Compounds containing a bis(azanylylidene)sulfonyl structure and their use in medicine - Patents.com

Abstract

Compounds of formula (I) containing a bis(azanylylidene)sulfonyl structure as PKR agonists and / or USP9X inhibitors can be used for the treatment of related diseases mediated and controlled by PKR and USP9X, including, but not limited to, sickle cell anemia, β-thalassemia, hereditary non-spherocytic anemia, hemolytic anemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia, congenital anemia, anemia associated with chronic disease, colon cancer, renal cancer, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, melanoma, lymphoma, glioblastoma, or multiple myeloma. [C1] TIFF2025500499000372.tif30156

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to compounds containing a diazanylidenesulfonyl structure and their use as PKR agonists and / or USP9X inhibitors in the treatment of related diseases. [Background technology]

[0002] Hemoglobin (Hb) is an oxygen-binding tetrameric protein found in red blood cells (RBCs). Fetal hemoglobin (HbF) consists of two α chains and two γ chains (α2γ2). HbF is converted to α2β2 hemoglobin (HbA) by the globin switching developmental regulatory mechanism between 6 and 12 months of age. Mutations in the β or α chain genes can result in structural abnormalities in HbA, reduced production, or abnormal HbA formation, which can reduce the oxygen-carrying capacity of RBCs. Diseases caused by these mutations are called hemoglobinopathies. Common hemoglobinopathies include β-thalassemia and sickle cell disease (SCD) (Nat Genet 50, 478-480 (2018)).

[0003] β-thalassemia is an autosomal recessive genetic disease. Point mutations or deletions in the β-chain gene result in partial or complete inhibition of β-chain synthesis, leading to an imbalance between α- and β-chains. The α-chain accumulates near the cell membrane to form insoluble hemichrome, reducing the total oxygen-carrying capacity of RBCs and increasing free heme and iron. This increases the concentration of reactive oxygen species (ROS), which oxidize cell membrane proteins and lipids, causing cell lysis and premature apoptosis, inhibiting RBC differentiation and maturation. Therefore, RBCs in β-thalassemia patients consume more ATP, which is an important factor in shortening RBC lifespan and increasing hemolysis (Int J Mol Sci 22, 7229 (2021)). Patients with β-thalassemia exhibit a range of clinical manifestations, from asymptomatic non-transfusion-dependent β-thalassemia (NTDT) to transfusion-dependent β-thalassemia (TDT), which is primarily related to the degree of β-chain deficiency. Patients with TDT produce very little HbA and typically develop anemia after HbF is converted to HbA. It is estimated that 5% of the world's population has at least one β-thalassemia gene mutation, with approximately 300,000 β-thalassemia patients worldwide, distributed throughout the Mediterranean and Southeast Asia (N Engl J Med 371, 1908-1916 (2014)). In China, the disease is primarily found in the area south of the Yangtze River. A 2017 meta-analysis found that the incidence of β-thalassemia in mainland China was 2.21% (Sci Rep 7, 920 (2017)).

[0004] SCD is an autosomal dominant hemoglobinopathy. Hemoglobin S (HbS) has a glutamic acid substitution at position 6 of the β-peptide chain with valine, which predisposes it to polymerization and sickle cell formation upon deoxygenation. Clinical symptoms include chronic hemolytic anemia, organ and tissue damage due to chronic ischemia, splenic infarction, susceptibility to infection, and vaso-occlusive crisis (VOC) (Lancet 376, 2018-2031 (2010)). SCD mutations are distributed worldwide, including in African Americans (approximately 7%-10%), sub-Saharan Africa (30%), Mediterranean countries (especially Greece), the Middle East (0.2%-27%), and India (13%) (J Neonatal Screen 4, 31 (2018)). In summary, the global prevalence of SCD is estimated to be approximately 300 million people (Engl J Med 375, 435-442 (2016)). In patients with β-thalassemia and SCD, an imbalance in the α-chain / non-α-chain ratio leads to ineffective hematopoiesis (IE), which induces apoptosis of erythroid progenitors. This, along with increased apoptosis, leads to anemia, splenomegaly, and decreased hepcidin production, resulting in systemic iron overload. IE is the primary etiological and pathological hallmark of β-thalassemia. The bone marrow of patients with β-thalassemia has approximately six times the erythroid progenitor content and four times the apoptosis rate of healthy individuals (Int J Mol Sci 22, 7229 (2021)). Furthermore, patients with SCD have a shortened lifespan of circulating red blood cells and undergo late erythroblast death in the body.

[0005] Hematopoietic stem cell (HSC) transplantation is currently the only treatment for the two hemolytic anemia disorders mentioned above. However, it is limited by donor availability, the need for post-transplant immunosuppression, and relatively high treatment costs. Only a very small proportion of patients are suitable for this treatment. Supportive care includes blood transfusions, folic acid supplementation, splenectomy, and iron chelator therapy to reduce iron overload. Therapies currently being investigated to improve IE caused by an imbalance in the α-chain / non-α-chain ratio include three aspects: gene therapy, protein therapy, and small molecule compound therapy.

[0006] Regarding gene therapy, in 2018, it was reported that 22 TDT patients obtained significant clinical benefit using autologous HSCs with the LentiGlobin BB305 vector encoding the T87Q mutant, but no curative outcomes were achieved (N Engl J Med 378, 1479-1493 (2018)). Furthermore, based on CRISPR-Cas9 technology, the number of blood transfusions in severe SCD patients can be reduced by inhibiting BCL11A using CTX001 to induce HbF (N Engl J Med 384, 252-260 (2021)).

[0007] The recombinant fusion protein luspatercept (ACE-536) was approved in 2019 for the treatment of adult patients with TDT. Luspatercept binds to the transforming growth factor-β superfamily ligand, inhibits the SMAD2 / 3 pathway, promotes RBC maturation, and can reduce the number of transfusions required by patients (Cell Mol Med 24, 6162-6177 (2020)). Crizanlizumab, an FDA-approved monoclonal antibody against P-selectin, is used to reduce VOC generation by reducing the interaction between endothelial cells and circulating blood cells, but it does not alter HbS aggregation (J Pain Res 14, 849-856 (2021)).

[0008] Although there are currently many treatment options mentioned above, these therapies, including hematopoietic stem cell transplantation, gene therapy, recombinant fusion protein therapy, and treatment with blood transfusion and iron chelators, generally have drawbacks such as the risk of surgical complications, a significant economic burden, and an impact on patients' quality of life. There remains a huge unmet need. In contrast, chemical small molecule pharmaceutical therapy offers unique clinical advantages.

[0009] Among small molecule compounds, ruxolitinib, a Janus kinase 2 inhibitor, can improve IE and reduce splenomegaly in a mouse model of β-thalassemia (Blood 131, 263-265 (2018)). Bitopertin (RO-4917838), an orally available, potent, and highly selective glycine transporter 1 inhibitor, can improve anemia and hemolysis in patients with β-thalassemia and improve RBC survival in vivo (Br J Haematol 194, 474-477 (2021)). VIT-2763, an orally active small molecule ferroportin inhibitor, blocks iron efflux by inhibiting the binding of hepcidin to ferroportin (J Clin Invest 130, 491-506 (2020)). Inducing sustained production of HbF can alleviate clinical symptoms in patients with β-chain abnormalities. For example, hydroxyurea (HU), which is clinically used to treat SCD, can stimulate HbF production and reduce HbS aggregation. However, HU inhibits bone marrow function. IMR-687, a phosphodiesterase (PDE9) inhibitor, inhibits PDE9, increases intracellular cGMP levels, and stimulates HbF production, demonstrating therapeutic efficacy in preclinical SCD models (Haematologica 105, 623-631 (2020)).

[0010] Pyruvate kinase (PK) is a key enzyme in glycolysis, catalyzing the conversion of phosphoenolpyruvate to enolpyruvate, generating adenosine triphosphate (ATP). R-type pyruvate kinase (PKR) is expressed in mature RBCs. Loss of PKR function due to genetic mutations results in reduced ATP production, leading to hemolytic anemia and hemoglobinopathies such as β-thalassemia and SCD. Therefore, stimulating PKR to increase ATP in red blood cells may play a positive role in the treatment of patients with PKR deficiency, such as β-thalassemia and SCD.

[0011] Currently, a growing number of research papers have been published on small molecule drugs targeting PKR. However, compared with other common targets, there are still relatively few studies on small molecule drugs. The main ones are as follows:

[0012] Mitapivat (AG-348), an oral small molecule allosteric agonist, demonstrated efficacy and safety in clinical trials in patients with PKR deficiency (N Engl J Med 381, 933-944 (2019)).

[0013] FORMA Therapeutics, Inc. discloses pyrrolopyrrole compounds as PKR agonists in WO2018175474 and WO2020061255.

[0014] Global Blood Therapeutics Inc. discloses pyrrolidinopyrazole compounds as pyruvate kinase activators in WO2021202796.

[0015] Agios Pharmaceuticals Inc. discloses azetidine arylsulfonamide derivative compounds as pyruvate kinase modulators in WO2012083246, WO2011002817, WO2012092442, WO2014139325, and the like.

[0016] All of the above-mentioned compounds related to PKR effects are different from those of the present invention. Considering the current state of hemoglobinopathy treatment, it is urgent to provide more comprehensive treatment and clinical drug options that are more cost-effective, reduce the risk of complications, and improve the quality of life of patients to meet urgent clinical needs.

[0017] Ubiquitination, a post-translational protein modification, is dynamically regulated by ubiquitinating and deubiquitinating enzymes (DUBs). This is a fundamental mechanism for controlling protein turnover and stability in the body. The fundamental function of DUBs is to regulate protein stability, interaction, or cellular localization within cells by specifically removing ubiquitin from ubiquitinated proteins (Biomark Res 9, 66(2021)). DUBs are involved in various cellular life processes, including DNA methylation, DNA damage repair, survival, differentiation, and apoptosis. Dysregulation of ubiquitin balance is particularly implicated in the development of human diseases, including cancer, infectious diseases, neurodegenerative diseases, and immune disorders, making DUBs attractive drug targets.

[0018] The human genome expresses nearly 100 DUBs, which are primarily classified into five families: the ubiquitin carboxy-terminal hydrolase (UCH) family, the ubiquitin-specific protease (USP / UBP) family, the Otubaim (OTU) family, the Josephin domain protein family, and the JAMM family. USPs are the largest subclass of DUBs, with at least 54 members in humans. Most USPs, particularly USP9X, USP10, USP18, USP22, and USP28, have both tumorigenic and tumor-suppressive functions. Different DUBs play distinct roles in tumorigenesis, primarily by affecting the stability, enzymatic activity, or cellular localization of their substrate proteins. The distinct roles of USP9X in human cancer depend on its different substrates (Cancer Med 8, 6730-6740 (2019)).

[0019] USP9X inhibits colon, kidney, and pancreatic cancer by stabilizing FBW7 (a tumor suppressor that targets the ubiquitination of oncoproteins such as c-MYC), AMOT (a YAP1 inhibitor), and LATS2 (a kinase that inhibits the Hippo pathway) substrate molecules (Biochim Biophys Acta Rev Cancer 1872, 188312 (2019)). USP9X has shown significant tumor suppressive effects in a USP9X knockout colon cancer mouse model (J Clin Invest 128, 1326-1337 (2018)).

[0020] On the other hand, USP9X is overexpressed in various malignant tumors. In breast cancer, lung cancer, melanoma, lymphoma, and glioblastoma, upregulated USP9X expression promotes tumorigenesis and enhances resistance to chemotherapy drugs. For example, USP9X can stabilize CEP131 (a key protein in centrosome amplification that prevents cell division and induces tumorigenesis), SMURF1 (a key E3 ligase controlling cell migration), and YAP1 (a downstream transcription factor of the Hippo pathway) in breast cancer cells. Therefore, USP9X may induce malignant transformation, cancer cell survival, distant metastasis, and chemotherapy resistance in breast cancer by regulating these oncogenic signaling pathways (Nat Commun 8, 14866 (2017)). Degrasin (WP1130) is a selective DUB inhibitor that inhibits the DUB activity of USP9X, USP5, USP14, and UCH37, leading to the rapid accumulation of polyubiquitinated proteins in aberrant protein inclusion bodies and tumor cell apoptosis. The compound EOAI3402143 dose-dependently inhibits the activity of USP9X and USP24, increasing tumor cell apoptosis and inhibiting cancer progression in multiple myeloma (Blood 125, 3588-3597 (2015)). USP9X expression in pancreatic cancer cells is positively correlated with gemcitabine resistance, and USP9X inhibition can sensitize pancreatic cancer cells to gemcitabine (Cancer Lett 436, 129-138 (2018)). Low expression of USP9X in tumor cells reduces MCL-1, which may increase sensitivity to imatinib (Biomark Res 9, 66 (2021)), cisplatin, and doxorubicin (Cancer (Basel). 11, 344 (2019)).

[0021] Studies have shown that USP9X is an indicator of poor prognosis in glioma, lymphoma, multiple myeloma, and esophageal cancer, while its expression status is associated with good prognosis in patients with colorectal cancer and pancreatic cancer (Diagn Pathol 8, 177 (2013), Nature 486, 266-270 (2012)). Considering the above, it is likely that USP9X is a potential context-dependent USP regulated by various upstream molecules in tumor cells (Biochim Biophys Acta Rev Cancer 1872, 188312 (2019)).

[0022] Protein ubiquitination downstream of immune signaling pathways is crucial for the positive and negative regulation of nearly all immune responses, particularly T cell activation. Numerous studies have demonstrated that modulating ubiquitin-dependent pathways can significantly alter T cell activation and enhance antitumor responses. The deubiquitinating enzymes USP9X and USP12 positively regulate the NF-κB pathway by removing inhibitory ubiquitin chains from BCL10, thereby blocking the assembly of the CBM signaling complex, which plays a key role in signaling from antigen receptors to NF-κB in T and B cells. Therefore, USP9X-deficient T cells exhibit reduced levels of NF-κB activation upon T cell receptor activation (Am J Physiol Cell Physiol 317, C534-C543 (2019)).

[0023] The development of T cell-focused immunotherapy is a hot research area. Tumor PD-L1 levels are a key determinant of tumor immunity, and studies have shown that cancer cells exploit EGFR signaling to stabilize PD-L1 expression and evade T cell immunity (Nat Commun 12, 2346 (2021)). PD-L1 can be stabilized by OTUB1, USP9X, and USP7. Inhibiting or eliminating these DUBs can restimulate antitumor responses and sensitize cancer cells to T cell killing (Cancer Med 7, 4004-4011 (2018)). USP9X-targeted inhibitors offer promising alternatives for improving targeted tumor immunotherapy (Int J Mol Sci 22, 10800 (2021)).

[0024] USP9X-targeting cancer therapeutics are being actively developed, and highly specific USP9X small molecule inhibitors have shown great potential for tumor inhibition, chemotherapy resistance, T cell activation, and PD-L1 stabilization.

[0025] Exemplary USP9X small molecule inhibitors include pyrrolopyrrole or pyrazolopyrrolidine compounds as USP9X inhibitors disclosed by FORMA Therapeutics Inc. in WO2020061261.

[0026] In light of the above, there is a need to design new compounds with potential medical value to fulfill unmet clinical needs. Summary of the Invention [Problem to be solved by the invention]

[0027] In order to solve the above-mentioned problems existing in the prior art, the object of the present invention is to provide new compounds containing a diazanylidenesulfonyl structure as PKR agonists and / or USP9X inhibitors for the prevention and treatment of PKR and / or USP9X mediated related diseases, such as sickle cell anemia, β-thalassemia, colon cancer, kidney cancer, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, melanoma, lymphoma, glioblastoma, or multiple myeloma. [Means for solving the problem]

[0028] First, the present invention provides a compound of Formula I, or an isomer, pharmaceutically acceptable salt, or solvate thereof: [ka]

[0029] During the ceremony, R 1 , R 2 , and R 3 is independently -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR b , -SR b , -NR c R d , -S(O)2R e , -S(O)NR c R d , -S(O)R e , -S(O)NR c R d , -NR c S(O)2R e , -NR c S(O)Re , -C(O)R f , or -C(O)OR g wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R a , -OR b , -SR b , -NO2, -NR c R d , -S(O)2R e , -S(O)NR c R d , -S(O)R e , -S(O)NR c R d , -NR c S(O)2R e , -NR c S(O)R e , -C(O)R f , and -C(O)OR g or optionally substituted with one or more substituents selected from: Alternatively, R 1 and R 2 , R 1 and R 3 , or R 2 and R 3 are optionally joined together with the atoms to which they are attached to form -(C3-C8)cycloalkyl, a 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, -(C5-C8)spirocyclyl, a 5- to 8-membered spiroheterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, a 7- to 14-membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, or a 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; R 4 is -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR b , -SR b , -NR c R d , -S(O)2R e , -S(O)NR c R d , -S(O)R e , -S(O)NR c R d , -NR c S(O)2R e , -NR c S(O)R e , -C(O)R f , -C(O)OR g , or -NR c (CR h R i ) t -R a wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R a , -OR b , -SR b , -NO2, -NR c R d , -S(O)2R e , -S(O)NR c R d , -S(O)R e , -S(O)NR c R d , -NR c S(O)2R e , -NR c S(O)R e , -C(O)R f , and -C(O)OR g and optionally substituted with one or more substituents selected from: t is 0, 1, 2, or 3; R a , R b , R c , R d , Re , R f , R g , R h , and R i is, in each occurrence, independently selected from -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -SH, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -C(O)H, or -C(O)OH, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is ═O, halogen, -CN, -OH, -SH, -NO2, -NH2, -S(O)2H, -S(O)2NH2, -S(O) )H, —S(O)NH, —NHS(O)H, —NHS(O)H, —C(O)H, —C(O)OH, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, and 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, or wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each substituted with one or more substituents selected from —S(O)2OH, —S(O)OH, —NHS(O)2OH, or —NHS(O)OH; or R a , R b , R c , R d , R e , R f , R g , R h , and R iis, in each occurrence, independently -S(O)2OH, -S(O)OH, -NHS(O)2OH, or -NHS(O)OH; Alternatively, R a , R b , R c , R d , R e , R f , R g , R h , and R i Any two groups on adjacent atoms, together with the atoms to which they are attached, may be optionally joined to form a C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, a (C3-C8)cycloalkyl, or a 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, and one or more R a is optionally replaced by

[0030] In some embodiments, the present invention provides certain isomeric compounds of Formula I above, having formula I-1 or I-2. [ka]

[0031] In some embodiments, the present invention provides compounds of Formula I, I-1, or I-2 above, where R 1 and R 2 may further independently be selected from:

[0032] In one embodiment, R 1 and R 2 is independently -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR b , or -NR c R d wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R a , -OR b , -NO2, and -NR c R d or optionally substituted with one or more substituents selected from: Alternatively, R 1 and R 2 are optionally joined together with the atom to which they are attached to form -(C3-C8)cycloalkyl or a 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R a , R b , R c , and R d is, in each occurrence, independently selected from -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C 14aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each optionally substituted with one or more substituents selected from =O, halogen, -CN, -OH, -NO2, -NH2, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, and a 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S.

[0033] In another embodiment, R 1 and R 2 are independently selected from -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C8 aryl, 5- to 8-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, 7- to 14-membered fused ring groups containing 0-4 heteroatoms independently selected from O, N, and S, -OR b , or -NR c R d wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R a , -OR b , -NO2, and -NR c R d or optionally substituted with one or more substituents selected from: Alternatively, R 1 and R 2 are optionally joined together with the atoms to which they are attached to form -(C3-C8)cycloalkyl or a 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R a , R b , Rc , and R d is independently, in each occurrence, -H, halogen, -OH, -NH, -CN, -NO, -(C-C)alkyl, -(C-C)cycloalkyl, 3- to 6-membered heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S, C-C aryl, 5- to 8-membered heteroaryl having 1-4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group having 0-4 heteroatoms independently selected from O, N, and S, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each optionally substituted with one or more substituents selected from =O, halogen, -CN, -OH, -NO, -NH, -(C-C)alkyl, -(C-C)cycloalkyl, and 3- to 6-membered heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S.

[0034] In another embodiment, R 1 and R 2 are independently -H, -F, -Cl, -Br, -OH, -NH2, -CN, -NO2, -(C1-C6) straight chain alkyl, -(C1-C6) branched alkyl, -(C3-C6) cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C8 aryl, 7-14 membered bicyclic or tricyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, -OR b , or -NR c R d wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of -F, -Cl, -Br, -CN, -R a , -OR b , and -NR c R d or optionally substituted with one or more substituents selected from: Alternatively, R 1 and R 2are optionally joined together with the atoms to which they are attached to form -(C3-C8)cycloalkyl or a 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R a , R b , R c , and R d is independently, in each occurrence, -H, -F, -Cl, -Br, -OH, -NH, -CN, -NO, -(C-C)alkyl, -(C-C)cycloalkyl, 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C-C aryl, or 5- to 8-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO, -NH, and -(C-C)alkyl.

[0035] In another embodiment, R 1 and R 2 are independently -H, -F, -Cl, -Br, -OH, -NH2, -CN, -NO2, -(C1-C6) straight chain alkyl, -(C1-C6) branched alkyl, -(C3-C6) cycloalkyl, or 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein each of said alkyl, cycloalkyl, or heterocyclyl is selected from -F, -Cl, -Br, -CN, -R a , -OR b , and -NR c R d or optionally substituted with one or more substituents selected from: Alternatively, R 1 and R 2 are optionally joined together with the atoms to which they are attached to form -(C3-C8)cycloalkyl or a 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; Ra , R b , R c , and R d is independently, in each occurrence, -H, -F, -Cl, -Br, -OH, -NH, -CN, -NO, -(C-C)alkyl, -(C-C)cycloalkyl, or a 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein said alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO, -NH, and -(C-C)alkyl.

