JAK inhibitor compounds and uses thereof

Abstract

The invention relates to a JAK inhibitor compound and application thereof. Specifically, the invention discloses a compound shown as a 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 invention also relates to application of the compound in medicine. # imgabs0 #

Description

[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, which can be used to inhibit Janus kinase (JAK). The present invention also relates to a composition comprising the compound, and the use of the compound and the composition in preparing a medicament for treating and / or preventing a disease or condition associated with JAK. 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 involves many diseases, including but not limited to cancer, cardiovascular disease, allergy, 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 gone through nearly 30 years. JAK is a family of intracellular non-receptor tyrosine kinases that play an important role in the cytokine receptor signaling pathway through interaction with signal transducers and activators of transcription (STAT). The JAK / STAT signaling pathway is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. Compared with other signaling pathways, the transmission process of this signaling pathway is relatively simple. It is mainly composed of three components, namely tyrosine kinase associated receptor, tyrosine kinase JAK, and signal transducer and activator of transcription STAT.

[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, IL-21, etc.), GM-CSF (granulocyte / macrophage colony stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PRL (prolactin), EPO (erythropoietin), TPO (thrombopoietin), PDGF (platelet-derived factor) and interferons (including IFN-α, IFN-β, IFN-γ, etc.). These cytokines and growth factors have corresponding receptors on the cell membrane. The common feature of these receptors is that the receptors themselves do not have kinase activity, but the intracellular segment has a binding site for the tyrosine kinase JAK. After the receptor binds to the ligand, the tyrosine residues of various target proteins are phosphorylated through the activation of the JAK bound to it to achieve signal transmission from the extracellular to the intracellular.

[0007] JAK is a cytoplasmic tyrosine kinase that transduces cytokine signals from membrane receptors to STAT transcription factors. As mentioned above, JAK is the abbreviation of Janus kinase in English. Janus is the two-faced god in Roman mythology who controls the beginning and the end. It is called Janus kinase because JAK can phosphorylate both the cytokine receptors bound to it and multiple signaling molecules containing specific SH2 domains. The JAK protein family includes 4 members: JAK1, JAK2, JAK3 and TYK2. They have 7 JAK homology domains (JH) in their structure. The JH1 domain is the kinase region, which encodes the kinase protein; the JH2 domain is the "pseudo" kinase region, which regulates the activity of JH1; JH3-JH7 form a four-in-one domain that regulates the binding of JAK to the receptor.

[0008] STAT is a type of cytoplasmic protein that can bind to the DNA in the regulatory region of target genes and is a downstream substrate of JAK. Currently, seven members of the STAT family have been discovered, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT proteins can be structurally divided into the following functional segments: N-terminal conserved sequence, DNA binding region, SH3 domain, SH2 domain and C-terminal transcriptional activation region. Among them, the most conserved and functionally important segment is the SH2 domain, which has a core sequence "GTFLLRFSS" that is exactly the same as the SH2 domain of the tyrosine kinase Src.

[0009] The JAK-STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Currently, most of the research related to disease and drug innovation is focused on inflammatory diseases and tumor diseases. Among them, inflammatory diseases mainly include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis and Crohn's disease; while tumor diseases mainly involve myelofibrosis, polycythemia vera and essential thrombocythemia. In addition, mutations in the JAK molecule itself can also lead to acute myeloid leukemia (AML), acute lymphocytic 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] JAK is a very important drug target. JAK inhibitors developed for this target are mainly used to screen therapeutic drugs for blood system diseases, tumors, rheumatoid arthritis and psoriasis. JAK-1, JAK-2 and TYK-2 are expressed in various tissue cells of the human body, and JAK-3 is mainly expressed in various hematopoietic tissue cells, mainly in bone marrow cells, thymus cells, NK cells and activated B lymphocytes and T lymphocytes. Studies have shown that JAK2 inhibitors are suitable 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 suitable as immunosuppressants (e.g., U.S. Patent 6,313,129; Borie et al., Curr. Opin. Investigational Drugs, 2003, 4: 1297).

[0011] At present, the JAK inhibitors approved by FDA and EMA include Tofacitinib, Ruxolitinib, Oclacitinib, etc. JAK inhibitors in the middle and late stages of clinical trials include Filgotinib, Peficitinib, etc.

[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 adult patients who have an inadequate response to or intolerance to methotrexate. It is the first oral JAK inhibitor approved for the treatment of RA. It was subsequently approved by Japan's PMDA for marketing in March 2013 under the trade name Xeljanz. On March 16, 2017, Pfizer China announced that CFDA had formally approved Pfizer's application for the marketing of an oral JAK inhibitor. It is reported that the drug is approved for the treatment of adult patients with moderate to severe rheumatoid arthritis who have an insufficient response to or intolerance to methotrexate. At present, tofacitinib is close to approval for indications such as psoriasis, ulcerative colitis, and juvenile idiopathic arthritis; clinical trials for indications such as Crohn's disease and alopecia areata have also entered the mid-to-late clinical stage. The main side effects of tofacitinib are severe infection rate and increased low-density lipoprotein 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]

[0014] Ruxolitinib, an inhibitor of JAK1 and JAK2, was jointly developed by Incyte and Novartis and was approved for marketing by the US FDA in November 2011. It is also the first approved drug specifically for the treatment of myelofibrosis. It was approved by the EMA in August 2012 and approved for marketing by the Japanese PMDA in July 2014. The drug is sold by Incyte in the United States under the trade name Jakafi and by Novartis in Europe and Japan under the trade name Jakavi. Ruxolitinib is undergoing a number of mid- to late-stage clinical trials, with indications covering a variety of cancers, GVHD (rejection), alopecia areata, allergic dermatitis, rheumatoid arthritis, vitiligo, psoriasis, etc. The most common hematological adverse reactions of ruxolitinib (incidence > 20%) are thrombocytopenia and anemia. The most common non-hematological adverse reactions (incidence > 10%) are bruises, dizziness, and headaches.

