JAK inhibitor compound and use thereof

Abstract

The present invention relates to a JAK inhibitor compound and the use thereof. Specifically, disclosed in the present invention is a compound as shown in formula (I), 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. The present invention also relates to the use of the compound in medicine.

Description

JAK inhibitor compounds and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 202311017417.4, filed on August 11, 2023, entitled “JAK inhibitor compounds and uses thereof,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention provides a class of novel compounds with pharmaceutical activity that can be used to inhibit Janus kinases (JAKs). The present invention also relates to compositions comprising the compounds, and the use of the compounds and the compositions in the preparation of medicaments for treating and / or preventing diseases or conditions associated with JAKs. Background Art

[0004] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine and serine / threonine kinases. Inappropriate kinase activity due to mutation, overexpression or inappropriate regulation, dysregulation or imbalance, and excessive or insufficient production of growth factors or cytokines is involved in many diseases, including but not limited to cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases (e.g., Alzheimer's disease). Inappropriate kinase activity triggers a variety of biological cell reactions, which are related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility involved in the above-mentioned and related diseases. Therefore, protein kinases have become an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases plays an important role in cytokine signal transduction (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253).

[0005] Since the first JAK was discovered in the early 1990s, the development of JAK inhibitors has spanned nearly 30 years. JAKs are a family of intracellular non-receptor tyrosine kinases that play a crucial role in cytokine receptor signaling pathways through interactions with signal transducers and activators of transcription (STATs). The JAK / STAT signaling pathway participates in many important biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. Compared to other signaling pathways, this pathway is relatively simple, consisting primarily of three components: tyrosine kinase-associated receptors, tyrosine kinase JAKs, and signal transducers and activators of transcription (STATs).

[0006] Many cytokines and growth factors transmit signals through the JAK-STAT signaling pathway, including interleukins (such as IL-2-7, IL-9, IL-10, IL-15, and IL-21), GM-CSF (granulocyte / macrophage colony-stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PRL (prolactin), EPO (erythropoietin), TPO (thrombopoietin), PDGF (platelet-derived growth factor), and interferons (including IFN-α, IFN-β, and IFN-γ). These cytokines and growth factors have corresponding receptors on the cell membrane. A common feature of these receptors is that they lack kinase activity themselves, but their intracellular domains contain binding sites for the tyrosine kinase JAK. Upon ligand binding, the receptors activate the bound JAKs, which phosphorylate tyrosine residues on various target proteins, thereby transmitting signals from the extracellular to the intracellular domain.

[0007] JAKs are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. As mentioned above, JAK stands for Janus kinase, referring to the two-faced god of Roman mythology, representing both beginnings and endings. They are called Janus kinases because they can phosphorylate both bound cytokine receptors and multiple signaling molecules containing specific SH2 domains. The JAK protein family includes four members: JAK1, JAK2, JAK3, and TYK2. They structurally possess seven JAK homology domains (JH). The JH1 domain is the kinase domain that encodes the kinase protein; the JH2 domain is a "pseudo" kinase domain that regulates the activity of JH1; and JH3-JH7 form a four-in-one domain that regulates JAK binding to receptors.

[0008] STATs are cytoplasmic proteins that bind to DNA in the regulatory regions of target genes and serve as downstream substrates of JAKs. Seven members of the STAT family have been identified: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. STAT proteins are structurally divided into several functional domains: an N-terminal conserved sequence, a DNA-binding region, a SH3 domain, an SH2 domain, and a C-terminal transcriptional activation region. The most conserved and functionally important domain is the SH2 domain, which has a core sequence identical to that of the SH2 domain of the tyrosine kinase Src (Src).

[0009] The JAK-STAT signaling pathway has a wide range of functions, participating in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. Currently, research related to diseases and drug innovation is mostly focused on inflammatory diseases and tumors. Among them, inflammatory diseases mainly include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis, and Crohn's disease; while tumors mainly involve myelofibrosis, polycythemia vera, and essential thrombocythemia. In addition, mutations in JAK molecules themselves can also lead to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), breast ductal carcinoma and non-small cell lung cancer (NSCLC), polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic myeloid leukemia (CML), etc.

[0010] JAKs are a very important class of drug targets. JAK inhibitors developed for this target are primarily used to screen for therapeutics for hematologic diseases, tumors, rheumatoid arthritis, and psoriasis. JAK-1, JAK-2, and TYK-2 are expressed in various tissue cells throughout the human body, while JAK-3 is primarily expressed in hematopoietic tissue cells, primarily bone marrow cells, thymocytes, NK cells, and activated B and T lymphocytes. Studies have shown that JAK2 inhibitors are useful for myeloproliferative diseases (Santos et al., Blood, 2010, 115:1131; Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16:129; Atallah E. and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9:663), and JAK3 inhibitors are useful as immunosuppressants (e.g., U.S. Patent 6,313,129; Borie et al., Curr. Opin. Investigational Drugs, 2003, 4:1297).

[0011] Currently, JAK inhibitors approved by the FDA and EMA include Tofacitinib, Ruxolitinib, and Oclacitinib. JAK inhibitors in late-stage clinical trials include Filgotinib and Peficitinib.

[0012] Tofacitinib, a JAK3 inhibitor, was developed by Pfizer and approved by the FDA in November 2012 for the treatment of moderate to severe rheumatoid arthritis in adults who have had an inadequate response to or intolerance to methotrexate. It was the first oral JAK inhibitor approved for the treatment of RA. It was subsequently approved for marketing by the Japanese PMDA in March 2013 under the trade name Xeljanz. On March 16, 2017, Pfizer China announced that the CFDA had formally approved Pfizer's application for marketing approval of its oral JAK inhibitor. The drug is reportedly approved for the treatment of moderate to severe rheumatoid arthritis in adults who have had an inadequate response to or intolerance to methotrexate. Currently, tofacitinib is nearing approval for indications such as psoriasis, ulcerative colitis, and juvenile idiopathic arthritis; clinical trials for Crohn's disease and alopecia areata have entered mid-to-late stages. The main side effects of tofacitinib include serious infection rates and increased low-density lipoprotein cholesterol levels. The most common adverse reactions are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat, and nasopharyngitis. In addition, clinical studies have reported that tofacitinib can cause side effects such as anemia and neutropenia.

[0013] Ruxolitinib, a JAK1 and JAK2 inhibitor, was jointly developed by Incyte and Novartis and was approved by the US FDA in November 2011. It was the first drug specifically approved for the treatment of myelofibrosis. It received EMA approval in August 2012 and Japanese PMDA approval in July 2014. The drug is marketed by Incyte in the US under the trade name Jakafi and by Novartis in Europe and Japan under the trade name Jakavi. Ruxolitinib is currently in multiple late-stage clinical trials for indications including various cancers, graft-versus-host disease (GVHD), alopecia areata, atopic dermatitis, rheumatoid arthritis, vitiligo, and psoriasis. The most common hematologic adverse reactions (incidence >20%) with ruxolitinib are thrombocytopenia and anemia. The most common non-hematologic adverse reactions (incidence >10%) are bruising, dizziness, and headache.

[0014] Oclacitinib, approved by the US FDA in 2013, is used to control pruritus and atopic dermatitis caused by canine allergic dermatitis. Oclacitinib is a novel JAK and JAK1-dependent cytokine inhibitor. Oclacitinib is not only a very effective JAK1 inhibitor, but also inhibits the function of JAK1-dependent cytokines in some anti-allergic, inflammatory, and pruritic responses. It has minimal effect on cytokines that are not involved in activating JAK1. Oral administration of 0.4-0.6 mg / kg of oclacitinib twice daily is safe and effective for the treatment of pruritus caused by allergic dermatitis. During treatment, oclacitinib can relieve itching within 24 hours. In experiments, more than 70% of experimental animals (dogs) had a greater than 50% reduction in pruritus by day 7. However, oclacitinib is not yet suitable for the treatment of human diseases.

[0015] Filgotinib, a JAK1 inhibitor, completed Phase III clinical trials in September 2018 for the treatment of rheumatoid arthritis. Filgotinib is also currently in Phase II / III clinical trials for the treatment of ulcerative colitis and Crohn's disease. Filgotinib is a selective JAK1 inhibitor with IC50 values ​​of 10nM, 28nM, 810nM, and 116nM for JAK1, JAK2, JAK3, and TYK2, respectively.

[0016] Peficitinib, a JAK1 and JAK3 inhibitor, is being developed by Astellas and is currently in Phase III clinical trials for the treatment of rheumatoid arthritis. A Phase II clinical study for the treatment of psoriasis has been completed. Peficitinib is a novel, oral JAK inhibitor that inhibits the enzymatic activities of JAK1, JAK2, JAK3, and TYK2 with IC50 values ​​of 3.9 nM, 5.0 nM, 0.71 nM, and 4.8 nM, respectively.

[0017] Although some JAK inhibitors have been approved for marketing and a large number are in clinical trials, these JAK inhibitors are not satisfactory in terms of efficacy or safety. Therefore, there is always a need for JAK inhibitors with better efficacy and / or fewer side effects.

[0018] Summary of the Invention

[0019] One object of the present invention is to provide a new class of JAK inhibitors that can replace existing JAK inhibitors, thereby providing more options for the treatment of JAK-related diseases.

[0020] A further object of the present invention is to provide a new class of JAK inhibitors that are more effective and / or safer than existing JAK inhibitors.

[0021] In a first aspect, the present invention provides compounds of formula (I) as JAK inhibitors:

[0022] or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein:

[0023] L is C=O, O=S=O, CH2 or a covalent bond; and

[0024] R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom; and

[0025] R3 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -SR 12 、-OR 12 、-CN、halogen、-NO2、-SF5、-SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl or 5-11 membered bicycloheteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7Aryl, 5-7 membered heteroaryl, C 7- 11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, and optionally substituted by one or more substituents each independently selected from the following groups: -OH, -CN, -SH, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ),-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12), -C(=O)-OR 12 、-C(=O)H、-C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring; and

[0026] The number of R2 is 0, 1, 2, 3 or 4, and R2 is selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ),-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 、-C(=O)H、-C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; and p is 1, 2 or 3; and

[0027] R a Selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ),-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-8 Alkyl, C2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl is optionally substituted by 1, 2, 3 or 4 R b replace; and

[0028] R b Selected from H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R5)(R6), -N(R 11 )(C(=O)R 12 )、-CON(R7)(R8)、-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7- 11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 、-C(=O)H、-C(=O)R12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ;and

[0029] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 are each independently H or selected from the following group: C 1-6 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -CF3, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0030] In some preferred embodiments of the present invention, in formula (I), L is C=O, O=S=O or CH2. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O. In some particularly preferred embodiments of the present invention, in formula (I), L is O=S=O. In some particularly preferred embodiments of the present invention, in formula (I), L is CH2. In some other embodiments of the present invention, in formula (I), L is a connecting bond.