[0036] In another embodiment, R 2 is -H, -F, -Cl, or -Br; R 1 are -H, -F, -Cl, -Br, -OH, -NH2, -(CH2) q CH3, -(CH2) q OH, -CH(OH)(CH2) q CH3, -C(OH)((CH2) q CH3)2, [ka] -(CH2) q NH2, -(CH2) q NH(CH2) q CH3, -(CH2) q N((CH2) q CH3)2, a 3- to 6-membered heterocycloalkyl containing one N atom, or a -(C1-C6)alkyl substituted with a 3- to 6-membered heterocycloalkyl containing one N atom; q, in each occurrence, is independently 0, 1, 2, 3, or 4; Alternatively, R 1 and R 2may optionally be joined together with the atoms to which they are attached to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, or 2,3-dihydrobenzofuran ring; or R 1 and R 2 may optionally be joined together with the atoms to which they are attached to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, 2,3-dihydrobenzofuran ring, or tetrahydro-2H-pyran.

[0037] In another embodiment, R 2 is -H, -F, -Cl, or -Br; R 1 are -H, -F, -Cl, -Br, -OH, -NH2, [ka] Is it; Alternatively, R 1 and R 2 are optionally bonded together with the atoms to which they are attached, [ka] Can be formed; Alternatively, R 1 and R 2 are optionally bonded together with the atoms to which they are attached, [ka] can be formed.

[0038] In another embodiment, R 2 is -H, -F, -Cl, or -Br; R 1 are -H, -F, -Cl, -Br, -OH, -NH2, -CH3, -CH(OH)CH3, -(CH2) qCH3, -(CH2) q OH, -CH(OH)(CH2) q CH3, -C(OH)((CH2) q CH3)2, -C(OH)((CH2) q CH3)(CH3), -C(OH)(CH3)2, [ka] -CH2F, -CHF2, -(CH2) q CH2F, -(CH2) q CHF2, -CH2Cl, -CHCl2, -(CH2) q CH2Cl, -(CH2) q CHCl2, -(CH2) q NH2, -NHCH3, -NH(CH2) q CH3, -(CH2) q NHCH3, -(CH2) q NH(CH2) q CH3, -N(CH3)2, -N((CH2) q CH3)2, -(CH2) q N(CH3)((CH2) q CH3), -(CH2) q N(CH3)2, -(CH2) q N((CH2) q CH3)2, a 3- to 6-membered heterocycloalkyl containing one N atom, or a -(C1-C6)alkyl substituted with a 3- to 6-membered heterocycloalkyl containing one N atom; q is, in each occurrence, independently 1, 2, 3, or 4; Alternatively, R 1 and R 2 are optionally joined together with the atoms to which they are attached to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, oxetane, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, 2,3-dihydrobenzofuran ring, or tetrahydro-2H-pyran.

[0039] In another embodiment, R 2is -H, -F, -Cl, or -Br; R 1 are -H, -F, -Cl, -Br, -OH, -NH2, [ka] Is it; Alternatively, R 1 and R 2 are optionally bonded together with the atoms to which they are attached, [ka] Can be formed; Alternatively, R 1 and R 2 are optionally bonded together with the atoms to which they are attached, [ka] can be formed.

[0040] In some embodiments, in the compounds of formula I, I-1, or I-2 provided by the present invention, R 1 and R 2 R is independently one of the options and combinations described above. 3 may further independently be selected from:

[0041] In one embodiment, R 3 is -H, halogen, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring group is independently selected from ═O, halogen, —CN, —R a , -OR b, -NO2, and -NR c R d and optionally substituted with one or more substituents selected from: R a , R b , R c , and R d is, in each occurrence, independently selected from -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each optionally substituted with one or more substituents selected from =O, halogen, -CN, -OH, -NO2, -NH2, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, and a 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S.

[0042] In another embodiment, R 3 is -H, halogen, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or 7-14 membered bicyclic or tricyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring group is selected from ═O, halogen, -CN, -R a , -OR b , -NO2, and -NRc R d and optionally substituted with one or more substituents selected from: R a , R b , R c , and R d is independently, in each occurrence, -H, halogen, -OH, -NH, -CN, -NO, -(C-C)alkyl, -(C-C)cycloalkyl, 3- to 6-membered heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S, C-C aryl, 5- to 8-membered heteroaryl having 1-4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group having 0-4 heteroatoms independently selected from O, N, and S, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each optionally substituted with one or more substituents selected from =O, halogen, -CN, -OH, -NO, -NH, -(C-C)alkyl, -(C-C)cycloalkyl, and 3- to 6-membered heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S.

[0043] In another embodiment, R 3 is -H, -F, -Cl, -Br, -(C1-C6) alkyl, -(C3-C6) cycloalkyl, C6-C8 aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered bicyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, or fused ring groups is selected from -F, -Cl, -Br, -CN, -R a , and -OR b and optionally substituted with one or more substituents selected from: R a and R bis independently in each occurrence -H, halogen, -OH, -NH, -CN, -NO, -(C-C)alkyl, -(C-C)cycloalkyl, or 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein said alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO, -NH, and -(C-C)alkyl.

[0044] In another embodiment, R 3 is —H, —F, —Cl, —Br, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, or benzopyrrolidinyl, wherein said pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, or benzopyrrolidinyl is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —O—(C1-C6)alkyl, —O—(C3-C6)cycloalkyl, piperazinyl, and piperazinyl substituted with any number of halogens or —(C1-C6)alkyl.

[0045] In another embodiment, R 3 -H, -F, -Cl, -Br, -CH3, -CH2CH3, pyridyl, [ka] is.

[0046] In another embodiment, R 3 is -H, -F, -Cl, -Br, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, pyridyl, phenyl, naphthyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl, or [ka] wherein the pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl, or [ka] is optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C1-C6)alkyl, -O-(C3-C6)cycloalkyl, -(C1-C6)haloalkyl, -(C3-C6)halocycloalkyl, -O-(C1-C6)haloalkyl, -O-(C3-C6)halocycloalkyl, pyrazolyl, pyrazolyl substituted with any number of halogens or -(C1-C6)alkyl, piperazinyl, piperazinyl substituted with any number of halogens or -(C1-C6)alkyl; The above ring [ka] is a 3- to 6-membered saturated or unsaturated heterocyclyl linked via an N atom, and the heterocyclyl optionally contains, in addition to the N atom, 1 to 2 heteroatoms independently selected from O, N, and S.

[0047] In another embodiment, R 3 are -H, -F, -Cl, -Br, -CH3, -CH2CH3, [ka] is.

[0048] In some embodiments, in the compounds of formula I, I-1, or I-2 provided by the present invention, R 1 , R 2 , and R 3 R is independently one of the options and combinations described above. 4 may further be selected from the following:

[0049] In a first type of embodiment, R4 teeth, [ka] and; X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t -, or -O-; where R c , R h , R i and t are as optionally defined wherever they occur herein; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each R j is independently -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -SH, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -C(O)H, or -C(O)OH, wherein the alkyl, alkoxy, alkenyl, alkynyl, Each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is selected from -H, =O, halogen, -CN, -OH, -SH, -NO2, -NH2, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -C(O)H, -C(O)OH, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, or 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or each of said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is optionally substituted with one or more substituents selected from -S(O)OH, -S(O)OH, -NHS(O)OH, or -NHS(O)OH; or each R j is independently optionally -O-(C3-C6)cycloalkyl, -S(O)2OH, -S(O)OH, -NHS(O)2OH, or -NHS(O)OH; m is an integer selected from 0 to 6; n is 0, 1, or 2.

[0050] In some embodiments of the first type, R 4 teeth, [ka] and; X is a chemical bond, -CH2-, -CH2CH2-, -NHCH2-, -NHCH2CH2-, or -O-; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each R j are independently -H, halogen, -OH, -NH, -CN, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkyl or -(C1-C6)alkoxy substituted with any number of halogens, oxazolyl, thiazolyl, and triazolyl; m is an integer selected from 0 to 6; n is 0, 1, or 2.

[0051] In some embodiments of the first type, R 4 teeth, [ka] and; X is a chemical bond, -CH2-, -CH2CH2-, -NHCH2-, -NHCH2CH2-, or -O-; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each Rj are independently -H, halogen, -OH, -NH, -CN, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkoxy, -O-(C3-C6)cycloalkyl, -(C1-C6)alkyl substituted with any number of halogens, -(C1-C6)alkoxy substituted with any number of halogens, -(C3-C6)cycloalkyl substituted with any number of halogens, -O-(C3-C6)cycloalkyl substituted with any number of halogens, oxazolyl, thiazolyl, and triazolyl; m is an integer selected from 0 to 6; n is 0, 1, or 2.

[0052] In a second type of embodiment, R 4 teeth, [ka] and; X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t -, or -O-; where R c , R h , R i and t are as optionally defined wherever they occur herein; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each R jis independently -H, halogen, -OH, -NH2, -CN, -NO2, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -SH, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -C(O)H, or -C(O)OH, wherein the alkyl, alkoxy, alkenyl, alkynyl, and aryl groups are as defined above. Each of the aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from =O, halogen, -CN, -OH, -SH, -NO2, -NH2, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -C(O)H, -C(O)OH, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, or 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or each of said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is substituted with one or more substituents selected from -S(O)OH, -S(O)OH, -NHS(O)OH, or -NHS(O)OH; or R j is independently optionally =O, -S(O)OH, -S(O)OH, -NHS(O)OH, or -NHS(O)OH; m and p are independently integers selected from 0 to 6; n is 0, 1, or 2; Ring A is (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S.

[0053] In some embodiments of the second type, R 4 teeth, [ka] and; X is a chemical bond, -CH2-, -CH2CH2-, -NHCH2-, -NHCH2CH2-, or -O-; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each R j are independently -H, halogen, -OH, -NH, -CN, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkyl or -(C1-C6)alkoxy substituted with any number of halogens, oxazolyl, thiazolyl, or triazolyl; m and p are independently integers selected from 0 to 6; n is 0, 1, or 2; Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine, or triazine.

[0054] In some embodiments of the second type, R 4 teeth, [ka] and; X is a chemical bond, -CH2-, -CH2CH2-, -NHCH2-, -NHCH2CH2-, or -O-; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each R j are independently -H, halogen, -OH, -NH, -CN, =O, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkyl substituted with any number of halogens, -(C1-C6)alkoxy substituted with any number of halogens, oxazolyl, thiazolyl, or triazolyl; m and p are independently integers selected from 0 to 6; n is 0, 1, or 2; Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine, triazine, 4,5-dihydro-1H-imidazole, or 1,3-dioxolane.

[0055] In some other specific embodiments, R 4 furthermore, [ka] can be selected as

[0056] In some other specific embodiments, R 4 furthermore, [ka] can be selected as

[0057] As a first preferred option, in some embodiments, the present invention provides a compound of Formula I, I-1, or I-2, or an isomer, pharmaceutically acceptable salt, or solvate thereof: [ka] During the ceremony, R 1 and R 2 are independently -H, -F, -Cl, -Br, -OH, -NH2, -CN, -NO2, -(C1-C6) straight chain alkyl, -(C1-C6) branched alkyl, -(C3-C6) cycloalkyl, or 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein each of said alkyl, cycloalkyl, or heterocyclyl is selected from -F, -Cl, -Br, -CN, -R a , -OR b , and -NR c R d or optionally substituted with one or more substituents selected from: Alternatively, R 1 and R 2 may optionally be joined together with the atom to which they are attached to form -(C3-C8)cycloalkyl or a 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R 3 is -H, -F, -Cl, -Br, -(C1-C6) alkyl, -(C3-C6) cycloalkyl, C6-C8 aryl, or a 7-14 membered bicyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, aryl, or fused ring groups is selected from -F, -Cl, -Br, -CN, -Ra , and -OR b and optionally substituted with one or more substituents selected from: R a , R b , R c , and R d is independently, in each occurrence, -H, -F, -Cl, -Br, -OH, -NH, -CN, -NO, -(C-C)alkyl, -(C-C)cycloalkyl, or 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein said alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO, -NH, and -(C-C)alkyl; R 4 teeth, [ka] and; X is a chemical bond, -CH2-, -CH2CH2-, -NHCH2-, -NHCH2CH2-, or -O-; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each R j are independently -H, halogen, -OH, -NH, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C1-C6)alkyl substituted with any number of halogens, -O-(C1-C6)alkyl substituted with any number of halogens, oxazolyl, thiazolyl, or triazolyl; or each R jmay further independently be selected from: =O, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(C3-C6)cycloalkyl substituted with any number of halogens, and -O-(C3-C6)cycloalkyl substituted with any number of halogens; m and p are independently 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine, or triazine; or, ring A is 4,5-dihydro-1H-imidazole or 1,3-dioxolane.

[0058] As a second preferred option, in some embodiments, the present invention provides a compound of Formula I, I-1, or I-2, or an isomer, pharmaceutically acceptable salt, or solvate thereof: [ka] During the ceremony, R 2 is -H, -F, -Cl, or -Br; R 1 are -H, -F, -Cl, -Br, -OH, -NH2, -(CH2) q CH3, -(CH2) q OH, -CH(OH)(CH2) q CH3, -C(OH)((CH2) q CH3)2, [ka] -(CH2) q NH2, -(CH2) q NH(CH2) q CH3, -(CH2) q N((CH2) qCH3)2, a 3- to 6-membered heterocycloalkyl containing one N atom, or -(C1-C6)alkyl substituted with a 3- to 6-membered heterocycloalkyl containing one N atom; or R 1 teeth, [ka] -CH2F, -CHF2, -(CH2) q CH2F, -(CH2) q CHF2, -CH2Cl, -CHCl2, -(CH2) q CH2Cl, or -(CH2) q CHCl2; q, in each occurrence, is independently 0, 1, 2, 3, or 4; Alternatively, R 1 and R 2 may optionally be joined together with the atoms to which they are attached to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, or 2,3-dihydrobenzofuran ring; or R 1 and R 2 may optionally combine together with the atoms to which they are attached to form a tetrahydro-2H-pyran or an oxetane.

[0059] R 3 is —H, —F, —Cl, —Br, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, or benzopyrrolidinyl, wherein said pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, or benzopyrrolidinyl is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —O—(C1-C6)alkyl, —O—(C3-C6)cycloalkyl, piperazinyl, and piperazinyl substituted with any number of halogens or —(C1-C6)alkyl; or R 3 teeth [ka] where the ring [ka] is a 3- to 6-membered saturated or unsaturated N-containing heterocyclyl linked via an N atom, said heterocyclyl optionally containing, in addition to said N atom, 1 to 2 heteroatoms independently selected from O, N, and S; [ka] is optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C1-C6)alkyl, -O-(C3-C6)cycloalkyl, -(C1-C6)haloalkyl, -(C3-C6)halocycloalkyl, -O-(C1-C6)haloalkyl, -O-(C3-C6)halocycloalkyl, pyrazolyl, pyrazolyl substituted with any number of halogens or -(C1-C6)alkyl, piperazinyl, piperazinyl substituted with any number of halogens or -(C1-C6)alkyl.

[0060] R 4 teeth, [ka] and; X is a chemical bond, -CH2-, -CH2CH2-, -NHCH2-, -NHCH2CH2-, or -O-; [ka] represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH, or CH, and Y 2 and Y 3 are not simultaneously both N; Each R jare independently -H, halogen, -OH, -NH, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C1-C6)alkyl substituted with any number of halogens, -O-(C1-C6)alkyl substituted with any number of halogens, oxazolyl, thiazolyl, or triazolyl; or each R j may further independently be selected from =O, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(C3-C6)cycloalkyl substituted with any number of halogens, or -O-(C3-C6)cycloalkyl substituted with any number of halogens; m and p are independently 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine, or triazine; or, ring A is 4,5-dihydro-1H-imidazole or 1,3-dioxolane.

[0061] As a third preferred option, in some embodiments, the present invention provides a compound of Formula I, I-1, or I-2, or an isomer, pharmaceutically acceptable salt, or solvate thereof: [ka] During the ceremony, R 2 is -H, -F, -Cl, or -Br; R 1 are -H, -F, -Cl, -Br, -OH, -NH2, [ka] or R 1 teeth, [ka] Is it; Alternatively, R1 and R 2 are optionally bonded together with the atoms to which they are attached, [ka] or R 1 and R 2 are optionally bonded together with the atoms to which they are attached, [ka] can be formed; R 3 -H, -F, -Cl, -Br, -CH3, -CH2CH3, pyridyl, [ka] or R 3 teeth, [ka] and; R 4 teeth, [ka] or R 4 teeth, [ka] is.

[0062] The present invention preferably provides the compounds shown in the table below, or an isomer, pharmaceutically acceptable salt, or solvate thereof. [ka] [ka] [ka]

[0063] The present invention preferably further provides the compounds shown in the table below, or an isomer, pharmaceutically acceptable salt, or solvate thereof. [ka]

[0064] The present invention preferably further provides the compounds shown in the table below, or an isomer, pharmaceutically acceptable salt, or solvate thereof. [ka] [ka] [ka] [ka]

[0065] Based on the above, the present invention further provides a compound of formula II, or an isomer, pharmaceutically acceptable salt, or solvate thereof. [ka] In formula II, R 3 and R 4 represents any corresponding R in the compounds of formula I, I-1, or I-2 above. 3 and R 4 Defined as; Each R j is independently -H, halogen, -OH, -NH2, -CN, =O, -NO2, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -SH, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -S(O)2OH, -S(O)OH, -NHS(O)2OH or -NHS(O)OH, -C(O)H, or -C(O)OH, wherein the alkyl, alkoxy, alkenyl, alkynyl, Each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is selected from -H, =O, halogen, -CN, -OH, -SH, -NO2, -NH2, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -S(O)2OH, -S(O)OH, -NHS(O)2OH or -NHS(O)OH, -C(O)H, -C(O)OH, O, N, and S, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from -H, =O, halogen, -CN, -OH, -SH, -NO2, -NH2, -S(O)2H, -S(O)2NH2, -S(O)H, -S(O)NH2, -NHS(O)2H, -NHS(O)H, -S(O)OH, -NHS(O)2OH or -NHS(O)OH, -C(O)H, -C(O)OH, O, N, and S, C6-C 14 optionally substituted with one or more substituents selected from aryl or 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; m is independently an integer selected from 0 to 6; v is 0 or 1; Ring B is (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S.

[0066] In some other specific embodiments, Each R jare independently -H, halogen, -OH, -NH, -CN, =O, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkyl substituted with any number of halogens, -(C1-C6)alkoxy substituted with any number of halogens, oxazolyl, thiazolyl, and triazolyl; The ring B is (C3-C8)cycloalkyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C6-C 14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered bicyclic or tricyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S.

[0067] In some other specific embodiments, Ring B is a 3- to 7-membered oxacycloalkyl or an 8- to 10-membered azabicyclic fused heteroaryl, or ring B is oxacycloheptane, oxacyclohexane, tetrahydrofuran, oxetane, oxacyclopropane, 1H-indole, or isoindoline.

[0068] In some other specific embodiments, The above ring B is [ka] is.

[0069] The present invention preferably provides the compounds shown in the table below, or an isomer, pharmaceutically acceptable salt, or solvate thereof. [ka]

[0070] Based on the above, the present invention further provides a deuterated compound of formula I or II above, or an isomer, pharmaceutically acceptable salt, or solvate thereof. [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R j , m, v, and ring B may be any of the corresponding R 1 , R 2 , R 3 , R 4 , R j , m, v, and ring B are defined as Any one or more H in the compounds of formula I or II is replaced with D.

[0071] In some other specific embodiments, In compounds of formula I or II, the structure " [ka] " in which one or more H's are replaced by D, or R 4 In the compound of formula I or II, any one or more H in the structure " [ka] " All H in " has been replaced with D.

[0072] In some other specific embodiments, If selected as H, R 1 , R 2 , or R 3 are independently optionally substituted with D.

[0073] The present invention preferably provides the compounds shown in the table below, or an isomer, pharmaceutically acceptable salt, or solvate thereof. [ka]

[0074] Based on the above, the present invention further provides a key intermediate of formula III for preparing the compounds of formula I or II above. [ka] During the ceremony, R 10 is -H or an amino protecting group, and R 20 is -H, an amino protecting group, or [ka] and R 4 is any corresponding R in the compounds of formula I or II above. 4 Is defined as; Alternatively, R 10 is -H, an amino protecting group, [ka] where R 1 , R 2 , and R 3 is any corresponding R in the compounds of formula I or II above. 1 , R 2 , and R 3 m, v, R j and ring B may be any of the corresponding m, v, R in the compounds of formula I or II described above. j , and ring B is defined as R 20 is —H or an amino protecting group.

[0075] In some other specific embodiments, Each of the aforementioned amino protecting groups is independently selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht, or -Alloc.

[0076] In some other specific embodiments, Any one or more H in the compound of formula III is replaced with D.

[0077] The present invention preferably provides the intermediate compounds shown in the table below. [ka]

[0078] In the present invention, when a subsequent technical solution further defines an earlier technical solution, it may only further define some of the technical features, in which case the undefined technical features may have the definitions in the earlier technical solution or the definitions at the places where they appear, if necessary.

[0079] As described above, the present invention provides a class of compounds having the structural features of general formula I. Research has found that this class of compounds can effectively stimulate PKR and / or inhibit USP9X kinase activity, thereby preventing or treating diseases associated with kinases such as PKR and / or USP9X. Specifically, the compounds of the present invention have high PKR agonist activity and / or USP9X inhibitory activity. Other experimental data have shown that the exposure of the compounds of the present invention to rats through oral administration can reach 1700 h*ng / mL or more.

[0080] Second, the present invention further provides a pharmaceutical composition comprising any one of the compounds of the present invention described above. The pharmaceutical composition further comprises a pharmaceutically acceptable excipient. The pharmaceutical composition can be provided in any pharmaceutically acceptable dosage form and administration route. Acceptable dosage forms include, but are not limited to, tablets, capsules, granules, pills, pastes, powders, tinctures, films, patches, liniments, implants, injections, lozenges, drops, sprays, aerosols, nebulizers, gels, suppositories, ointments, etc. Acceptable administration routes include, but are not limited to, oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal, or pulmonary (inhalation) administration.