[0015]

[0016] Oclacitinib, approved by the US FDA in 2013, is used to control pruritus and atopic dermatitis caused by canine allergic dermatitis. Oclacitinib is a new 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 itch responses. It has little effect on cytokines that are not involved in activating JAK1. Oral administration of 0.4-0.6 mg / kg of oclacitinib twice a day is safe and effective for the treatment of pruritus caused by allergic dermatitis. During treatment, administration of oclacitinib can relieve itching within 24 hours. In experiments, more than 70% of experimental animals (dogs) reduced the itching response by more than 50% on the 7th day. However, oclacitinib cannot yet be used to treat human diseases.

[0017]

[0018] Filgotinib, a JAK1 inhibitor, completed Phase III clinical trials in September 2018 for the treatment of rheumatoid arthritis. At the same time, Filgotinib is 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.

[0019]

[0020] Peficitinib, a JAK1 and JAK3 inhibitor, is developed by Astellas and is currently in Phase III clinical trials for the treatment of rheumatoid arthritis. Phase II clinical studies for the treatment of psoriasis have been completed. Peficitinib is a new oral JAK inhibitor that inhibits the enzyme activities of JAK1, JAK2, JAK3 and TYK2 with IC50 values ​​of 3.9nM, 5.0nM, 0.71nM and 4.8nM, respectively.

[0021]

[0022] Although some JAK inhibitors have been approved for marketing and a large number of JAK inhibitors are in clinical research, 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. Summary of the invention

[0023] One object of the present invention is to provide a new class of JAK inhibitors to replace existing JAK inhibitors, thereby providing more options for the treatment of JAK-related diseases.

[0024] 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.

[0025] In a first aspect, the present invention provides compounds of formula (I) as JAK inhibitors:

[0026]

[0027] or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, wherein:

[0028] L is C=O, O=S=O, CH2 or a covalent bond; and

[0029] 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

[0030] 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, C1-6 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 independently selected from the following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4Haloalkoxy, 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

[0031] 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, C5-7 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 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(=

[0032] O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; and p is 1, 2 or 3; and

[0033] 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 12AND-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

[0034] 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(=

[0035] 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 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 )、-N(R11 )(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

[0036] 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.

[0037] 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.

[0038] 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 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. 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 even 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 .

[0039] In the above-mentioned embodiment of the present invention, deuterium (i.e. 2The substitution of a H atom on the group R1 of the compound of formula (I) with a heavier isotope (H, also referred to as D) may provide some unexpected therapeutic benefits, and the inventors of the present application speculate that such benefits may be caused by 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 found that after the H atom on the group R1 of the compound of formula (I) is substituted with a deuterium isotope, the activity of the compound of formula (I) in inhibiting JAK1, JAK2, JAK3 and / or TYK2 enzymes is unexpectedly improved, for example, as shown 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).

[0040] 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, 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 connected 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 connected 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)(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 N 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), 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 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 N atoms connected to them 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 N 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.

[0042] 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 substituted 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 N atoms connected to them 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 connected to them 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 connected to them 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 N 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.

[0043] 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 1-6Haloalkoxy, 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 N atoms connected to them 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 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, 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 substituted 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 N atoms connected to them 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 N atoms connected to them 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 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, 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(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 N atoms connected to them 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, 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 N atoms connected to them 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 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, 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 Haloalkoxy, 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 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 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, 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 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, 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 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 -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)(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 substituted; 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 substituted; 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 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, 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 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, 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 Haloalkoxy, 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 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, 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 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, 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 N 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.

[0044] 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; 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 N atoms connected to them 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; 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 substituted 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 N 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.

[0045] 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 N atoms connected to them 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 N atoms connected to them 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 N atoms connected to them 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 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 morpholinyl 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 1-6A 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 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)(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 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)(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 N 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.

[0046] 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 N atoms connected to them 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 substituted 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 N atoms connected to them 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 1-6Alkyl, 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 -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 N atoms connected to them 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 N atoms connected to them 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 N atoms connected to them 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 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)(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 N 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.

[0047] 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 N atoms connected to them 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 substituted 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 N atoms connected to them 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 N atoms connected to them 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 N atoms connected to them 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 N atoms connected to them 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 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 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 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 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 N 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.

[0048] 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 The cycloalkyl and 4-10 membered heterocycloalkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, 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 The cycloalkyl groups are each 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 Haloalkyl, 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 Haloalkyl, 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 2 R2, which are fluorine and ethyl, respectively. In some particularly preferred embodiments of the present invention, in formula (I), there is 1 R2, and R2 is ethyl.

[0049] In some preferred embodiments of the present invention, in formula (I), R3 is replaced by 0, 1, 2, 3 or 4 R a Replace, 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 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 In some preferred embodiments of the present invention, in formula (I), R3 is replaced by 0, 1, 2, 3 or 4 R a Replace, 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 the -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 Replace, 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 Replace, and each R aindependently 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 Replace, 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 Replace, and each R a independently selected from methyl, ethyl, hydroxy, -CN, piperidinyl, morpholinyl, piperazinyl, cyclopropyl, wherein piperidinyl, morpholinyl, piperazinyl are 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 substituted by 0 or 1 R a Replace, and each R a are independently selected from methyl, ethyl, hydroxyl, -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), R aIn 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.

[0050] 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

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] 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) except R1, including but not limited to the embodiment in which R2 and / or R3 are isotope-labeled substituents or are non-isotope-labeled substituents.

[0057] 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).

[0058] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may exist in the R configuration or the S configuration, and the various isomers thus constituted are optical isomers. Optical isomers include all diastereomers, enantiomers, mesomers, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0059] The term "geometric isomer" means that when a double bond exists in a compound, 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 a mixture thereof.

[0060] The term "tautomer" refers to an isomer resulting from the rapid movement of an atom in a molecule between two positions. Those skilled in the art will appreciate that tautomers can be mutually transformed and may coexist in a state of equilibrium. The "compound represented by formula (I)" described herein also encompasses any tautomer of the compound of formula (I).