[0031] In some preferred embodiments of the present invention, in formula (I), R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom. In some more preferred embodiments of the present invention, in formula (I), R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms. In some still more preferred embodiments of the present invention, in formula (I), R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms. In some particularly preferred embodiments of the present invention, in formula (I), R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 .

[0032] In the above embodiment of the present invention, deuterium (i.e. 2Substitution of the H atom of the group R1 of the compound of formula (I) with a heavier isotope (e.g., deuterium, also referred to as D) may provide certain unexpected therapeutic benefits. The inventors of the present application speculate that such benefits may be due to significantly greater metabolic stability (e.g., significantly increased in vivo half-life or significantly reduced dosage requirements). In addition, the inventors of the present application have discovered that substitution of the H atom of the group R1 of the compound of formula (I) with a deuterium isotope unexpectedly enhances the inhibitory activity of the compound of formula (I) against JAK1, JAK2, JAK3, and / or TYK2 enzymes, as demonstrated by the IC of the deuterated compound. 50 The value is reduced to the corresponding non-deuterated compound IC 50 One-half, one-third, one-quarter or even lower (it is generally believed in the art that simple deuteration will not have such a huge impact on pharmacological activity).

[0033] In some preferred embodiments of the present invention, in formula (I), R3 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, and R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5 (wherein R3 is optionally substituted by 1, 2, 3 or 4 R a In some preferred embodiments of the present invention, in formula (I), R3 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, and R 17 、R 18 As defined above (wherein R3 is optionally replaced by 1, 2, 3 or 4 R a In some preferred embodiments of the present invention, in formula (I), R3 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and R 17 、R 18 As defined above (wherein R3 is optionally replaced by 1, 2, 3 or 4 R a In some preferred embodiments of the present invention, in formula (I), R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 5-11 Bicycloalkyl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 5-11 membered bicyclic heteroalkyl, and R 17 、R 18 As defined above (wherein R3 is optionally replaced by 1, 2, 3 or 4 R a In some preferred embodiments of the present invention, in formula (I), R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and R 17 、R 18 As defined above (wherein R3 is optionally replaced by 1, 2 or 3 R a In some preferred embodiments of the present invention, in formula (I), R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, and R 17 、R 18As defined above (wherein R3 is optionally replaced by 1, 2 or 3 R a In some preferred embodiments of the present invention, in formula (I), R3 is -N(R 17 )(R 18 ), C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl or C 1-4 Alkyl, and R 17 、R 18 As defined above (wherein R3 is optionally replaced by 1, 2 or 3 R a In some preferred embodiments of the present invention, in formula (I), R3 is -N(H)(C 1-3 alkyl), -N(H)(3-6 membered cycloalkyl), -N(H)(3-7 membered heterocycloalkyl), -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 1- 3 alkoxy, C 3-6 Cycloalkyl, 4-6 membered nitrogen heterocycloalkyl or oxygen heterocycloalkyl, phenyl, 5-6 membered nitrogen heteroaryl or C 1-4 Alkyl; or R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the N atoms to which they are attached together form a 4-10 membered ring (wherein R3 is optionally replaced by 1, 2 or 3 R a In some particularly preferred embodiments of the present invention, in formula (I), R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, -N(H)(CH3), -N(H)(CH2CH3), -N(H)(CH2CH2OH), -N(H)(CH2CH2CH2OH), -N(H)(CH2CH(CH3)OH), -N(H)(CH2CH2CN), -N(CH3)(CH3), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl), pyrazinyl, pyridazinyl, pyrrolidinyl, pyrazolyl, piperidinyl, phenyl, azetidinyl, morpholinyl, piperazinyl or tetrahydropyranyl; or R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the N atoms to which they are attached together form a 5-membered ring (wherein R3 is optionally replaced by 1, 2 or 3 R asubstituted). In some particularly preferred embodiments of the present invention, in formula (I), R3 is cyclopropyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is cyclobutyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is cyclopentyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is cyclohexyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is methyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is ethyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is propyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is butyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is pyrazinyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is pyridazinyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is pyrrolidinyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is pyrazolyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is piperidinyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is phenyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is azetidinyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is morpholinyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is piperazinyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is tetrahydropyranyl. In some particularly preferred embodiments of the present invention, in formula (I), R3 is methoxy. In some particularly preferred embodiments of the present invention, in formula (I), R3 is ethoxy. In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(CH2CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(CH2CH(CH3)OH). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(CH3)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(cyclopropyl).In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(H)(tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (I), R3 is -N(R). 17 )(R 18 ), and R 17 、R 18 and the nitrogen atom to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0034] In some preferred embodiments of the present invention, in formula (I), R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some preferred embodiments of the present invention, in formula (I), R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some preferred embodiments of the present invention, in formula (I), R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 In some preferred embodiments of the present invention, in formula (I), R 17 、R 18 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, and is optionally substituted with one or more -OH, -CN. In some preferred embodiments of the present invention, in formula (I), R 17 、R 18 and the nitrogen atoms to which they are attached together form a 4-10 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some preferred embodiments of the present invention, in formula (I), R17 、R 18 and the nitrogen atom to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0035] In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5 or -SC 1-4 Alkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, or C 1-6 Alkoxy; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18and the N atoms to which they are attached together form a 3-10 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyridyl, morpholinyl, -N(H)(CH3), -N(H)(CH2CH3), -N(H)(CH2CH2OH), -N(H)(CH2CH2CH2OH), -N(H)(CH2CH(CH3)OH), -N(H)(CH2CH2CN), -N(CH3)(CH3), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl); or R3 is -N(R 17 )(R 18 ), and R 17 、R 18and the N atoms to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is methoxy. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is ethoxy. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is cyclopropyl. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is morpholinyl. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is -N(H)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is -N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O and R3 is -N(H)(CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O and R3 is -N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O and R3 is -N(H)(CH2CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O and R3 is -N(H)(CH2CH(CH3)OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O and R3 is -N(CH3)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O and R3 is -N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O and R3 is -N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is -N(H)(tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, and R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the nitrogen atom to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0036] In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 5-11 Bicycloalkyl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 5-11 membered bicyclic heteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3- 7-membered cycloalkyl, 3-7-membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a Substituted and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl or C 1-6 Alkoxy; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-10 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, -N(H)(CH3), -N(H)(CH2CH3), -N(H)(CH2CH2OH), -N(H)(CH2CH2CH2OH), -N(H)(CH2CH(CH3)OH), -N(H)(CH2CH2CN), -N(CH3)(CH3), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl); or R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the nitrogen atoms to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3- 7-membered cycloalkyl, 3-7-membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is -N(H)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is -N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a and R3 is -N(H)(CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a and R3 is -N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is -N(H)(CH2CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a and R3 is -N(H)(CH2CH(CH3)OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is -N(CH3)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a and R3 is -N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is -N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is -N(H)(tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6Alkoxy, and R3 is 0, 1, 2, 3 or 4 R a substituted; and R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the nitrogen atom to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0037] In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 5-11 Bicycloalkyl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 5-11 membered bicyclic heteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is -SC 1- 4 alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; R3 is -N(R 17 )(R18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0038] In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl or C 1-6 Alkoxy; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-10 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, -N(H)(CH3), -N(H)(CH2CH3), -N(H)(CH2CH2OH), -N(H)(CH2CH2CH2OH), -N(H)(CH2CH(CH3)OH), -N(H)(CH2CH2CN), -N(CH3)(CH3), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl); or R3 is -N(R 17 )(R 18 ), and R 17 、R 18and the nitrogen atoms to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is a methoxy group. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is an ethoxy group. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is a cyclopropyl group. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is a cyclopropyl group. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is morpholinyl. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1- 4 alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH(CH3)OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(CH3)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the nitrogen atom to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0039] In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(R 17 )(R 18 ), C1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 5-11 Bicycloalkyl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 5-11 membered bicyclic heteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms; R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1- 6 alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(R 17 )(R 18 ), C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, or C 1-6 Alkoxy; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-10 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, -N(H)(CH3), -N(H)(CH2CH3), -N(H)(CH2CH2OH), -N(H)(CH2CH2CH2OH), -N(H)(CH2CH(CH3)OH), -N(H)(CH2CH2CN), -N(CH3)(CH3), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl); or R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the nitrogen atoms to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is a methoxy group. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is ethoxy. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is a cyclopropyl group. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is morpholinyl. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(CH2CH(CH3)OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(CH3)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(H)(tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms, and R3 is -N(R 17 )(R 18 ), and R 17 、R 18and the nitrogen atom to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0040] In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 ; R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 5-11 Bicycloalkyl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 5-11 membered bicyclic heteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O; R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 ; R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(R 17 )(R 18 ), 3-7 membered heterocycloalkyl, C 3-7 Cycloalkyl or C 1-6 Alkoxy; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7Heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-10 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, -N(H)(CH3), -N(H)(CH2CH3), -N(H)(CH2CH2OH), -N(H)(CH2CH2CH2OH), -N(H)(CH2CH(CH3)OH), -N(H)(CH2CH2CN), -N(CH3)(CH3), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl); or R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the nitrogen atoms to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is methoxy. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is ethoxy. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is cyclopropyl. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D10 , and R3 is morpholinyl. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(CH2CH2CH2OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(CH2CH(CH3)OH). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(CH3)(CH3). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D10 , and R3 is -N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(H)(tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (I), L is C=O, R1 is C 1-6 Alkyl, wherein all H atoms on R1 are replaced by D atoms, for example, R1 is CD3, C2D6, C3D8 or C4D 10 , and R3 is -N(R 17 )(R 18 ), and R 17 、R 18 and the nitrogen atom to which they are attached together form a 5-membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0041] In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1, 2 or 3, and R2 is selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, wherein the -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2 or 3 substituents each independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1, 2 or 3, and R2 is selected from halogen, C 1-6Alkyl and C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1, 2 or 3, and R2 is selected from halogen, C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from halogen, C 1-6 Alkyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine, methyl, ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine, ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1, and R2 is selected from fluorine, ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 2, and R2 is selected from fluorine, ethyl. In some particularly preferred embodiments of the present invention, in formula (I), there are two R2, each of which is fluoro and ethyl. In some particularly preferred embodiments of the present invention, in formula (I), there is one R2, and R2 is ethyl.