[0081] Third, the present invention further provides use of the compound or pharmaceutical composition of the present invention for preventing or treating a disease, wherein the compound or pharmaceutical composition stimulates PKR or inhibits USP9X, thereby preventing or treating the associated disease.

[0082] As PKR agonists, administering an effective amount of the compounds or pharmaceutical compositions of the present invention to activate PKR helps to prolong the lifespan of red blood cells in a patient and is useful for preventing or treating conditions associated with symptoms such as hereditary non-spherocytic hemolytic anemia, hemolytic anemia (e.g., chronic hemolytic anemia caused by phosphoglycerate kinase deficiency), hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g., congenital anemia (e.g., enzymopathy)), or anemia associated with chronic disease. In some embodiments, the disease or disorder is hereditary non-spherocytic hemolytic anemia. In some embodiments, the disease is hemolytic anemia (e.g., in patients diagnosed with PKD), SCD (e.g., sickle cell anemia), or thalassemia (e.g., β-thalassemia).

[0083] As USP9X inhibitors, the administration of an effective amount of the compound or pharmaceutical composition of the present invention to inhibit USP9X is useful for preventing or treating USP9X-mediated diseases, such as cancers and tumors, including, but not limited to, colon cancer, kidney cancer, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, melanoma, lymphoma, glioblastoma, and multiple myeloma.

[0084] Based on the corresponding applicability of the compounds or pharmaceutical compositions provided by the present invention as PKR agonists and / or USP9X inhibitors, the present invention further provides corresponding pharmaceutical uses thereof, which can be applied in the preparation of medicaments for treating corresponding diseases. DETAILED DESCRIPTION OF THE INVENTION

[0085] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0086] "Alkyl" refers to an aliphatic hydrocarbon group, and may be a substituted or unsubstituted saturated hydrocarbon group. The alkyl moiety may be a straight-chain or branched alkyl. For example, -(C1-C6)alkyl or -(C1-C3)alkyl. -(C1-C6)alkyl refers to an alkyl having 1 to 6 carbon atoms, such as an alkyl having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like. The alkyl may be substituted or unsubstituted with one or more substituents, including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, heteroaryl, amido, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.

[0087] "Alkenyl" refers to a substituted or unsubstituted unsaturated hydrocarbyl having a carbon-carbon double bond within its structure. The alkenyl moiety may be a straight-chain or branched alkenyl. For example, -(C2-C6)alkenyl or -(C2-C4)alkenyl. -(C2-C6)alkenyl refers to an alkenyl having 2 to 6 carbon atoms, such as an alkenyl having 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Non-limiting examples of alkenyl include vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, n-hexenyl, and the like. The alkenyl may be substituted or unsubstituted with one or more substituents, including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, heteroaryl, amido, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.

[0088] "Alkynyl" refers to a substituted or unsubstituted unsaturated hydrocarbyl having a carbon-carbon triple bond within its structure. The alkynyl moiety may be a straight-chain or branched alkynyl. For example, -(C2-C6)alkynyl or -(C2-C4)alkynyl. -(C2-C6)alkynyl refers to an alkynyl having 2 to 6 carbon atoms, such as 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, n-hexynyl, and the like. The alkynyl may be substituted or unsubstituted with one or more substituents, including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, heteroaryl, amido, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.

[0089] "Ring" refers to a covalently closed structure, including, for example, carbocycles (e.g., aryl, cycloalkyl, or cycloalkenyl), heterocyclyls (e.g., heteroaryl, heterocycloalkyl, or heterocycloalkenyl), aromatic groups (e.g., aryl or heteroaryl), and non-aromatic groups (e.g., cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl), which may be substituted or unsubstituted. Rings may be optionally substituted and may be monocyclic or polycyclic. Exemplary polycyclic rings generally include bicyclic and tricyclic rings. Rings of the present application typically have 3 to 20 ring atoms, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms.

[0090] The term "membered" refers to the number of skeletal atoms constituting the ring. Typical five-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene, and typical six-membered rings include, for example, cyclohexyl, cyclohexenyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, and benzene. A ring containing a heteroatom as a skeletal atom is a heterocycle.

[0091] "Heteroatom" refers to an atom other than carbon and hydrogen. One or more of the heteroatoms in the heterocycle of the present application can be independently selected from, but not limited to, O, S, N, Si, and P.

[0092] The term "aromatic group" refers to a cyclic group having a conjugated π-electron system, including aryl, in which all skeletal atoms constituting the ring are carbon atoms, and heteroaryl, in which the skeletal atoms constituting the ring include heteroatoms. "Aryl" preferably refers to a monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system of 6 to 14 carbon atoms (6-14 members), preferably 6 to 10 atoms, such as phenyl or naphthyl, which may be substituted or unsubstituted. Phenyl is more preferred. "Heteroaryl" preferably refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms and 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms, in which the heteroatoms are selected from oxygen, sulfur, and nitrogen, and in which the heteroaryl may be substituted or unsubstituted. Heteroaryl is preferably a 5- to 10-membered ring and contains 1 to 3 heteroatoms; more preferably a 5- or 6-membered ring and contains 1 to 2 heteroatoms; for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, etc. are preferred, and imidazolyl, thiazolyl, pyrazolyl, or pyrimidinyl, thiazolyl are preferred; and pyrazolyl, such as 1H-pyrazol-4-yl, or thiazolyl is more preferred. A heteroaryl ring can be fused with an aryl, heterocycloalkyl, cycloalkyl ring, or another heteroaryl to form a fused heteroaryl. The fused heteroaryl is preferably an 8- to 10-membered fused heteroaryl, and includes, but is not limited to, indolyl, such as 1H-indol-5-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, such as 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, or 1H-benzo[d]imidazolyl, such as 1H-benzo[d]imidazol-6-yl.

[0093] A "non-aromatic group" refers to a cyclic group that does not have a conjugated π-electron system and is not aromatic. Non-aromatic groups are also commonly referred to as alicyclic groups or radicals, and include cycloalkyl or cycloalkenyl groups in which the skeletal atoms of the ring are all carbon atoms, and heterocycloalkyl or heterocycloalkenyl groups in which the skeletal atoms of the ring include heteroatoms.

[0094] "Fused" refers to rings that share adjacent pairs of carbon atoms, typically bicyclic or tricyclic fused rings.

[0095] A "fused ring group" includes a "fused non-aromatic group" and a "fused aromatic group," a "fused non-aromatic group" includes a "fused cycloalkyl," a "fused heterocycloalkyl," a "fused cycloalkenyl," and a "fused heterocycloalkenyl," and a "fused aromatic group" includes a "fused aryl" and a "fused heteroaryl," all of which may be substituted or unsubstituted.

[0096] "Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent containing 1 to 3 rings, including monocycloalkyl, bicycloalkyl, and tricycloalkyl, and having 3 to 20, preferably 3 to 10, carbon atoms capable of forming a ring (i.e., 3- to 10-membered cycloalkyl, -(C3-C 10 ) also known as cycloalkyl), for example, 3-8, 3-7, 3-6, 5-6. Cycloalkyl includes the following rings: [ka] Preferably, the cycloalkyl is selected from monovalent cycloalkyls derived from: and is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. The cycloalkyl may be substituted or unsubstituted.

[0097] When a cycloalkyl is linked to two groups depending on the structure or circumstances, it should be understood that the cycloalkyl is a divalent group, i.e., has two linking sites. In this case, it may be referred to as a cycloalkylene group. Examples of preferred cycloalkylene groups include, but are not limited to, monocyclic structures such as cyclopropylene, cyclobutylene, cyclopentylene (e.g., cyclopenta-1,2-diyl, cyclopenta-1,3-diyl), cyclohexylene (e.g., cyclohexa-1,2-diyl, cyclohexa-1,3-diyl, cyclohexa-1,4-diyl), cycloheptanylene, or cyclooctanylene.

[0098] "Heterocycloalkyl" and "cycloheteroalkyl" are used interchangeably and refer to a saturated non-aromatic monocyclic, fused, bridged, or spirocyclic ring containing one or more (e.g., 1, 2, 3, or 4) heteroatoms. Heteroatoms include N, O, S, or SO2 ( [ka] ), preferably N, O, and / or S. A heterocycloalkyl can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, or 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) monocyclic, bicyclic, or tricyclic group. Exemplary heterocycloalkyls include those having the following rings: [ka] These heterocycloalkyl groups include, but are not limited to, monovalent groups derived from [ka] It can also be represented by a commonly understood structural formula, such as:

[0099] When a heterocycloalkyl is linked to two groups depending on the structure or circumstances, it should be understood that the heterocycloalkyl is a divalent group, i.e., has two linking sites. In this case, it may be referred to as a heterocycloalkylene group. Examples of heterocycloalkylene groups include, for example: [ka] Examples of divalent groups formed from the above-mentioned groups include, but are not limited to, the following.

[0100] "Cycloalkenyl" refers to a cyclic hydrocarbon substituent that contains 1 to 3 rings and one or more double bonds, but none of the rings has a completely conjugated π-electron system, and is not aromatic, and includes monocycloalkenyl, bicycloalkenyl, and tricycloalkenyl, and has 3 to 20, preferably 3 to 10, carbon atoms capable of forming a ring (i.e., 3- to 10-membered cycloalkenyl, -(C3-C 10 ) also known as cycloalkenyl), for example, 3 to 8, 3 to 7, 3 to 6, or 5 to 6 rings. Cycloalkenyl includes the following rings: [ka] Preferably, the cycloalkenyl group is selected from monovalent cycloalkenyl groups derived from the following formula: and more preferably selected from cyclopropenyl, cyclopentenyl, and cyclohexenyl. The cycloalkenyl group may be substituted or unsubstituted. When the cycloalkenyl group is linked to two groups depending on the structure and circumstances, it is understood that the cycloalkenyl group is a divalent group, i.e., has two linking sites. In this case, the cycloalkenyl group may be referred to as a cycloalkenylene group.

[0101] "Heterocycloalkenyl" refers to an unsaturated non-aromatic monocyclic, fused, bridged, or spiro ring containing one or more (e.g., 1, 2, 3, or 4) heteroatoms. Heteroatoms include N, O, S, or SO2 ( [ka] ), preferably N, O, and / or S. A heterocycloalkenyl can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, or 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) monocyclic, bicyclic, or tricyclic group. Exemplary heterocycloalkenyl groups include the following rings: [ka] These heterocycloalkenyl groups include, but are not limited to, monovalent groups derived from: [ka] It can also be represented by a commonly understood structural formula, such as: When a heterocycloalkenyl is linked to two groups depending on the structure and circumstances, it should be understood that the heterocycloalkenyl is a divalent group, i.e., has two linking sites. In this case, it is sometimes referred to as a heterocycloalkenylene group.

[0102] "Oxo" means that a hydrogen on a carbon is replaced with =O.

[0103] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0104] "Haloalkyl" refers to an alkyl in which at least one hydrogen has been replaced with a halogen atom, for example, CF3.

[0105] "Substituted" means that one or more hydrogen atoms in a group, preferably up to five (e.g., 1, 2, 3, 4, or 5), more preferably 1 to 3 hydrogen atoms, can be independently replaced with the corresponding number of substituents. Obviously, substituents exist only at their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogen may be unstable when bonded to carbon atoms with unsaturated (e.g., olefinic) bonds.

[0106] An "inhibitor" refers to a substance that reduces enzyme activity.

[0107] "Agonist" refers to a substance that increases enzyme activity.

[0108] "Optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur; it indicates that the event or circumstance may or may not occur.

[0109] As used herein, the term "substituted or unsubstituted" means that any group is mono- or polysubstituted (including multiple substitutions on the same moiety) with specified substituents, to the extent permitted by the chemical formula, and each substituent may be located at any available position on the group and may be linked via any available atom on the substituent. "Any available position" refers to any position on the group that is chemically accessible by methods known in the art or taught herein and that does not result in an overly unstable molecule. When there are more than one substituent on a group, each substituent is defined independently of any other substituent, and therefore each substituent may be the same or different.

[0110] Regarding "stereoisomerism," the term "stereoisomer" used herein refers to compounds of the present invention that contain one or more asymmetric centers and may exist in the form of a racemate, a racemic mixture, a single enantiomer, a diastereomeric mixture, or a single diastereoisomer. Because compounds of the present invention may have asymmetric centers, two optical isomers exist. The scope of the present invention encompasses all possible optical isomers and mixtures thereof. When compounds of the present invention contain olefinic double bonds, the scope of the present invention includes cis- and trans-isomers unless otherwise specified. Compounds of the present invention may exist in the form of tautomers (a type of functional isomer) in which the position of hydrogen is changed due to a shift in one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures of all compounds are all within the scope of the present invention.

[0111] As used herein, the term "compounds of the invention" is intended to encompass compounds of general formula (I) and (II) as defined herein, or preferred or specific embodiments thereof (such as compounds of formula (I-1) and (I-2) and including exemplary compounds), as well as stereoisomers, pharmaceutically acceptable salts, tautomers, or solvates thereof.

[0112] As used herein, the term "pharmaceutically acceptable" means molecular entities and compositions that are approved or approvable by national authorities or listed in generally recognized pharmacopoeias for use in animals, particularly humans, or that do not produce adverse allergic or other untoward reactions when administered in appropriate amounts to animals, including humans.

[0113] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and alkali addition salts.

[0114] As used herein, the term "individual" includes humans and non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal individuals. As used herein, "non-human animals" include all vertebrates, including non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0115] The "pharmaceutical composition" referred to in this invention refers to a composition comprising one or more of the compounds of formula (I), formula (I-1), formula (I-2), or formula (II), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, and a carrier or excipient generally accepted in the art for delivering the compound having the above biological activity to an organism (e.g., human).

[0116] As used herein, the term "pharmaceutical combination" refers to the combination of a compound of the present invention with another active agent to achieve the objectives of the present invention. The other active agent may be one or more additional compounds of the present invention, or a second or additional (e.g., third) compound that is compatible with the compound of the present invention, i.e., does not adversely affect each other, or has complementary activities. Such active agents are present in a suitable combination in amounts effective to achieve the intended purpose. The other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or may be administered in separate, discrete units from the compound of the present invention. If administered separately, the administration may be simultaneous or sequential. If administered sequentially, the administration may be close in time or distant in time.

[0117] It should be understood that in selecting groups in the structure of the compounds of the present invention, the groups that connect, coordinate, or influence each other should be selected appropriately, subject to the rules of chemical valence bonding.

[0118] According to the content of the present invention, other modifications, substitutions or changes can be made in various forms in accordance with common technical knowledge and means in the relevant technical field without departing from the basic technical idea of ​​the present invention described above. [Example]

[0119] In order to further illustrate the present invention, the active compounds provided by the present invention and their preparation and use will be described in detail below in conjunction with examples.

[0120] The following abbreviations or terms have the following meanings: Grubbs 2 stands for second generation Grubbs catalyst. DMF stands for N,N-dimethylformamide. DMSO stands for dimethyl sulfoxide. HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. DIPEA stands for N,N-diisopropylethylamine. Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium. Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. -Cbz represents a benzyloxycarbonyl protecting group. -Boc represents a tert-butoxycarbonyl protecting group. -Fmoc represents a 9-fluorenylmethoxycarbonyl protecting group. -PMB represents a p-methoxybenzyl protecting group. -Bn represents a benzyl protecting group. -Trt represents a trityl protecting group. -Tos represents a tosyl protecting group. -Pht represents a phthalyl protecting group. -Alloc represents an allyloxycarbonyl protecting group. Tris buffer refers to tris(hydroxymethyl)aminomethane buffer. -TBS represents tert-butyldimethylsilyl. -TBDPS represents tert-butyldiphenylsilyl.

[0121] This patent further provides methods for synthesizing the aforementioned compounds. The synthetic methods of the present invention are primarily based on preparations reported in the chemical literature or use commercially available chemical reagents as starting materials for related syntheses.

[0122] method [ka]

[0123] In the above reaction scheme, "R A "teeth [ka] where R 4 is as defined wherever it appears in the present invention. C "teeth, [ka] where R 1 , R 2 , R 3 , R j , m, v, and ring B are as defined wherever they occur in the present invention. B " is protected by a protecting group R C and when the protecting group is removed, R B is R C Protecting groups include, but are not limited to, -TBS or -TBDPS.

[0124] The following steps involve the use of compound ZR A and compound ZRB Here, "Z" reacts with the amino group to form R A or R B of" [ka] " is a group that can be attached onto a compound ZR, and the condensation reaction is preferably a condensation reaction between a sulfonyl chloride and an amino group, or a condensation reaction between a carboxy group and an amino group, and "Z" can be a functional group independently selected in each compound, including, but not limited to, -Cl, -F, -Br, and -OH. A is Cl-R A and the compound ZR B OH-R B It is preferable that:

[0125] Process 1 Compound A was dissolved in tetrahydrofuran, and then triethylamine and compound ZR A After the reaction is completed, the product is extracted with ethyl acetate three times, and the combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by chromatography to obtain compound B.

[0126] Process 2 Compound B is dissolved in trifluoroacetic acid and reacted at 60°C. After the reaction is completed, the product is concentrated to dryness and then purified by chromatography to obtain compound C.

[0127] Process 3 Compound C was dissolved in DMF, and then compound ZR B , HATU, and DIPEA are added in that order and allowed to undergo condensation reaction at 25°C. After the reaction is complete, the reaction solution is poured into water and extracted three times with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by chromatography to obtain compound D.

[0128] Process 4 Compound D is dissolved in a tetrahydrofuran solution, and then tetrabutylammonium fluoride is added to carry out a deprotection reaction, ultimately yielding compound E.

[0129] Example 1: Preparation of (S)-1-(1'-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 1)

[0130] The synthesis steps are as follows: [ka]

[0131] Step 1: Preparation of 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (Compound 1A) [ka]

[0132] 5-Bromopyridine-2,3-diol (13.0 g, 68.4 mmol) was dissolved in DMF (130 mL), and then 1,2-dibromoethane (19.3 g, 102.6 mmol) and potassium carbonate (28.3 g, 205 mmol) were added. The reaction mixture was stirred at 100 °C overnight until the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 1A.

[0133] MS (ESI) m / z 216.0 (M+H) + .

[0134] Step 2: Preparation of 7-(benzylthio)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (Compound 1B) [ka]

[0135] Under argon protection, 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (1.0 g, 4.6 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of benzyl mercaptan (570 mg, 4.6 mmol), Pd2(dba)3 (240 mg, 0.23 mmol), Xantphos (270 mg, 0.46 mmol), and DIPEA (1,190 mg, 9.3 mmol). The reaction mixture was stirred overnight at 80 °C. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 1B.

[0136] MS (ESI) m / z 260.1 (M+H) + .

[0137] Step 3: Preparation of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride (Compound 1C) [ka]

[0138] 7-(Benzylthio)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (800 mg, 3 mmol) and 1,3-dichloro-5,5-dimethylhydantoin (820 mg, 6 mmol) were dissolved in a mixture of acetonitrile (30 mL), acetic acid (0.75 mL), and water (0.5 mL). The reaction mixture was stirred overnight at 25 °C. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 1C.

[0139] MS (ESI) m / z 236.0 (M+H) + .

[0140] Step 4: Preparation of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid (Compound 1D) [ka]

[0141] (S)-3-Hydroxy-2-phenylpropionic acid (900 mg, 5.4 mmol) and 4-dimethylaminopyridine (1.32 g, 10.8 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of tert-butylchlorodiphenylsilane (1.64 g, 6 mmol). The reaction mixture was stirred overnight at 25 °C. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified using a C-18 column to obtain compound 1D.

[0142] MS (ESI) m / z 405.2 (M+H) + .

[0143] Step 5: Preparation of benzyl 3-methyleneazetidine-1-carboxylate (Compound 1E) [ka]

[0144] Benzyl 3-oxoazetidine-1-carboxylate (86.6 g, 268 mmol) and methyltriphenylphosphonium bromide (50 g, 243.5 mmol) were dissolved in tetrahydrofuran (500 mL), followed by the addition of potassium t-butoxide (40.9 g, 365.5 mmol). The mixture was stirred overnight at 25 °C. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified using a silica gel column to obtain compound 1E.

[0145] MS (ESI) m / z 204.1 (M+H) + .

[0146] Step 6: Preparation of 1-benzyl 1'-(tert-butyl)2H,2'H-[3,3'-diazetidinylidene]-1,1'(4H,4'H)-dicarboxylate (Compound 1F) [ka]

[0147] Benzyl 3-methyleneazetidine-1-carboxylate (39 g, 191.9 mmol) and tert-butyl 3-methyleneazetidine-1-carboxylate (32.47 g, 191.9 mmol) were dissolved in dichloroethane (2000 mL), and then Grubbs 2 (16.29 g, 19.19 mmol) was added. The mixture was stirred at 50° C. for 48 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified using a silica gel column to obtain compound 1F.

[0148] MS (ESI) m / z 345.2 (M+H) + .

[0149] Step 7: Preparation of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-benzyl carboxylate (compound 1G) [ka]

[0150] 1'-(tert-butyl) 2H,2'H-[3,3'-diazetidinylidene]-1,1'(4H,4'H)-1-benzyl dicarboxylate (3.2 g, 9.29 mmol) was dissolved in ethyl acetate (32 mL), and then p-toluenesulfonic acid (1.6 g, 9.29 mmol) was added. The reaction mixture was stirred at 50°C for 6 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified using a silica gel column to obtain compound 1G.

[0151] MS (ESI) m / z 245.1 (M+H) + .

[0152] Step 8: Preparation of benzyl 1'-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 1H) [ka]

[0153] 1',4'-Dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-benzyl carboxylate (100 mg, 0.41 mmol) and triethylamine (82.5 mg, 0.82 mmol) were dissolved in tetrahydrofuran (4 mL), and then 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride (96.5 mg, 0.41 mmol) was added, and the mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was separated and purified using a silica gel column to obtain compound 1H.