[0061] Unless otherwise indicated, references herein to “compounds of formula (I)” or “compounds of formula (I)” or “compounds of the present invention” also encompass isotope-labeled compounds wherein any atom in the compound is replaced by an isotope atom thereof.

[0062] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compound of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the atoms usually found in nature.

[0063] 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.

[0064] Certain isotope-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.

[0065] 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.

[0066] Using positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission topography (PET) research to detect the substrate receptor occupancy state.

[0067] 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.

[0068] 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 occur in the compounds of formula (I).

[0069] 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, cyclaminate, 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 from 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 hemi-sulfate and hemi-calcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahland Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0070] 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 whether they exist in solvated or unsolvated forms.

[0071] 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.

[0072] To avoid ambiguity, the following definitions are given for the terms used in this article. Unless otherwise specified, the meanings of the terms used in this article are as follows.

[0073] The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to humans. Preferably, the term refers to any national regulatory agency certified by regulatory agencies such as CFDA (China), EMEA (Europe), FDA (USA) for use in mammals, preferably humans.

[0074] "Prodrug" refers to a derivative that is converted into the compound of the present invention by reaction with an enzyme, gastric acid, etc. under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc., each catalyzed by an enzyme.

[0075] "Metabolites" refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

[0076] The term "hydroxy" refers to -OH.

[0077] The term "halogen" or "halo" refers to -F, -Cl, -Br, or -I.

[0078] The term "cyano" refers to -CN.

[0079] 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 10 can be independently selected, that is, R9 in R1 and R9 in R2 can be the same or different, and R 10 R in R2 10 For example, when there are two R1s, both of which are -N(R9)(R 10 ), R9 and R 10 can be independently selected, that is, R9 in the first R1 can be the same as or different from R9 in the second R1. 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 .

[0080] 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.

[0081] As used herein, the term "independently" means that when there are more than one substituent, the substituents may be the same or different.

[0082] As used herein, the term "optional" or "optionally" means that the event it describes can or cannot occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

[0083] 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).

[0084] 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 The term "alkyl" includes in its definition the term "C 1-6 Examples of alkyl groups 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.

[0085] 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 (having 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 exist in pure E form, pure Z form, or any mixture thereof.

[0086] 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 the point of attachment to another group. Alkynyl includes, but is 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.

[0087] As used in this article, the term “C 3-7 "Cycloalkyl" refers to a cycloalkyl group having 3 to 7 carbon atoms forming a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. The cycloalkyl group may be optionally substituted by one or more suitable substituents.

[0088] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl group having m carbon atoms forming a ring and (nm) heteroatoms forming a ring, the heteroatoms being 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, azeptan. Heterocycloalkyl groups may be optionally substituted with one or more suitable substituents.

[0089] As used in this article, 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.

[0090] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl 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 includes, but is not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine. The heteroaryl group may be optionally substituted with one or more suitable substituents.

[0091] As used in this article, 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.

[0092] As used herein, the term "n-membered bicyclic heteroaryl" refers to a bicyclic heteroaryl 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 includes, but is not limited to, quinoline, isoquinoline, benzothiazole, etc. The bicyclic heteroaryl may be optionally substituted with one or more suitable substituents.

[0093] As used herein, the term "11-15 membered tricyclic group" includes, but is not limited to, acridine, etc. The 11-15 membered tricyclic group may be optionally substituted with one or more suitable substituents.

[0094] 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 An alkyl group (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). 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 group (up to a perhaloalkyl group, 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 Alkyl groups (i.e., methyl or ethyl) (up to fully halogenated alkyl, 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, etc.

[0095] 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 The term "alkoxy" includes within its definition the term "C 1-3 Alkoxy". Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, etc. The alkoxy group may be optionally substituted with one or more suitable substituents.

[0096] 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:

[0097] "1 to 4 substituents" means 1, 2, 3 or 4 substituents;

[0098] "1 to 3 substituents" means 1, 2 or 3 substituents;

[0099] "3-12 membered ring" means a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring;

[0100] "3-14 membered ring" means a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered ring;

[0101] "3-8 membered ring" means a 3-, 4-, 5-, 6-, 7- or 8-membered ring;

[0102] "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 );

[0103] "1-6 carbon atoms" or "C 1-6 ” means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6);

[0104] "1-4 carbon atoms" or "C 1-4 ” means 1 (C1), 2 (C2), 3 (C3) or 4 carbon atoms (C4);

[0105] "2-6 carbon atoms" or "C 2-6 ” means 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6);

[0106] “C 3-8 ” means 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7) or 8 carbon atoms (C8);

[0107] "3-8 ring atoms" means 3, 4, 5, 6, 7 or 8 ring atoms.

[0108] Therefore, numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also include any subranges thereof, and each subrange is also deemed to be disclosed herein.

[0109] 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.

[0110] The pharmaceutical composition of the present invention can be formulated into a dosage form suitable for oral administration, external use (including but not limited to external application, spraying, etc.), parenteral administration (including subcutaneous, intramuscular, cortical 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 external use. More preferably, the pharmaceutical composition of the present invention is formulated into a dosage form (preparation) suitable for oral administration.

[0111] If a solid carrier is used, the preparation can be in tablets, placed in a hard gel capsule in the form of a powder or granules, or in the form of a lozenge or a lozenge. The solid carrier may include conventional excipients, such as adhesives, fillers, tableting lubricants, disintegrants, wetting agents, etc. If necessary, the tablet may be coated with a conventional technique film. 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. The liquid preparation may include conventional additives, such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavoring agents and / or coloring agents. For parenteral administration, the carrier usually includes at least 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. The 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).

[0112] 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).

[0113] These compositions can also include various excipients, for example, preservatives, wetting agents, emulsifiers and dispersants. The inhibition of the action 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).

[0114] 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), which 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); The invention can be prepared by mixing (a) agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarder (e.g., paraffin); (f) absorption promoter (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.

