaza-8,10-dioxahexane[11.9.1.015,20.014,22.07,11.04,12]tetradecano-4(12),5,7(11),15(16),17,19,21-heptaen-3-one(91)

[0666] Compound 91 was prepared by using compound 90 as a raw material instead of compound 11, following step K of Example I-1.

[0667] LC-MS (m / z): 405 [M+H] + .

[0668] Step L: (1R,13R)-5,5-difluoro-13-hydroxy-19-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-15,22-diaza-4,6-dioxahexane[11.9.1.03,7.02,10.014,22.016,21]tetrazol-2(3),7(8),9,14(15),16(17),18,20-heptaen-11-one(92)

[0669] Compound 92 was prepared by using compound 91 as a raw material instead of compound 12, following step L of Example I-1.

[0670] LC-MS (m / z): 497 [M+H] + .

[0671] Step M: [({5-[(1R,13R)-5,5-difluoro-13-hydroxy-11-oxonyl-15,22-diaza-4,6-dioxahexane[11.9.1.03,7.02,10.014,22.016,21]tetaro-2(3),7(8),9,14(15),16(21),17,19-heptaen-19-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (14)

[0672] Compound 93 was prepared by using compound 92 as a raw material instead of compound 13, following step Q of Example I-1.

[0673] LC-MS (m / z): 618 [M+H] + .

[0674] Step N: (1R,13R)-19-[2-(aminocyclobutyl)pyrimidin-5-yl]-5,5-difluoro-13-hydroxy-15,22-diaza-4,6-dioxahexane[11.9.1.03,7.02,10.014,22.016,21]tetradecano-2(3),7(8),9,14(15),16(21),17,19-heptaen-11-one (I-291)

[0675] Compound I-291 was prepared by using compound 93 as a raw material instead of compound 14, following step R of Example I-1.

[0676] LC-MS (m / z): 518 [M+H] + .

[0677] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.05-7.99(m,2H),7.92(d,J=2.4Hz,1H),7.57(d,J=7.6Hz,1H),7.14(d,J=7.6Hz ,1H),5.27-5.23(m,1H),3.89-3.84(m,1H),3.18-3.15(m,1H),2.81-2.65(m,2H),2.28-2.17(m,4H),1.88-1.77(m,2H).

[0678] The following examples illustrate the synthesis of the corresponding brominated derivatives using the same starting materials as in Example I-291, and the preparation of the brominated derivatives via coupling reactions with compound 92 from Example I-291:

[0679]

[0680] The NMR data of the compounds prepared in the above embodiments are as follows:

[0681]

[0682]

[0683] Example I-321: (1R,13R)-19-[2-(aminocyclobutyl)pyrimidin-5-yl]-3-[(difluoromethyl)oxy]-10-oxa-9,15,22-triazahexane[11.9.1.014,22.02,7.08,12.016,21]tetradecano-2(3),4,6,8(9),11,14(15),16(21),17,19-nonaen-13-ol (I-321)

[0684]

[0685] Step A: [({5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-[(Z)-(dimethylamino)methylylidene]-11-hydroxy-13-oxylidene-2,9-diazapentacyclo[9.8.1.03,8.014,19.02,10]eicosuccinate-3(8),4,6,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (94)

[0686] [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxylidene-3,10-diazapentacyclo[9.8.1.012,17.04,9.02,10]eicoseno-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 14, 60.3 mg, 0.1 mol) was dissolved in dry tetrahydrofuran (5 mL), and 4-(dimethylamino)-2,2,5-trimethyl-5-aza-3-oxahexane (0.5 mL) was added at room temperature. The reaction solution was stirred at room temperature for 16 hours, and the reaction solution was directly concentrated to give the title compound 94 (65.8 mg, 100%).

[0687] LC-MS (m / z): 659 [M+H] + .

[0688] Step B: [({5-[(1R,13R)-3-[(difluoromethyl)oxy]-13-hydroxy-10-oxa-9,15,22-triazahexane[11.9.1.014,22.02,7.08,12.016,21]tetrazol-2(3),4,6,8(9),11,14(15),16(21),17,19-nonen-19-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (95)

[0689] [({5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-[(Z)-(dimethylamino)methylylidene]-11-hydroxy-13-oxylidene-2,9-diazapentacyclo[9.8.1.03,8.014,19.02,10]eicoseno-3(8),4,6,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}cyclobutyl)amino]methaneic acid-2-methylpropyl-2-yl ester (compound 94, 65.8 mg, 0.1 mol) was dissolved in acetonitrile (10 mL), and hydroxylamine hydrochloride (140 mg, 2 mmol) was added at room temperature. The reaction solution was stirred at 60 °C for 4 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain the title compound 95 (31.5 mg, 50%).

[0690] LC-MS (m / z): 629 [M+H] + .

[0691] Step C: (1R,13R)-19-[2-(aminocyclobutyl)pyrimidin-5-yl]-3-[(difluoromethyl)oxy]-10-oxa-9,15,22-triazahexane[11.9.1.014,22.02,7.08,12.016,21]tetradecano-2(3),4,6,8(9),11,14(15),16(21),17,19-nonaen-13-ol (I-321)

[0692] Compound I-321 was prepared by using compound 95 as a raw material instead of compound 14, following step R of Example I-1.

[0693] LC-MS (m / z): 529 [M+H] + .

[0694] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.52(s,1H),8.05-7.99(m,2H),7.92(d,J=2.4Hz,1H),7.51(dd,J=7.6,2.4Hz,1H),7.32-7.31(m ,1H),7.16(dd,J=7.6,2.4Hz,1H),6.98(t,J=57.6Hz,1H),5.27-5.23(m,1H),2.95-2.65(m,2H),2.30-2.20(m,4H),1.88-1.80(m,2H).