[0154] MS (ESI) m / z 444.1 (M+H) + .

[0155] Step 9: Preparation of 7-((1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-ylsulfonyl)-2,3-dihydro-[1,4]dioxino[2.3-b]pyridine) (Compound 1I) [ka]

[0156] Benzyl 1'-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (120 mg, 0.27 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 60°C overnight. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified using a silica gel column to obtain compound 1I.

[0157] MS (ESI) m / z 310.1 (M+H) + .

[0158] Step 10: Preparation of (S)-3-((tert-butyldiphenylsilyl)oxy)-1-(1′-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-1′,4′-dihydro-2H,2′H-[3,3′-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 1J) [ka]

[0159] (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid (80 mg, 0.2 mmol) and 7-((1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-ylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine) (61 mg, 0.2 mmol) were dissolved in DMF (5 mL), followed by the addition of HATU (112 mg, 0.3 mmol) and DIPEA (77 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness and subjected to reverse-phase high-pressure liquid chromatography to prepare compound 1J.

[0160] MS (ESI) m / z 695.3 (M+H) + .

[0161] Step 11: Preparation of (S)-1-(1'-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 1) [ka]

[0162] (S)-3-((tert-butyldiphenylsilyl)oxy)-1-(1'-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (50 mg, 0.087 mmol) was dissolved in tetrahydrofuran (5 mL), and then tetrabutylammonium fluoride (45.5 mg, 0.17 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness and subjected to reverse-phase high-pressure liquid chromatography to prepare Compound 1 of Example 1.

[0163] MS (ESI) m / z 458.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 7.71 (s, 1H), 7.51-7.20 (m, 5H), 4.87 (s, 1H), 4.80-4.72 (m, 1H), 4.60 (s, 2H), 4.50-4.30 (m, 8H), 4.30-4.20 (m, 1H), 3.96 (s, 1H), 3.75-3.55 (m, 2H).

[0164] Example 2: Preparation of (S)-1-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 2) [ka]

[0165] Compound 2 of Example 2 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride.

[0166] MS (ESI) m / z 457.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.20 (m, 7H), 7.13 - 7.11 (m, 1H), 4.85 - 4.7 (m, 2H), 4.40 - 4.20 (m, 11H), 3.95 - 3.85 (m, 1H), 3.75 - 3.70 (m, 1H), 3.50 - 3.40 (m, 1H).

[0167] Example 3: Preparation of (S)-1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 3) [ka]

[0168] Compound 3 of Example 3 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with benzo[d]thiazole-6-sulfonyl chloride.

[0169] MS (ESI) m / z 456.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.77 (s, 1H), 8.35-8.24 (m, 1H), 7.90 (d, J = 9.4 Hz, 1H), 7.21 (d, J = 14.2 Hz, 5H), 4.64 (d, J = 12.5 Hz, 2H), 4.34-4.10 (m, 7H), 3.81 (d, J = 10.0 Hz, 1H), 3.61-3.50 (m, 1H), 3.40 (d, J = 7.1 Hz, 1H).

[0170] Example 4: Preparation of (S)-3-hydroxy-2-phenyl-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 4) [ka]

[0171] Compound 4 of Example 4 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride.

[0172] MS (ESI) m / z 400.0(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.11 (d, J = 11.6 Hz, 1H), 7.95 (d, J = 5.3 Hz, 1H), 7.71 (s, 1H), 7.28-7.19 (m, 5H), 4.68 (d, J = 13.2 Hz, 1H), 4.50 (s, 4H), 4.37-4.23 (m, 2H), 4.17 (d, J = 14.6 Hz, 1H), 3.85 (q, J = 9.0 Hz, 1H), 3.58 (d, J = 10.4 Hz, 1H), 3.50-3.40 (m, 2H).

[0173] Example 5 Preparation of (S)-3-hydroxy-1-(1'-((4-methoxyphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 5) [ka]

[0174] Compound 5 of Example 5 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with p-methoxybenzenesulfonyl chloride.

[0175] MS (ESI) m / z 429.5(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.80-7.65 (m, 2H), 7.20 (m, 7H), 4.83-4.60 (m, 2H), 4.24 (d, J = 30.9 Hz, 7H), 3.82 (s, 4H), 3.60-3.54 (m, 1H), 3.41 (d, J = 10.1 Hz, 1H).

[0176] Example 6 Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 6) [ka]

[0177] Step 1: Preparation of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid (Compound 6A) [ka]

[0178] 3-Hydroxy-2-phenylpropionic acid (1.0 g, 6.0 mmol) and 4-dimethylaminopyridine (1.47 g, 12 mmol) were dissolved in dichloromethane (10 mL), and then tert-butylchlorodiphenylsilane (1.54 g, 9 mmol) was added and the reaction mixture was stirred overnight at 25° C. After completion of the reaction, the reaction solution was concentrated to dryness and purified using a silica gel column to obtain compound 6A.

[0179] MS (ESI) m / z 405.2 (M+H) + .

[0180] Step 2: Preparation of benzyl 1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 6B) [ka]

[0181] Benzyl 3-(azetidin-3-ylidene)azetidine-1-carboxylate (500 mg, 2.05 mmol) and triethylamine (413 mg, 4.1 mmol) were dissolved in tetrahydrofuran (20 mL), and then 4-(difluoromethoxy)benzenesulfonyl chloride (500 mg, 2.05 mmol) was added. The reaction mixture was stirred at 25° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 6B.

[0182] MS (ESI) m / z 451.1 (M+H) + .

[0183] Step 3: Preparation of 1-((4-(difluoromethoxy)phenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazetidinylidene (Compound 6C) [ka]

[0184] Benzyl 1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (750 mg, 1.66 mmol) was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified using a silica gel column to obtain compound 6C.

[0185] MS (ESI) m / z 317.1 (M+H) + .

[0186] Step 4: Preparation of 3-((tert-butyldiphenylsilyl)oxy)-1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 6D) [ka]

[0187] 3-((tert-Butyldiphenylsilyl)oxy)-2-phenylpropionic acid (109 mg, 0.3 mmol) and 1-((4-(difluoromethoxy)phenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazetidinylidene (85 mg, 0.3 mmol) were dissolved in DMF (5 mL), followed by the addition of HATU (157 mg, 0.4 mmol) and DIPEA (104 mg, 0.8 mmol). The reaction mixture was stirred at 25°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness and subjected to reverse-phase high-pressure liquid chromatography to prepare compound 6D.

[0188] MS (ESI) m / z 703.2 (M+H) + .

[0189] Step 5: Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 6) [ka]

[0190] 3-((tert-Butyldiphenylsilyl)oxy)-1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (100 mg, 0.14 mmol) and tetrabutylammonium fluoride (37 mg, 0.14 mmol) were dissolved in tetrahydrofuran (5 mL), and the reaction mixture was stirred at 25°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness and subjected to reverse-phase high-pressure liquid chromatography to prepare compound 6 of Example 6.

[0191] MS (ESI) m / z 465.2(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 7.91 - 7.88 (m, 2H), 7.45 - 7.43 (m, 2H), 7.30 - 7.20 (m, 5H), 4.72 - 4.69 (m, 1H), 4.60 (s, 2H), 4.36 - 4.15 (m, 7H), 4.95 - 4.85 (m, 1H), 3.65 - 3.60 (m, 1H), 3.50 - 3.40 (m, 1H).

[0192] Example 7 Preparation of (S)-1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 7) [ka]

[0193] Compound 7 of Example 7 was obtained by the same preparation method as in Example 6, except that in Step 4 of Example 6, 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0194] MS (ESI) m / z 465.1(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 7.91 - 7.88 (m, 2H), 7.45 - 7.43 (m, 2H), 7.30 - 7.20 (m, 5H), 6.06 (s, 1H), 4.72 - 4.69 (m, 1H), 4.36 - 4.15 (m, 7H), 4.95 - 4.85 (m, 1H), 3.65 - 3.60 (m, 1H), 3.50 - 3.40 (m, 2H).

[0195] Example 8 Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-hydroxy-2-phenylethan-1-one (Compound 8) [ka]

[0196] Compound 8 of Example 8 was obtained by the same preparation method as in Example 6, except that in Step 4 of Example 6, 2-hydroxy-2-phenylacetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0197] MS (ESI) m / z 451.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.90 (m, 2H), 7.45 (s, 2H), 7.30 (d, J = 21.5 Hz, 5H), 5.85 (s, 1H), 5.04 (s, 1H), 4.65 (d, J = 13.9 Hz, 1H), 4.52 (d, J = 14.1 Hz, 1H), 4.29 (s, 6H).

[0198] Example 9 Preparation of (S)-3-hydroxy-2-phenyl-1-(1'-((4-(trifluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 9) [ka]

[0199] Compound 9 of Example 9 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 4-(trifluoromethoxy)benzenesulfonyl chloride.

[0200] MS (ESI) m / z 483.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.99-7.96(m, 2H), 7.67-7.65 (d, J = 0.8 Hz, 2H), 7.30-7.22 (m, 5H), 4.81-4.69 (m, 2H), 4.36-4.18 (m, 7H), 3.90-3.86 (t, J = 0.8 Hz, 1H), 3.63-3.60 (m, 1H), 3.47-3.43 (m, 1H).

[0201] Example 10: Preparation of (S)-1-(1'-(4-fluorophenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 10) [ka]

[0202] Compound 10 of Example 10 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 4-fluorobenzenesulfonyl chloride.

[0203] MS (ESI) m / z 417.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.99-7.96(m, 2H), 7.67-7.65 (d, J = 0.8 Hz, 2H), 7.30-7.22 (m, 5H), 4.81-4.69 (m, 2H), 4.36-4.18 (m, 7H), 3.90-3.86 (t, J = 0.8 Hz, 1H), 3.63-3.60 (m, 1H), 3.47-3.43 (m, 1H).

[0204] Example 11: Preparation of (S)-1-(1'-(3-fluoro-4-difluoromethoxyphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 11) [ka]

[0205] In step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 3-fluoro-4-difluoromethoxybenzenesulfonyl chloride, and the same preparation method as in Example 1 was used to obtain compound 11 of Example 11.

[0206] MS (ESI) m / z 483.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.89 (m, 1H), 7.89-7.62 (m, 2H), 7.44-7.22 (m, 6H), 4.82-4.79 (m, 1H), 4.72-4.69 (d, J = 28.0 Hz, 1H), 4.34-4.20 (m, 7H), 3.89-3.84 (m, 1H), 3.64-3.58 (m, 1H), 3.47-3.43 (m, 1H).

[0207] Example 12 Preparation of (S)-1-(1'-((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 12) [ka]

[0208] Step 1: Preparation of tert-butyl 6-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 12B) [ka]

[0209] 6-Bromo-3,4-dihydro-2H-1,4-benzoxazine (2 g, 9.34 mmol), 4-dimethylaminopyridine (114 mg, 0.93 mmol), and triethylamine (1.42 g, 14 mmol) were dissolved in tetrahydrofuran (40 mL), and then di-tert-butyl dicarbonate (2 g, 9.34 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate (60 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 12B.

[0210] MS (ESI) m / z 314.0 (M+H) +.

[0211] Step 2: Preparation of tert-butyl 6-(benzylthio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 12C) [ka]

[0212] tert-Butyl 6-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (500 mg, 1.59 mmol), benzyl mercaptan (236.8 mg, 1.91 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (92 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.07 mmol), and N,N-diisopropylethylamine (617 mg, 4.77 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 40 °C for 16 h. After completion of the reaction, the reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate (40 mL). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure, and the residue was separated and purified using a silica gel column to obtain compound 12C.

[0213] MS (ESI) m / z 358.1 (M+H) + .

[0214] Step 3: Preparation of tert-butyl 6-(chlorosulfonyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 12D) [ka]

[0215] tert-Butyl 6-(benzylthio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (500 mg, 1.39 mmol) was dissolved in a mixed solvent (acetonitrile:acetic acid:water = 40:1.5:1, 25 mL) and 1,3-dichloro-5,5-dimethylhydantoin (547.6 mg, 2.78 mmol) was added with stirring at 0 °C. The mixture was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate (60 mL * 3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the residue was purified using a silica gel column to obtain compound 12D.

[0216] Compound 12 of Example 12 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, tert-butyl 6-(chlorosulfonyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride.

[0217] MS (ESI) m / z 456.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.34-7.21 (m, 6H), 7.0 (s, 1H), 6.89-6.84 (m, 2H), 6.33 (s, 1H), 4.82-4.79 (t, J = 0.8 Hz, 1H), 4.73-4.70 (d, J = 1.2 Hz, 1H), 4.38-4.21 (m, 10H), 3.91-3.85 (m, 1H), 3.63-3.59 (m, 1H), 3.47-3.43 (m, 1H).

[0218] Example 13 Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-hydroxyethan-1-one (Compound 13) [ka]

[0219] Step 1: Preparation of tert-butyl 6-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 13A) [ka]

[0220] 6-Bromo-2H-benzo[b][1,4]oxazine-4(3H)-tert-butyl carboxylate (500 mg, 1.59 mmol) was added to dry tetrahydrofuran (10 mL). The reaction mixture was purged with nitrogen three times, then maintained under nitrogen. The mixture was cooled to -78 °C and n-butyllithium (122 mg, 1.91 mmol) was slowly added dropwise. The mixture was then stirred at -78 °C for 0.5 h. Diethyl oxalate (256 mg, 1.75 mmol) was added dropwise to the reaction mixture, which was then heated to room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness and purified using a silica gel column to obtain compound 13A.

[0221] MS (ESI) m / z 336.1 (M+H) + .

[0222] Step 2: Preparation of tert-butyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 13B) [ka]

[0223] 6-(2-Ethoxy-2-oxoacetyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate tert-butyl ester (170 mg, 0.50 mmol) was added to tetrahydrofuran (8 mL) and stirred at 0 °C. Sodium borohydride (29 mg, 0.76 mmol) was added. The mixture was then stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 13B.

[0224] MS (ESI) m / z 338.1 (M+H) + .

[0225] Step 3: Preparation of 2-(4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-hydroxyacetic acid (Compound 13C) [ka]

[0226] 6-(2-Ethoxy-1-hydroxy-2-oxoethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate tert-butyl ester (170 mg, crude product) and lithium hydroxide hydrate (106 mg, 2.52 mmol) were added to a mixture of tetrahydrofuran (3 mL) and water (3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was adjusted to pH 4-5 using 2N hydrochloric acid in an ice bath, diluted with water, and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the residue was purified using a silica gel column to obtain compound 13C.

[0227] MS (ESI) m / z 310.1 (M+H) + .

[0228] Compound 13 of Example 13 was obtained by the same preparation method as in Example 6, except that 2-(4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-hydroxyacetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 4 of Example 6.

[0229] MS (ESI) m / z 508.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95-7.88 (d, J = 8 Hz, 2H), 7.49-7.43 (d, J = 8 Hz, 3H), 6.56-6.51 (m, 2H), 6.41-6.39 (m, 1H), 5.76 (s, 1H), 5.49-5.48 (d, J = 4 Hz, 1H), 4.81-4.79 (d, J = 8 Hz, 1H), 4.61-4.57 (d, J = 16 Hz, 1H), 4.42-4.38 (d, J = 16 Hz, 1H), 4.27 (s, 6H), 4.07-4.05 (m, 2H), 3.22 (s, 2H).

[0230] Example 14 Preparation of (1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)(4-phenyltetrahydro-2H-pyran-4-yl)methanone (Compound 14) [ka]

[0231] Step 1: Preparation of methyl 4-phenyltetrahydro-2H-pyran-4-carboxylate (compound 14B) [ka]

[0232] Methyl 2-phenylacetate (2.0 g, 13.32 mmol) was dissolved in tetrahydrofuran (40.0 mL), the reaction mixture was cooled to 0 °C, and sodium hydride (1.06 g, 26.64 mmol) was added slowly in several portions. The reaction mixture was stirred at 0 °C for 30 minutes, followed by the dropwise addition of 2-iodoethyl ether (3.47 g, 10.65 mmol). After the addition was complete, the reaction mixture was stirred at 0 °C for 10 minutes and then slowly heated to room temperature. The reaction mixture was then heated to 50 °C and stirred for 18 hours. Upon completion of the reaction, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 14B.

[0233] MS (ESI) m / z 221.1 (M+H) + .

[0234] Step 2: Preparation of 4-phenyltetrahydro-2H-pyran-4-carboxylic acid (compound 14C) [ka]

[0235] Methyl 4-phenyltetrahydro-2H-pyran-4-carboxylate (1.0 g, 4.54 mmol) was dissolved in methanol (10 mL) and water (10 mL), and then sodium hydroxide (544.8 mg, 13.62 mmol) was added. The reaction solution was stirred at 50 °C for 3 hours. After completion of the reaction, the reaction system was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 14C.

[0236] MS (ESI) m / z 338.1 (M+H) + .

[0237] Compound 14 of Example 14 was obtained by the same preparation method as in Example 6, except that 4-phenyltetrahydro-2H-pyran-4-carboxylic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 4 of Example 6.

[0238] MS (ESI) m / z 505.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.88-7.84 (m, 2H), 7.46-7.23 (m, 8H), 4.30-4.10 (m, 6H), 3.97 (s, 2H), 3.78-3.63 (m, 2H), 3.52 (t, J = 11.0 Hz, 2H), 2.15 (d, J = 13.5 Hz, 2H), 1.91-1.72 (m, 2H).

[0239] Example 15 Preparation of 1-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(3-methoxyphenyl)-3-(methylamino)propan-1-one (Compound 15) [ka]

[0240] Step 1: Preparation of methyl 2-(3-methoxyphenyl)acrylate (compound 15B) [ka]

[0241] Methyl 2-(3-methoxyphenyl)acetate (2.00 g, 11.10 mmol) was added to N,N-dimethylformamide (20.0 mL), followed by potassium carbonate (3.83 g, 27.75 mmol), trioxymethylene (1.19 g, 13.32 mmol), and tetrabutylammonium iodide (410.0 mg, 1.11 mmol). The reaction solution was reacted at 80 °C for 30 minutes. After completion of the reaction, the product was purified using a silica gel column to obtain compound 15B.

[0242] MS (ESI) m / z 193.1 (M+H) + .

[0243] Step 2: Preparation of methyl 2-(3-methoxyphenyl)-2-(methylamino)acetate (Compound 15C) [ka]

[0244] Methyl 2-(3-methoxyphenyl)acrylate (2.02 g, 10.5 mmol) was added to a methylamine tetrahydrofuran solution (20.0 mL), and the mixture was reacted at room temperature for 4 hours. Compound 15C was obtained by separation and purification using a silica gel column.

[0245] MS (ESI) m / z 224.1 (M+H) + .

[0246] Step 3: Preparation of methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propionate (Compound 15D) [ka]

[0247] Methyl 2-(3-methoxyphenyl)-2-(methylamino)acetate (2.00 g, 8.96 mmol) and 4-dimethylaminopyridine were dissolved in dichloromethane (10.0 mL), and triethylamine (1.81 g, 17.92 mmol) and di-tert-butyl dicarbonate (1.95 g, 8.96 mmol) were added. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, water was added to quench the reaction, and the pH was adjusted to 5-6 with 2N aqueous hydrochloric acid. The reaction mixture was then extracted with ethyl acetate (20.0 mL x 3). The combined organic layer was washed with saturated sodium chloride (20.0 mL) and dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 15D.

[0248] MS (ESI) m / z 324.2 (M+H) + .

[0249] Step 4: Preparation of 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propionic acid (Compound 15E) [ka]

[0250] Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propionate (669.0 mg, 2.07 mmol) was dissolved in tetrahydrofuran (5.0 mL) and water (5.0 mL), and lithium hydroxide (99.1 mg, 4.14 mmol) was added. The reaction was carried out at room temperature for 16 hours. After completion of the reaction, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 15E.

[0251] MS (ESI) m / z 310.2 (M+H) + .

[0252] Compound 15 of Example 15 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0253] MS (ESI) m / z 500.2 (M+H) + . 1 H NMR (400MHz,DMSO-d6) δ 7.28-7.22 (m,3H),7.06-7.04 (m,1H), 6.85-6.81 (m,3H), 4.34-4.30 (m,6H), 4.10-3.81 (m,9H), 3.71 (s,3H), 3.15-3.04 (m,1H), 2.28 (s,3H).

[0254] Example 16 Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 16) [ka]

[0255] Step 1: Preparation of methyl 2-(4-fluorophenyl)-3-hydroxypropionate (compound 16B) [ka]

[0256] Methyl 4-fluorophenylacetate (1.0 g, 5.95 mmol) and paraformaldehyde (562.5 mg, 6.24 mmol) were dissolved in dimethyl sulfoxide (40 mL), followed by the addition of sodium methoxide (16.1 mg, 0.30 mmol). The reaction solution was allowed to react at room temperature for 4 hours. Upon completion, water was added to the reaction system to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 16B.

[0257] MS (ESI) m / z 199.1 (M+H) + .

[0258] Step 2: Preparation of 2-(4-fluorophenyl)-3-hydroxypropionic acid (compound 16C) [ka]

[0259] Methyl 2-(4-fluorophenyl)-3-hydroxypropionate (600.0 mg, 3.03 mmol) was dissolved in methanol (9.0 mL) and water (6.0 mL), and then sodium hydroxide (242.2 mg, 6.05 mmol) was added. The reaction solution was stirred at 50 °C for 3 hours. After the reaction was completed, the reaction solution was adjusted to pH 2 using 1N aqueous hydrochloric acid and extracted with dichloromethane (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give a white solid compound. The residue was purified using a silica gel column to give compound 16C.

[0260] MS (ESI) m / z 185.1 (M+H) + .

[0261] Compound 16 of Example 16 was obtained by the same preparation method as in Example 6, except that 2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 4 of Example 6.