[0042] In some preferred embodiments of the present invention, in formula (I), R3 is replaced by 0, 1, 2, 3 or 4 R a Replaced, and each R a Independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein the -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3- 7-membered cycloalkyl, 3-10-membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl is optionally substituted by 1, 2, 3 or 4 R b In some preferred embodiments of the present invention, in formula (I), R3 is replaced by 0, 1, 2, 3 or 4 R a Replaced, and each R a Independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, wherein said -SC 1-4 Alkyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R b In some preferred embodiments of the present invention, in formula (I), R3 is replaced by 0, 1, 2, 3 or 4 R a Replaced, and each R a Independently selected from halogen, -OH, -CN, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, wherein the C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R b In some preferred embodiments of the present invention, in formula (I), R3 is replaced by 0, 1, 2, 3 or 4 R a Replaced, and each Ra Independently selected from halogen, -OH, -CN, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, wherein the C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl optionally substituted by 1, 2 or 3 R b In some preferred embodiments of the present invention, in formula (I), R3 is substituted by 0 or 1 R1, and each R a Independently selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-7 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-7 membered heterocycloalkyl, optionally substituted by 1, 2 or 3 R b In some preferred embodiments of the present invention, in formula (I), R3 is replaced by 0 or 1 R a Replaced, and each R a Independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocycloalkyl, optionally substituted by 1, 2 or 3 R b In some particularly preferred embodiments of the present invention, in formula (I), R3 is replaced by 0 or 1 R a Replaced, and each R a independently selected from methyl, ethyl, hydroxy, -CN, piperidinyl, morpholinyl, piperazinyl, cyclopropyl, wherein piperidinyl, morpholinyl, piperazinyl is optionally substituted by 1, 2, 3 or 4 C 1-3 In some particularly preferred embodiments of the present invention, in formula (I), R3 is replaced by 0 or 1 R a Replaced, and each R a are independently selected from methyl, ethyl, hydroxy, -CN, piperidinyl, morpholinyl, 1-methylpiperazinyl, and cyclopropyl. In some particularly preferred embodiments of the present invention, in formula (I), R a In some particularly preferred embodiments of the present invention, in formula (I), R a In some particularly preferred embodiments of the present invention, in formula (I), R a In some particularly preferred embodiments of the present invention, in formula (I), R a In some particularly preferred embodiments of the present invention, in formula (I), Ra In some particularly preferred embodiments of the present invention, in formula (I), R a In some particularly preferred embodiments of the present invention, in formula (I), R a In some particularly preferred embodiments of the present invention, in formula (I), R a In some particularly preferred embodiments of the present invention, in formula (I), R a It is cyclopropyl.

[0043] The preferred options of each substituent mentioned in the above various preferred embodiments can be combined with each other, and various combinations thereof are within the scope of the present invention. In the most preferred embodiment of the present invention, the compound of formula (I) is the specific compound shown below. That is, the compound of formula (I) is selected from

[0044] In addition to the embodiment in which R1 in the compound of formula (I) is an isotope-labeled substituent, the above-mentioned embodiment of the present invention also includes other substituents in the compound of formula (I) other than R1, including but not limited to the embodiment in which R2 and / or R3 are isotope-labeled substituents or are not isotope-labeled substituents.

[0045] For the sake of simplicity, the "compound represented by formula (I)" or "compound of formula (I)" or "compound of the present invention" mentioned below also includes any optical isomers, geometric isomers, tautomers or mixtures of isomers of the compound of formula (I).

[0046] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can exist in the R configuration or the S configuration, and the various isomers thus formed are optical isomers. Optical isomers include all diastereomers, enantiomers, meso-isomers, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0047] The term "geometric isomer" means that when a compound has a double bond, the compound may exist as cis-isomers, trans-isomers, E-isomers and Z-isomers. Geometric isomers include cis-isomers, trans-isomers, E-isomers, Z-isomers or mixtures thereof.

[0048] The term "tautomer" refers to isomers resulting from the rapid shift of an atom between two positions in a molecule. Those skilled in the art will appreciate that tautomers can interconvert and, under certain conditions, may reach an equilibrium state and coexist. The term "compound of formula (I)" herein also encompasses any tautomer of the compound of formula (I).

[0049] Unless otherwise indicated, references herein to "compounds represented by formula (I)" or "compounds of formula (I)" or "compounds of the present invention" also encompass isotopically labeled compounds in which any atom in the compound is replaced by an isotope atom thereof.

[0050] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic number but a different atomic mass or mass number than the atom usually found in nature.

[0051] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C. 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O. 17 O and 18 O, and isotopes of sulfur such as 35 S.

[0052] Certain isotopically labeled compounds of formula (I) (e.g., those containing a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. In view of the ease of incorporation and the convenience of detection means, the radioactive isotope deuterium (i.e. 2 H, also referred to as D) and carbon-14 (i.e. 14 C) is particularly useful for this purpose.

[0053] Using deuterium (i.e. 2 Substitution with heavier isotopes such as H, also referred to as D) may afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements) and hence are preferred.

[0054] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission topography (PET) studies to detect substrate receptor occupancy status.

[0055] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used in an analogous manner to the methods described in the Examples and Preparations appended herein.

[0056] The compounds of formula (I) may exist in the form of pharmaceutically acceptable salts, for example, acid addition salts and / or base addition salts of the compounds of formula (I). Unless otherwise indicated, "pharmaceutically acceptable salts" as used herein include acid addition salts or base addition salts that may be present in the compounds of formula (I).

[0057] Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamates, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, hexadecanoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed with bases which form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemi-salts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0058] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, compounds of formula (I) are encompassed within the scope of the present invention regardless of whether they exist in solvated or unsolvated forms.

[0059] Certain compounds of the present invention may exist in different crystalline or amorphous forms. Regardless of the form in which they exist, the compounds of formula (I) are included within the scope of the present invention.

[0060] To avoid ambiguity, the following definitions are given for the terms used in this document. Unless otherwise specified, the meanings of the terms used in this document are as follows.

[0061] The term "pharmaceutically acceptable" refers to a compound, carrier or molecule that is suitable for administration to a human. Preferably, the term refers to a compound, carrier or molecule that is approved by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA) for use in mammals, preferably humans.

[0062] "Prodrug" refers to a derivative that is converted into the compound of the present invention by reactions with enzymes, gastric acid, etc. under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc., each catalyzed by an enzyme.

[0063] "Metabolites" refer to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

[0064] The term "hydroxy" refers to -OH.

[0065] The term "halogen" or "halo" refers to -F, -Cl, -Br, or -I.

[0066] The term "cyano" refers to -CN.

[0067] In the present invention, when a certain type of substituent exists in multiple groups, each substituent is selected independently of each other, that is, these substituents can be the same or different. For example, when there are 2, 3 or 4 R1, these R1 can be the same or different. For example, when there are 2, 3 or 4 R2, these R2 can be the same or different. For example, when R1 and R2 are both -N(R9)(R 10 ), R9 and R in R1 and R2 10 Can be independently selected, that is, R9 in R1 and R9 in R2 can be the same or different, R 10 and R in R2 10 They can be the same or different. For example, when there are two R1s, both of which are -N(R9)(R 10 ), R9 and R 10 Can be selected independently, that is, R9 in the first R1 and R9 in the second R1 can be the same or different, and R 10 With the R in the second R1 10 The above description applies to R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 , R3, R 14 、R 15 、R 16 、R 17 、R 18 .

[0068] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

[0069] As used herein, the term "independently" means that when there are more than one substituent, the substituents may be the same or different.

[0070] As used herein, the term "optional" or "optionally" means that the event it describes may or may not occur. For example, a group "optionally substituted" means that the group may be unsubstituted or substituted.

[0071] As used herein, the term "heteroatom" refers to oxygen (O), nitrogen (N), or S (O) m (wherein m can be 0, 1 or 2, i.e. a sulfur atom S, or a sulfoxide group SO, or a sulfonyl group S(O)2).

[0072] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, the alkyl group has 1-8, or 1-6, or 1-3 carbon atoms. For example, the term "C 1-8 "Alkyl" refers to a straight or branched chain radical having 1 to 8 carbon atoms. 1-8 "Alkyl" includes in its definition the term "C 1-6 "C1-C3 alkyl" and "C1-C4 alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0073] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms. For example, the term "C 2-8 "Alkenyl" refers to a straight or branched unsaturated atomic group (with at least one carbon-carbon double bond) having 2-8 carbon atoms. The double bond may or may not be the point of attachment to another group. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. The alkenyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents. When the compound of formula (I) contains an alkenyl group, the alkenyl group may be present in pure E form, pure Z form, or any mixture thereof.

[0074] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms. For example, the term "C 2-8 "Alkynyl" refers to a straight or branched unsaturated atomic group (having at least one carbon-carbon triple bond) having 2-8 carbon atoms. The triple bond may or may not be a point of attachment to another group. Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like. Alkynyl groups may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0075] As used herein, the term “C 3-7 "Cycloalkyl" refers to a cycloalkyl group having 3 to 7 carbon atoms forming the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl. The cycloalkyl group may be optionally substituted by one or more suitable substituents.

[0076] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl group having m carbon atoms and (nm) heteroatoms forming the ring, wherein the heteroatoms are selected from O, S, and N. For example, 3-7 membered heterocycloalkyl groups include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine, oxepane, thiepane, and azepane. Heterocycloalkyl groups may be optionally substituted with one or more suitable substituents.

[0077] As used herein, the term “C 5-7 The term "aryl" refers to an aromatic group having an aromatic ring containing 5 to 7 carbon atoms, preferably phenyl.