[0695] The following examples illustrate the synthesis of corresponding five-membered ring compounds using the appropriate starting materials, following the synthetic method described in Examples I-321:

[0696]

[0697]

[0698] The NMR data of the compounds prepared in the above embodiments are as follows:

[0699]

[0700] Example I-326: (2R,12R)-6-[2-(aminocyclobutyl)pyrimidin-5-yl]-20-[(difluoromethyl)oxy]-3,10,14,15-tetraazahexane[15.3.1.12,12.014,21.03,11.04,9]tetradosuccinate-1(20),4(9),5,7,10,15,17(21),18-octaen-12-ol (I-326)

[0701]

[0702] Step A: (1R)-7-chloro-1-{6-[(difluoromethyl)oxy]-1-[(4-methylphenyl)dioxane-λ6-thio]indazol-7-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (96)

[0703] Compound 96 was synthesized by replacing 6-[(difluoromethyl)oxy]-1H-indazole-7-carboxaldehyde with 2-bromo-6-[(difluoromethyl)oxy]benzene-1-carboxaldehyde as a starting material, following the synthesis steps in Example I-1.

[0704] LC-MS (m / z): 543 [M+H] + .

[0705] Step B: (1R)-7-chloro-1-{6-[(difluoromethyl)oxy]-1-[(4-methylphenyl)dioxane-λ6-thio]indazol-7-yl}-1,2-dihydrospiro[benzo[d]pyrrolo[2,1-b]imidazol-3,2'-oxacyclopropane](97)

[0706] Trimethyl sulfoxide (246.0 mg, 1.2 mol) was dissolved in dimethyl sulfoxide (5 mL), and sodium hydride (48 mg, 1.2 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, and then (1R)-7-chloro-1-{6-[(difluoromethyl)oxy]-1-[(4-methylphenyl)dioxane-λ6-thio]indazol-7-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (compound 96, 542 mg, 1.0 mmol) was added. The mixture was heated to room temperature and reacted for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 97 (529 mg, 95%, crude product).

[0707] LC-MS (m / z): 557 [M+H] + .

[0708] Step C: (3R,13R)-9-chloro-15-[(difluoromethyl)oxy]-1,5,12,20-tetraazahexacyclo[16.2.1.13,13.014,21.06,11.04,12]tetradosuccin-4(5),6(7),8,10,14(21),15,17,19-octaen-3-ol(98)

[0709] (1R)-7-chloro-1-{6-[(difluoromethyl)oxy]-1-[(4-methylphenyl)dioxane-λ6-thio]indazol-7-yl}-1,2-dihydrospiro[benzo[d]pyrrolo[2,1-b]imidazol-3,2'-oxacyclopropane] (compound 97, 529.0 mg, 0.95 mol) was dissolved in acetonitrile (10 mL), potassium carbonate (387.6 mg, 2.85 mmol) was added at room temperature, and the mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain the title compound 98 (76 mg, 19%).

[0710] LC-MS (m / z): 403 [M+H] + .

[0711] Step D: (2R,12R)-20-[(difluoromethyl)oxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,10,14,15-tetraazahexacyclo[15.3.1.12,12.014,21.03,11.04,9]tetradosuccinate-1(20),4(5),6,8,10,15,17(21),18-octaen-12-ol(99)

[0712] Compound 99 was prepared by using compound 98 as a raw material instead of compound 12, following step L of Example I-1.

[0713] LC-MS (m / z): 495 [M+H] + .

[0714] Step E: [({5-[(2R,12R)-20-[(difluoromethyl)oxy]-12-hydroxy-3,10,14,15-tetraazahexane[15.3.1.12,12.014,21.03,11.04,9]tetradosuccinate-1(20),4(9),5,7,10,15,17(21),18-octaen-6-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (100)

[0715] Compound 100 was prepared by using compound 99 as a raw material instead of compound 13, following step Q of Example I-1.

[0716] LC-MS (m / z): 616 [M+H] + .

[0717] Step F: (2R,12R)-6-[2-(aminocyclobutyl)pyrimidin-5-yl]-20-[(difluoromethyl)oxy]-3,10,14,15-tetraazahexane[15.3.1.12,12.014,21.03,11.04,9]tetradosuccinate-1(20),4(9),5,7,10,15,17(21),18-octaen-12-ol(I-326)

[0718] Compound I-326 was prepared by using compound 100 as a raw material instead of compound 14, following step R of Example I-1.

[0719] LC-MS (m / z): 516 [M+H] + .

[0720] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.07-7.99(m,3H),7.92(d,J=2.0Hz,1H),7.75(dd,J=7.6,2.4Hz,1H),7.01(d ,J=7.6Hz,1H),6.98(t,J=57.6Hz,1H),5.05-4.73(m,3H),2.81-2.59(m,2H),2.29-2.20(m,4H),1.88-1.79(m,2H).

[0721] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Examples I-326:

[0722]

[0723] The NMR data of the compounds prepared in the above embodiments are as follows:

[0724]

[0725] Example I-337: (3S,13R)-9-[2-(aminocyclobutyl)pyrimidin-5-yl]-15-[(difluoromethyl)oxy]-2,5,12,21-tetraazahexane[16.3.1.13,13.014,22.06,11.04,12]tetradecano-1(21),4(5),6(7),8,10,14(22),15,17,19-nonaen-3-carboxynitrile (I-337)

[0726]

[0727] Step A: (1R)-7-chloro-1-{1-chloro-7-[(difluoromethyl)oxy]isoquinolin-8-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (101)

[0728] Compound 101 was synthesized by replacing 1-chloro-7-[(difluoromethyl)oxy]isoquinoline-8-carboxaldehyde with 2-bromo-6-[(difluoromethyl)oxy]benzene-1-carboxaldehyde as a starting material, following the synthesis steps in Example I-1.

[0729] LC-MS (m / z): 434 [M+H] + .

[0730] Step B: (1R)-3-[(E)-[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]azine]-7-chloro-1-{1-chloro-7-[(difluoromethyl)oxy]isoquinoline-8-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium (102)

[0731] Compound 102 was prepared by using compound 101 as a raw material instead of compound 10, following step A of Example I-288.

[0732] LC-MS (m / z): 537 [M+H] + .

[0733] Step C: (1R,3S)-3-{[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-7-chloro-1-{1-chloro-7-[(difluoromethyl)oxy]isoquinoline-8-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-carboxynitrile (103)

[0734] (1R)-3-[(E)-[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]azine]-7-chloro-1-{1-chloro-7-[(difluoromethyl)oxy]isoquinolin-8-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (compound 102, 537.0 mg, 1.0 mol) was dissolved in tetrahydrofuran (5 mL), and cesium fluoride (167.3 mg, 1.10 mmol) and trimethylcyanosilane (108.9 mg, 1.10 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and the solution was directly concentrated and separated by column chromatography to obtain the title compound 103 (444 mg, 79%).