[0115] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or lactose as well as high molecular weight polyethylene glycols.

[0116] 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 can contain opacifiers, and they can also be compositions that release the active compound or various active 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 can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0117] 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, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide ammonium), 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 of these substances, etc., commonly used in the art.

[0118] Besides these inert diluents, the composition may also include, for example, wetting agents, emulsifying and suspending agents, perfuming agents, flavoring agents, and perfuming agents.

[0119] In addition to the active compounds, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0120] 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.

[0121] The topical dosage form of the compound 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 form, such as a water-in-oil-in-water (W / O / W) form or an oil-in-water-in-oil (O / W / O) emulsion form, or prepared in the form of an aqueous dispersion or a lipid dispersion, a gel or an aerosol.

[0122] The topical dosage form of the compound of the present invention may include additives and formulation aids, such as emulsifiers, thickeners, gelling agents, water fixatives, spreaders, stabilizers, dyes, spices and preservatives. Suitable emulsifiers include stearic acid, triethanolamine and PEG-40-stearate. Suitable thickeners include glyceryl monostearate and PEG600. Suitable preservatives include propylparaben and chlorocresol. Suitable spreaders include dimethicone and polydimethylcyclosiloxane. Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol 600.

[0123] The topical dosage form of the compound of the present invention may include ointments, lotions, gels, emulsions, microemulsions, sprays, skin patches, etc., which can be topically applied to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, and alopecia. In particular, the topical dosage form of the compound of the present invention is an ointment, which can be topically applied to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, and alopecia.

[0124] 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.

[0125] In a third aspect, the present invention provides use of a compound as described above 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 as described above in the preparation of a medicament for treating and / or preventing a disease or condition associated with JAK.

[0126] “JAK-associated diseases or conditions” include, but are not limited to:

[0127] Arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis;

[0128] 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 Kogan's syndrome), ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I diabetes or juvenile-onset diabetes, or thyroiditis;

[0129] Cancer or tumors, including digestive tract / gastrointestinal cancer, colorectal cancer, liver cancer, skin cancer (including mast cell tumors 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, myoma, 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);

[0130] Diabetes, including type 1 diabetes or diabetic complications;

[0131] 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, Moren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eyes), blisters, iridocyclitis, sarcoidosis, endocrine eye disease, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization;

[0132] Intestinal inflammation, allergies or conditions, including Crohn's disease and / or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis or mastocytosis;

[0133] 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;

[0134] Skin diseases, conditions or disorders, including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other itchy conditions, vitiligo, hair loss;

[0135] Allergic reactions, including mammalian allergic dermatitis (including equine allergic disease 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;

[0136] 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;

[0137] 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, pancreatic islets, kidney, limb, liver, lung, muscle, myoblasts, nerve, pancreas, skin, small intestine or trachea) or xenotransplantation.

[0138] 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. Wherein, the patient is preferably a mammal, more preferably a human patient. Wherein the route of administration may be oral, topical (including but not limited to external application, spraying, etc.), parenteral (including subcutaneous, intramuscular, cortical and intravenous) administration, bronchial administration or nasal administration, etc. Wherein, preferably administered orally or topically. More preferably administered orally.

[0139] 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 have potentially good safety.

[0140] Preferably, the present invention provides the following embodiments:

[0141] Embodiment 1. A compound of formula (I):

[0142]

[0143] or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, wherein:

[0144] L is C=O, O=S=O, CH2 or a covalent bond; and

[0145] 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

[0146] R3 is H, -N(R17 )(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 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, 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 following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, 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 N atoms to which they are attached together form a 3-14 membered ring; and

[0147] 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(R11 )(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 following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, 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(=

[0148] O)2-N(R9)(R 10 ),-SR 12 AND-OR 12 ; and p is 1, 2 or 3; and

[0149] 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, C1-8 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

[0150] 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(=

[0151] 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

[0152] 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 1-4Alkyl-, 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] Embodiment 5. A compound according to any one of Embodiments 1 to 4, 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 R3 is H, -N(R 17 )(R 18 ), C 1-6Alkoxy, -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.

[0157] 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.

[0158] 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 substituted by 0, 1, 2, 3 or 4 R a replace.

[0159] 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 1-6 Alkoxy, 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.

[0160] 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.

[0161] 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 is optionally substituted by one or more -OH, -CN, -SH, halogen, -NO2, -SF5.

[0162] 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 N 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.

[0163] Embodiment 12. A compound according to any one of Embodiments 1 to 4, 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 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, 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 Haloalkyl, 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 N 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.

[0164] Embodiment 13. A compound according to any one of Embodiments 1-12, 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 there are 1, 2 or 3 R2, and R2 is selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, 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 The cycloalkyl and 4-10 membered heterocycloalkyl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0165] Embodiment 14. A compound according to any one of Embodiments 1-12, 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 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 The cycloalkyl groups are each 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 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0166] Embodiment 15. A compound according to any one of Embodiments 1-12, 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 there are 1 or 2 R2, and R2 is selected from halogen, C 1-6 alkyl.

[0167] Embodiment 16. 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 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 C1-6 Alkyl, 5-7 membered heterocycloalkyl, C 3-7 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R b replace.

[0168] Embodiment 17. A compound according to any one of Embodiments 1-12 or its optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound is selected from:

[0169]

[0170]

[0171] Embodiment 18. A compound according to any one of Embodiments 1-12 or its optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound is selected from:

[0172]

[0173]

[0174]

[0175]

[0176] 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 thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0177] 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.

[0178] 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.

[0179] 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 isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the composition according to Embodiment 19 to a patient in need thereof.

[0180] 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.

[0181] The present invention is further illustrated and described below in conjunction with specific embodiments. Example

[0182] The compounds of formula (I) of the present invention can be synthesized by various 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, with reference to the exemplary schemes in this patent, those skilled in the art can easily design other synthetic routes for compounds of formula (I) by appropriately adjusting reactants, reaction conditions and protecting groups.