[0078] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from O, S, and N. For example, 5-7 membered heteroaryl groups include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, and pyridine. The heteroaryl group may be optionally substituted with one or more suitable substituents.

[0079] As used herein, the term “C 7-11 The term "bicyclic aryl" refers to a bicyclic aryl group having 7 to 11 carbon atoms, such as naphthalene, indene, etc. The bicyclic aryl group may be optionally substituted by one or more suitable substituents.

[0080] As used herein, the term "n-membered bicyclic heteroaryl" refers to a bicyclic heteroaryl group having m carbon atoms forming an aromatic bicyclic ring and (nm) heteroatoms forming an aromatic bicyclic ring, wherein the heteroatoms are selected from O, S and N. For example, 7-11 membered bicyclic heteroaryl groups include, but are not limited to, quinoline, isoquinoline, benzothiazole, etc. The bicyclic heteroaryl group may be optionally substituted with one or more suitable substituents.

[0081] As used herein, the term "11-15 membered tricyclyl" includes, but is not limited to, acridine, etc. The 11-15 membered tricyclyl may be optionally substituted with one or more suitable substituents.

[0082] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). For example, the term "C 1-6 "Haloalkyl" refers to a C 1-6 Alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); the term "C 1-3 "Haloalkyl" refers to a C 1-3 alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); and the term "C 1-2 "Haloalkyl" refers to a C 1-2 An alkyl group (i.e., methyl or ethyl) (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C1 haloalkyl" refers to a methyl group having 1, 2, or 3 halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, and the like.

[0083] As used herein, the term "alkoxy" refers to an alkyl group that is single-bonded to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. The alkoxy group can be depicted as alkyl-O-. The term "C 1-6 "Alkoxy" refers to a straight or branched chain alkoxy group containing 1 to 6 carbon atoms. The term "C 1-6 "Alkoxy" includes in its definition the term "C 1-3 Alkoxy". Alkoxy includes but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy and the like. Alkoxy may be optionally substituted with one or more suitable substituents.

[0084] In this article, the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent a list of all integers within the range, and the range is only used as a simplified representation. For example:

[0085] "1-4 substituents" means 1, 2, 3 or 4 substituents;

[0086] "1-3 substituents" means 1, 2 or 3 substituents;

[0087] "3-12 membered ring" means a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring;

[0088] "3-14 membered ring" means a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered ring;

[0089] "3-8 membered ring" means a 3-, 4-, 5-, 6-, 7- or 8-membered ring;

[0090] "1-12 carbon atoms" or C 1-12 ” means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7), 8 (C8), 9 (C9), 10 (C 10 ), 11 (C 11 ) or 12 carbon atoms (C 12 );

[0091] "1-6 carbon atoms" or "C 1-6 ” means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6);

[0092] "1-4 carbon atoms" or "C 1-4 ” means 1 (C1), 2 (C2), 3 (C3) or 4 carbon atoms (C4);

[0093] "2-6 carbon atoms" or "C 2-6 ” means 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6);

[0094] “C 3-8 ” means 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7) or 8 carbon atoms (C8);

[0095] "3-8 ring atoms" means 3, 4, 5, 6, 7 or 8 ring atoms.

[0096] Therefore, numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also encompass any subranges thereof, and each subrange is also considered to be disclosed herein.

[0097] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound as described above or its optical isomers, geometric isomers, tautomers or isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0098] The pharmaceutical composition of the present invention can be formulated into a dosage form suitable for oral administration, topical application (including but not limited to external application, spraying, etc.), parenteral administration (including subcutaneous, intramuscular, intradermal and intravenous), bronchial administration or nasal administration as needed. Among them, preferably, the pharmaceutical composition of the present invention is formulated into a dosage form (preparation) suitable for oral administration or topical application. More preferably, the pharmaceutical composition of the present invention is formulated into a dosage form (preparation) suitable for oral administration.

[0099] If a solid carrier is used, the preparation can be tableted, placed in a hard gel capsule in the form of a powder or granules, or in the form of a lozenge or pastille. Solid carriers may include conventional excipients, such as adhesives, fillers, tableting lubricants, disintegrants, wetting agents, etc. If necessary, the tablets may be film-coated by conventional techniques. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, ointment, soft gel capsule, a sterile carrier for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product reconstituted with water or other appropriate carriers before use. Liquid preparations may include conventional additives, such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavorings and / or coloring agents. For parenteral administration, typically the carrier at least comprises sterile water for the most part, but saline solutions, glucose solutions, etc. may also be used. Injectable suspensions may also be used, in which case conventional suspending agents may be used. Conventional preservatives, buffering agents, etc. may also be added to parenteral dosage forms. Pharmaceutical compositions are prepared by conventional techniques appropriate to the desired formulation containing an appropriate amount of the active ingredient (ie, the compound of formula (G), the compound of formula (G') or the compound of formula (I) of the present invention).

[0100] Compositions suitable for parenteral injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate).

[0101] These compositions can also include various excipients, for example, preservatives, wetting agents, emulsifiers and dispersants. The inhibition of the effect of microorganisms can be ensured by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents can also be included, for example, sugar, sodium chloride, etc. The absorption of injectable pharmaceutical dosage forms can be extended by using delayed absorption agents (for example, aluminum monostearate and gel).

[0102] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate) and may also include: (a) fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar); (e.g., fat-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarding agents (e.g., paraffin); (f) absorption promoters (e.g., quaternary ammonium compounds); (g) wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) adsorbents (e.g., kaolin and bentonite) and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), or mixtures thereof.

[0103] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, for example, lactose and high molecular weight polyethylene glycols as excipients.

[0104] Solid dosage forms (e.g., tablets, dragees, capsules, pills, and granules) can be prepared using coatings and shells (e.g., enteric coatings and others known in the art). They may contain opacifiers, and they may also be compositions that release the active compound or compounds in a delayed manner in a certain part of the intestine. Examples of useful embedding compositions are polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0105] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide), oils (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof, etc., commonly used in the art.

[0106] Besides such inert diluents, the composition may also include, for example, wetting agents, emulsifying and suspending agents, perfuming, flavoring, and perfuming agents.

[0107] In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

[0108] The topical dosage forms of the compound of the present invention include ointments, powders, sprays and inhalants. The active ingredient is mixed with a physiologically acceptable carrier and any required preservative, buffer or propellant under aseptic conditions. Ophthalmic formulations, eye ointments, powders and solutions are also included within the scope of the present invention.

[0109] The topical formulations of the compounds of the present invention can be in the form of a water-in-oil (W / O) or oil-in-water (O / W) emulsion, a multiple emulsion such as a water-in-oil-in-water (W / O / W) emulsion or an oil-in-water-in-oil (O / W / O) emulsion, or can be prepared in the form of an aqueous dispersion or lipid dispersion, a gel or an aerosol.

[0110] The topical formulations of the compounds of the present invention may contain additives and formulation aids such as emulsifiers, thickeners, gelling agents, water fixatives, spreaders, stabilizers, dyes, fragrances, and preservatives. Suitable emulsifiers include stearic acid, triethanolamine, and PEG-40 stearate. Suitable thickeners include glyceryl monostearate and PEG 600. Suitable preservatives include propyl paraben and chlorocresol. Suitable spreaders include dimethicone and polydimethylcyclosiloxane. Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol 600.

[0111] The topical dosage forms of the compounds of the present invention may include ointments, lotions, gels, emulsions, microemulsions, sprays, skin patches, etc., which can be applied topically to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, and alopecia. In particular, the topical dosage forms of the compounds of the present invention are ointments, which can be applied topically to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, and alopecia.

[0112] The amount of the compound of formula (I) in the pharmaceutical composition and dosage form can be appropriately determined by those skilled in the art as needed. For example, the compound of formula (I) can be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.

[0113] In a third aspect, the present invention provides use of a compound as described above or its optical isomers, geometric isomers, tautomers or isomer mixtures, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or a composition as described above in the preparation of a medicament for treating and / or preventing a disease or condition associated with JAK.

[0114] "JAK-associated diseases or conditions" include, but are not limited to:

[0115] Arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis;

[0116] Autoimmune diseases or disorders, including single organ or single cell type autoimmune disorders, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic invasive hepatitis, ulcerative colitis, and membranous glomerulopathy, those involving systemic autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis, and bullous pemphigoid), and other O-cell (humoral) or T-cell autoimmune diseases (including Colgan's syndrome), ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type 1 diabetes or juvenile-onset diabetes, or thyroiditis;

[0117] Cancer or tumor, including digestive tract / gastrointestinal cancer, colorectal cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, myeloma, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, myeloma (including multiple myeloma), myeloproliferative disorders, proliferative diabetic retinopathy, or disorders related to angiogenesis (including solid tumors);

[0118] Diabetes, including type 1 diabetes or diabetic complications;

[0119] ocular diseases, disorders, or conditions, including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis associated with Behcet's disease and phakic uveitis), keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoplakia, ocular pemphigus, Mollen's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), blisters, iridocyclitis, sarcoidosis, endocrine eye diseases, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization;

[0120] Intestinal inflammation, allergies, or conditions, including Crohn's disease and / or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis;

[0121] Neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury, stroke, glutamate neurotoxicity, or hypoxia; ischemia / reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, or platelet aggregation;

[0122] Skin diseases, conditions or disorders, including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other itchy conditions, vitiligo, hair loss;

[0123] Allergic reactions, including mammalian allergic dermatitis (including equine allergic diseases such as bite allergy), summer eczema, Culex itch syndrome (sweet itch), emphysema, inflammatory airway disease, recurrent airway obstruction, airway hyperresponsiveness or chronic obstructive pulmonary disease;

[0124] Asthma and other obstructive airway diseases, including chronic or refractory asthma, advanced asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma or dust asthma;

[0125] Transplant rejection, including islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection (e.g., bone marrow, cartilage, cornea, heart, intervertebral disc, islets, kidney, limb, liver, lung, muscle, myoblasts, nerve, pancreas, skin, small intestine, or trachea), or xenotransplantation.