[0735] LC-MS (m / z): 564 [M+H] + .

[0736] Step D: (1R,3S)-3-amino-7-chloro-1-{1-chloro-7-[(difluoromethyl)oxy]isoquinoline-8-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-carboxylonitrile (104)

[0737] (1R,3S)-3-{[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-7-chloro-1-{1-chloro-7-[(difluoromethyl)oxy]isoquinolin-8-yl}-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-carboxynitrile (compound 103, 444.0 mg, 0.79 mol) was dissolved in trifluoroacetic acid (5 mL), stirred at room temperature for 2 hours, and then directly concentrated to give the title compound 104 (351 mg, 97%).

[0738] LC-MS (m / z): 460 [M+H] + .

[0739] Step E: (3S,13R)-9-chloro-15-[(difluoromethyl)oxy]-2,5,12,21-tetraazahexacyclo[16.3.1.13,13.014,22.06,11.04,12]tetradecyl-1(21),4(5),6(7),8,10,14(22),15,17,19-nonaene-3-carboxynitrile(105)

[0740] (1'R,3'R)-1'-{6-bromo-2-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[2,1-b]imidazole] (compound 104, 351 mg, 0.76 mmol), palladium acetate (35.8 mg, 0.16 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (89.2 mg, 0.16 mmol), and potassium carbonate (658 mg, 4.77 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After concentration, the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain title compound 105 (102.8 mg, 32%).

[0741] LC-MS (m / z): 424 [M+H] + .

[0742] Step F: (3S,13R)-15-[(difluoromethyl)oxy]-9-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-2,5,12,21-tetraazahexane[16.3.1.13,13.014,22.04,12.06,11]tetratetrazol-1(22),4(5),6(7),8,10,14(15),16,18(19),20-nonaenoen-3-carboxynitrile(106)

[0743] Compound 106 was prepared by using compound 105 as a raw material instead of compound 12, following step L of Example I-1.

[0744] LC-MS (m / z): 516 [M+H] + .

[0745] Step G: [({5-[(2R,12S)-12-cyano-21-[(difluoromethyl)oxy]-3,10,13,15-tetraazahexane[16.3.1.12,12.014,22.03,11.04,9]tetratridecyl-1(22),4(5),6,8,10,14(15),16,18(19),20-nonen-6-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (107)

[0746] Compound 107 was prepared by using compound 106 as a raw material instead of compound 13, following step Q of Example I-1.

[0747] LC-MS (m / z): 637 [M+H] + .

[0748] Step H: (3S,13R)-9-[2-(aminocyclobutyl)pyrimidin-5-yl]-15-[(difluoromethyl)oxy]-2,5,12,21-tetraazahexacyclo[16.3.1.13,13.014,22.06,11.04,12]tetradecano-1(21),4(5),6(7),8,10,14(22),15,17,19-nonaenoen-3-carboxynitrile (I-337)

[0749] Compound I-337 was prepared by using compound 107 as a raw material instead of compound 14, following step R of Example I-1.

[0750] LC-MS (m / z): 537 [M+H] + .

[0751] 1H NMR(400MHz,MeOD-d4)δ.8.74(s,2H),8.10(d,J=5.2Hz,1H),8.05-7.98(m,3H),7.93(d,J=2.0Hz,1H),7.48(dd,J=5.2,1.2Hz, 1H),7.38(d,J=9.2Hz,1H),6.97(t,J=57.6Hz,1H),5.11-5.08(m,1H),3.13-2.99(m,2H),2.28-2.20(m,4H),1.89-1.79(m,2H).

[0752] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Examples I-337:

[0753]

[0754] The NMR data of the compounds prepared in the above embodiments are as follows:

[0755]

[0756]

[0757] Example I-332: (1R,12R)-16-[2-(aminocyclobutyl)pyrimidin-5-yl]-10-[(difluoromethyl)oxy]-13,20-diaza-2-oxahexane[10.9.1.01,4.06,11.013,21.014,19]tetra-6(7),8,10,14(15),16,18,20-heptaen-5-one (I-332)

[0758]

[0759] Step A: 2-[(1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl]-3-hydroxypropionate methyl ester (108)

[0760] Methyl 3-hydroxypropionate (208.0 mg, 2.0 mol) was dissolved in tetrahydrofuran (10 mL). Diisopropylaminolithium (2 M, 2 mL, 4.0 mmol) was added at -78 °C, and the mixture was stirred for half an hour. Then, (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (compound 10, 854 mg, 2.0 mmol) was added at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours, and the reaction mixture was quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 108 (690 mg, 65%).

[0761] LC-MS (m / z): 531 [M+H] + .

[0762] Step B: (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,2'-oxetane]-3'-carboxylic acid methyl ester (109)

[0763] Methyl 2-[(1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl]-3-hydroxypropionate (compound 108, 690.0 mg, 1.3 mol) was dissolved in tetrahydrofuran (10 mL). Triethylamine (262 mg, 2.6 mmol) and p-toluenesulfonyl chloride (592 mg, 3.12 mmol) were added at room temperature, and the mixture was stirred at room temperature for half an hour. The reaction solution was quenched with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and dissolved in tetrahydrofuran (10 mL). Potassium tert-butoxide (582 mg, 5.2 mmol) was added at room temperature, and the mixture was stirred for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution (10 mL). Extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 109 (232 mg, 35%).

[0764] LC-MS (m / z): 513 [M+H] + .

[0765] Step C: [(1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,2'-oxetane]-3'-yl]methanethioic acid-S-ethyl ester (110)

[0766] Trimethylaluminum (2M, 537.0 mg, 1.0 mol) was added dropwise to a dichloromethane solution (5 mL) containing ethanethiol (167.3 mg, 1.10 mmol) at 0 °C. The mixture was stirred at room temperature for half an hour, then cooled to 0 °C. Methyl (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,2'-oxetane]-3'-carboxylate (compound 109, 232 mg, 0.45 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with isopropyl ether (20 mL), quenched with a small amount of water, filtered, and directly concentrated. Column chromatography was then used to separate the reaction mixture into the title compound 110 (205 mg, 84%).