[0183] 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

[0184] Synthetic route

[0185]

[0186] Synthesis method

[0187] Synthesis of 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (Int 1-2)

[0188] Add 467kg of dichloromethane, 35.4kg of 6-bromo-1H-indazole-3-carboxaldehyde (Int1-1), 5.30kg of TsOH (toluenesulfonic acid) to a clean 500L kettle, cool to 0-10°C, add 15.91kg of DHP (dihydropyran) in batches, control the temperature within the range of 0-10°C, and after the addition is completed, heat to 20-30°C and react for 3±1 hours. When the raw material reaction is complete, stop the reaction. Slowly add the reaction solution to 44.2kg of 8% sodium bicarbonate aqueous solution, stir for 0.5h, control the temperature within the range of 10-20°C, filter the system, and let the filtrate stand for separation. The organic phase is dried with sodium sulfate and concentrated to dryness, then slurried 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.

[0189] 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, add 198kg of dichloromethane, then add 15.0kg of Int 1-2, 15.0kg of tert-butyl 3,4-diaminopyrrolidine-1-carboxylate (Int 1-3), and add 9.45kg of NBS (N-bromosuccinimide) to the kettle in batches. Control the temperature in the range of 15 to 30°C. After the addition is completed, stir the reaction for 4 hours and control the temperature in the range of 20 to 30°C. Add 2.40kg of Int 1-3, add 1.50kg of NBS to the kettle in batches, control the temperature within the range of 15-30°C, complete the addition, stir and react for 1 hour, and control the temperature within the range of 20-30°C. Add 2.40kg of Int 1-3, add 1.50kg of NBS to the kettle in batches, control the temperature within the range of 15-30°C, complete the addition, stir and react for 1 hour, and control the temperature within the range of 20-30°C. Slowly pour the reaction solution into 49.95kg of 5% sodium sulfite aqueous solution, then add 43.80kg of 10% potassium carbonate aqueous solution, adjust pH ≥ 9, stir for 0.5 hour, and control the temperature within the range of 10-20°C. The mixture was allowed to stand for separation, and 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, and the vacuum degree was ≤-0.07 MPa. After drying for 12 hours, the material was collected to obtain 18.6 kg of the target product Int 1-4, LC-MS m / z (ESI) [M+H] + For C 22H 29 The calculated value of BrN5O3 is: 490.2; the measured value is: 490.1.

[0190] 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)

[0191] Add 143.2 kg of DMSO (dimethyl sulfoxide) and 18.6 kg of Int 1-4, stirring and heating at 35-40°C, add 16.0 kg of 2-iodoxybenzoic acid (IBX) prepared in advance in DMSO (61.4 kg) solution to the system, control the temperature within the range of 35-40°C, after the addition is completed, stir at this temperature for 5 hours, cool the system to 20-30°C, then slowly add the system to 233 kg of 3.3% sodium sulfite aqueous solution, add 38.9 kg of 10% potassium carbonate aqueous solution and 98.4 kg of tert-butyl methyl ether, stir and filter, rinse the filter cake once with 57.5 kg of tert-butyl methyl ether, let the filtrate stand for separation, extract the aqueous phase once with the filtrate after rinsing, combine the organic phases, and then wash once with 116 kg of water, dry the organic phase with sodium sulfate and concentrate to obtain 18.4 kg of brown oil Int 1-5, which is directly used in the next step.

[0192] 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)

[0193] Add 65.5 kg of tetrahydrofuran (THF) to a clean 500L reactor, protect with nitrogen, stir and cool down to 0-10°C, add 1.76 kg of sodium hydrogen (60%) to the system in batches, release gas during addition, protect with nitrogen flow, control the temperature in the range of 0-10°C, stir for 0.5 hours, and drop the prepared Int 1-5 (18.4kg) of THF (49.1kg) solution, temperature controlled in the range of 0-10 ℃, nitrogen flow protection, dropwise addition is completed, 7.36kg of 2-(trimethylsilyl)ethoxymethoxychlor (SEMCl) is added dropwise to the system, temperature controlled in the range of 0-10 ℃, nitrogen flow protection, dropwise addition is completed, temperature is raised to 10-20 ℃, stirred for 1 hour, after the reaction is completed, the system is cooled to 0-10 ℃, and then under nitrogen protection, the system is slowly added to 115kg of 20% ammonium chloride aqueous solution, temperature controlled in the range of 0-20 ℃, stirred for 0.5 hour, separated, 56.7kg of tert-butyl methyl ether is added to the aqueous phase, 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 with sodium sulfate and concentrated to dryness, 72.7kg of methanol is added to the system, stirred for 2h, and the temperature is controlled in the range of 5-15 ℃. The system was filtered, and the filter cake was refluxed and recrystallized with 35.1 kg of acetonitrile, and 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, and the vacuum degree was ≤-0.07 MPa. After drying for seven hours, 10.1 kg of off-white powder solid Int 1 was obtained, LC-MS m / z (ESI) [M+H] + For C 28 H 41 The calculated value of BrN5O4Si is: 618.2; the measured value is: 618.2.

[0194] Synthesis of Synthetic Intermediate Int 2: Synthesis of 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)

[0195]

[0196] Int 2 can be obtained by a synthetic method similar to that of Int 1 using appropriate starting materials, LC-MS m / z (ESI) [M+H] + For C 29 H 47 The calculated value of BrN5O4Si2 is: 664.2; the measured value is: 664.2.

[0197] Example 1: (R)-2-(6-(5-fluoro-4-hydroxy-2-(methyl-d3)phenyl)-1H-indazol-3-yl)-N-(2-hydroxy Propyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide (Compound 1)

[0198]

[0199] Synthesis route of compound 1:

[0200]

[0201] Synthesis method:

[0202] Synthetic intermediate 1-1: 2-(Benzyloxy)-4-bromo-1-fluorobenzene

[0203] 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 stirred at room temperature for 3 h. After the reaction was completed, water was added to the reaction solution, 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 by silica gel column to obtain 2.8 g of intermediate 1-1 with a yield of 95.1%.