[0262] MS (ESI) m / z 483.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.91-7.89 (d, J = 7.7 Hz, 2H), 7.63-7.29 (m, 5H), 7.12-7.09 (m, 2H), 4.85 (s, 1H), 4.70 (d, J = 12.7 Hz, 1H), 4.39-4.22 (m, 7H), 3.85-3.83 (m, 1H), 3.70-3.64 (m, 1H), 3.51-3.41 (m, 1H).

[0263] Example 17 Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-3-methyl-2-phenylbutan-1-one (Compound 17) [ka]

[0264] Step 1: Preparation of 3-hydroxy-3-methyl-2-phenylbutyric acid (compound 17B) [ka]

[0265] 2-Phenylacetic acid (0.7 g, 5.14 mmol) was dissolved in tetrahydrofuran (11.0 mL) and isopropylmagnesium chloride (1.06 g, 10.28 mmol, 2 M) was added dropwise at room temperature. After the addition, the reaction solution was stirred at 40 °C for 1 hour. Acetone (328.5 mg, 5.66 mmol) was then added, and the reaction solution was stirred at 40 °C for 1 hour. The reaction solution was adjusted to pH 2 with 3N hydrochloric acid, and the aqueous phase was extracted with dichloromethane (50 mL * 3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The mixture was concentrated to give a white solid compound. The residue was purified using a silica gel column to give compound 17B.

[0266] MS (ESI) m / z 195.1 (M+H) + .

[0267] Compound 17 of Example 17 was obtained by the same preparation method as in Example 6, except that 3-hydroxy-3-methyl-2-phenylbutyric acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 4 of Example 6.

[0268] MS (ESI) m / z 493.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90-7.88 (m, 2H), 7.63-7.19 (m, 8H), 4.91 (s, 1H), 4.75-4.72 (d, J = 13.3 Hz, 1H), 4.28-4.22 (m, 7H), 3.50 (s, 1H), 1.13 (s, 3H), 0.98 (s, 3H).

[0269] Example 18 Preparation of 1-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 18) [ka]

[0270] Compound 18 of Example 15 was obtained by the same preparation method as in Example 1, except that 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 10 of Example 1.

[0271] MS (ESI) m / z 475.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.34-7.24 (m, 4H), 7.14-7.10 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 4.83-4.81 (m, 1H), 4.31-4.30 (m, 5H), 4.00-3.85 (m, 8H), 3.52-3.39 (m, 2H).

[0272] Example 19 Preparation of 1-(1'-((2,3-dihydro-[1,4]dioxolane[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 19) [ka]

[0273] Compound 19 of Example 19 was obtained by the same preparation method as in Example 6, except that 2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 10 of Example 1.

[0274] MS (ESI) m / z 476.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.28(s, 1H), 7.66 (s, 1H), 7.33-7.27 (m, 2H), 7.17 - 7.10 (m, 2H), 4.87 - 4.85 (m,1H), 4.75 - 4.68 (m, 1H), 4.55-4.53 (m, 2H), 4.40 - 4.21 (m, 9H), 3.85-3.80 (m, 1H), 3.70 - 3.55 (m, 2H).

[0275] Example 20 Preparation of (S)-1-(1'-((8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 20) [ka]

[0276] Step 1: Preparation of 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Compound 20B) [ka]

[0277] 5-Bromo-3-fluorobenzene-1,2-diol (500 mg, 2.42 mmol), 1,2-dibromoethane (680.67 mg, 3.62 mmol), and potassium carbonate (1.0 g, 7.25 mmol) were added to N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 20B.

[0278] MS (ESI) m / z 233.0 (M+H) + .

[0279] Step 2: Preparation of 7-(benzylthio)-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Compound 20C) [ka]

[0280] 7-Bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (330 mg, 1.42 mmol), benzyl mercaptan (175.88 mg, 1.42 mmol), N,N-diisopropylethylamine (365.35 mg, 2.83 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (64.84 mg, 70.81 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (81.94 mg, 141.61 μmol) were added to 1,4-dioxane (6 mL), and the reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 20C.

[0281] MS (ESI) m / z 277.1 (M+H) + .

[0282] Step 3: Preparation of 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride (compound 20D) [ka]

[0283] 7-(Benzylthio)-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (200 mg, 723.78 μmol) and 1,3-dichloro-5,5-dimethylhydantoin (285.20 mg, 1.45 mmol) were added to acetonitrile (7.5 mL), acetic acid (0.19 mL), and water (0.13 mL), and the reaction mixture was stirred at 25° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column to obtain compound 20D.

[0284] MS (ESI) m / z 253.0 (M+H) + .

[0285] Compound 20 of Example 20 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride.

[0286] MS (ESI) m / z 475.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.31-7.15 (m, 7H), 4.73- 4.70 (d, J = 13.0 Hz, 1H), 4.42 -4.30 (m, 12H), 3.90-3.87 (m, 1H), 3.47-3.44 (m, 1H), 3.33-3.31 (m, 1H).

[0287] Example 21 Preparation of 2-amino-1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylethan-1-one (Compound 21) [ka]

[0288] Compound 21 of Example 21 was obtained by the same preparation method as in Example 6, except that 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 4 of Example 6.

[0289] MS (ESI) m / z 450.1 (M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 7.91-7.89 (m, 2H), 7.45-7.43 (m, 3H), 7.32-7.22 (m, 5H), 4.72-4.69 (d, J = 10.4 Hz, 1H), 4.37-4.19 (m, 8H), 2.12 (s, 2H).

[0290] Example 22 Preparation of 2-amino-1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)ethan-1-one (Compound 22) [ka]

[0291] Compound 22 of Example 22 was obtained by the same preparation method as in Example 6, except that in Step 4 of Example 6, 2-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)acetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0292] MS (ESI) m / z 468.1 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.91-7.89 (d, J = 8.8 Hz, 2H), 7.46-7.27 (m, 5H), 7.14-7.10 (m, 2H), 4.69 (s, 1H), 4.40-4.22 (m, 8H), 2.34-2.32 (m, 2H).

[0293] Example 23 Preparation of 2-amino-1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(3-(trifluoromethyl)phenyl)ethan-1-one (Compound 23) [ka]

[0294] Compound 23 of Example 23 was obtained by the same preparation method as in Example 6, except that 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)acetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 4 of Example 6.

[0295] MS (ESI) m / z 518.1 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.92-7.90 (d, J = 8.8 Hz, 2H), 7.67-7.51 (m, 4H), 7.46-7.44 (d, J = 8.5 Hz, 2H), 4.80-4.75 (d, J = 13.7 Hz, 1H), 4.53-4.21 (m, 8H), 2.33-2.27 (d, J = 24.7 Hz, 2H).

[0296] Example 24 Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)ethan-1-one (Compound 24) [ka]

[0297] Step 1: Preparation of 2-methyl-4-hydroxymethylbenzo[d]thiazole (Compound 24B) [ka]

[0298] 4-Bromo-2-methyl-1,3-benzothiazole (200 mg, 876.77 μmol) and tributylstannylmethanol (430 mg, 1.34 mmol) were dissolved in 1,4-dioxane (5 mL), tetrakis(triphenylphosphine)palladium (100 mg, 86.58 μmol) was added at room temperature, and the resulting mixture was stirred at 100 °C for 16 h under nitrogen protection. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to give compound 24B.

[0299] MS (ESI) m / z 180.0 (M+H) + .

[0300] Step 2: Preparation of 2-methylbenzo[d]thiazole-4-carbaldehyde (Compound 24C) [ka]

[0301] Oxalyl chloride (70 mg, 551.50 μmol) was slowly added dropwise to a solution of dimethyl sulfoxide (65 mg, 831.91 μmol) in dichloromethane (3 mL) at −78°C, and the resulting mixture was stirred at −78°C for 0.5 h under nitrogen protection. Then, a solution of 2-methyl-4-hydroxymethylbenzo[d]thiazole (50 mg, 278.96 μmol) in dichloromethane (2 mL) was added at the same temperature, and the resulting mixture was stirred at this temperature for 1 h. Then, triethylamine (0.3 mL) was added, and the resulting mixture was stirred for 0.5 h, heated to room temperature, and then stirred for another 0.5 h. After completion of the reaction, the reaction mixture was quenched with 10 mL of brine. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 24C.

[0302] MS (ESI) m / z 178.0(M+H) + .

[0303] Step 3: Preparation of 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetonitrile (Compound 24D) [ka]

[0304] 2-Methyl-1,3-benzothiazole-4-carbaldehyde (110 mg, 620.69 μmol) was dissolved in dichloromethane (3 mL), and trimethylsilyl cyanide (180 mg, 1.82 mmol) and zinc iodide (100 mg, 313.48 μmol) were added at room temperature. The resulting mixture was stirred at room temperature under nitrogen protection for 2 hours. The reaction mixture was quenched with 10 mL of brine. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 24D.

[0305] MS (ESI) m / z 205.1 (M+H) + .

[0306] Step 4: Preparation of methyl 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetate (Compound 24E) [ka]

[0307] 2-Hydroxy-2-(2-methyl-1,3-benzothiazol-4-yl)acetonitrile (110 mg, 538.56 μmol) was dissolved in methanol (3 mL), and concentrated hydrochloric acid (3 mL) was added dropwise. The resulting mixture was stirred at 60 °C for 2 h under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated and the pH of the solution was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 24E.

[0308] MS (ESI) m / z 238.0 (M+H) + .

[0309] Step 5: Preparation of 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetic acid (Compound 24F) [ka]

[0310] Methyl 2-hydroxy-2-(2-methyl-1,3-benzothiazol-4-yl)acetate (125 mg, 526.82 μmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (3 mL), followed by the addition of lithium hydroxide monohydrate (100 mg, 2.44 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the pH of the solution was adjusted to 5-6 with 2N dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 24F.

[0311] MS (ESI) m / z 224.1 (M+H) + .

[0312] In Step 4 of Example 6, 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid was replaced with 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetic acid, and the same preparation method as in Example 6 was used to obtain compound 24 of Example 24.

[0313] MS (ESI) m / z 522.1 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.96 - 7.90 (m, 3H), 7.65 - 7.29 (m, 5H), 5.88 - 5.78 (m, 2H), 4.85 - 4.59 (m, 2H), 4.31 - 4.23 (m, 6H), 2.77 (s, 3H).

[0314] Example 25 Preparation of (S)-1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 25) [ka]

[0315] Compound 25 of Example 25 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0316] MS (ESI) m / z 474.1 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.82 (s, 1H), 8.35-8.33 (d, J = 8.0 Hz, 1H), 7.96-7.94 (d, J = 8.0 Hz, 1H), 7.30-7.27 (m, 2H), 7.13-7.08 (m, 2H), 4.82 (s, 1H), 4.69-4.66 (d, J = 12.0 Hz, 1H), 4.35-4.16 (m, 8H), 3.83 (s, 1H), 3.64-3.61 (m, 1H).

[0317] Example 26 Preparation of 2-(3-chlorophenyl)-1-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-(methylamino)propan-1-one (Compound 26) [ka]

[0318] Compound 26 of Example 26 was obtained by the same preparation method as in Example 6, except that 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chlorophenyl)propionic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 10 of Example 1.

[0319] MS (ESI) m / z 504.1 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.36-7.24 (m, 6H), 7.07-7.05 (d, J = 26.1, 1H), 4.40-4.30 (m, 4H), 4.02-3.92 (m, 8H), 3.34 (s, 5H), 3.07-3.05 (m, 1H), 1.23 (s, 1H).

[0320] Example 27 Preparation of (S)-1-(1'-((3-fluoro-4-(oxazol-2-yl)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 27) [ka]

[0321] Step 1: Preparation of 4-bromo-N-(2,2-dimethoxyethyl)-2-fluorobenzamide (Compound 27B) [ka]

[0322] 4-Bromo-2-fluorobenzoic acid (3 g, 13.70 mmol) was dissolved in dichloromethane (40 mL), and then N,N-diisopropylethylamine (3.53 g, 27.40 mmol) and N,N-carbonyldiimidazole (2.17 g, 15.07 mmol) were added. The reaction mixture was stirred at 25 °C for 30 minutes. 2,2-Dimethoxyethylamine (1.58 g, 15.07 mmol) was added to the above mixture and stirred at 25 °C for an additional 4 hours. After the reaction was complete, the product was purified by silica gel column chromatography to obtain compound 27B.

[0323] MS (ESI) m / z 306.1 (M+H) + .

[0324] Step 2: Preparation of 2-(4-bromo-2-fluorophenyl)oxazole (Compound 27C) [ka]

[0325] 4-Bromo-N-(2,2-dimethoxyethyl)-2-fluoro-benzamide (2.1 g, 6.86 mmol) was added to polyphosphoric acid (20 mL) and reacted for 5 hours at 90° C. After completion of the reaction, the product was separated and purified using a silica gel column to obtain compound 27C.

[0326] MS (ESI) m / z 243.0 (M+H) + .

[0327] Step 3: Preparation of 2-(4-(benzylthio)-2-fluorophenyl)oxazole (Compound 27D) [ka]

[0328] Benzyl mercaptan (410.51 mg, 3.31 mmol), N,N-diisopropylethylamine (1.07 g, 8.26 mmol), tris(dibenzylideneacetone)dipalladium (342.09 mg, 330.52 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (382.74 mg, 661.04 μmol) were added to a solution of 2-(4-bromo-2-fluorophenyl)oxazole (0.8 g, 3.31 mmol) in 1,4-dioxane (10 mL), and the mixture was stirred at 90 °C for 3 hours under nitrogen protection. After completion of the reaction, the mixture was purified using a silica gel column to obtain compound 27D.

[0329] MS (ESI) m / z 286.3 (M+H) + .

[0330] Step 4: Preparation of 3-fluoro-4-(oxazol-2-yl)benzenesulfonyl chloride (compound 27E) [ka]

[0331] 2-(4-benzylsulfanyl-2-fluorophenyl)oxazole (0.7 g, 2.45 mmol) was dissolved in a mixture of dichloromethane (10 mL), water (176.63 mg, 9.81 mmol), and glacial acetic acid (735.98 mg, 12.27 mmol), and then sulfonyl chloride (1.32 g, 9.81 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 5 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 27E.

[0332] MS (ESI) m / z 262.0 (M+H) + .

[0333] In step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 3-fluoro-4-(oxazol-2-yl)benzenesulfonyl chloride, and the same preparation method as in Example 1 was used to obtain compound 27 of Example 27.

[0334] MS (ESI) m / z 484.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.37-8.35 (m, 1H), 8.02-8.01 (m, 1H), 7.74-7.73 (m, 1H), 7.53 (s, 1H), 7.27-7.21 (m, 5H), 4.81-4.79 (t, J = 0.8 Hz, 1H), 4.71-4.68 (d, J = 1.2 Hz, 1H), 4.35-4.21 (m, 7H), 3.88-3.87 (m, 1H), 3.62-3.58 (m, 1H), 3.48-3.42 (m, 1H).

[0335] Example 28 Preparation of 2-(3-chloro-4-fluoro-2-methoxyphenyl)-1-(1'-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-(methylamino)propan-1-one (Compound 28) [ka]

[0336] Step 1: Preparation of methyl 2-(4-fluoro-2-methoxyphenyl)acetate (Compound 28B) [ka]

[0337] 2-(4-Fluoro-2-methoxyphenyl)acetic acid (1.0 g, 5.43 mmol) was dissolved in anhydrous methanol (100 mL), and then thionyl chloride (1.29 g, 10.8 mmol) was slowly added. The reaction solution was reacted at 70 °C for 3 hours. After the reaction was completed, the product was separated and purified using a silica gel column to obtain compound 28B.

[0338] MS (ESI) m / z 199.1 (M+H) + .

[0339] Step 2: Preparation of methyl 2-(4-fluoro-2-methoxyphenyl)acrylate (Compound 28C) [ka]

[0340] Methyl 2-(4-fluoro-2-methoxyphenyl)acetate (900.0 mg, 4.54 mmol) was dissolved in N,N-dimethylformamide (100.0 mL), followed by the addition of potassium carbonate (1.57 g, 11.4 mmol), paraformaldehyde (518.3 mg, 5.76 mmol), and tetrabutylammonium bromide (167.7 mg, 0.45 mmol). The reaction mixture was stirred at 60°C for 1 hour. After completion of the reaction, the product was purified using a silica gel column to obtain compound 28C.

[0341] MS (ESI) m / z 211.1 (M+H) + .

[0342] Step 3: Preparation of methyl 2-(4-fluoro-2-methoxyphenyl)-3-(methylamino)propionate (Compound 28D) [ka]

[0343] Methyl 2-(4-fluoro-2-methoxyphenyl)acrylate (515.0 mg, 2.45 mmol) was dissolved in a solution of methylamine in tetrahydrofuran (20 mL), and the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 28D.

[0344] MS (ESI) m / z 242.1 (M+H) + .

[0345] Step 4: Preparation of methyl 3-(tert-butoxycarbonyl)(methyl)amino)-2-(4-fluoro-2-methoxyphenyl)propionate (Compound 28E) [ka]

[0346] Methyl 2-(4-fluoro-2-methoxyphenyl)-3-(methylamino)propionate (406 mg, 1.68 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of triethylamine (340 mg, 3.37 mmol). The reaction mixture was cooled to 0°C, and di-tert-butyl dicarbonate (440 mg, 2.02 mmol) was slowly added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 28E.

[0347] MS(ESI) m / z 342.1(M+H) + .

[0348] Step 5: Preparation of methyl 3-(tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propionate (Compound 28F) [ka]

[0349] Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(4-fluoro-2-methoxyphenyl)propionate (393 mg, 1.15 mmol) was dissolved in N,N-dimethylformamide (100.0 mL), and then N-chlorosuccinimide (461.3 mg, 3.45 mmol) was added. The reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 28F.

[0350] MS (ESI) m / z 376.1 (M+H) + .

[0351] Step 6: Preparation of 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propionic acid (Compound 28G) [ka]

[0352] Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propionate (302 mg, 0.81 mmol) was dissolved in tetrahydrofuran (50 mL) and water (50 mL), and then lithium hydroxide (38.6 g, 1.61 mmol) was added. The reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 28G.

[0353] MS (ESI) m / z 362.1 (M+H) + .

[0354] Compound 28 of Example 28 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride, and in Step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid was replaced with 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propionic acid.

[0355] MS (ESI) m / z 552.1 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.25-7.21 (m, 3H), 7.13-7.10 (d, J = 8.0 Hz, 1H), 7.04-7.02 (d, J = 8.0 Hz, 1H), 4.45-4.15 (m, 6H), 3.98 (s, 6H), 3.78 (s, 3H), 2.96-2.94 (d, J = 8.0 Hz, 1H), 2.20 (s, 2H), 1.41-0.82 (m, 4H).

[0356] Example 29 Preparation of (1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)(4-phenyltetrahydro-2H-pyran-4-yl)methanone (Compound 29) [ka]

[0357] Compound 29 of Example 29 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 4-phenyltetrahydro-2H-pyran-4-carboxylic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0358] MS (ESI) m / z 496.2 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.78-8.75 (d, J = 1.9 Hz, 1H), 8.32-8.29 (d, J = 8.5 Hz, 1H), 7.92-7.87 (m, 1H), 7.37-7.31 (m, 2H), 7.28-7.19 (m, 3H), 4.31-4.16 (m, 6H), 3.97-3.87 (m, 2H), 3.71-3.67 (m, 2H), 3.56-3.44 (m, 2H), 2.17-2.07 (m, 2H), 1.83-1.76 (m, 2H).

[0359] Example 30 Preparation of (S)-1-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 30) [ka]

[0360] Compound 30 of Example 30 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride, and in Step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid was replaced with (S)-2-(4-fluorophenyl)-3-hydroxypropionic acid.

[0361] MS (ESI) m / z 475.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.34-7.24 (m, 4H), 7.14-7.10 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 4.83-4.81 (m, 1H), 4.31-4.30 (m, 5H), 4.00-3.85 (m, 8H), 3.52-3.39 (m, 2H).

[0362] Example 31 Preparation of (R)-1-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 31) [ka]

[0363] Compound 31 of Example 31 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride, and in Step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid was replaced with (R)-2-(4-fluorophenyl)-3-hydroxypropionic acid.

[0364] MS (ESI) m / z 475.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.34-7.24 (m, 4H), 7.14-7.10 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 4.83-4.81 (m, 1H), 4.31-4.30 (m, 5H), 4.00-3.85 (m, 8H), 3.52-3.39 (m, 2H).

[0365] Example 32 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-(naphthalen-2-yl)propan-1-one (Compound 32) [ka]

[0366] Step 1: Preparation of methyl 3-hydroxy-2-(naphthalen-2-yl)propionate (compound 32B) [ka]

[0367] Methyl 2-(naphthalen-2-yl)acetate (1.0 g, 4.99 mmol) and paraformaldehyde (449.9 mg, 4.99 mmol) were dissolved in dimethyl sulfoxide (40.0 mL), and then sodium methoxide (27.0 mg, 0.50 mmol) was added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 32B.

[0368] MS (ESI) m / z 231.1 (M+H) + .

[0369] Step 2: Preparation of 3-hydroxy-2-(naphthalen-2-yl)propionic acid (compound 32C) [ka]

[0370] Methyl 3-hydroxy-2-(naphthalen-2-yl)propionate (260.0 mg, 1.13 mmol) was dissolved in a mixture of tetrahydrofuran (60.0 mL) and water (40.0 mL), and then sodium hydroxide (45.2 mg, 1.13 mmol) was added. The reaction solution was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (100 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the solution was used directly in the next reaction step.