[0126] In a fourth aspect, the present invention provides a method for treating a disease or condition associated with JAK, the method comprising administering a therapeutically effective amount of a compound as described above, or its optical isomers, geometric isomers, tautomers, or isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, or compositions as described above, to a patient in need thereof. The patient is preferably a mammal, more preferably a human patient. The route of administration may be oral, topical (including but not limited to topical application, spraying, etc.), parenteral (including subcutaneous, intramuscular, cortical, and intravenous), bronchial, or nasal. Preferably, the administration is oral or topical. More preferably, the administration is oral.

[0127] Unexpectedly, the compounds of the present invention have demonstrated excellent efficacy as JAK kinase inhibitors in experiments (superior to existing JAK kinase inhibitors, such as Filgotinib), and potentially have good safety.

[0128] Preferably, the present invention provides the following embodiments:

[0129] Embodiment 1. A compound of formula (I):

[0130] or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein:

[0131] L is C=O, O=S=O, CH2 or a covalent bond; and

[0132] R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom; and

[0133] R3 is H, -N(R 17 )(R 18 ), C1-6 Alkoxy, -SR 12 、-OR 12 、-CN、halogen、-NO2、-SF5、-SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl or 5-11 membered bicycloheteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7- 11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, and optionally substituted by one or more substituents each independently selected from the following groups: -OH, -CN, -SH, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ),-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 、-C(=O)H、-C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring; and

[0134] The number of R2 is 0, 1, 2, 3 or 4, and R2 is selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R12 )、-C(=O)-N(R9)(R 10 ),-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 、-C(=O)H、-C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; and p is 1, 2 or 3; and

[0135] R a Selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ),-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl is optionally substituted by 1, 2, 3 or 4 R b replace; and

[0136] R b Selected from H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R5)(R6), -N(R 11 )(C(=O)R 12 )、-CON(R7)(R8)、-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR12 AND-OR 12 , wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7- 11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 、-C(=O)H、-C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ;and

[0137] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 are each independently H or selected from the following group: C 1-6 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -CF3, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0138] Embodiment 2. The compound according to embodiment 1, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein L is C=O, O=S=O or CH2.

[0139] Embodiment 3. The compound according to any one of Embodiments 1-2, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 A haloalkoxy group, wherein at least one H atom on R1 is replaced by a D atom, and preferably all H atoms on R1 are replaced by D atoms.

[0140] Embodiment 4. The compound according to any one of Embodiments 1-2, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms.

[0141] Embodiment 5. The compound according to any one of Embodiments 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group, C 5-11 Bicycloalkyl or 5-11 membered bicycloheteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Halogenated alkyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0142] Embodiment 6. The compound according to any one of Embodiments 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl or 5-11 membered bicyclic heteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a replace.

[0143] Embodiment 7. The compound according to any one of Embodiments 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl or 5-7 membered heteroaryl, and R3 is replaced by 0, 1, 2, 3 or 4 R a replace.

[0144] Embodiment 8. The compound according to any one of Embodiments 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is -N(R 17 )(R 18 ), C 1-6Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, and R3 is replaced by 0, 1, 2 or 3 R a replace.

[0145] Embodiment 9. The compound according to any one of Embodiments 1-4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0146] Embodiment 10. The compound according to any one of Embodiments 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is -N(R 17 )(R 18 ), where R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Haloalkyl and C 3-7 Cycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0147] Embodiment 11. The compound according to any one of Embodiments 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is -N(R 17 )(R 18 ), where R 17 、R 18 and the nitrogen atom to which they are attached together form a 4-10 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0148] Embodiment 12. The compound according to any one of Embodiments 1-4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein L is C=O, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom, and R3 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 5- 11 Bicycloalkyl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 5-11 membered bicyclic heteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 、R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-7 Halogenated alkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5; or R 17 、R 18 and the nitrogen atoms to which they are attached together form a 3-14 membered ring, and the ring is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0149] Embodiment 13. A compound according to any one of Embodiments 1 to 12, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein 1, 2 or 3 R2 are present and R2 is selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, wherein the -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7Cycloalkyl, 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2 or 3 substituents each independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0150] Embodiment 14. The compound according to any one of Embodiments 1-12, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein there are 1, 2 or 3 R2, and R2 is selected from halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0151] Embodiment 15. The compound according to any one of Embodiments 1-12, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein there are 1 or 2 R2, and R2 is selected from halogen, C 1- 6 alkyl.

[0152] Embodiment 16. The compound according to any one of Embodiments 1-12, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is replaced by 0 or 1 R a Replace, and R a Selected from halogen, -OH, -CN, C 1-6 Alkyl, 5-7 membered heterocycloalkyl, C 3-7 Cycloalkyl, wherein the C 1-6 Alkyl, 5-7 membered heterocycloalkyl, C 3-7 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R b replace.

[0153] Embodiment 17. The compound according to any one of Embodiments 1-12, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein the compound is selected from:

[0154] Embodiment 18. The compound according to any one of Embodiments 1-12, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein the compound is selected from:

[0155] Embodiment 19. A pharmaceutical composition comprising a compound as described in any one of Embodiments 1-18 or its optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt, or a prodrug, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0156] Embodiment 20. Use of a compound according to any one of Embodiments 1-18 or its optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt, or a prodrug, or a metabolite thereof, or a composition according to Embodiment 19 in the preparation of a medicament for treating and / or preventing a disease or condition associated with JAK.

[0157] Embodiment 21. The use according to embodiment 20, wherein the disease or disorder associated with JAK is selected from arthritis, autoimmune diseases or disorders, cancer or tumors, diabetes, eye diseases, disorders or conditions, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions or disorders, allergies, asthma and other obstructive airway diseases, transplant rejection.

[0158] Embodiment 22. A method for treating and / or preventing a disease or condition associated with JAK, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1-18 or its optical isomers, geometric isomers, tautomers or isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, or the composition according to Embodiment 19 to a patient in need thereof.

[0159] Embodiment 23. The use according to embodiment 22, wherein the disease or disorder associated with JAK is selected from arthritis, autoimmune diseases or disorders, cancer or tumors, diabetes, eye diseases, disorders or conditions, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions or disorders, allergies, asthma and other obstructive airway diseases, transplant rejection.

[0160] The present invention will be further illustrated and described below with reference to the accompanying drawings and specific embodiments. Example

[0161] The compounds of formula (I) of the present invention 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), which are well known in the field of synthetic chemistry. Obviously, by referring to the exemplary schemes in this patent, those skilled in the art can easily design synthetic routes for other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0162] Synthetic intermediate Int 1: tert-butyl 2-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0163] Synthesis route

[0164] Synthesis method

[0165] Synthesis of 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (Int 1-2)

[0166] To a clean 500L kettle, add 467kg of dichloromethane, 35.4kg of 6-bromo-1H-indazole-3-carboxaldehyde (Int 1-1), and 5.30kg of TsOH (p-toluenesulfonic acid). Cool to 0-10°C, then add 15.91kg of DHP (dihydropyran) in portions, controlling the temperature between 0-10°C. Once the addition is complete, raise the temperature to 20-30°C and react for 3±1 hours. Once the raw materials have reacted, stop the reaction. Slowly add the reaction solution to 44.2kg of 8% sodium bicarbonate aqueous solution, stir for 0.5h, controlling the temperature between 10-20°C, filter the system, and allow the filtrate to stand for separation. The organic phase is dried over sodium sulfate and concentrated to dryness. Then, slurry is added with 39.6kg of ethyl acetate and 120kg of n-heptane at 15-25°C for 2 hours. Filter the system, and rinse the filter cake once with 12.0kg of n-heptane. The filter cake was dried to obtain 34.0 kg of the target product Int 1-2.

[0167] Synthesis of tert-butyl 2-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate) (Int 1-4) To a clean 500L kettle, 198kg of dichloromethane was added, followed by 15.0kg of Int 1-2 and 15.0kg of tert-butyl 3,4-diaminopyrrolidine-1-carboxylate (Int 1-3). 9.45kg of NBS (N-bromosuccinimide) was added to the kettle in batches, and the temperature was controlled within the range of 15-30°C. After the addition was completed, the reaction was stirred for 4 hours, and the temperature was controlled within the range of 20-30°C. Add an additional 2.40 kg of Int 1-3, and add 1.50 kg of NBS to the kettle in batches. Control the temperature between 15 and 30°C. After the addition is complete, stir and react for 1 hour while controlling the temperature between 20 and 30°C. Add an additional 2.40 kg of Int 1-3, and add 1.50 kg of NBS to the kettle in batches. Control the temperature between 15 and 30°C. After the addition is complete, stir and react for 1 hour while controlling the temperature between 20 and 30°C. Slowly pour the reaction solution into 49.95 kg of 5% sodium sulfite aqueous solution, then add 43.80 kg of 10% potassium carbonate aqueous solution, adjust the pH to ≥9, and stir for 0.5 hour while controlling the temperature between 10 and 20°C. The liquid was allowed to stand and separated. The aqueous phase was extracted once with 48.3 kg of dichloromethane. The organic phases were combined, dried over magnesium sulfate, and concentrated to dryness. The system was slurried with 55.5 kg of tert-butyl methyl ether at 5-15 ° C for 2 hours, filtered, and the filter cake was rinsed once with 5.00 kg of tert-butyl methyl ether. The filter cake was vacuum dried at 35-45 ° C with a vacuum degree of ≤-0.07 MPa. The material was dried for 12 hours and then collected to obtain 18.6 kg of the target product Int 1-4. LC-MS m / z (ESI) [M+H] + Targeting C 22 H 29 The calculated value of BrN5O3 is: 490.2; the measured value is: 490.1.

[0168] Synthesis of tert-butyl 2-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(H)-carboxylate (Int 1-5)

[0169] Add 143.2 kg of DMSO (dimethyl sulfoxide) and 18.6 kg of Int 1-4, stirring and heating at 35-40 ° C, 16.0 kg of 2-iodoxybenzoic acid (IBX) prepared in advance in DMSO (61.4 kg) was added dropwise to the system, and the temperature was controlled in the range of 35-40 ° C. After the addition was completed, it was stirred at this temperature for 5 hours, the system was cooled to 20-30 ° C, and then the system was slowly added to 233 kg of 3.3% sodium sulfite aqueous solution, and then 38.9 kg of 10% potassium carbonate aqueous solution and 98.4 kg of tert-butyl methyl ether were added. After stirring, the filter cake was rinsed once with 57.5 kg of tert-butyl methyl ether, and the filtrate was allowed to stand for separation. The aqueous phase was extracted once with the filtrate after rinsing, the organic phases were combined, and then washed once with 116 kg of water. The organic phase was dried over sodium sulfate and concentrated to obtain 18.4 kg of brown oil Int 1-5, which was directly used in the next step.