[0204] 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).

[0205] Synthetic intermediate 1-2: 2-(Benzyloxy)-1-fluoro-4-(methyl-d3)benzene

[0206] The 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 was replaced, 8 ml of dioxane was added to dissolve, and deuterated methylmagnesium iodide in ether solution (2.5 ml, 2.45 mmol) was slowly added to the solution at room temperature. After the addition was completed, 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, water was added to the reaction solution to quench, and ethyl acetate was used for extraction twice. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column, and eluted with pure petroleum ether to obtain 190.3 mg of intermediate 1-2 crude product, with a yield of 105.9%.

[0207] 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).

[0208] Synthetic intermediate 1-3: 1-(Benzyloxy)-4-bromo-2-fluoro-5-(methyl-d3)benzene

[0209] Dissolve the intermediate 1-2 (190.3 mg, 0.87 mmol) in 10 ml of acetonitrile, add copper bromide (579.1 mg, 2.60 mmol), and react at room temperature for 16 hours. After the reaction is completed, add water to the reaction solution and stir until the reaction solution is clear, extract with ethyl acetate twice, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, purify with silica gel column, and elute with pure petroleum ether to obtain 135.2 mg of intermediate 1-3 crude product, with a yield of 52.3%.

[0210] Synthetic intermediate 1-4: 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)-carboxylic acid tert-butyl ester

[0211] 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, Pd(dppf)Cl2.CH2Cl2 (37.1 mg, 0.05 mmol) and potassium acetate (133.1 mg, 1.36 mmol) were added, nitrogen was replaced, and the reaction was carried out at 100°C for 5.5 hours. Cool to room temperature, add 4 ml of water to the reaction solution, dissolve 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)-carboxylic acid tert-butyl ester (Int 2) in 4 ml of dioxane and add to the reaction solution, then add Pd(dppf)Cl2.CH2Cl2 (37.1 mg, 0.05 mmol) and potassium carbonate (187.3 mg, 1.36 mmol), replace nitrogen, and react at 100°C for 16 hours. After the reaction is completed, add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify with a silica gel column to obtain 103.4 mg of intermediate 1-4 with a yield of 28.3%.

[0212] 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).

[0213] 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

[0214] Dissolve the intermediate 1-4 (103.4 mg, 0.13 mmol) in 8 ml of dichloromethane, add zinc bromide (143.4 mg, 0.64 mmol), and react at room temperature for 16 hours. After the reaction is completed, add ammonia water to the reaction solution and stir until the reaction solution is clear, extract with dichloromethane twice, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain 89.8 mg of intermediate 1-5 crude product, with a yield of 98.8%. 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

[0215] Dissolve the intermediate 1-5 (35.0 mg, 0.05 mmol) in 8 ml of dichloromethane, add triphosgene (14.7 mg, 0.05 mmol) at 0°C, stir for 1 min, add triethylamine (0.1 ml, 0.50 mmol) dropwise, emit white smoke, stir for 5 minutes, TLC shows that the raw material disappears, the reaction solution is transferred to room temperature, add (R)-1-aminopropan-2-ol and react for 1 hour. After the reaction is completed, add water to the reaction solution, extract twice with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify with a silica gel column to obtain 28.3 mg of intermediate 1-6, with a yield of 69.9%.

[0216] 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

[0217] Intermediate 1-6 (28.3 mg, 0.03 mmol) was dissolved in 4 ml methanol, 10 mg palladium carbon was added, and the mixture was reacted at 45° C. for 1 hour. After the reaction was completed, the reaction solution was filtered through a diatomaceous earth pad, and the filtrate was concentrated to obtain 23.8 mg of crude intermediate 1-7, with a yield of 92.6%.

[0218] 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

[0219] The 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 the reaction was completed, the reaction solution was concentrated, and the concentrate was dissolved in methanol. Ammonia water was added to adjust the pH to alkaline, and the mixture was concentrated. Purification on a silica gel plate gave 3.2 mg of the final product 1, with a yield of 20.5%. LC-MS m / z (ESI) [M+H] + For C 23 H 20 The calculated value of D3FN6O3 is: 454.2; the measured value is: 454.3. 2: Cyclopropyl (2-(6-(5-fluoro-4-hydroxy-2-(methyl-d3)phenyl)-1H-indazol-3-yl)-4,6- Dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (Compound 2)

[0220]

[0221] Synthesis route of compound 2:

[0222]

[0223] Synthesis method:

[0224] 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

[0225] 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, and then acetyl chloride (9.6 mg, 0.09 mmol) was added, and stirred at room temperature for 0.5 hours. After the reaction was completed, water was added to quench, and DCM was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative plate to obtain 40.0 mg of intermediate 2-1 with a yield of 72.9%.

[0226] 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

[0227] Dissolve 2-1 (40.0 mg, 0.05 mmol) in 3 ml of methanol, add 4 mg of palladium carbon, replace hydrogen, react at 40 degrees for 2 hours, filter and concentrate the filtrate to obtain 2-2 (28.0 mg in total) with a yield of 79.2%.

[0228] Synthetic 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

[0229] The intermediate 2-2 (28.0 mg, 0.04 mmol) was dissolved in 4 ml methanol, 2 ml concentrated hydrochloric acid was added, reacted at 50°C for 6 hours, concentrated, dissolved in 5 ml methanol, 0.5 ml ammonia water was added, concentrated, and purified by reverse silica gel column to obtain the final product 4.2 mg, yield 24.3%. LC-MS m / z (ESI) [M+H] + For C 23 H 17 The calculated value of D3N2O5 is: 421.2; the measured value is: 421.2.