[0767] LC-MS (m / z): 543 [M+H] + .

[0768] Step D: [(1R)-7-chloro-1-{2-[(difluoromethyl)oxy]-6-(dihydroxyboryl)phenyl}-1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,2'-oxetane]-3'-yl]methanethioic acid-S-ethyl ester (111)

[0769] [(1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,2'-oxetane]-3'-yl]methanethioic acid-S-ethyl ester (compound 110, 205 mg, 0.37 mmol), pinacol diboronate (285 mg, 1.12 mmol), and potassium acetate (110 mg, 1.12 mmol) were dissolved in 1,4-dioxane (10 mg). In L), the reaction solution was protected with nitrogen. Tris(dibenzylacetone)dipalladium (34 mg, 0.04 mmol) and tricyclohexylphosphine tetrafluoroborate (14.72 mg, 0.04 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The temperature was raised to 100 °C and stirred for 16 hours. After the reaction was completed, a small amount of sodium periodate was added and stirred for 10 minutes. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound 111 (116 mg, 62%).

[0770] LC-MS (m / z): 509 [M+H] + .

[0771] Step E: (1R,12R)-16-chloro-10-[(difluoromethyl)oxy]-13,20-diaza-2-oxahexane[10.9.1.01,4.014,19.013,21.06,11]tetracodone-6(7),8,10,14(15),16,18,20-heptaen-5-one(112)

[0772] [(1R)-7-chloro-1-{2-[(difluoromethyl)oxy]-6-(dihydroxyboryl)phenyl}-1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,2'-oxetane]-3'-yl]methanethioic acid-S-ethyl ester (compound 111, 116 mg, 0.23 mmol) and cesium carbonate (75 mg, 0.23 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction solution was protected with nitrogen. Tris(dibenzylideneacetone)dipalladium (17 mg, 0.02 mmol) and thiophene-2-carboxylic acid cuprous (43.7 mg, 0.23 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 50 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel thin-layer chromatography to obtain the title compound 112 (22 mg, 23%).

[0773] LC-MS (m / z): 403 [M+H] + .

[0774] Step F: (1R,12R)-10-[(difluoromethyl)oxy]-16-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-13,20-diaza-2-oxahexane[10.9.1.01,4.06,11.013,21.014,19]tetracodone-6(7),8,10,14(15),16,18,20-heptaen-5-one(113)

[0775] Compound 113 was prepared by using compound 112 as a raw material instead of compound 12, following step L of Example I-1.

[0776] LC-MS (m / z): 516 [M+H] + .

[0777] Step G: [({5-[(1R,12R)-10-[(difluoromethyl)oxy]-5-oxoylide-13,20-diaza-2-oxahexane[10.9.1.01,4.06,11.014,19.013,21]tetradosuccinate-6(7),8,10,14(15),16,18,20-heptaen-16-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (114)

[0778] Compound 114 was prepared by using compound 113 as a raw material instead of compound 13, following step Q of Example I-1.

[0779] LC-MS (m / z): 616 [M+H] + .

[0780] Step H: (1R,12R)-16-[2-(aminocyclobutyl)pyrimidin-5-yl]-10-[(difluoromethyl)oxy]-13,20-diaza-2-oxahexane[10.9.1.01,4.06,11.013,21.014,19]tetra-6(7),8,10,14(15),16,18,20-heptaen-5-one (I-332)

[0781] Compound I-332 was prepared by using compound 114 as a raw material instead of compound 14, following step R of Example I-1.

[0782] LC-MS (m / z): 516 [M+H] + .

[0783] 1 H NMR(400MHz,MeOD-d4)δ.8.75(s,2H),8.05-7.99(m,2H),7.91(d,J=2.4Hz,1H),7.65(dd,J=8.4,2.4Hz,1H),7.31-7.27(m,1H),7.21(dd, J=8.4,2.4Hz,1H),6.97(t,J=57.6Hz,1H),5.23-5.17(m,1H),4.29-3.98(m,3H),2.86-2.61(m,2H),2.29-2.20(m,4H),1.91-1.79(m,2H).

[0784] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Examples I-332:

[0785]

[0786] Biological evaluation

[0787] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0788] The HEK-Blue TNF-α reporter assay – hTNF-α test method: The cell line used was HEK-BlueTNF-α cells; the stimulus was recombinant human TNF-α; and the detection conditions were Quanti-Blue™ assay. The HEK Blue TNF-α protocol was as follows: Cells were cultured and prepared for detection according to the manufacturer's instructions; HEK Blue TNF-α cells were detected during the exponential growth phase; growth medium was aspirated, and cells were washed twice with PBS to remove phenol red; the cells were then resuspended in the test medium to an appropriate concentration. Only cells with a viability greater than 90% were used for assay; 25 μL of compound dilution was transferred to a 384-well plate; 5 μL of TNF-α protein solution was added to a 384-well plate; the plates were centrifuged at 1000 rpm for 1 minute and incubated at 37°C for 1 hour; 20 μL of HEK Blue TNF-α cells were seeded into a 384-well plate; the cells were incubated at 37°C under a 5% CO2 atmosphere for 20 hours; 5 μL of cell supernatant was transferred to each well of a 384-well assay plate; 20 μL of QUANTI blue solution was added to each well; the plates were incubated at 37°C for 1 hour; SEAP levels were measured at 620 nm using a spectrophotometer; the experimental data were processed using Graphpad to calculate the half-maximal inhibitory concentration (IC50) based on nonlinear fitting of compound concentration and corresponding inhibition rate. 50 .