[0170] Synthesis of tert-butyl 2-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (Int 1)

[0171] Add 65.5 kg of tetrahydrofuran (THF) to a clean 500 L reactor, protect with nitrogen, stir and cool to 0-10 ° C, add 1.76 kg of sodium hydrogen (60%) to the system in batches, release gas during the addition, protect with nitrogen flow, control the temperature in the range of 0-10 ° C, stir for 0.5 hours, and add the prepared Int 1-5 (18.4kg) of THF (49.1kg) solution, temperature control in the range of 0 to 10 ℃, nitrogen flow protection, dropwise addition is complete, 7.36kg of 2- (trimethylsilyl) ethoxymethoxy chloride (SEMCl) is added dropwise to the system, temperature control in the range of 0 to 10 ℃, nitrogen flow protection, dropwise addition is complete, temperature rise 10 to 20 ℃, stirring for 1 hour, after the reaction is complete, the system is cooled to 0 to 10 ℃, and then under nitrogen protection, the system is slowly added to 115kg of 20% ammonium chloride aqueous solution, temperature control in the range of 0 to 20 ℃, stirring for 0.5 hour, separation, aqueous phase is added 56.7kg of tert-butyl methyl ether, extracted once, the organic phases are combined, and then washed once with 38.5kg of 20% sodium chloride aqueous solution, the organic phase is dried over sodium sulfate and concentrated to dryness, 72.7kg of methanol is added to the system, stirred for 2h, and the temperature control is in the range of 5 to 15 ℃. The system was filtered, and the filter cake was refluxed and recrystallized with 35.1 kg of acetonitrile. The temperature was controlled in the range of 70-80°C. After the solution was clarified, the temperature was lowered to 20-30°C, and the system was filtered. The filter cake was rinsed once with 7.36 kg of acetonitrile. The filter cake was vacuum dried at 35-45°C with a vacuum degree of ≤-0.07 MPa. After drying for seven hours, 10.1 kg of off-white powdery solid was obtained. Int 1, LC-MS m / z (ESI) [M+H] + Targeting C 28 H 41 The calculated value of BrN5O4Si is: 618.2; the measured value is: 618.2.

[0172] Synthesis of Synthetic Intermediate Int 2: tert-Butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-(2-(trimethylsilyl)methoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (Int 2)

[0173] Int 2 can be obtained by a similar synthetic method to that of Int 1 using appropriate starting materials. LC-MS m / z (ESI) [M+H] + Targeting C 29 H 47 The calculated value of BrN5O4Si2 is: 664.2; the measured value is: 664.2.

[0174] Example 1: (R)-2-(6-(5-fluoro-4-hydroxy-2-(methyl-d3)phenyl)-1H-indazol-3-yl)-N-(2-hydroxypropyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide (Compound 1)

[0175] Synthesis route of compound 1:

[0176] Synthesis method:

[0177] Synthetic intermediate 1-1: 2-(benzyloxy)-4-bromo-1-fluorobenzene

[0178] 5-Bromo-2-fluorophenol (2.0 g, 10.47 mmol) and benzyl bromide (2.2 g, 12.57 mmol) were dissolved in 20 ml of acetonitrile, potassium carbonate (2.2 g, 15.71 mmol) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, water was added to the reaction solution and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 2.8 g of intermediate 1-1, with a yield of 95.1%.

[0179] 1 H NMR (400MHz, CDCl3) δ7.52-7.32(m,5H),7.17(dd,J=7.5Hz,J=2.3Hz,1H),7.10-6.92(m,2H),5.14(s,2H).

[0180] Synthetic intermediate 1-2: 2-(benzyloxy)-1-fluoro-4-(methyl-d3)benzene

[0181] Intermediate 1-1 (230.0 mg, 0.82 mmol) was placed in a three-necked flask, and tetrakistriphenylphosphine palladium (94.5 mg, 0.082 mmol) was added. The nitrogen atmosphere was replaced, and 8 ml of dioxane was added to dissolve the mixture. Deuterated methylmagnesium iodide in ether (2.5 ml, 2.45 mmol) was slowly added dropwise to the solution at room temperature. After the addition was complete, the reaction solution was placed in an 80°C oil bath and reacted for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and quenched with water. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column using pure petroleum ether as the eluent to obtain 190.3 mg of crude intermediate 1-2 in a yield of 105.9%.

[0182] 1H NMR (400MHz, CDCl3) δ7.52-7.31 (m, 5H), 6.99 (dd, J = 11.3Hz, J = 8.2Hz, 1H), 6.85 (d d, J=8.1Hz, J=2.1Hz, 1H), 6.72 (ddd, J=8.2Hz, J=4.3Hz, J=2.1Hz, 1H), 5.14 (s, 2H).

[0183] Synthetic intermediate 1-3: 1-(benzyloxy)-4-bromo-2-fluoro-5-(methyl-d3)benzene

[0184] Intermediate 1-2 (190.3 mg, 0.87 mmol) was dissolved in 10 ml of acetonitrile, and copper bromide (579.1 mg, 2.60 mmol) was added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution and stirred until the solution became clear. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column using pure petroleum ether as the eluent to obtain 135.2 mg of crude intermediate 1-3, with a yield of 52.3%.

[0185] Synthetic intermediate 1-4: tert-butyl 2-(6-(4-(benzyloxy)-5-fluoro-2-(methyl-d3)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)methoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0186] Intermediate 1-3 (135.2 mg, 0.45 mmol) and diboron pinacol ester (126.6 mg, 0.50 mmol) were dissolved in 8 ml of dioxane, and Pd(dppf)Cl2.CH2Cl2 (37.1 mg, 0.05 mmol) and potassium acetate (133.1 mg, 1.36 mmol) were added. The nitrogen atmosphere was replaced and the reaction was carried out at 100°C for 5.5 hours. After cooling to room temperature, the reaction mixture was added with 4 ml of water. Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-(2-(trimethylsilyl)methoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (Int 2) was dissolved in 4 ml of dioxane and added to the reaction mixture. Pd(dppf)Cl2.CH2Cl2 (37.1 mg, 0.05 mmol) and potassium carbonate (187.3 mg, 1.36 mmol) were then added. The atmosphere was purged with nitrogen and the reaction was continued at 100°C for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 103.4 mg of Intermediate 1-4 in a yield of 28.3%.

[0187] 1 H NMR (400MHz, CDCl3) δ8.53-8.46(m,1H),7.63-7.56(m,1H),7.53-7.50(m,2H),7.47-7.30(m,5H),7.27-7.19(m,1H),5.97-5.93(m,2H), 5.82-5.77(m,2H),5.24(d,J=20.7Hz,2H),4.76-4.54(m,4H),3.67-3.56(m,4H),1.57(s,9H),0.97-0.90(m,4H),-0.03--0.06(m,18H).

[0188] Synthetic intermediate 1-5: 6-(4-(benzyloxy)-5-fluoro-2-(methyl-d3)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)methoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

[0189] Intermediate 1-4 (103.4 mg, 0.13 mmol) was dissolved in 8 ml of dichloromethane, and zinc bromide (143.4 mg, 0.64 mmol) was added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, aqueous ammonia was added to the reaction solution and stirred until the solution became clear. The mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 89.8 mg of crude intermediate 1-5 (98.8% yield).

[0190] Synthetic intermediate 1-6: (R)-2-(6-(4-(benzyloxy)-5-fluoro-2-(methyl-d3)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(2-hydroxypropyl)-1-((2-(trimethylsilyl)methoxy)methyl ester)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide

[0191] Intermediate 1-5 (35.0 mg, 0.05 mmol) was dissolved in 8 ml of dichloromethane. Triphosgene (14.7 mg, 0.05 mmol) was added at 0°C and stirred for 1 min. Triethylamine (0.1 ml, 0.50 mmol) was added dropwise, resulting in the emission of white smoke. After stirring for 5 minutes, TLC indicated the disappearance of the starting material. The reaction solution was brought to room temperature and (R)-1-aminopropan-2-ol was added, allowing the reaction to proceed for 1 hour. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to yield 28.3 mg of Intermediate 1-6, a yield of 69.9%.

[0192] Synthetic intermediate 1-7: (R)-2-(6-(5-fluoro-4-hydroxy-2-(methyl-d3)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(2-hydroxypropyl)-1-((2-(trimethylsilyl)methoxy)methyl ester)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide

[0193] Intermediate 1-6 (28.3 mg, 0.03 mmol) was dissolved in 4 ml of methanol, and 10 mg of palladium on carbon was added. The mixture was reacted at 45°C for 1 hour. After the reaction was completed, the reaction solution was filtered through a celite pad, and the filtrate was concentrated to obtain 23.8 mg of crude intermediate 1-7, with a yield of 92.6%.

[0194] Synthesis of final product 1: (R)-2-(6-(5-fluoro-4-hydroxy-2-(methyl-d3)phenyl)-1H-indazol-3-yl)-N-(2-hydroxypropyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide

[0195] Intermediate 1-7 (23.8 mg, 0.03 mmol) was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added. The mixture was reacted at 50°C for 6 hours. After completion of the reaction, the reaction solution was concentrated, and the concentrate was dissolved in methanol. Ammonia was added to adjust the pH to alkaline. The product was concentrated and purified on a silica gel plate to obtain 3.2 mg of the final product 1, with a yield of 20.5%. LC-MS m / z (ESI) [M+H] + Targeting C 23 H 20 The calculated value of D3FN6O3 is: 454.2; the measured value is: 454.3.