[0230] 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)ketone methanesulfonate (Compound 3)

[0231]

[0232] Synthesis route of compound 3:

[0233]

[0234] Synthesis method:

[0235] Synthetic intermediate 3-1: 2-(Benzyloxy)-4-(ethyl-d5)-1-fluorobenzene

[0236] THF (80.0 mL), compound 1-1 (13.0 g, 1.00 eq) and Pd(dppf)Cl2·H2Cl2 (780 mg) were added to the reaction flask, and (ethyl-D5) magnesium bromide (9.59 g, 1.50 eq) was added to the reaction flask at 20-30°C. The reaction was stirred at 65°C for 12 hours. After the reaction solution was quenched by adding 100 mL of 1N hydrochloric acid (HCl), 100 mL of ethyl acetate was added for extraction, and 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 gave 11.0 g of compound 3-1 as a yellow oil. 1 HNMR: (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)

[0237] Synthetic intermediate 3-2: 1-(Benzyloxy)-4-bromo-5-(ethyl-d5)-2-fluorobenzene

[0238] Add compound 3-1 (11.0 g, 1.00 eq) and 100 mL of acetonitrile (ACN) to a reaction flask. Add NBS (8.32 g, 1.00 eq) to a reaction flask at 20-30°C. React at 20-30°C for 1 hour. Concentrate the reaction solution, add 100 mL of water, extract with ethyl acetate (100 mL*2), combine the organic phases, and concentrate under reduced pressure. Dissolve the concentrate with 200 mL of ethyl acetate and purify it on a silica gel pad. Concentrate to obtain 15.0 g of compound 3-2 as a yellow oil.

[0239] 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).

[0240] Synthetic intermediate 3-3: 2-(4-(benzyloxy)-2-(ethyl-d5)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0241] 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) respectively, and reacted at 110-120° C. for 2 hours under nitrogen protection. The reaction solution was filtered and the filtrate was concentrated. 100 mL of water was added to the concentrated solution, and then extracted with 100 mL of methyl tert-butyl ether (MTBE), and the organic phase was concentrated. Concentration gave 17.0 g of compound 3-3 as a yellow oil.

[0242] 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).

[0243] 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

[0244] 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) respectively. Pd(dppf)Cl2·H2Cl2 (244 mg, 0.01 eq) was added to the reaction bottle under nitrogen protection. If it was not dissolved after addition, the temperature was raised to 70-80 ° C and reacted for 2 hours. The reaction solution was concentrated, and the concentrate was extracted with 250 mL of MTBE. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The concentrate was mixed with silica gel, brushed with a silica gel pad, first eluted with petroleum ether, and then eluted with petroleum ether: ethyl acetate = 1:1. The eluent with the product was collected and rotary evaporated to obtain 14.0 g of compound 3-4 as a brown paste. LC-MS m / z (ESI) [M+H] + For C 43 H 50 The calculated value of D5FN5O5Si is: 773.4; the measured value is: 773.3.

[0245] 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).

[0246] 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

[0247] Compound 3-4 (14.0 g, 1.00 eq) was added to DCM (70.0 mL), and ZnBr2 (16.3 g, 4.00 eq) was added at 20-30 ° C. After the addition, the reaction solution was clear and the reaction was stirred at 20-30 ° C for 3.5 hours. 37.8 mL of 28% ammonia water was added to the reaction solution, and the reaction was stirred at 20-30 ° C for 10 minutes. The system was severely emulsified. After rotary evaporation to remove DCM, the residue was extracted with 155 mL of MTBE, the reaction solution was filtered, and the filtrate was concentrated. 100 mL of water was added to the concentrated solution, and then extracted with 100 mL of MTBE. The organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated. Concentration gave 10.0 g of compound 3-5, a brown paste, which was directly used in the next step.

[0248] 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

[0249] Add triphosgene (1.80g, 0.41eq) to DCM (20.0mL), cool to 0-5°C, and under nitrogen protection, drop a mixed solution of compound 3-5 (10.0g, 1.00eq) and 80.0mL DCM into the above reaction solution, control the temperature within the range of 0-5°C, and stir to react for 10 minutes. Control the temperature within the range of 0-5°C, drop triethylamine (TEA, 12.0g, 8.00eq) into the reaction system, and stir to react for 10 minutes. Then add (S)-pyrrolidin-3-ol hydrochloride (2.75g, 1.50eq) to the reaction solution at once, and then heat to 20-30°C and stir to react for 1 hour. 100 mL of water was added to the reaction system to quench and dilute the reaction, and 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, filtered through a silica gel pad, and the eluent was evaporated to dryness to obtain 6.00 g of compound 3-6, which was brown and foamy. LC-MS m / z (ESI) [M+H] + For C 43 H 49 The calculated value of D5FN6O5Si is: 786.4; the measured value is: 786.2.

[0250] 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

[0251] 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 hydrogen replacement three times, the mixture was reacted at 20-30 ° C for 3 hours under a hydrogen atmosphere. The reaction was stopped, the reaction solution was passed through a diatomaceous earth pad, the filter cake was rinsed with 100 mL of THF, and 600 mg of wet palladium carbon was added after the filtrate was combined. After hydrogen replacement three times, the mixture was reacted at 20-30 ° C for 7.5 hours under a hydrogen atmosphere. The reaction was stopped, the reaction solution was passed through a diatomaceous earth pad, the filter cake was rinsed with 100 mL of THF, and 600 mg of wet palladium carbon was added after the filtrate was combined. After hydrogen replacement three times, the mixture was reacted at 20-30 ° C for another 14 hours under a hydrogen atmosphere. 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 directly used in the next step reaction.