[0371] Compound 32 of Example 32 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(naphthalen-2-yl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0372] MS (ESI) m / z 506.1 (M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.78-8.77 (d, J = 4.0 Hz, 1H), 8.31-8.29 (d, J = 8.0 Hz, 1H), 7.92-7.90 (m, 1H), 7.85-7.80 (m, 3H), 7.72 (s, 1H), 7.47-7.44 (m, 2H), 7.40-7.33 (m, 1H), 4.80-4.78 (m, 1H), 4.72 (s, 1H), 4.34-4.26 (m, 6H), 4.19 (s, 1H), 3.95-3.92 (m, 1H), 3.77-3.74 (m, 1H), 3.57-3.53 (m, 1H).

[0373] Example 33 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl(1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propan-1-one (Compound 33) [ka]

[0374] Step 1: Preparation of methyl 2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (Compound 33B) [ka]

[0375] Methyl 2-(3-bromophenyl)acetate (5.0 g, 21.83 mmol), 1-methylpiperazine (3.3 g, 32.74 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.3 g, 2.18 mmol), and cesium carbonate (10.7 g, 32.74 mmol) were dissolved in toluene (100 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium (399.8 mg, 0.44 mmol). After the addition was complete, the reaction mixture was heated to 110 °C under nitrogen protection and stirred for 16 h. After the reaction was complete, water was added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate (150 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 33B.

[0376] MS (ESI) m / z 249.2 (M+H) + .

[0377] Step 2: Preparation of methyl 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propionate (Compound 33C) [ka]

[0378] Methyl 2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (1.8 g, 7.25 mmol) and paraformaldehyde (685.6 mg, 7.61 mmol) were dissolved in dimethyl sulfoxide (90.0 mL), and sodium methoxide (39.2 mg, 0.72 mmol) was added. The reaction solution was reacted at 50°C for 4 hours. Water was added to dilute the reaction solution. The aqueous phase was extracted with dichloromethane (100 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 33C.

[0379] MS (ESI) m / z 279.2 (M+H) + .

[0380] Step 2: Preparation of 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propionic acid (compound 33D) [ka]

[0381] Methyl 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propionate (90.0 mg, 0.32 mmol) was dissolved in methanol (2.5 mL) and water (2.5 mL), and then sodium hydroxide (25.9 mg, 0.64 mmol) was added and the reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, concentrated, and used directly in the next reaction step.

[0382] MS (ESI) m / z 265.2 (M+H) + .

[0383] Compound 33 of Example 33 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0384] MS (ESI) m / z 554.2 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.81-8.80 (d, J = 1.7 Hz, 1H), 8.33-8.31 (d, J = 8.6 Hz, 1H), 7.5-7.94 (m, 1H), 7.11-7.07 (m, 1H), 6.78-6.76 (m, 2H), 6.64-6.62 (d, J = 7.6 Hz, 1H), 4.71-4.63 (m, 2H), 4.42-4.11 (m, 7H), 3.88-3.81 (m, 1H), 3.54-3.49 (m, 1H), 3.44-3.38 (m, 1H), 3.17-2.97 (m, 4H), 2.47-2.38 (m, 4H), 2.21 (s, 3H).

[0385] Example 34 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propan-1-one (Compound 34) [ka]

[0386] Step 1: Preparation of methyl 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (Compound 34B) [ka]

[0387] Methyl 2-(4-bromophenyl)acetate (1.0 g, 4.37 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (604.7 mg, 4.80 mmol), and potassium carbonate (1.2 g, 8.74 mmol) were dissolved in a 4:1 mixture of dioxane and water (20.0 mL), followed by the addition of tetrakis(triphenylphosphine)palladium (504.5 mg, 0.44 mmol). After the addition was complete, the reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 h. After the reaction was complete, water was added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate (50.0 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 34B.

[0388] MS (ESI) m / z 231.2 (M+H) + .

[0389] Step 2: Preparation of methyl 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propionate (Compound 34C) [ka]

[0390] Methyl 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (800.0 mg, 3.47 mmol) and paraformaldehyde (313.0 mg, 3.47 mmol) were dissolved in dimethyl sulfoxide (50.0 mL), and then sodium methoxide (62.6 mg, 0.35 mmol) was added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 34C.

[0391] MS (ESI) m / z 261.2 (M+H) + .

[0392] Step 3: Preparation of 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propionic acid (compound 34D) [ka]

[0393] Methyl 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propionate (200.0 mg, 0.77 mmol) was dissolved in a mixture of methanol (6.0 mL) and water (4.0 mL), and then sodium hydroxide (61.5 mg, 1.54 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, concentrated, and used directly in the next reaction step.

[0394] MS (ESI) m / z 267.1 (M+H) + .

[0395] Compound 34 of Example 34 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0396] MS (ESI) m / z 536.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.81-8.80 (d, J = 1.6 Hz, 1H), 8.32-8.31 (d, J = 8.6 Hz, 1H), 8.06 (s, 1H), 7.95-7.92 (d, J = 8.6, 1H), 7.79 (s, 1H), 7.45-7.43 (d, J = 8.2 Hz, 2H), 7.20-7.18 (d, J = 8.2 Hz, 2H), 4.77-4.74 (t, J = 5.3 Hz, 1H), 4.68-4.65 (m, 1H), 4.44-4.12 (m, 7H), 3.90-3.81 (m, 4H), 3.60-3.54 (m, 1H), 3.49-3.40 (m, 1H).

[0397] Example 35 Preparation of (S)-3-hydroxy-1-(1'-((2-methylbenzo[d]thiazol-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 35) [ka]

[0398] Step 1: Preparation of 6-(benzylthio)-2-methylbenzo[d]thiazole (Compound 35B) [ka]

[0399] 6-Bromo-2-methylbenzo[d]thiazole (2.0 g, 8.77 mmol), benzyl mercaptan (1.3 g, 10.52 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.5 g, 0.88 mmol), and N,N-diisopropylethylamine (3.4 g, 26.30 mmol) were dissolved in 1,4-dioxane (50.0 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium (401.4 mg, 0.44 mmol). After the addition was complete, the reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After the reaction was complete, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (150.0 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 35B.

[0400] MS (ESI) m / z 272.1 (M+H) + .

[0401] Step 2: Preparation of 2-methylbenzo[d]thiazole-6-sulfonyl chloride (compound 35C) [ka]

[0402] 6-(Benzylthio)-2-methylbenzo[d]thiazole (1.0 g, 3.68 mmol) was dissolved in a mixture of acetonitrile (40.0 mL), acetic acid (1.5 mL), and water (1.0 mL). 1,3-Dichloro-5,5-dimethylhydantoin (1.5 g, 7.37 mmol) was then added to the reaction mixture at 0°C. After the addition was complete, the reaction mixture was allowed to react at room temperature for 4 hours. After the reaction was complete, water was added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 35C.

[0403] MS (ESI) m / z 248.0 (M+H) + .

[0404] Compound 35 of Example 35 was obtained by the same preparation method as in Example 1, except that 2-methylbenzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride in Step 8 of Example 1.

[0405] MS (ESI) m / z 470.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.66-8.65 (d, J = 1.6 Hz, 1H), 8.15-8.13 (d, J = 8.5 Hz, 1H), 7.89-7.86 (d, J = 8.5, 1H), 7.29-7.19 (m, 5H), 4.79-4.76 (t, J = 5.2 Hz, 1H), 4.69-4.65 (m, 1H), 4.33-4.15 (m, 7H), 3.90-3.84 (m, 1H), 3.61-3.57 (m, 1H), 3.47-3.42 (m, 1H),2.87 (s, 3H).

[0406] Example 36 Preparation of 1-(1'-((2,2-difluorobenzo[d][1,3]dioxolan-5-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 36) [ka]

[0407] Step 1: Preparation of 5-(benzylthio)-2,2-difluorobenzo[d][1,3]dioxolane (Compound 36B) [ka]

[0408] 5-Bromo-2,2-difluoro-1,3-benzodioxolane (400 mg, 1.69 mmol) and benzyl mercaptan (280 mg, 2.25 mmol) were dissolved in dioxane (10 mL), followed by the addition of sodium tert-butoxide (400.00 mg, 4.16 mmol), palladium acetate (40.00 mg, 178.57 μmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (100 mg, 160.60 μmol). After the addition was complete, the reaction mixture was placed under a nitrogen atmosphere and stirred at 100 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature. Water was added to dilute the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30.0 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 36B.

[0409] MS (ESI) m / z 280.1(M+H) + .

[0410] Step 2: Preparation of 2,2-difluorobenzo[d][1,3]dioxolane-5-sulfonyl chloride (compound 36C) [ka]

[0411] 2,2-Difluoro-5-phenylthio-1,3-benzodioxolane (270 mg, 963.29 μmol) was dissolved in acetonitrile (20 mL), acetic acid (0.75 mL), and water (0.5 mL), and then 5-dimethyl-imidazolidine-2,4-dione (380 mg, 1.93 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was placed under a nitrogen atmosphere and stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated and the pH was adjusted to 6-7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (30.0 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 36C.

[0412] MS (ESI) m / z 257.0(M+H) +.

[0413] Compound 36 of Example 36 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 2,2-difluorobenzo[d][1,3]dioxolane-5-sulfonyl chloride, and in Step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0414] MS (ESI) m / z 497.1 (M+H) + . 1 H-NMR (400 MHz, DMSO- d6) δ 7.92 (s, 1H), 7.74 - 7.68 (m, 2H), 7.31-7.28 (m, 2H), 7.11 (t, J = 8.8 Hz, 2H), 4.83 - 4.80 (m, 1H), 4.70 (d, J = 12.4 Hz, 1H), 4.38 - 4.19 (m, 7H), 3.87 - 3.81 (m, 1H), 3.66 - 3.63 (m, 1H), 3.47 - 3.42 (m, 1H).

[0415] Example 37 Preparation of (1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)(3-phenyltetrahydrofuran-3-yl)methanone (Compound 37) [ka]

[0416] Step 1: Preparation of 4-phenyl-3,6-dihydro-2H-pyran (Compound 37B) [ka]

[0417] An arylmagnesium bromide solution (2.8N, 12.86 mL, 36 mmol) was slowly added to a solution of tetrahydro-4H-pyran-4-one (3.0 g, 29.97 mmol) in tetrahydrofuran (300 mL) at −78° C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then purified using a silica gel column to obtain compound 37B.

[0418] MS (ESI) m / z 161.1 (M+H) + .

[0419] Step 2: Preparation of 3-phenyltetrahydrofuran-3-carboxaldehyde (compound 37C) [ka]

[0420] 4-Phenyl-3,6-dihydro-2H-pyran (1 g, 6.24 mmol) and sodium carbonate (1.7 g, 16.04 mmol) were dissolved in dichloromethane (150 mL), and m-chloroperbenzoic acid (2.4 g, 13.95 mmol) was added at 0 °C. The mixture was then stirred at room temperature under a nitrogen atmosphere for 3 hours. After the reaction was complete, saturated aqueous sodium carbonate (50 mL) was added to the mixture, and ethyl acetate (50 mL*3) was added until the reaction mixture separated from the organic layer. The organic extract was dried over anhydrous magnesium sulfate and purified using a silica gel column to obtain compound 37C.

[0421] MS (ESI) m / z 177.1 (M+H) + .

[0422] Step 3: Preparation of 3-phenyltetrahydrofuran-3-carboxylic acid (compound 37D) [ka]

[0423] 3-Phenyltetrahydrofuran-3-carboxaldehyde (250 mg, 1.42 mmol) and 2-methylbut-2-ene (2.25 mL) were dissolved in n-butanol (45 mL) and 2-methylbut-2-ene (2.25 mL). Sodium chlorite (520 mg, 4.62 mmol) and potassium dihydrogen phosphate (440 mg, 3.24 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (10 mL * 3), and the organic phases were combined. Compound 37D was obtained by separation and purification using a silica gel column.

[0424] MS (ESI) m / z 193.1 (M+H) + .

[0425] Compound 37 of Example 37 was obtained by the same preparation method as in Example 6, except that 3-phenyltetrahydrofuran-3-carboxylic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid in Step 4 of Example 6.

[0426] MS (ESI) m / z 491.1(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.88 - 7.84 (m, 2H), 7.63 - 7.21 (m, 8H), 4.27 - 4.17 (m, 7H), 3.99 (s, 2H), 3.83 - 3.77 (m, 3H), 2.60 - 2.55 (m, 1H), 2.23 - 2.16 (m, 1H).

[0427] Example 38 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(3-chloro-4-fluorophenyl)-3-(methylamino)propan-1-one (Compound 38) [ka]

[0428] Step 1: Preparation of methyl 2-(3-chloro-4-fluorophenyl)acrylate (Compound 38B) [ka]

[0429] (3-Chloro-4-fluorophenyl)boronic acid (1.0 g, 5.74 mmol), methyl 2-bromoacrylate (860.2 mg, 32.74 mmol), and potassium phosphate (2.2 g, 10.43 mmol) were dissolved in a 4:1 mixture of dioxane and water (25.0 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (378.5 mg, 0.52 mmol). After the addition was complete, the reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 h. After the reaction was complete, the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (150.0 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 38B.

[0430] MS (ESI) m / z 215.2 (M+H) + .

[0431] Step 2: Preparation of methyl 2-(3-chloro-4-fluorophenyl)-3-(methylamino)propionate (Compound 38C) [ka]

[0432] Methyl 2-(3-chloro-4-fluorophenyl)acrylate (395.0 mg, 1.84 mmol) was dissolved in a solution of methylamine in tetrahydrofuran (8.0 mL). The reaction solution was reacted at room temperature for 16 hours. After completion of the reaction, the mixture was purified using a silica gel column to obtain compound 38C.

[0433] MS (ESI) m / z 246.1 (M+H) + .

[0434] Step 3: Preparation of methyl 3-(tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propionate (compound 38D) [ka]

[0435] 2-(3-chloro-4-fluorophenyl)-3-(methylamino)propionate (276.0 mg, 1.12 mmol), N,N-dimethylaminopyridine (13.7 mg, 0.11 mmol), and triethylamine (227.4 mg, 2.25 mmol) were dissolved in dichloromethane (5 mL), and then di-tert-butyl dicarbonate (244.9 mg, 1.12 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 38D.

[0436] MS (ESI) m / z 346.1 (M+H) + .

[0437] Step 4: Preparation of 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propionic acid (Compound 38E) [ka]

[0438] Methyl 3-(tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propionate (245.0 mg, 0.71 mmol) was dissolved in a mixture of methanol (5.0 mL) and water (5.0 mL), followed by the addition of lithium hydroxide monohydrate (59.5 mg, 1.42 mmol). The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (100 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give a white solid compound, which was used directly in the next reaction step.

[0439] Compound 38 of Example 38 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0440] MS (ESI) m / z 521.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.82 (s, 1H), 8.37-8.31 (d, J = 8.5 Hz, 1H), 7.98-7.91 (d, J = 8.5 Hz, 1H), 7.49-7.42 (d, J = 8.5 Hz, 1H), 7.37-7.21 (m, 2H), 4.70-4.61 (m, 1H), 4.43-4.13 (m, 7H), 3.73-3.64 (t, J = 7.0 Hz, 1H), 3.00-2.89 (m, 1H), 2.64-2.55 (m, 2H), 2.21 (s, 3H).

[0441] Example 39 Preparation of (S)-3-hydroxy-1-(1'-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 39) [ka]

[0442] Step 1: Preparation of 6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound 39B) [ka]

[0443] 6-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.5 g, 2.34 mmol), paraformaldehyde (140.3 mg, 4.67 mmol), and sodium cyanoborohydride (234.8 mg, 3.74 mmol) were dissolved in acetonitrile (30 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 hours, and then glacial acetic acid (0.5 mL) was added. After the reaction was complete, water was added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 39B.

[0444] MS (ESI) m / z 228.0 (M+H) + .

[0445] Step 2: Preparation of 6-(benzylthio)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 39C) [ka]

[0446] 6-Bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.45 g, 1.77 mmol), benzyl mercaptan (0.26 g, 3.54 mmol), tris(dibenzylideneacetone)dipalladium (0.09 g, 0.09 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.1 g, 0.18 mmol), and N,N-diisopropylethylamine (686 mg, 5.31 mmol) were dissolved in a mixture of methanol (7.0 mL) and water (3.0 mL). After addition was complete, the reaction mixture was allowed to stir at room temperature overnight. After completion of the reaction, the product was purified using a silica gel column to obtain compound 39C.

[0447] MS (ESI) m / z 272.3 (M+H) + .

[0448] Step 3: Preparation of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride (compound 39D) [ka]

[0449] 6-(benzylthio)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (375 mg, 1.38 mmol) was added to a mixed solvent (acetonitrile:acetic acid:water = 40:1.5:1) (25 mL), and 1,3-dichloro-5,5-dimethylhydantoin (545 mg, 2.76 mmol) was added under stirring at 0 °C. The mixture was then stirred at room temperature for 3 hours. After completion of the reaction, the mixture was purified using a silica gel column to obtain compound 39D.

[0450] Compound 39 of Example 39 was obtained by the same preparation method as in Example 1, except that 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride in Step 8 of Example 1.

[0451] MS (ESI) m / z 470.2(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.29-7.21 (m, 5H), 7.01-6.99 (m, 1H), 6.92-6.87 (m, 2H), 4.79-4.76 (t, J = 10.8 Hz, 1H), 4.73-4.70 (t, J = 13.2 Hz, 1H), 4.31-4.24 (m, 9H), 3.89-3.88 (m, 1H), 3.62-3.60 (m, 1H), 3.48-3.47 (m, 1H), 3.28 (s, 2H), 2.89 (s, 3H).

[0452] Example 40 Preparation of (S)-6-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 40) [ka]

[0453] Compound 40 of Example 40 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride.

[0454] MS (ESI) m / z 470.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.38-7.17 (m, 8H), 4.81-4.79 (m, 1H), 4.78-4.70 (m, 3H), 4.29-4.26 (m, 7H), 3.91-3.87 (m, 1H), 3.63-3.61 (m, 1H), 3.46-3.42 (m, 1H).

[0455] Example 41 Preparation of (S)-6-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 41) [ka]

[0456] Compound 41 of Example 41 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride.

[0457] MS (ESI) m / z 484.2(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.48-7.46 (d, 2H), 7.39 (s, 1H), 7.30-7.23 (m, 6 H), 4.81-4.70 (m, 4H), 4.31-4.19 (m, 8H), 3.91-3.85 (m, 1H), 3.63-3.60 (m, 1H), 3.51-3.43 (m, 2H).

[0458] Example 42 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propan-1-one (Compound 42) [ka]

[0459] Step 1: Preparation of ethyl 3-amino-2-(3-chloro-4-fluorophenyl)propionate (Compound 42B) [ka]

[0460] Ethyl 3-(tert-butoxycarbonylamino)-2-(3-chloro-4-fluorophenyl)propionate (1 g, 2.89 mmol) was dissolved in HCl-1,4-dioxane (200 mL), and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 42B.

[0461] MS (ESI) m / z 246.1 (M+H) + .

[0462] Step 2: Preparation of ethyl 2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propionate (Compound 42C) [ka]

[0463] Ethyl 3-amino-2-(3-chloro-4-fluorophenyl)propionate (801 mg, 3.26 mmol) was dissolved in methanol (30 mL), and N,N-diisopropylethylamine (842.74 mg, 6.52 mmol) and paraformaldehyde (587.39 mg, 6.52 mmol) were added at room temperature. After the addition was complete, the reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 6 hours. After the reaction was complete, the mixture was purified using a silica gel column to obtain compound 42C.

[0464] MS (ESI) m / z 274.1 (M+H) + .

[0465] Step 3: Preparation of 2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propionic acid (compound 42D) [ka]

[0466] Ethyl 2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propionate (391 mg, 1.43 mmol) was dissolved in ethanol (7 mL) and water (7 mL), and lithium hydroxide (119.99 mg, 2.86 mmol) was added at room temperature. After the addition was complete, the reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was purified using a silica gel column to obtain compound 42D.

[0467] MS (ESI) m / z 246.2 (M+H) + .

[0468] Compound 42 of Example 42 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0469] MS (ESI) m / z 535.1 (M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.82 (s, 1H), 8.35-8.33 (d, J = 8.5 Hz, 1H), 7.96-7.94 (d, J = 8.5 Hz, 1H), 7.49-7.47 (d, J = 7.1 Hz, 1H), 7.33-7.29 (m, 2H), 4.68-4.65 (d, J = 13.2 Hz, 1H), 4.48 - 4.15 (m, 7H), 3.74 - 3.71 (m, 1H), 2.78 - 2.67 (m, 1H), 2.37-2.33 (m, 1H), 2.09 (s, 6H).

[0470] Example 43 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)ethan-1-one (Compound 43) [ka]

[0471] Step 1: Preparation of 2-(3-bromophenyl)-2-hydroxyacetic acid (compound 43B) [ka]

[0472] 3-Bromobenzaldehyde (1.85 g, 10.0 mmol) was added to tetrahydrofuran (40 mL), trimethylsilyl cyanide (1.1 g, 11.0 mmol) was added to the solution, and one drop of a 1N tetrahydrofuran solution of tetrabutylammonium fluoride was added dropwise. The reaction solution was stirred at room temperature for 1 hour, and then the solvent was removed by rotary evaporation under reduced pressure. 6N aqueous hydrochloric acid (10 mL) was added to the residual oil and heated to reflux for 3 hours. The reaction mixture was cooled to 0 °C, and the pH was adjusted to 1 by dropwise addition of 10N sodium hydroxide solution. After the reaction was completed, the mixture was extracted with ethyl acetate (60 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 43B.

[0473] MS (ESI) m / z 230.1 (M−H) + .

[0474] Step 2: Preparation of methyl 2-(3-bromophenyl)-2-hydroxyacetate (compound 43C) [ka]

[0475] (3-Bromophenyl)glycolic acid (500 mg, 2.16 mmol) was added to methanol (10 mL), and thionyl chloride (773 mg, 6.49 mmol) was added dropwise to the reaction solution at room temperature. After the addition was complete, the reaction system was stirred at 60°C for 3 hours. After the reaction was complete, the product was purified using a silica gel column to obtain compound 43C.