[0789] Table 1, IC50 values ​​of example compounds 50

[0790]

[0791]

[0792] Note: A represents IC 50 Values ​​less than 10 nM, B indicates IC 50 Values ​​between 10 nM and 100 nM, where C represents IC. 50 Value greater than 100 nM

[0793] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A compound of Formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. in: For single or double bonds, when When it is a double bond, It is a single bond; W 1 Selected from carbon, nitrogen, oxygen, or sulfur, W 2 Selected from carbon, nitrogen, or sulfur, W 3 For carbon, W 4 W 5 W 6 W 7 W 8 W 9 and W 10 Each is independently selected from carbon or nitrogen; R 1 Selected from halogens, hydroxyl groups, amino groups, cyano groups, carboxyl groups, acetyl groups, substituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 deuterated alkyl groups, substituted or unsubstituted C1-C3 haloalkyl groups, substituted or unsubstituted C1-C3 hydroxyalkyl groups, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl groups, substituted or unsubstituted C1-C3 halohydroxyalkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C1-C3 deuterated alkoxy groups, substituted or unsubstituted C1-C3 haloalkoxy groups, substituted or unsubstituted C2-C3 alkenyl groups, substituted or unsubstituted C2-C3 deuterated alkenyl groups, and substituted or unsubstituted C2-C3 haloalkenyl groups. Substituted or unsubstituted C2-C3 ynyl group, substituted or unsubstituted C2-C3 deuterated ynyl group, substituted or unsubstituted C2-C3 haloynyl group, substituted or unsubstituted C3-C5 cycloalkyl group, substituted or unsubstituted C3-C5 deuterated cycloalkyl group, substituted or unsubstituted C3-C5 halocycloalkyl group, substituted or unsubstituted 3-5 membered deuterated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 3-5 membered halocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(O)2R a9 Substituted or unsubstituted -(CH2) m10 P(O)R a10 R a11 The term "substitution" refers to a substituent that selectively contains 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, or 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S. or When W 1 When it is nitrogen, R 1 and R 2 W connecting it 1 Together with carbon atoms, they form substituted or unsubstituted, saturated or unsaturated 3- to 4-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 alkyl, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl, deuterium or halogen-substituted or unsubstituted 3- to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents; or When W 1 When it is carbon, R 1 and R 2 W connecting it 1 Together with carbon atoms, they form substituted or unsubstituted, saturated or unsaturated C3-C8 cycloalkyl groups; substituted or unsubstituted, saturated or unsaturated 3-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S; substituted or unsubstituted 5-6 membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, etc. C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents; or When W 4 When it is carbon, R 3 and W 4 W connecting it 2 and W 3 Together they form ring D, which is selected from substituted or unsubstituted, saturated or unsaturated C3-C8 cycloalkyl groups, substituted or unsubstituted, saturated or unsaturated 4-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, and substituted or unsubstituted C6-C8 cycloalkyl groups. 10 Aryl, substituted or unsubstituted, 5- to 14-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; wherein "substituted" refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 alkyl, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl, deuterium or halogen-substituted or unsubstituted 3- to 5-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents; R 2 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, oxo, thio, =NR c1 =N-OR c2 Substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 deuterated alkyl, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl, substituted or unsubstituted C1-C3 halohydroxyalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 deuterated alkoxy, substituted or unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C2-C3 alkenyl, substituted or unsubstituted C2-C3 deuterated alkenyl, substituted or unsubstituted C2-C3 haloalkenyl, substituted or unsubstituted C2-C3 ynyl, substituted or unsubstituted C2-C3 deuterated ynyl, substituted or unsubstituted C2-C3 haloynyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted C3-C5 deuterated cycloalkyl, substituted or unsubstituted C3-C5 halocycloalkyl, substituted or unsubstituted 3-5 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 3-5 membered deuterated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(O)2R a9 Substituted or unsubstituted -(CH2) m10 P(O)R a10 R a11 The term "substitution" refers to a substituent that selectively contains 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, or 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S. R 3 Selected from halogen, hydroxyl, amino, cyano, carboxyl, oxo, thio, =NR c1 =N-OR c2 Substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 deuterated alkyl, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl, substituted or unsubstituted C1-C3 halohydroxyalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 deuterated alkoxy, substituted or unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C2-C3 alkenyl, substituted or unsubstituted C2-C3 deuterated alkenyl, substituted or unsubstituted C2-C3 haloalkenyl, substituted or unsubstituted C2-C3 ynyl, substituted or unsubstituted C2-C3 deuterated ynyl, substituted or unsubstituted C2-C3 haloynyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted C3-C5 deuterated cycloalkyl, substituted or unsubstituted C3-C5 halocycloalkyl, substituted or unsubstituted 3-5 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 3-5 membered deuterated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(O)2R a9 Substituted or unsubstituted -(CH2) m10 P(O)R a10 R a11 The term "substitution" refers to a substituent that selectively contains 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 hydroxyalkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkenyl groups substituted or unsubstituted with deuterium or halogen, C2-C3 alkynyl groups substituted or unsubstituted with deuterium or halogen, C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen, or 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S. Or, R 2 and R 3 Together with the atoms connecting them, they form a ring C, wherein the ring C is selected from substituted or unsubstituted saturated or unsaturated C3-C8 cycloalkyl groups, substituted or unsubstituted saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups containing 1 to 4 heteroatoms selected from N, O, and S, or substituted or unsubstituted C6-C8 cycloalkyl groups. 10 Aryl, substituted or unsubstituted, 5- to 14-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; wherein "substituted" refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted C1-C3 alkyl, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen-substituted or unsubstituted C3-C5 cycloalkyl, deuterium or halogen-substituted or unsubstituted 3- to 5-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents; R 4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, acetyl, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 deuterated alkenyl, substituted or unsubstituted C1-C6 haloalkenyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl. substituted or unsubstituted C1-C6 deuterated hydroxyalkyl, substituted or unsubstituted C1-C6 halohydroxyalkyl, substituted or unsubstituted saturated or unsaturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C8 deuterated cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C8 halocycloalkyl, substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted saturated or unsaturated 3-8 membered deuterated heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted C6-C6 deuterated heterocyclic groups, substituted or unsubstituted C6-C6 deuterated heterocyclic groups, substituted or unsubstituted C1-C6 deuterated hydroxyalkyl, substituted or unsubstituted C1-C6 halohydroxyalkyl, substituted or unsubstituted C3-C6 deuterated ... 