[0196] Example 2: Cyclopropyl (2- (6- (5-fluoro-4-hydroxy-2- (methyl-d3) phenyl) -1H-indazol-3-yl) -4,6-dihydropyrrolo [3,4-d] imidazole-5 (1H) -yl) ketone (Compound 2)

[0197] Synthesis route of compound 2:

[0198] Synthesis method:

[0199] Synthetic intermediate 2-1: (2-(6-(4-(benzyloxy)-5-fluoro-2-(methyl-d3)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)methoxy)methyl ester)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(cyclopropyl)methanone

[0200] Intermediate 1-5 (50.0 mg, 0.07 mmol) was dissolved in 10 ml of dichloromethane (DCM). Triethylamine (10.8 mg, 0.11 mmol) was added at room temperature, followed by acetyl chloride (9.6 mg, 0.09 mmol). The mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, the mixture was quenched with water and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate to afford 40.0 mg of Intermediate 2-1 in a yield of 72.9%.

[0201] Synthetic intermediate 2-2: cyclopropyl (2-(6-(5-fluoro-4-hydroxy-2-(methyl-d3)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)methoxy)methyl ester)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone

[0202] 2-1 (40.0 mg, 0.05 mmol) was dissolved in 3 ml of methanol, and 4 mg of palladium carbon was added to replace the hydrogen. The mixture was reacted at 40°C for 2 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain 28.0 mg of 2-2 with a yield of 79.2%.

[0203] Synthesis of compound 2: cyclopropyl (2- (6- (5-fluoro-4-hydroxy-2- (methyl-d3) phenyl) -1H-indazol-3-yl) -4,6-dihydropyrrolo [3,4-d] imidazole-5 (1H) -yl) ketone

[0204] Intermediate 2-2 (28.0 mg, 0.04 mmol) was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 6 hours. The mixture was concentrated, dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. The mixture was then purified using a reverse-phase silica gel column to obtain 4.2 mg of the final product in a yield of 24.3%. LC-MS m / z (ESI) [M+H] + Targeting C 23 H 17 The calculated value of D3N2O5 is: 421.2; the measured value is: 421.2.

[0205] Example 3: (S)-(2-(6-(2-(ethyl-d5)-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone methanesulfonate (Compound 3)

[0206] Synthesis route of compound 3:

[0207] Synthesis method:

[0208] Synthetic intermediate 3-1: 2-(benzyloxy)-4-(ethyl-d5)-1-fluorobenzene

[0209] THF (80.0 mL), compound 1-1 (13.0 g, 1.00 eq), and Pd(dppf)Cl2·H2Cl2 (780 mg) were added to a reaction flask. (Ethyl-D5)magnesium bromide (9.59 g, 1.50 eq) was added to the flask at 20-30°C. The reaction was stirred at 65°C for 12 hours. The reaction solution was quenched with 100 mL of 1N hydrochloric acid (HCl) and extracted with 100 mL of ethyl acetate. The organic phase was concentrated. The concentrate was dissolved in 200 mL of ethyl acetate and purified by passing through a silica gel pad. Concentration afforded 11.0 g of compound 3-1 as a yellow oil. 1 H NMR: (400MHz, CDCl3) δ7.39-7.48(m, 5H), 6.99-7.03(m, 1H), 6.85-6.87(m, 1H), 6.75(m, 1H), 5.15(s, 2H)

[0210] Synthetic intermediate 3-2: 1-(benzyloxy)-4-bromo-5-(ethyl-d5)-2-fluorobenzene

[0211] Compound 3-1 (11.0 g, 1.00 eq) and 100 mL of acetonitrile (ACN) were added to a reaction flask. NBS (8.32 g, 1.00 eq) was added to the reaction flask at 20-30°C. The reaction was allowed to react at 20-30°C for 1 hour. The reaction solution was concentrated, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined and concentrated under reduced pressure. The concentrate was dissolved in 200 mL of ethyl acetate and purified on a silica gel pad. Concentration afforded 15.0 g of compound 3-2 as a yellow oil.

[0212] 1 H NMR (400MHz, CDCl3) δ7.24-7.35 (m, 5H), 7.16-7.19 (m, 1H), 6.77-6.81 (m, 1H), 5.03 (s, 2H).

[0213] Synthetic intermediate 3-3: 2-(4-(benzyloxy)-2-(ethyl-d5)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0214] Compound 3-2 (14.0 g, 1.00 eq), B2Pin2 (12.1 g, 1.00 eq), Pd(dppf)Cl2·H2Cl2 (780 mg, 0.02 eq), and potassium acetate (AcOK, 14.1 g, 3.00 eq) were added to dioxane (150 mL) and reacted at 110-120°C under nitrogen for 2 hours. The reaction solution was filtered and the filtrate was concentrated. 100 mL of water was added to the concentrate, followed by extraction with 100 mL of methyl tert-butyl ether (MTBE). The organic phase was concentrated to afford 17.0 g of compound 3-3 as a yellow oil.

[0215] 1 H NMR (400MHz, CDCl3): δ7.34-7.46(m, 6H), 6.84-6.86(m, 1H), 5.18(s, 2H), 1.35(s, 12H).

[0216] Synthetic intermediate 3-4: tert-butyl 2-(6-(4-(benzyloxy)-2-(ethyl-d5)-5-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0217] Compound 3-3 (12.0 g, 1.11 eq), compound Int 1 (18.5 g, 1.00 eq), K3PO4 (12.7 g, 2.00 eq), and 44.0 mL of water were added to dioxane (150 mL). Under nitrogen, Pd(dppf)Cl2·H2Cl2 (244 mg, 0.01 eq) was added to the reaction flask. If the mixture did not dissolve after addition, the mixture was heated to 70-80°C and allowed to react for 2 hours. The reaction solution was concentrated and extracted with 250 mL of MTBE. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was mixed with silica gel and applied to a silica gel pad. The elution was first performed with petroleum ether and then with petroleum ether:ethyl acetate (1:1). The eluate containing the product was collected and rotary evaporated to yield 14.0 g of compound 3-4 as a brown paste. LC-MS m / z (ESI) [M+H] + Targeting C 43 H 50 The calculated value of D5FN5O5Si is: 773.4; the measured value is: 773.3.

[0218] 1H NMR (400MHz, CDCl3): δ8.43-8.48(m, 1H), 7.47-7.51(m, 2H), 7.40-7.42(m, 3H), 6 .95-7.08(m,3H),6.01-6.04(m,1H),5.87-5.93(m,1H),5.74-5.77(m,1H),5.21( s,1H),4.52-4.65(m,4H),4.02-4.03(m,1H),3.76(m,1H),3.56-3.62(m,2H),2.5 9(m,1H),2.12-2.19(m,2H),1.71-1.74(m,4H),1.55(s,9H),-0.07~-0.05(s,9H).

[0219] Synthetic intermediate 3-5: 6-(4-(benzyloxy)-2-(ethyl-d5)-5-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

[0220] Compound 3-4 (14.0 g, 1.00 eq) was added to DCM (70.0 mL). ZnBr2 (16.3 g, 4.00 eq) was added at 20-30°C. The reaction mixture became clear after the addition was complete, and the reaction was stirred at 20-30°C for 3.5 hours. 37.8 mL of 28% aqueous ammonia was added to the reaction mixture, and the mixture was stirred at 20-30°C for 10 minutes. The system became severely emulsified, and the DCM was removed by rotary evaporation. The residue was extracted with 155 mL of MTBE, the reaction mixture was filtered, and the filtrate was concentrated. 100 mL of water was added to the concentrate, followed by extraction with 100 mL of MTBE. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Concentration afforded 10.0 g of compound 3-5 as a brown paste, which was used directly in the next reaction.

[0221] Synthetic intermediate 3-6: (2-(6-(4-(benzyloxy)-2-(ethyl-d5)-5-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone

[0222] Triphosgene (1.80 g, 0.41 eq) was added to DCM (20.0 mL) and the temperature was lowered to 0-5°C. Under nitrogen, a mixed solution of compound 3-5 (10.0 g, 1.00 eq) and 80.0 mL of DCM was added dropwise to the reaction mixture, maintaining the temperature between 0-5°C. The mixture was stirred and reacted for 10 minutes. Triethylamine (TEA, 12.0 g, 8.00 eq) was added dropwise to the reaction mixture, maintaining the temperature between 0-5°C. The mixture was stirred and reacted for 10 minutes. (S)-pyrrolidin-3-ol hydrochloride (2.75 g, 1.50 eq) was then added to the reaction mixture all at once, and the temperature was raised to 20-30°C with stirring for 1 hour. 100 mL of water was added to the reaction system to quench and dilute the reaction. The mixture was stirred at 20-30°C for 30 minutes and then allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate and then spin-dried. The mixture was filtered through a silica gel pad and the eluate was evaporated to dryness to obtain 6.00 g of compound 3-6 as brown foam. LC-MS m / z (ESI) [M+H] + Targeting C 43 H 49 The calculated value of D5FN6O5Si is: 786.4; the measured value is: 786.2.

[0223] Synthetic intermediate 3-7: (2-(6-(2-(ethyl-d5)-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone

[0224] Compound 3-6 (6.00 g, 1.00 eq) was added to THF (60.0 mL). Under nitrogen protection, 600 mg of wet palladium carbon was added. After replacing the atmosphere with hydrogen three times, the mixture was reacted at 20-30°C for 3 hours. The reaction was stopped, the reaction solution was passed through a celite pad, the filter cake was rinsed with 100 mL of THF, the filtrate was combined, 600 mg of wet palladium carbon was added, the atmosphere was replaced with hydrogen three times, and the mixture was reacted at 20-30°C for 7.5 hours. The reaction was stopped, the reaction solution was passed through a celite pad, the filter cake was rinsed with 100 mL of THF, the filtrate was combined, 600 mg of wet palladium carbon was added, the atmosphere was replaced with hydrogen three times, and the mixture was reacted at 20-30°C for another 14 hours. The reaction was stopped, the reaction solution was passed through a celite pad, the filtrate was rotary evaporated to dryness, 12.0 mL MTBE was added to the concentrate, and the concentrate was concentrated to obtain 5.00 g of compound 3-7, which was used directly in the next reaction.