[0476] MS (ESI) m / z 268.1 (M+Na) + .

[0477] Step 3: Preparation of methyl 2-(3-bromophenyl)-2-((tert-butyldiphenylsilyl)oxy)acetate (Compound 43D) [ka]

[0478] Methyl 2-(3-bromophenyl)-2-hydroxyacetate (400 mg, 1.63 mmol), tert-butylchlorodiphenylsilane (539 mg, 1.96 mmol), and imidazole (278 mg, 4.08 mmol) were added to tetrahydrofuran (8 mL) and stirred at 40° C. for 16 hours. After completion of the reaction, the mixture was purified using a silica gel column to obtain compound 43D.

[0479] MS (ESI) m / z 507.2 (M+Na) + .

[0480] Step 4: Preparation of methyl 2-((tert-butyldiphenylsilyl)oxy)-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (Compound 43E) [ka]

[0481] Methyl 2-(3-bromophenyl)-2-((tert-butyldiphenylsilyl)oxy)acetate (400 mg, 0.83 mmol), 1-methylpiperazine (124 mg, 1.24 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (48 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (43 mg, 0.04 mmol), and cesium carbonate (540 mg, 1.65 mmol) were added to 1,4-dioxane (10 mL). The mixture was purged with nitrogen three times and stirred at 100 °C overnight. After completion of the reaction, the product was purified using a silica gel column to obtain compound 43E.

[0482] MS (ESI) m / z 542.6 (M+Na) + .

[0483] Step 5: Preparation of methyl 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (Compound 43F) [ka]

[0484] Methyl 2-((tert-butyldiphenylsilyl)oxy)-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (350 mg, 0.74 mmol) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (386 mg, 1.48 mmol) was added, and the reaction mixture was stirred at 50°C overnight. After the reaction was completed, 50 mL of water was added to dilute the product, which was then extracted with ethyl acetate (50 mL*3) and water. The combined organic phase was dried over anhydrous sodium sulfate and purified using a silica gel column to obtain compound 43F.

[0485] MS (ESI) m / z 256.3 (M+H) + .

[0486] Step 6: Preparation of 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid (compound 43G) [ka]

[0487] Methyl 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (150 mg, 0.56 mmol) and sodium hydroxide (45 mg, 1.12 mmol) were dissolved in a mixture of methanol (3 mL) and water (3 mL), and the reaction mixture was then stirred at 25°C for 3 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 43G.

[0488] MS (ESI) m / z 249.2(MH) + .

[0489] Compound 43 of Example 43 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0490] MS (ESI) m / z 540.2(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.80 - 8.79 (d, J = 1.6 Hz, 1H), 8.34-8.32 (d, J = 8.4 Hz, 1H), 7.95-7.92 (m, 1H), 7.14-7.10 (t, J = 15.6 Hz, 1H), 6.86-6.69 (m, 3H), 5.69-5.67 (d, J = 5.2 Hz, 1H), 4.93-4.92 (d, J = 5.6 Hz, 1H), 4.62-4.22 (m, 8H), 3.09-3.06 (t, J = 10 Hz, 4H), 2.43-2.41 (t, J = 9.6 Hz, 4H), 2.21 (s, 3H).

[0491] Example 44 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-(4-methoxyphenyl)propan-1-one (Compound 44) [ka]

[0492] Step 1: Preparation of methyl 3-hydroxy-2-(4-methoxyphenyl)propionate (compound 44B) [ka]

[0493] Methyl 2-(4-methoxyphenyl)acetate (1.0 g, 5.55 mmol), paraformaldehyde (524.4 mg, 5.83 mmol), and sodium methoxide (15 mg, 0.28 mmol) were dissolved in dimethyl sulfoxide (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the product was purified using a silica gel column to obtain compound 44B.

[0494] MS (ESI) m / z 211.0 (M+H) + .

[0495] Step 2: Preparation of 3-hydroxy-2-(4-methoxyphenyl)propionic acid (compound 44C) [ka]

[0496] Methyl 3-hydroxy-2-(4-methoxyphenyl)propionate (0.49 g, 2.33 mmol) and lithium hydroxide monohydrate (0.2 g, 4.66 mmol) were dissolved in a mixture of methanol (7.0 mL) and water (3.0 mL). After the addition was complete, the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the product was purified using a silica gel column to obtain compound 44C.

[0497] MS (ESI) m / z 197.0(M+H) + .

[0498] Compound 44 of Example 44 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(4-methoxyphenyl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0499] MS (ESI) m / z 486.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.81-8.80 (d, J = 2 Hz, 1H), 8.34-8.32 (d, J = 8.8 Hz, 1H), 7.95-7.92 (m, 1H), 7.14-7.12 (d, J = 8.8 Hz, 2H), 6.83-6.81 (d, J = 8.8 Hz, 2H), 4.73-4.63 (m, 2H), 4.34-4.23 (m, 6H), 3.83-3.80 (m, 1H), 3.69 (s, 3H), 3.54-3.50 (m, 1H), 3.41-3.37 (m, 2H).

[0500] Example 45 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-(p-tolyl)propan-1-one (Compound 45) [ka]

[0501] Step 1: Preparation of methyl 3-hydroxy-2-(p-tolyl)propionate (compound 45B) [ka]

[0502] Methyl 2-(p-tolyl)acetate (0.5 g, 3.05 mmol) and paraformaldehyde (287.8 mg, 3.20 mmol) were dissolved in dimethyl sulfoxide (2.0 mL), followed by the addition of sodium methoxide (8.2 mg, 0.31 mmol). The reaction mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 45B.

[0503] MS (ESI) m / z 195.1 (M+H) + .

[0504] Step 2: Preparation of 3-hydroxy-2-(p-tolyl)propionic acid (compound 45C) [ka]

[0505] Methyl 2-(p-tolyl)acetate (380.0 mg, 1.96 mmol) was dissolved in a mixture of methanol (9.0 mL) and water (6.0 mL), and then sodium hydroxide (156.5 mg, 3.91 mmol) was added. The reaction solution was stirred at 25 °C for 16 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated and used directly in the next reaction step.

[0506] Compound 45 of Example 45 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(p-tolyl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0507] MS (ESI) m / z 470.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.81 (s, 1H), 8.34-8.32 (d, J = 9.1 Hz, 1H), 7.95-7.93 (d, J = 8.4 Hz, 1H), 7.09-7.08 (m, 4H), 4.73 -4.60 (m, 2H), 4.34 - 4.07 (m, 7H), 3.85-3.84(m, 1H), 3.54-3.52 (m, 1H), 3.40- 3.38 (m, 1H), 2.23 (s, 3H).

[0508] Example 46 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(3-fluorophenyl)-3-hydroxypropan-1-one (Compound 46) [ka]

[0509] Step 1: Preparation of methyl 2-(3-fluorophenyl)-3-hydroxypropionate (compound 46B) [ka]

[0510] Methyl 2-(3-fluorophenyl)acetate (1.0 g, 5.95 mmol) was dissolved in dimethyl sulfoxide (10 mL), followed by the addition of sodium methoxide (100 mg, 1.85 mmol) and paraformaldehyde (535 mg, 5.94 mmol) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. Water was added to dilute the reaction mixture, and the aqueous phase was extracted with ethyl acetate (10.0 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 46B.

[0511] MS (ESI) m / z 199.2 (M+H) + .

[0512] Step 2: Preparation of 2-(3-fluorophenyl)-3-hydroxypropionic acid (compound 46C) [ka]

[0513] Methyl 2-(3-fluorophenyl)-3-hydroxypropionate (610 mg, 3.08 mmol) was dissolved in methanol (6 mL) and water (6 mL), and lithium hydroxide (650 mg, 27.14 mmol) was added at room temperature. After the addition was complete, the reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. After the reaction was complete, the reaction mixture was concentrated and the pH was adjusted to 3-4 with 1N hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate (10.0 mL * 3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. Compound 46C was obtained by separation and purification using a silica gel column.

[0514] MS (ESI) m / z 183.1 (M−H) - .

[0515] Compound 46 of Example 46 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 2-(3-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0516] MS (ESI) m / z 474.1(M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.81-8.80 (m, 1H), 8.34 - 8.32 (m, 1H), 7.95-7.93 (m, 1H), 7.34-7.28 (m, 1H), 7.09-7.03 (m, 3H), 4.38-4.16 (m, 8H), 3.86 - 3.81 (m, 1H), 3.66-3.58 (m, 2H), 3.51- 3.44 (m, 1H).

[0517] Example 47 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylethan-1-one (Compound 47) [ka]

[0518] Compound 47 of Example 47 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, phenylacetic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0519] MS (ESI) m / z 426.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.82 (s, 1H), 8.35-8.33 (d, J=8.0 Hz, 1H), 7.96-7.94 (d, J=8.0 Hz, 1H), 7.27-7.15 (m, 5H), 4.54-4.22 (m, 8H), 3.44 (s, 2H).

[0520] Example 48 Preparation of 1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-(pyridin-3-yl)propan-1-one (Compound 48) [ka]

[0521] Step 1: Preparation of methyl 3-hydroxy-2-(pyridin-3-yl)propionate (compound 48B) [ka]

[0522] Methyl 2-(3-pyridyl)acetate (1.0 g, 6.62 mmol) was dissolved in dimethyl sulfoxide (10 mL), followed by the addition of sodium methoxide (120 mg, 666.67 μmol) and paraformaldehyde (600 mg, 6.67 mmol) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. Water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (30.0 mL*3), and the combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. Compound 48B was obtained by purification using a silica gel column.

[0523] MS (ESI) m / z 182.1 (M+H) + .

[0524] Step 2: Preparation of 3-hydroxy-2-(pyridin-3-yl)propionic acid (compound 48C) [ka]

[0525] Methyl 3-hydroxy-2-(2-pyridyl)propionate (140 mg, 772.68 μmol) was dissolved in a mixture of methanol (2 mL), water (2 mL), and tetrahydrofuran (2 mL), and lithium hydroxide (350 mg, 8.33 mmol) was added at room temperature. After the addition was complete, the reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. After the reaction was complete, the reaction mixture was concentrated and the pH was adjusted to 3-4 using 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10.0 mL*3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. Compound 48C was obtained by purification using a silica gel column.

[0526] MS (ESI) m / z 168.1 (M+H) + .

[0527] Compound 48 of Example 48 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(pyridin-3-yl)propionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0528] MS (ESI) m / z 457.1(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.81- 8.79 (m, 1H), 8.43- 8.42(m, 2H), 8.37-8.32 (m, 1H), 7.96 - 7.93 (m, 1H), 7.68 -7.66 (m, 1H), 7.32 - 7.28 (m, 1H), 4.91 - 4.88 (m, 1H), 4.75 - 4.67 (m, 1H), 4.44 - 4.17 (m, 7H), 3.88 - 3.82 (m, 1H), 3.68 - 3.64 (m, 1H), 3.53 - 3.48 (m, 1H).

[0529] Example 49 Preparation of (S)-1-(1'-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 49) [ka]

[0530] In Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-6-sulfonyl chloride (the synthesis method was the same as in Example 20D), and the same preparation method as in Example 1 was used to obtain compound 49 of Example 49.

[0531] MS (ESI) m / z 458.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.54-7.50 (t, J = 1.6 Hz, 2H), 7.32-7.21 (m, 5H), 4.50-4.46 (m, 1H), 4.37-4.30 (m, 11H), 3.91-3.86 (t, J = 1.0 Hz, 1H), 3.64-3.61 (m, 2H), 3.48-3.44 (m, 1H).

[0532] Example 50 Preparation of (S)-1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 50) [ka]

[0533] Step 1: Preparation of methyl 2-(4-fluorophenyl)-3-hydroxypropionate (compound 50B) [ka]

[0534] Methyl 2-(4-fluorophenyl)acetate (2.0 g, 11.89 mmol) was dissolved in dimethyl sulfoxide (20 mL), followed by the addition of paraformaldehyde (1.2 g, 12.49 mmol), followed by the slow addition of sodium methoxide solution (32.1 mg, 594.66 μmol). The reaction mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, water was added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 50B.

[0535] MS (ESI) m / z 199.0 (M+H) + .

[0536] Step 2: Preparation of 2-(4-fluorophenyl)-3-hydroxypropionic acid (compound 50C)

[0537] Methyl 2-(4-fluorophenyl)-3-hydroxypropionate (1.5 g, 7.47 mmol) was dissolved in a mixture of methanol (15 mL) and water (10 mL), followed by the addition of sodium hydroxide (597.4 mg, 14.94 mmol). The reaction mixture was incubated at 50°C for 3 hours. TLC confirmed the completion of the reaction. The reaction mixture was adjusted to an acidic pH using 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 50C.

[0538] MS (ESI) m / z 185.0 (M+H) + .

[0539] The same preparation method as in Example 1 was employed, except that in step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, followed by chiral separation of the product to obtain compound 50 of Example 50.

[0540] MS (ESI) m / z 474.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.81-8.80 (d, J=4.0 Hz, 1H), 8.34-8.32 (d, J=8.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.29-7.25 (m, 2H), 7.11-7.07 (m, 2H), 4.68-4.65 (m, 1H), 4.34-4.25 (m, 7H), 3.82-3.79 (m, 1H), 3.62-3.60 (m, 1H), 3.44-3.40 (m, 2H).

[0541] Example 51 Preparation of (R)-1-(1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-fluorophenyl)-3-hydroxypropan-1-one (Compound 51) [ka]

[0542] The same preparation method as in Example 1 was used, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, followed by chiral separation of the product to obtain compound 51 of Example 51.

[0543] MS (ESI) m / z 474.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.81-8.80 (d, J=4.0 Hz, 1H), 8.34-8.32 (d, J=8.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.29-7.25 (m, 2H), 7.11-7.07 (m, 2H), 4.68-4.65 (m, 1H), 4.34-4.25 (m, 7H), 3.82-3.79 (m, 1H), 3.62-3.60 (m, 1H), 3.44-3.40 (m, 2H).

[0544] Example 52 Preparation of (1'-(benzo[d]thiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)(1H-indol-3-yl)methanone (Compound 52) [ka]

[0545] Compound 52 of Example 52 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 1H-indole-3-carboxylic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0546] MS (ESI) m / z 451.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 9.73-9.63 (t, J = 4 Hz, 1H), 8.85-8.84 (d, J = 0.4 Hz, 1H), 8.36-8.34 (d, J = 0.8 Hz, 1H), 8.05-8.03 (d, J = 0.8 Hz, 1H), 7.99-7.96 (m, 1H), 7.69-7.68 (d, J = 0.4 Hz, 1H), 7.42-7.40 (d, J = 0.8 Hz, 1H), 7.16-7.06 (m, 2H), 59-4.40 (m, 8H).

[0547] Example 53 Preparation of 3-hydroxy-2-(4-methoxyphenyl)-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 53) [ka]

[0548] Compound 53 of Example 53 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(4-methoxyphenyl)propionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0549] MS (ESI) m / z 430.1(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 8.81-8.79 (m, 1H), 8.17-8.13 (m, 1H), 7.99-7.97 (d, J = 8.0 Hz, 1H), 7.76-7.73 (m, 1H), 7.18-7.15 (m, 2H), 6.87-6.83 (m, 2H), 4.76-4.68 (m, 2H), 4.53 (s, 4H), 4.35-4.18 (m, 3H), 3.89-3.81 (m, 1H), 3.71 (s, 3H), 3.57-3.53 (m, 1H), 3.42-3.37 (m, 1H).

[0550] Example 54 Preparation of (S)-2-(4-fluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 54) [ka]

[0551] The same preparation method as in Example 1 was used, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, followed by chiral separation of the product to obtain compound 54 of Example 54.

[0552] MS (ESI) m / z 418.1(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 8.81-8.80 (d, J = 4.7 Hz, 1H), 8.17-8.13 (m, 1H), 7.99-7.97 (d, J = 7.7 Hz, 1H), 7.77-7.73 (m, 1H), 7.32-7.29 (m, 2H), 7.14-7.09 (m, 2H), 4.83-4.70 (m, 2H), 4.54-4.19 (m, 7H), 3.87-3.82 (m, 1H), 3.66-3.63 (m, 1H), 3.46-3.42 (m, 1H).

[0553] Example 55 Preparation of (R)-2-(4-fluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 55) [ka]

[0554] The same preparation method as in Example 1 was used, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, followed by chiral separation of the product to obtain Compound 55 of Example 55.

[0555] MS (ESI) m / z 418.1(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 8.81-8.80 (d, J = 4.7 Hz, 1H), 8.17-8.13 (m, 1H), 7.99-7.97 (d, J = 7.7 Hz, 1H), 7.77-7.73 (m, 1H), 7.32-7.29 (m, 2H), 7.14-7.09 (m, 2H), 4.83-4.70 (m, 2H), 4.54-4.19 (m, 7H), 3.87-3.82 (m, 1H), 3.66-3.63 (m, 1H), 3.46-3.42 (m, 1H).

[0556] Example 56 Preparation of (1H-indol-3-yl)(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)methanone (Compound 56) [ka]

[0557] Compound 56 of Example 56 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 1H-indole-3-carboxylic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0558] MS (ESI) m / z 395.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.84 (s, 1H), 8.19-8.16 (t, J = 1.2 Hz, 1H), 8.08-8.06 (d, J = 0.8 Hz, 1H), 8.02-8.00 (d, J = 0.8 Hz, 1H), 7.77-7.73 (d, J = 1.6 Hz, 2H), 7.43-7.41 (d, J = 0.8 Hz, 1H), 7.17-7.08 (m, 2H), 4.60(s, 8H).

[0559] Example 57 Preparation of 3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(p-tolyl)propan-1-one (Compound 57) [ka]

[0560] Compound 57 of Example 57 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(p-tolyl)propionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0561] MS (ESI) m / z 414.1(M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 8.80-8.79 (m, 1H), 8.17-8.13 (m, 1H), 7.99-7.96 (m, 1H), 7.76-7.73 (m, 1H), 7.14-7.08 (m, 4H), 4.77-4.68 (m, 2H), 4.53 (s, 4H), 4.35-4.18 (m, 3H), 3.89-3.83 (m, 1H), 3.58-3.55 (m, 1H), 3.44-3.39 (m, 1H), 2.25 (s, 3H).

[0562] Example 58 Preparation of (4-phenyltetrahydro-2H-pyran-4-yl)(1'-(pyridin-2-ylsulfonyl-(1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)methanone (Compound 58) [ka]

[0563] Compound 58 of Example 58 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 4-phenyltetrahydro-2H-pyran-4-carboxylic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0564] MS (ESI) m / z 440.2(M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 8.78-8.76 (m, 1H), 8.16-8.11 (m, 1H), 7.95-7.93 (d, J = 8.0 Hz, 1H), 7.76-7.73 (m, 1H), 7.40-7.25 (m, 5H), 4.46-3.99 (m, 8H), 3.73-3.70 (m, 2H), 3.56-3.51 (m, 2H), 2.18-2.15 (d, J = 13.5 Hz, 2H), 1.85-1.78 (m, 2H).

[0565] Example 59 Preparation of 2-(3-chloro-4-fluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 59) [ka]

[0566] Step 1: Preparation of methyl 2-(3-chloro-4-fluorophenyl)-3-hydroxypropionate (Compound 59B) [ka]

[0567] Methyl 2-(3-chloro-4-fluorophenyl)acetate (2.2 g, 10.61 mmol) and paraformaldehyde (477.9 mg, 5.31 mmol) were dissolved in dimethyl sulfoxide (40.0 mL), followed by the addition of sodium methoxide (191.1 mg, 1.06 mmol, 30%). The reaction solution was allowed to react at room temperature for 4 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 59B.

[0568] MS (ESI) m / z 233.0 (M+H) + .

[0569] Step 2: Preparation of 2-(3-chloro-4-fluorophenyl)-3-hydroxypropionic acid (compound 59C) [ka]

[0570] Methyl 2-(3-chloro-4-fluorophenyl)-3-hydroxypropionate (2.0 g, 8.60 mmol) was dissolved in tetrahydrofuran (60 mL) and water (40 mL), and then sodium hydroxide (687.8 mg, 17.19 mmol) was added. The reaction solution was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (100 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give a yellow oily compound, which was used directly in the next reaction step.

[0571] Compound 59 of Example 59 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(3-chloro-4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0572] MS (ESI) m / z 452.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.82-8.81 (m, 1H), 8.19-8.14 (m, 1H), 8.00-7.97 (m, 1H), 7.78-7.74 (m, 1H), 7.51-7.49 (m, 1H), 7.37-7.31 (m, 2H), 4.94-4.87 (m, 1H), 4.78-4.40 (m, 6H), 4.38-4.19 (m, 2H), 3.87-3.77 (m, 2H), 3.55-3.43 (m, 1H).

[0573] Example 60 Preparation of 3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(pyridin-3-yl)propan-1-one (Compound 60) [ka]

[0574] Compound 60 of Example 60 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 3-hydroxy-2-(pyridin-3-yl)propionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0575] MS (ESI) m / z 401.1(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 8.81-8.79 (m, 1H), 8.47-8.44 (m, 2H), 8.18-8.13 (m, 1H), 7.99-7.97 (d, J = 8.0 Hz, 1H), 7.77-7.69 (m, 2H), 7.34-7.31 (m, 1H), 4.94-4.92 (m, 1H), 4.76-4.73 (d, J = 12.6 Hz, 1H), 4.55-4.46 (m, 5H), 4.35-4.21 (m, 2H), 3.91-3.85 (m, 1H), 3.70 (m, 1H), 3.55-3.50 (m, 1H)

[0576] Example 61 Preparation of 2-(3,4-difluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 61) [ka]

[0577] Step 1: Preparation of methyl 2-(3,4-difluorophenyl)-3-hydroxypropionate (Compound 61B) [ka]

[0578] Methyl 2-(3,4-difluorophenyl)acetate (0.5 g, 2.69 mmol) and paraformaldehyde (241.9 mg, 2.69 mmol) were dissolved in dimethyl sulfoxide (10.0 mL), followed by the addition of sodium methoxide (48.4 mg, 0.27 mmol, 30%). The reaction solution was allowed to react at room temperature for 4 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 50C.