10 The aryl group, substituted or unsubstituted, comprises 5-10 membered heteroaryls containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen-substituted or unsubstituted, C1-C3 alkoxy groups selected from hydrogen, deuterium or halogen-substituted or unsubstituted, C1-C3 hydroxyalkyl groups selected from hydrogen, deuterium or halogen-substituted or unsubstituted, C3-C8 cycloalkyl groups selected from deuterium or halogen-substituted or unsubstituted, 3-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and C6-C membered heterocyclic groups selected from deuterium or halogen-substituted or unsubstituted. 10 5-10 membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, aryl, deuterium, or halogen substituted or unsubstituted; =NR c1 =N-OR c2 =CR c3 R c4 =SR c5 R c6 Substituents; Ring A is selected from C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or ring A is absent; R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted C6-C 10 The aryl group, substituted or unsubstituted, comprises 5-10 heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" refers to selectively containing 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen-substituted or unsubstituted C1-C3 alkoxy groups, deuterium or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl groups, deuterium or halogen-substituted or unsubstituted C3-C6 cycloalkyl groups, deuterium or halogen-substituted or unsubstituted 3-6 heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or deuterium or halogen-substituted or unsubstituted C6-C6 cycloalkyl groups. 10 A 5-10 membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted with aryl, deuterium, or halogen, provided that ring A is absent, R 5 It does not exist either; R 6 The group is composed of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted 3-6 membered heterocyclic groups, wherein "substituted" refers to a substituent selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen substituted or unsubstituted C1-C3 alkyl, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen substituted or unsubstituted C3-C6 cycloalkyl, or deuterium or halogen substituted or unsubstituted 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S. L is selected from the following: C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, saturated or unsaturated C3-C... 10 Cycloalkyl, saturated or unsaturated 3-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and B, C6-C 10 Aryl, comprising 1-4 heteroatoms selected from N, O, S and B, consisting of 5-10 membered heteroaryls; R 7 Selected from bonds, deuterium, halogens, amino groups, hydroxyl groups, cyano groups, carboxyl groups, oxo groups, thio groups, substituted or unsubstituted amide groups, substituted or unsubstituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 deuterated alkyl groups, substituted or unsubstituted C1-C3 haloalkyl groups, substituted or unsubstituted C1-C3 hydroxyalkyl groups, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl groups, substituted or unsubstituted C1-C3 halohydroxyalkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C1-C3 deuterated alkoxy groups, substituted or Unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C2-C3 alkenyl, substituted or unsubstituted C2-C3 deuterated alkenyl, substituted or unsubstituted C2-C3 haloalkynyl, substituted or unsubstituted C2-C3 deuterated alynyl, substituted or unsubstituted C2-C3 haloalkynyl, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted C1-C3 deuterated alkylamine, substituted or unsubstituted C1-C3 haloalkylamine, substituted or unsubstituted -(CH2) m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(=O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(=O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(=O)2R a9 Substituted or unsubstituted -(CH2) m10 P(=O)R a10 R a11 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16 Substituted or unsubstituted -(CH2) m15 S(=O)(=NR a17 )R a18 The term "substitution" refers to the selective presence of 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, hydrazine, cyano, carboxyl, acetyl, oxo, thio, deuterium- or halogen-substituted or unsubstituted, C1-C3 hydroxyalkyl groups selected from hydrogen, deuterium- or halogen-substituted or unsubstituted, C1-C3 alkoxy groups selected from hydrogen, deuterium- or halogen-substituted or unsubstituted, C2-C3 alkenyl groups selected from deuterium- or halogen-substituted or unsubstituted, C2-C3 alkynyl groups selected from deuterium- or halogen-substituted or unsubstituted, C3-C5 cycloalkyl groups selected from deuterium- or halogen-substituted or unsubstituted, and 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or -(CH2). m10 P(=O)R a10 R a11 -(CH2) m11 (=NR a12 -(CH2) m12 (=N-OR a13 -(CH2) m8 S(=O)2NHR a8 (CH2) m6 S(=O) m7 NR a7 -(CH2) m15 S(=O)(=NR a17 )R a18 Substituents; Ring B is selected from saturated or unsaturated C3-C. 10 Cycloalkyl, saturated or unsaturated, containing 1-5 3-12 membered heterocyclic groups selected from N, O, P, S, and Si heteroatoms, C6-C 10 Aryl, saturated or unsaturated, containing 1-5 5-12 membered heteroaryl groups selected from N, O, P, S, Si heteroatoms, or without ring B; R 8 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, amide, cyano, carboxyl, acetyl, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted saturated or unsaturated C3-C8 cycloalkyl, substituted or unsubstituted saturated or unsaturated 3-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(=O) m7 R a7 Substituted or unsubstituted -(CH2) m8 S(=O) m7 NHR a8 Substituted or unsubstituted -(CH2) m9 NHS (=O) m7 R a9 Substituted or unsubstituted -(CH2) m10 P(=O)R a10 R a11 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16 The term "substitution" refers to the selective presence of 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium- or halogen-substituted or unsubstituted C1-C3 hydroxyalkyl groups selected from hydrogen, deuterium- or halogen-substituted or unsubstituted C1-C3 alkoxy groups selected from hydrogen, deuterium- or halogen-substituted or unsubstituted C2-C3 alkenyl groups selected from alkenyl, deuterium- or halogen-substituted or unsubstituted C2-C3 alkynyl groups selected from alkenyl, deuterium- or halogen-substituted or unsubstituted C3-C5 cycloalkyl ... 8 It does not exist either; n1 is an integer of 0, 1, or 2; n2 is an integer of 0, 1, or 2; n3 is an integer of 0, 1, 2, 3 or 4; n4 is an integer of 0, 1, 2, 3 or 4; n5 is an integer of 0, 1, 2 or 3; n6 is an integer of 0, 1, 2, 3 or 4; n7 is an integer of 0, 1, 2, 3, 4, 5, or 6; R c1 R c2 R c3 R c4 R c5 R c6 R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R a10 R a11 R a12 R a13 R a14 R a15 R a16 R a17 R a18 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C3 deuterated alkyl, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 deuterated alkoxy, substituted or unsubstituted C1-C3 haloalkoxy, substituted or unsubstituted C1-C3 hydroxyalkyl, substituted or unsubstituted C1-C3 deuterated hydroxyalkyl. Substituted or unsubstituted C1-C3 halohydroxyalkyl, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted C1-C3 deuterated alkylamine, substituted or unsubstituted C1-C3 haloalkylamine, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C6 deuterated cycloalkyl, substituted or unsubstituted saturated or unsaturated C3-C6 halocycloalkyl, substituted or unsubstituted saturated or unsaturated 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, S, P, substituted or unsubstituted C6-C 10 The aryl, substituted or unsubstituted 3-6 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, S, and P; wherein "substituted" refers to a substituent selectively containing 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen substituted or unsubstituted C1-C3 alkyl, deuterium or halogen substituted or unsubstituted C1-C3 hydroxyalkyl, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen substituted or unsubstituted C3-C5 cycloalkyl, deuterium or halogen substituted or unsubstituted 3-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13, m14 and m15 are each an independent integer of 0, 1, 2, 3, 4, 5 or 6.