[0225] Synthetic intermediate 3-8: (S)-(2-(6-(2-(ethyl-d5)-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone

[0226] Take 40.0g of methanol and pass 27.0g of hydrochloric acid gas. The mass fraction of HCl / MeOH is calculated to be 40.3%. Compound 3-7 (5.00g, 1.00eq) is added to the above HCl / MeOH and reacted at 20-30°C for 17.5 hours. The reaction solution is filtered, and the filter cake is suspended in 50.0mL of ethanol. 6.00mL of ammonia water (28%) is added dropwise to the reaction system at 20-30°C to free the product. During the process, the solution is first clear, and then solids are precipitated. Stirring is continued at 20-30°C for 30 minutes. The suspension is filtered and the filter cake is evaporated to dryness to obtain 2.00g of off-white solid. 60.0mL of methanol is added thereto, and the mixture is slurried at 60-65°C for 5.5 hours. The mixture is cooled to 20-30°C and filtered. The filter cake is evaporated to dryness to obtain 1.50g of compound 3-8 as an off-white solid. LC-MS m / z (ESI) [M+H] + Targeting C 25 H 21 The calculated value of D5FN6O3 is: 482.2; the measured value is: 482.1.

[0227] Synthesis of compound 3: (S)-(2-(6-(2-(ethyl-d5)-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone methanesulfonate

[0228] Compound 3-8 (1.50 g, 1.00 eq) was added to ethyl acetate (30.0 mL). Under nitrogen, CH3SO3H (360 mg, 1.20 eq) was added dropwise at 10-20°C. The mixture was allowed to react at 10-20°C for 3 hours. The reaction mixture was filtered, and the filter cake was rinsed with 2.00 mL of ethyl acetate and evaporated to dryness to obtain 1.60 g of compound 3 as an off-white solid.

[0229] 1H NMR: (400MHz, DMSO) δ14.00 (s, 1H), 8.25-8.27 (m, 1H), 7.55 (s, 1H), 7.27-7.29 (m, 1H), 7.03-7.06 (m, 1H), 6.92-6.94 (m, 1H), 4.75 -4.78(m,2H),4.58(m,2H),4.29(s,1H),3.52-3.55(m,3H),3.41-3.43(m,2H),3.25(m,1H),2.32-2.34(m,3H),1.80-1.91(m,2H).

[0230] Example 4: 2-Fluoro-5-(methyl-d3)-4-(3-(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (Compound 12)

[0231] Synthesis route of compound 12:

[0232] Synthesis method:

[0233] Synthetic intermediate 12-1: 6-(4-(benzyloxy)-5-fluoro-2-(methyl-d3)phenyl)-3-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-trimethylsilyl)ethoxymethyl)-1H-indazole

[0234] Intermediate 1-5 (100.0 mg, 0.14 mmol) was dissolved in 10 ml of DCM. Aqueous formaldehyde (40%) (21 mg, 0.24 mmol) was added at room temperature and stirred at room temperature for 0.5 hours. Sodium triacetylborohydride (89 mg, 0.42 mmol) was then added and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was quenched with water and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate to afford 80.0 mg of Intermediate 12-1 in a yield of 78.4%.

[0235] Synthetic intermediate 12-2: 2-fluoro-5-(methyl-d3)-4-(3-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((-2-(trimethylsilyl)methoxy)phenyl)-1H-indazol-6-yl)phenol

[0236] 12-1 (20.0 mg, 0.03 mmol) was dissolved in 3 ml of methanol, 4 mg of palladium carbon was added, the hydrogen was replaced, and the reaction was carried out at 40° C. for 2 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain 12-2 (10.0 mg, yield 57%).

[0237] Synthesis of Compound 12: 2-Fluoro-5-(methyl-d3)-4-(3-(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

[0238] Intermediate 4-2 (10.0 mg, 0.02 mmol) was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 6 hours. The mixture was concentrated, dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. The mixture was then purified using a reverse-phase silica gel column to obtain 2.0 mg of the final product in a yield of 34.5%. LC-MS m / z (ESI) [M+H] + Targeting C 20 H 16 The calculated value of D3FN5O is: 367.2; the measured value is: 367.2.

[0239] Table 1: The following compounds were prepared according to the synthetic route of Example 1 using appropriate starting materials

[0240] Table 2: The following compounds were prepared according to the synthetic route of Example 2 using appropriate starting materials.

[0241] Table 3: The following compounds were prepared according to the synthetic route of Example 4 using appropriate starting materials

[0242] Table 4: The following compounds were prepared according to the synthetic route of Example 3 using appropriate starting materials

[0243] Example 11: Pharmacological Activity Evaluation I

[0244] 1. Experimental Principle

[0245] A drug screening system based on JAK1, JAK2, JAK3, and TYK2 kinases was used to test the inhibitory ability of small molecule compounds on kinase activity. Kinases undergo enzymatic reactions with their substrates IRS1, IGF1Rtide, and Poly(4:1Glu,Tyr), consuming ATP to produce ADP. The amount of the product was measured using ADP-Glo ​​reagent and luminescence to reflect kinase activity.

[0246] 2. Experimental Plan

[0247] 2.1 Experimental Materials and Instruments

[0248] 2. Kinase information

[0249] 2.1 Kinase reaction buffer:

[0250] 2.2 Kinase reaction conditions:

[0251] 2.3 Compound screening steps:

[0252] 1) Prepare 2x ATP / substrate solution and 2x kinase solution using kinase reaction buffer.

[0253] 2) Tofacitinib was tested for JAK1 / 2 / 3 inhibitory activity at a starting concentration of 1 μM, with a 1:4 dilution. For TYK2 inhibitory activity, the starting concentration was 10 μM, with a 1:4 dilution. The starting concentration of all test compounds was 0.5 μM, with a 1:4 dilution.

[0254] 3) Transfer 40 nL of compound dilution to a 384-well assay plate using an Echo 655. After centrifugation, add 2 μL of 2x kinase solution to the 384-well assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0255] 4) Add 2 μL of 2x substrate and ATP solution to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes.

[0256] 5) Transfer 4 μL of ADP-Glo ​​to a 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0257] 6) Transfer 8 μL of the detection solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0258] 7) Read the luminescence signal using a multifunctional microplate reader.

[0259] 3. Data Analysis

[0260] 3.1 The inhibition rate is calculated as follows:

[0261] % inhibition = 100% - (compound - positive control) / (negative control - positive control) * 100%

[0262] Negative control: DMSO

[0263] Positive control: Tofacitinib

[0264] 3.2 Calculating IC 50 And draw the inhibition curve of the compound:

[0265] The IC50 (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: Data analysis was performed using Graphpad 7.0 software.

[0266] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope))

[0267] X: log value of compound concentration Y: inhibition rate (% inhibition)

[0268] 4 Summary of compound detection results

[0269] The above experimental results show that the tested compounds of the present invention can simultaneously inhibit JAK1, JAK2, JAK3, and TYK2 at extremely low concentrations. The inhibitory activity of these example compounds is much higher than that of Tofacitinib. Compared with the corresponding non-deuterated compounds, the inhibitory activity of the compounds of the present invention is also unexpectedly significantly higher, which was difficult to predict before the present application.

[0270] While specific embodiments of the present invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the present invention. Rather, the words used in this specification are merely descriptive and are not restrictive. It will be apparent to those skilled in the art that various other changes and modifications may be made without departing from the general scope of this disclosure. Therefore, the appended claims are intended to include all such changes and modifications within the scope of the present invention.

Claims

1. A compound of formula (I): or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, wherein: L is C=O, O=S=O, CH2 or a covalent bond; and R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein at least one H atom on R1 is replaced by a D atom; and R3 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -SR 12 、-OR 12 、-CN、Halogen、-NO2、-SF5、-SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic, C 5-11 bicycloalkyl or 5-11 membered bicycloheteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 , R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7- 11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic, C 5-11 bicycloalkyl, 5-11 membered bicycloheteroalkyl, and optionally substituted by one or more substituents each independently selected from the following groups: -OH, -CN, -SH, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ), -C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 substituents each independently selected from the following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; or R 17 , R 18 and the N atoms to which they are attached together form a 3-14 membered ring; and The number of R2 is 0, 1, 2, 3 or 4, and R2 is selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ), -C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 substituents each independently selected from the following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; and p is 1, 2 or 3; and R a Selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-N(R9)(R 10 ), -C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the-SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl group and the 7-11-membered bicyclic heteroaryl group are optionally substituted by 1, 2, 3 or 4 R b replace; and R b Selected from H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R5)(R6), -N(R 11 )(C(=O)R 12 )、-CON(R7)(R8)、-C(=O)-R 12 、-C(=O)-OR 12 、-OC(=O)R 12 、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 , wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7- 11 The bicyclic aryl, and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R 11 )(C(=O)R 12 )、-C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 、-C(=O)-N(R9)(R 10 )、-N(R 11 )(S(=O)2R 12 )、-S(=O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ;and R5, R6, R7, R8, R9, R 10 , R 11 , R 12 Each is independently H or selected from the following group: C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -CF3, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

2. The compound according to claim 1, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein L is C=O, O=S=O or CH2.

3. The compound according to any one of claims 1 to 2, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Haloalkoxy, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms.

4. The compound according to any one of claims 1 to 2, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R1 is C 1-6 Alkyl, wherein at least one H atom on R1 is replaced by a D atom, preferably all H atoms on R1 are replaced by D atoms.

5. A compound according to any one of claims 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic, C 5-11 bicycloalkyl or 5-11 membered bicycloheteroalkyl, and R3 is replaced by 0, 1, 2, 3 or 4 R a Substitution; wherein R 17 , R 18 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Haloalkyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

6. The compound according to any one of claims 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, and optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

7. A compound according to any one of claims 1 to 4, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein R3 is -N(R 17 )(R 18 ), where R 17 , R 18 Each independently selected from H, C 1- 6 alkyl, C 1-6 Alkoxy, C 3-7 Haloalkyl and C 3-7 Cycloalkyl, and is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

8. The compound according to any one of claims 1 to 7, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein the compound is selected from:

9. The compound according to any one of claims 1 to 7, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein the compound is selected from:

10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 10 or its optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

11. Use of a compound according to any one of claims 1 to 9 or its optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a composition according to claim 10 in the preparation of a medicament for treating and / or preventing a disease or condition associated with JAK, preferably, the disease or condition associated with JAK is selected from arthritis, autoimmune diseases or conditions, cancer or tumors, diabetes, eye diseases, conditions or conditions, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions or conditions, allergies, asthma and other obstructive airway diseases, transplant rejection.

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