[0252] 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

[0253] Take 40.0g methanol, pass 27.0g hydrochloric acid gas, and calculate the mass fraction of HCl / MeOH to be 40.3%. Add compound 3-7 (5.00g, 1.00eq) to the above HCl / MeOH and react at 20-30°C for 17.5 hours. Filter the reaction solution, suspend the filter cake in 50.0mL ethanol, and add 6.00mL ammonia water (28%) to the reaction system at 20-30°C to free the product. During the process, the solution is clear at first, and then solids are precipitated. Continue to stir at 20-30°C for 30 minutes. Filter the suspension, evaporate the filter cake to obtain 2.00g of off-white solid. Add 60.0mL methanol, beat at 60-65°C for 5.5 hours, reduce to 20-30°C for filtration, and evaporate the filter cake to obtain 1.50g of compound 3-8, off-white solid, LC-MS m / z (ESI) [M+H] + For C 25 H 21 The calculated value of D5FN6O3 is: 482.2; the measured value is: 482.1.

[0254] Synthetic 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)ketone methanesulfonate

[0255] Compound 3-8 (1.50 g, 1.00 eq) was added to ethyl acetate (30.0 mL), and under nitrogen protection, (360 mg, 1.20 eq) CH3SO3H was added dropwise at 10-20°C, and the mixture was reacted at 10-20°C for 3 hours. The reaction solution 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.

[0256] 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).

[0257] Example 4: 2-Fluoro-5-(methyl-d3)-4-(3-(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole- 2-yl)-1H-indazol-6-yl)phenol (Compound 12)

[0258]

[0259] Synthesis route of compound 12:

[0260]

[0261] Synthesis method:

[0262] 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

[0263] Intermediate 1-5 (100.0 mg, 0.14 mmol) was dissolved in 10 ml DCM, and a formaldehyde aqueous solution (40%) (21 mg, 0.24 mmol) was added at room temperature, and stirred at room temperature for 0.5 hours, and then sodium triacetyl borohydride (89 mg, 0.42 mmol) was added, and stirred at room temperature for 2 hours. After the reaction was completed, water was added to quench, and DCM was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative plate to obtain 80.0 mg of intermediate 12-1 with a yield of 78.4%.

[0264] 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

[0265] 12-1 (20.0 mg, 0.03 mmol) was dissolved in 3 ml of methanol, 4 mg of palladium carbon was added, hydrogen was replaced, and 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 12-2 (10.0 mg in total) with a yield of 57%.

[0266] 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

[0267] The intermediate 4-2 (10.0 mg, 0.02 mmol) was dissolved in 4 ml methanol, 2 ml concentrated hydrochloric acid was added, reacted at 50°C for 6 hours, concentrated, dissolved in 5 ml methanol, 0.5 ml ammonia water was added, concentrated, and then purified by reverse silica gel column to obtain the final product 2.0 mg, with a yield of 34.5%. LC-MS m / z (ESI)

[0268] [M+H] + For C 20 H 16 The calculated value of D3FN5O is: 367.2; the measured value is: 367.2.

[0269] Table 1: The following compounds were prepared according to the synthetic route of Example 1 using appropriate starting materials

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276] Table 2: The following compounds were prepared according to the synthetic route of Example 2 using appropriate starting materials.

[0277]

[0278]

[0279]

[0280] Table 3: The following compounds were prepared according to the synthetic route of Example 4 using appropriate starting materials

[0281]

[0282]

[0283]

[0284] Table 4: The following compounds were prepared according to the synthetic route of Example 3 using appropriate starting materials

[0285]

[0286]

[0287]

[0288] Example 11: Pharmacological Activity Evaluation I

[0289] 1. Experimental Principle

[0290] The inhibitory ability of small molecule compounds on kinase activity is detected through a drug screening system based on JAK1, JAK2, JAK3, and TYK2 kinases. Kinases react with their substrates IRS1, IGF1Rtide, and Poly (4:1Glu, Tyr) to consume ATP to produce ADP, and the amount of the product is detected using ADP-Glo ​​reagent and luminescence method to reflect the activity of the kinase.

[0291] 2. Experimental Plan

[0292] 2.1 Experimental Materials and Instruments

[0293]

[0294] 2. Kinase information 2.1 Kinase reaction buffer:

[0295] name Working concentration Hepes 50mM <![CDATA[MgCl2]]> 10mM Brij35 0.01％ EGTA 1mM DTT 2mM <![CDATA[ddH2O]]> /

[0296] 2.2 Kinase reaction conditions:

[0297]

[0298] 2.3 Compound screening steps:

[0299] 1) Prepare 2x ATP / substrate solution and 2x kinase solution using kinase reaction buffer.

[0300] 2) In the test of JAK1 / 2 / 3 / inhibitory activity, the starting concentration of Tofacitinib was 1 μM, and the dilution was performed at a ratio of 1:4. In the test of TYK2 inhibitory activity, the starting concentration was 10 μM, and the dilution was performed at a ratio of 1:4. The starting concentration of the test compound was 0.5 μM, and the dilution was performed at a ratio of 1:4.

[0301] 3) Use Echo 655 to transfer 40 nL of compound dilution to 384 assay plate; after centrifugation, add 2 μL of 2x kinase solution to 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes;

[0302] 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.

[0303] 5) Transfer 4 μL ADP-Glo ​​to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0304] 6) Transfer 8 μL of the detection solution to a 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0305] 7) Use a multifunctional microplate reader to read the luminescence signal.

[0306] 3. Data Analysis

[0307] 3.1 The inhibition rate is calculated as follows:

[0308] % Inhibition = 100% - (Compound - Positive Control) / (Negative Control - Positive Control) * 100%

[0309] Negative control: DMSO

[0310] Positive control: Tofacitinib

[0311] 3.2 Calculation of IC 50 And draw the inhibition curve of the compound:

[0312] 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.

[0313] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope))

[0314] X: log value of compound concentration Y: inhibition rate (% inhibition)

[0315] 4 Summary of compound detection results

[0316]

[0317]

[0318] 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, and 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.

[0319] Although 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. More specifically, the words used in this specification are merely descriptive and non-restrictive. It is obvious to those skilled in the art that various other changes and modifications may be made without departing from the general scope of the present disclosure. Therefore, in the appended claims, it is intended to include all these 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 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 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 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, 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 following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, 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 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 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 following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, 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 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 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 following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Haloalkyl, 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 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 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.

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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