2. The compound of Formula I according to claim 1, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that, Preferably, W 1 Selected from carbon, nitrogen, or oxygen, W 2 Selected from carbon or nitrogen, W 3 W 4 W 5 W 6 W 7 W 8 W 9 and W 10 It is carbon; Preferably, when W 4 When it is carbon, R 3 and W 4 W connecting it 2 and W 3 Together they form ring D, wherein ring D is selected from substituted or unsubstituted saturated or unsaturated 5-6 membered heterocyclic groups containing 1 to 3 selected N or O, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected N and O; wherein "substituted" means selectively containing 1 to 2 oxo groups or C1-C3 alkyl groups; More preferably, when W 4 When it is carbon, R 3 and W 4 W connecting it 2 and W 3 Together they form a ring D, the structure of which is selected from: Preferably, R 1 Selected from halogens, hydroxyl groups, amino groups, cyano groups, carboxyl groups, acetyl groups, substituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C3-C5 cycloalkyl groups, substituted or unsubstituted 4-5 membered deuterated heterocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted 4-5 membered halocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted -(CH2) groups. m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 The term "substitution" refers to the selective presence of 1 to 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, and oxo groups. More preferably, when W 1 When it is nitrogen, R 1 and R 2 W connecting it 1 Together with carbon atoms, they form 3-4 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S; More preferably, when W 1 When it is carbon, R 1 and R 2 W connecting it 1 Together with carbon atoms, they form C4-C5 cycloalkanes or contain one or two 4-5 membered heterocyclic groups selected from N and O; More preferably, R 1 Selected from halogen, hydroxyl, amino, cyano, vinyl, ethynyl, cyclopropyl, or when W 1 When it is nitrogen, R 1 and R 2 W connecting it 1 Together with carbon atoms, it forms a 4-membered heterocyclic group containing one nitrogen atom, or when W... 1 When it is carbon, R 1 and R 2 W connecting it 1 Together with carbon atoms, it forms cyclobutane or contains a 4-membered heterocyclic group selected from N or O atoms; Preferably, R 2 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted 4-5 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted 4-5 membered deuterated heterocyclic group containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted 4-5 membered halocyclic heterocyclic group containing 1 or 2 heteroatoms selected from N and O, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(O) m7 NR a7 The term "substitution" refers to the selective presence of 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, and C3-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen. More preferably, R 2 Selected from hydrogen, deuterium, halogen, oxo group, thio group, methyl, ethyl, n-propyl, and isopropyl; Preferably, R 3 Selected from halogens, hydroxyl groups, amino groups, cyano groups, carboxyl groups, oxo groups, thio groups, substituted or unsubstituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C3-C5 cycloalkyl groups, substituted or unsubstituted 4-5 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N and O, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(O)R a3 Substituted or unsubstituted -(CH2) m4 C(O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(O)NR a5 R a6 The term "substitution" refers to the selective presence of 1 to 4 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, C1-C3 alkyl groups substituted or unsubstituted with deuterium or halogen, C1-C3 alkoxy groups substituted or unsubstituted with deuterium or halogen, and C4-C5 cycloalkyl groups substituted or unsubstituted with deuterium or halogen. More preferably, R 3 Selected from oxo groups, thio groups, and halogens; More preferably, R 2 and R 3 Together with the atoms that connect them, they form a ring C, wherein the ring C is selected from substituted or unsubstituted 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and O; wherein "substituted" means selectively containing 1 to 2 substituents selected from deuterium, halogen, cyano, oxo, thio, C1-C3 alkyl, and C1-C3 alkoxy. Preferably, R 4 Selected from substituted or unsubstituted C1-C3 alkoxy groups, wherein "substituted" means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, and halogen; Most preferably, R 4 Selected from Preferably, ring A is selected from a 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, or ring A is absent; The most preferred embodiment is ring A as follows: Or ring A does not exist; Preferably, R 5 The group is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, carboxyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, wherein "substituted" means selectively containing 1 to 2 C1-C3 alkyl, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy, provided that ring A is absent, R 5 It does not exist either; More preferably, R 5 It is a halogen; the condition is that R is halogen when ring A does not exist. 5 It does not exist either; Preferably, R 6 The group is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, wherein "substituted" means selectively containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, deuterium or halogen substituted or unsubstituted C1-C3 alkyl, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy; Most preferably, R 6 Selected from hydrogen, deuterium, and halogens; Preferably, L is selected from the following: C2-C4 alkynyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N, O, S and B, phenyl, and 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, S and B. More preferably, L is selected from: Preferably, R 7 Selected from bonds, deuterium, halogens, amino, hydroxyl, cyano, carboxyl, oxo, substituted or unsubstituted amide groups, substituted or unsubstituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted C2-C3 alkynyl groups, substituted or unsubstituted C1-C3 alkylamine groups, and substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(=O) m7 NR a7 Substituted or unsubstituted -(CH2) m8 S(=O)2NHR a8 Substituted or unsubstituted -(CH2) m9 NHS(=O)2R a9 Substituted or unsubstituted -(CH2) m10 P(=O)R a10 R a11 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16 Substituted or unsubstituted -(CH2) m15 S(=O)(=NR a17 )R a18 The term "substitution" refers to the selective presence of 1 to 4 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, hydrazine, cyano, carboxyl, acetyl, oxo, deuterium- or halogen-substituted or unsubstituted C1-C3 alkoxy, deuterium- or halogen-substituted or unsubstituted C2-C3 alkenyl, deuterium- or halogen-substituted or unsubstituted C2-C3 alkynyl, deuterium- or halogen-substituted or unsubstituted C3-C5 cycloalkyl, deuterium- or halogen-substituted or unsubstituted 4- or halogen-substituted 4- or 5-membered heterocyclic groups containing 1 or 2 heteroatoms selected from N and O, and -(CH2). m10 P(=O)R a10 R a11 -(CH2) m11 (=NR a12 -(CH2) m12 (=N-OR a13 -(CH2) m8 S(=O)2NHR a8 (CH2) m6 S(=O) m7 NR a7 -(CH2) m15 S(=O)(=NR a17 )R a18 Substituents; More preferably, R 7 Selected from key, or the following structures: Preferably, ring B is selected from saturated or unsaturated C3-C8 cycloalkyl groups, saturated or unsaturated 3-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, P, S and Si, and C6-C 10 Aryl, saturated or unsaturated, containing 1-4 5-10 membered heteroaryl groups selected from N, O, P, S and Si heteroatoms, or without ring B; More preferably, ring B is selected from the following structures or ring B does not exist: Preferably, R 8 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, imino, amide, cyano, carboxyl, acetyl, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C3 alkoxy, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted saturated or unsaturated C3-C4 cycloalkyl, substituted or unsubstituted -(CH2). m1 OR a1 Substituted or unsubstituted -(CH2) m2 C(=O)R a2 Substituted or unsubstituted -(CH2) m3 NHC(=O)R a3 Substituted or unsubstituted -(CH2) m4 C(=O)NHR a4 Substituted or unsubstituted -(CH2) m5 C(=O)NR a5 R a6 Substituted or unsubstituted -(CH2) m6 S(=O) m7 R a7 Substituted or unsubstituted -(CH2) m11 (=NR a12 ), substituted or unsubstituted -(CH2) m12 (=N-OR a13 ), substituted or unsubstituted -(CH2) m13 C(=O)OR a14 Substituted or unsubstituted -(CH2) m14 =CR a15 R a16 The term "substitution" refers to the selective presence of 1 to 3 C1-C3 alkyl groups selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium- or halogen-substituted or unsubstituted C1-C3 alkoxy groups, provided that ring B is absent, R 8 It does not exist either; More preferably, R 8 Selected from the following structures: Preferably, R c1 R c2 R c3 R c4 R c5 R c6 R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R a10 R a11 R a12 R a13 R a14 R a15 R a16 R a17 R a18 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylamine, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted saturated or unsaturated 3-6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, S, P, substituted or unsubstituted C6-C 10 The aryl group, substituted or unsubstituted, is a 3-6 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, S, and P; wherein "substituted" refers to a substituent selectively containing 1 to 4 C1-C3 alkyl groups selected from deuterium, halogen, hydroxyl, amino, cyano, carboxyl, acetyl, oxo, thio, deuterium or halogen substituted or unsubstituted C1-C3 alkyl, deuterium or halogen substituted or unsubstituted C1-C3 alkoxy, deuterium or halogen substituted or unsubstituted C2-C3 alkenyl, deuterium or halogen substituted or unsubstituted C2-C3 alkynyl, deuterium or halogen substituted or unsubstituted C3-C5 cycloalkyl, or deuterium or halogen substituted or unsubstituted C3-C5 cycloalkyl, or a 3-5 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S.

3. The compound of Formula I according to claim 1, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that, The compound is represented by the following formula II: in, Ring A, Ring B, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 W 1 W 2 W 3 W 4 W 10 The definitions of n1, n2, n3, n4, n5, n6 and n7 are the same as in claim 1.

4. The compound of Formula I according to claim 1, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that, The compound is represented by the following formula III: in, Ring A, Ring B, R 1 R 2 R 3 R 4 R 5 R 7 R 8 W 1 W 2 W 3 W 4 The definitions of n1, n2, n3, n4, n6 and n7 are the same as in claim 1.

5. The compound of formula I according to claim 1, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that, The compound is represented by the following formulas: III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9: Among them, rings A, B, C, D, and R 2 R 4 R 5 R 7 R 8 W 1 W 2 W 3 W 4 The definitions of n1, n3, n4, n6 and n7 are the same as those in any one of claims 1 to 5.

6. The compound of Formula I according to any one of claims 1 to 5, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that, It is selected from the following compounds:

7. A pharmaceutical composition comprising a compound or isotopically labeled compound of any one of the formulas I, II, III, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9 as claimed in any one of claims 1 to 6, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable excipient.

8. The use of a compound or isotopically labeled compound of any one of the formulas I, II, III, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9 according to any one of claims 1 to 6, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutical composition according to claim 7 in the preparation of a medicament for treating autoimmune diseases and neurological diseases; Preferably, the drug for treating autoimmune diseases and neurological diseases is a TNF-α inhibitor; Preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis; the neurological disease is selected from sarcoidosis, multiple sclerosis, neurobehçet's disease, chronic inflammatory demyelinating diseases, systemic inflammatory vasculitis, traumatic brain injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, neuropathic pain, and ischemic stroke.

9. A method for treating autoimmune diseases and neurological disorders, the method comprising administering to a subject in need an effective amount of a compound or isotopically labeled compound of any one of the formulas I, II, III, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9 according to any one of claims 1 to 6, or an optical isomer, geometric isomer, tautomer, or mixture of isomers thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutical composition according to claim 7; preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, bovine spongiform dermatitis, and other similar diseases. Tinea, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis or autoimmune orchitis; the neurological diseases mentioned are selected from sarcoidosis, multiple sclerosis, neurobehçet's disease, chronic inflammatory demyelinating diseases, systemic inflammatory vasculitis, traumatic brain injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, neuropathic pain, and ischemic stroke.

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