[0579] MS (ESI) m / z 217.2 (M+H) + .

[0580] Step 2: Preparation of 2-(3,4-difluorophenyl)-3-hydroxypropionic acid (compound 61C) [ka]

[0581] Methyl 2-(3,4-difluorophenyl)-3-hydroxypropionate (320.0 mg, 1.48 mmol) was dissolved in methanol (15.0 mL) and water (10.0 mL), and then sodium hydroxide (118.4 mg, 2.96 mmol) was added. The reaction solution was stirred at 50 °C for 3 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the solution was used directly in the next reaction step.

[0582] Compound 61 of Example 61 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(3,4-difluorophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0583] MS (ESI) m / z 436.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.82-8.78 (m, 1H), 8.18-8.14 (m, 1H), 8.00-7.95 (m, 1H), 7.79-7.74 (m, 1H), 7.39-7.32 (m, 2H), 7.15-7.11 (m, 1H), 4.90-4.87 (m, 1H), 4.73-4.69 (m, 1H), 4.55-4.44 (m, 5H), 4.34-4.21 (m, 2H), 3.85-3.80 (m, 1H), 3.69-3.65 (m, 1H), 3.50-3.45 (m, 1H).

[0584] Example 62: Preparation of 3-hydroxy-3-methyl-2-phenyl-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)butan-1-one (Compound 62) [ka]

[0585] Compound 62 of Example 62 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 3-hydroxy-3-methyl-2-phenylbutyric acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0586] MS (ESI) m / z 428.2(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.79-8.77 (m, 1H), 8.17-8.12 (m, 1H), 7.98-7.96 (d, J = 7.7 Hz, 1H), 7.75-7.72 (m, 1H), 7.38-7.22 (m, 5H), 4.89 (brs, 1H), 4.77-4.73 (m, 1H), 4.60-4.45 (m, 4H), 4.35-4.19 (m, 3H), 3.51 (s, 1H), 1.15 (s, 3H), 0.98 (s, 3H).

[0587] Example 63 Preparation of (S)-3-hydroxy-1-(1'-((1-methyl-1H-benzimidazol-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 63) [ka]

[0588] Step 1: Preparation of 6-(benzylthio)-1-methyl-1H-benzo[d]imidazole (Compound 63B) [ka]

[0589] 6-Bromo-1-methyl-1H-benzo[d]imidazole (1 g, 4.74 mmol) was dissolved in 1,4-dioxane, followed by the addition of benzyl mercaptan (588 mg, 4.74 mmol), DIPEA (1.22 g, 9.48 mmol), Pd(dba)CHCl (485 mg, 0.47 mmol), and Xantphos (548 mg, 0.95 mmol). After the addition was complete, the reaction was purged under nitrogen three times and then heated to 80 °C and stirred for 16 h. After completion of the reaction, the product was purified on a silica gel column to give compound 63B.

[0590] MS (ESI) m / z 255.1 (M+H) + .

[0591] Step 2: Preparation of 1-methyl-1H-benzo[d]imidazole-6-sulfonyl chloride (Compound 63C) [ka]

[0592] 6-(Benzylthio)-1-methyl-1H-benzo[d]imidazole (560 mg, 2.20 mmol) was dissolved in acetonitrile. Then, acetic acid (661 mg, 11.01 mmol), water (397 mg, 22.02 mmol), and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (868 mg, 4.40 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the product was purified by silica gel column chromatography to obtain compound 63C.

[0593] MS (ESI) m / z 231.0 (M+H) + .

[0594] Compound 63 of Example 63 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 1-methyl-1H-benzo[d]imidazole-6-sulfonyl chloride.

[0595] MS (ESI) m / z 453.2(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.17 - 8.04 (m, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.25 (dt, J = 13.8, 7.2 Hz, 5H), 4.77 (t, J = 5.2 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H), 4.28 (d, J = 21.7 Hz, 6H), 4.17 (d, J = 14.6 Hz, 1H), 3.96 (s, 3H), 3.86 (td, J = 9.4, 5.5 Hz, 1H), 3.59 (dd, J = 8.8, 5.3 Hz, 1H), 3.45 (dd, J = 9.8, 4.9 Hz, 1H).

[0596] Example 64 Preparation of (1'-(benzothiazol-6-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)(isoindolin-1-yl)methanone (Compound 64) [ka]

[0597] Compound 64 of Example 64 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in Step 10, 2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0598] MS (ESI) m / z 453.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 8.6, 1.9 Hz, 1H), 7.27 - 7.17 (m, 4H), 4.82 (m, 2H), 4.49 (m, 1H), 4.32 (m, 7H), 4.20 - 4.04 (m, 2H).

[0599] Example 65 Preparation of (S)-4-(1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-ylsulfonyl)benzonitrile (Compound 65) [ka]

[0600] Compound 65 of Example 65 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 4-cyanobenzenesulfonyl chloride.

[0601] MS (ESI) m / z 424.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.13 (m, 2H), 8.03 - 7.98 (m, 2H), 7.32 - 7.18 (m, 5H), 4.79 (t, J = 5.3 Hz, 1H), 4.70 (d, J = 12.5 Hz, 1H), 4.33 (d, J = 15.0 Hz, 6H), 4.19 (d, J = 14.4 Hz, 1H), 3.88 (m, 1H), 3.61 (dd, J = 8.8, 5.5 Hz, 1H), 3.45 (m, 1H).

[0602] Example 66 Preparation of (S)-1-(1'-(5-chloropyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 66) [ka]

[0603] Compound 66 of Example 66 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-chloropyridine-2-sulfonyl chloride.

[0604] MS (ESI) m / z 434.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.93 - 8.84 (m, 1H), 8.28 (dd, J = 8.4, 2.4 Hz, 1H), 7.99 (dd, J = 8.4, 0.7 Hz, 1H), 7.31 - 7.23 (m, 5H), 4.82 - 4.67 (m, 2H), 4.54 (d, J = 2.8 Hz, 4H), 4.39 - 4.21 (m, 3H), 3.89 (m, 1H), 3.63 (dd, J = 8.9, 5.4 Hz, 1H), 3.46 (m, 1H).

[0605] Example 67 Preparation of (S)-3-hydroxy-1-(1'-((5-methoxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 67) [ka]

[0606] Step 1: Preparation of 2-(benzylthio)-5-methoxypyridine (compound 67B) [ka]

[0607] 2-Bromo-5-methoxypyridine (1 g, 5.32 mmol) was dissolved in 1,4-dioxane, followed by the addition of benzyl mercaptan (660 mg, 5.32 mmol), DIPEA (1.37 g, 10.64 mmol), Pd(dba)CHCl (544 mg, 0.53 mmol), and Xantphos (615 mg, 1.06 mmol). After the addition was complete, the reaction mixture was purged under nitrogen three times and then heated to 80 °C and stirred for 16 h. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 67B.

[0608] MS (ESI) m / z 232.1(M+H) + .

[0609] Step 2: Preparation of 5-methoxypyridine-2-sulfonyl chloride (compound 67C) [ka]

[0610] 2-(Benzylthio)-5-methoxypyridine (1.3 g, 5.62 mmol) was dissolved in acetonitrile, followed by the addition of acetic acid (1.69 g, 28.1 mmol), water (1.01 g, 56.2 mmol), and NCS (1.5 g, 11.24 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the product was purified using a silica gel column to give compound 67C.

[0611] MS (ESI) m / z 208.0 (M+H) + .

[0612] Compound 67 of Example 67 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-methoxypyridine-2-sulfonyl chloride.

[0613] MS (ESI) m / z 430.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.9 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.65 (m, 1H), 7.33 - 7.20 (m, 5H), 4.80 (t, J = 5.3 Hz, 1H), 4.72 (d, J = 12.8 Hz, 1H), 4.54 - 4.42 (m, 4H), 4.41 - 4.27 (m, 2H), 4.25 - 4.16 (m, 1H), 3.93 (s, 4H), 3.62 (m, 1H), 3.46 (m, 1H).

[0614] Example 68 Preparation of (S)-3-hydroxy-2-phenyl-1-(1'-(pyridin-3-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 68) [ka]

[0615] Compound 68 of Example 68 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-3-sulfonyl chloride.

[0616] MS (ESI) m / z 400.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 2.3 Hz, 1H), 8.92 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (m, 1H), 7.72 (dd, J = 8.0, 4.9 Hz, 1H), 7.33 - 7.18 (m, 5H), 4.76 - 4.64 (m, 1H), 4.44 - 4.25 (m, 6H), 4.19 (d, J = 13.4 Hz, 1H), 3.88 (t, J = 9.5 Hz, 1H), 3.61 (dd, J = 8.8, 5.5 Hz, 1H), 3.45 (dd, J = 10.1, 5.5 Hz, 2H).

[0617] Example 69 Preparation of (S)-3-hydroxy-2-phenyl-1-(1'-(quinolin-8-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 69) [ka]

[0618] Compound 69 of Example 69 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, quinoline-8-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride.

[0619] MS (ESI) m / z 450.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 9.08 (dd, J = 4.2, 1.8 Hz, 1H), 8.56 (dd, J = 8.4, 1.8 Hz, 1H), 8.35 (m, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.71 (dd, J = 8.3, 4.2 Hz, 1H), 7.33 - 7.19 (m, 5H), 4.92 - 4.59 (m, 6H), 4.40 - 4.28 (m, 2H), 4.22 (m, 1H), 3.89 (t, J = 9.5 Hz, 1H), 3.62 (dd, J = 8.8, 5.5 Hz, 1H), 3.46 (dd, J = 10.1, 5.5 Hz, 1H).

[0620] Example 70 Preparation of (S)-6-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)nicotinonitrile (Compound 70) [ka]

[0621] Step 1: Preparation of 6-(benzylthio)nicotinonitrile (compound 70B) [ka]

[0622] 2-Bromo-5-cyanopyridine (2 g, 14.44 mmol) was dissolved in DMF, followed by the addition of benzylthiol (1.79 g, 14.44 mmol) and cesium carbonate (5.65 g, 17.33 mmol). After the addition was complete, the reaction mixture was heated to 60°C and stirred for 6 hours. After the reaction was complete, the product was purified using a silica gel column to obtain compound 70B. MS (ESI) m / z 227.1 (M+H) +

[0623] Step 2: Preparation of 5-cyanopyridine-2-sulfonyl chloride (compound 70C) [ka]

[0624] 6-(Benzylthio)nicotinonitrile (1 g, 4.42 mmol) was dissolved in a mixture of dichloromethane and water. The reaction mixture was cooled to 0°C, and concentrated hydrochloric acid was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 10 minutes, and then an aqueous solution of sodium hypochlorite was slowly added dropwise. After the addition was complete, the reaction mixture was kept at 0°C and stirred for 10 minutes, and then the liquid was rapidly separated. The organic phase was used directly in the next reaction step.

[0625] Compound 70 of Example 70 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-cyanopyridine-2-sulfonyl chloride.

[0626] MS (ESI) m / z 425.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (dd, J = 2.1, 0.9 Hz, 1H), 8.67 (dd, J = 8.2, 2.1 Hz, 1H), 8.14 (dd, J = 8.1, 0.9 Hz, 1H), 7.33 - 7.20 (m, 5H), 4.80 (t, J = 5.3 Hz, 1H), 4.73 (m, 1H), 4.63 - 4.52 (m, 4H), 4.34 (dd, J = 21.7, 8.2 Hz, 2H), 4.27 - 4.18 (m, 1H), 3.90 (m, 1H), 3.63 (dd, J = 8.9, 5.5 Hz, 1H), 3.47 (m, 1H).

[0627] Example 71 Preparation of 2-(4-(difluoromethyl)phenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 71) [ka]

[0628] Step 1: Preparation of methyl 2-(4-(difluoromethyl)phenyl)acetate (Compound 71B) [ka]

[0629] Diethylaminosulfur trifluoride (3.62 g, 22.45 mmol) was added to a solution of methyl 2-(4-formylphenyl)acetate (2.0 g, 11.22 mmol) in dichloromethane (10.0 mL). The mixture was stirred under nitrogen protection at 50°C for 3 hours. After completion of the reaction, the mixture was purified by silica gel column separation to obtain compound 71B.

[0630] MS (ESI) m / z 201.0 (M+H) + .

[0631] Step 2: Preparation of methyl 2-(4-(difluoromethyl)phenyl)-3-hydroxypropionate (Compound 71C) [ka]

[0632] Methyl 2-(4-(difluoromethyl)phenyl)acetate (1.5 g, 7.49 mmol) was dissolved in dimethyl sulfoxide (10.0 mL), followed by the addition of paraformaldehyde (681.13 mg, 7.57 mmol), followed by the slow addition of sodium methoxide solution (136.23 mg, 756.81 μmol, 30% purity). The reaction solution was allowed to react at room temperature for 3 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 71C.

[0633] MS (ESI) m / z 231.0 (M+H) + .

[0634] Step 3: Preparation of 2-(4-(difluoromethyl)phenyl)-3-hydroxypropionic acid (compound 71D) [ka]

[0635] Methyl 2-[4-(difluoromethyl)phenyl]-3-hydroxypropionate (300 mg, 1.30 mmol) was dissolved in a mixture of water (3.0 mL), methanol (3.0 mL), and tetrahydrofuran (3.0 mL), followed by the addition of lithium hydroxide (156.05 mg, 6.52 mmol). The mixture was stirred at 50°C for 3 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 71D.

[0636] MS (ESI) m / z 217.0 (M+H) + .

[0637] Compound 71 of Example 71 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(4-(difluoromethyl)phenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0638] MS (ESI) m / z 450.0 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.17-8.13 (t, 1H), 7.98-7.97 (m, 1H), 7.76-7.72 (m, 1H), 7.51-7.49 (d, J=6.8 Hz, 2H), 7.42-7.40 (m, J=6.8 Hz, 2H), 7.113-6.85 (t, 1 H), 4.87 (s, 1H), 4.75-4.72 (d, J=12.0 Hz, 1H), 4.54 (s, 4H), 4.40-4.19 (m, 3 H), 3.88 (s, 1H), 3.71 (s, 1H), 3.49 (s, 1H).

[0639] Example 72 Preparation of (S)-1-(1'-((5-ethoxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 72) [ka]

[0640] Step 1: Preparation of 2-(benzylthio)-5-ethoxypyridine (compound 72B) [ka]

[0641] 2-Bromo-5-ethoxypyridine (2 g, 9.9 mmol) was dissolved in 1,4-dioxane, followed by the addition of benzyl mercaptan (1.23 g, 9.9 mmol), DIPEA (3.28 mL, 19.8 mmol), Pd(dba)CHCl (1.02 g, 0.99 mmol), and Xantphos (1.15 g, 1.98 mmol). After the addition was complete, the reaction mixture was purged under nitrogen three times and then heated to 80 °C and stirred for 16 hours. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 72B.

[0642] MS (ESI) m / z 246.1 (M+H)+ .

[0643] Step 2: Preparation of 5-ethoxypyridine-2-sulfonyl chloride (compound 72C) [ka]

[0644] 2-(Benzylthio)-5-ethoxypyridine (2.3 g, 9.37 mmol) was dissolved in acetonitrile, and acetic acid (2.81 g, 46.85 mmol), water (1.69 g, 93.7 mmol), and 1,3-dichloroimidazolidine-2,4-dione (3.69 g, 18.74 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 72C.

[0645] MS (ESI) m / z 221.9 (M+H) + .

[0646] Compound 72 of Example 72 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-ethoxypyridine-2-sulfonyl chloride.

[0647] MS (ESI) m / z 444.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.63 (dd, J = 8.8, 2.9 Hz, 1H), 7.39 - 7.11 (m, 5H), 4.80 (t, J = 5.3 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 4.47 (s, 4H), 4.40 - 4.26 (m, 2H), 4.22 (q, J = 7.0 Hz, 3H), 3.89 (m, 1H), 3.62 (dd, J = 8.9, 5.5Hz, 1H), 3.46 (m, 1H), 1.37 (t, J = 6.9 Hz, 3H).

[0648] Example 73 Preparation of 3-fluoro-2-phenyl-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 73) [ka]

[0649] Compound 73 of Example 73 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 3-fluoro-2-phenylpropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0650] MS (ESI) m / z 402.1 (M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 8.79-8.78 (d, J = 8.0 Hz, 1H), 8.17-8.12 (m, 1H), 7.98-7.96 (d, J = 8.0 Hz, 1H), 7.76-7.72 (m, 1H), 7.37-7.33 (m, 2H), 7.31-7.23 (m, 3H), 4.89-4.72 (m, 2H), 4.56-4.52 (m, 4H), 4.44-4.21 (m, 4H), 4.06-3.99 (m, 1H).

[0651] Example 74 Preparation of 2-(2,4-difluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 74) [ka]

[0652] Step 1: Preparation of methyl 2-(2,4-difluorophenyl)-3-hydroxypropionate (compound 74B) [ka]

[0653] Methyl 2-(2,4-difluorophenyl)acetate (0.8 g, 4.30 mmol) and paraformaldehyde (387.1 mg, 4.30 mmol) were dissolved in dimethyl sulfoxide (5.0 mL), followed by the addition of sodium methoxide (77.4 mg, 0.43 mmol, 30%). The reaction solution was allowed to react at room temperature for 4 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 74B.

[0654] MS (ESI) m / z 217.2 (M+H) + .

[0655] Step 2: Preparation of 2-(2,4-difluorophenyl)-3-hydroxypropionic acid (compound 74C) [ka]

[0656] Methyl 2-(2,4-difluorophenyl)-3-hydroxypropionate (440.0 mg, 2.04 mmol) was dissolved in methanol (15.0 mL) and water (10.0 mL), and then sodium hydroxide (162.8 mg, 4.07 mmol) was added. The reaction solution was stirred at 50 °C for 3 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the solution was used directly in the next reaction step.

[0657] Compound 74 of Example 74 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(2,4-difluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0658] MS (ESI) m / z 436.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.80 (d, J = 3.8 Hz, 1H), 8.18-8.13 (t, J = 7.7 Hz, 1H), 7.99-7.97 (d, J = 7.7 Hz, 1H), 7.77-7.74 (t, J = 5.9 Hz, 1H), 7.45-7.39 (q, J = 7.7 Hz, 1H), 7.23-7.17 (t, J = 9.8 Hz, 1H), 7.07-7.02 (t, J = 8.4 Hz, 1H), 4.92-4.89 (m, 1H), 4.74-4.71 (m, 1H), 4.60-4.48 (m, 4H), 4.40-4.19 (m, 3H), 3.92-3.82 (m, 2H), 3.55-3.48 (m, 1H).

[0659] Example 75 Preparation of 2-(4-chlorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 75) [ka]

[0660] Step 1: Preparation of methyl 2-(4-chlorophenyl)-3-hydroxypropionate (Compound 75B) [ka]

[0661] Methyl 2-(4-chlorophenyl)acetate (2.0 g, 10.83 mmol) and paraformaldehyde (975.9 mg, 10.83 mmol) were dissolved in dimethyl sulfoxide (50.0 mL), and then sodium methoxide (195.1 mg, 1.08 mmol, 30%) was added. The reaction solution was reacted at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with water. The aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After completion of the reaction, the product was separated and purified using a silica gel column to obtain compound 75B.

[0662] MS (ESI) m / z 215.1 (M+H) +

[0663] Step 2: Preparation of 2-(4-chlorophenyl)-3-hydroxypropionic acid (compound 75C) [ka]

[0664] Methyl 2-(4-chlorophenyl)-3-hydroxypropionate (1.3 g, 6.06 mmol) was dissolved in methanol (45 mL) and water (30 mL), and then sodium hydroxide (484.5 mg, 12.11 mmol) was added. The reaction solution was stirred at 50 °C for 3 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the solution was used directly in the next reaction step.

[0665] Compound 75 of Example 75 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(4-chlorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0666] MS (ESI) m / z 434.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.81-8.80 (m, 1H), 8.17-8.12 (m, 1H), 7.99-7.97 (d, J = 7.7 Hz, 1H), 7.77-7.73 (m, 1H), 7.38-7.32 (m, 2H), 7.32-7.27 (m, 2H), 4.86-4.83 (t, J = 5.2 Hz, 1H), 4.73-4.20 (m, 8H), 3.88-3.82 (m, 1H), 3.67-3.63 (m, 1H), 3.49-3.44 (m, 1H).

[0667] Example 76 Preparation of (R)-2-(3-chloro-4-fluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 76) [ka]

[0668] The same preparation method as in Example 1 was used, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(3-chloro-4-fluorophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, followed by chiral separation of the product to obtain Compound 76 of Example 76.

[0669] MS (ESI) m / z 452.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.82-8.81 (m, 1H), 8.19-8.14 (m, 1H), 8.00-7.97 (m, 1H), 7.78-7.74 (m, 1H), 7.51-7.49 (m, 1H), 7.37-7.31 (m, 2H), 4.94-4.87 (m, 1H), 4.78-4.40 (m, 6H), 4.38-4.19 (m, 2H), 3.87-3.77 (m, 2H), 3.55-3.43 (m, 1H).

[0670] Example 77 Preparation of (S)-2-(3-chloro-4-fluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 77) [ka]

[0671] The same preparation method as in Example 1 was used, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(3-chloro-4-fluorophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, followed by chiral separation of the product to obtain compound 77 of Example 77.

[0672] MS (ESI) m / z 452.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.82-8.81 (m, 1H), 8.19-8.14 (m, 1H), 8.00-7.97 (m, 1H), 7.78-7.74 (m, 1H), 7.51-7.49 (m, 1H), 7.37-7.31 (m, 2H), 4.94-4.87 (m, 1H), 4.78-4.40 (m, 6H), 4.38-4.19 (m, 2H), 3.87-3.77 (m, 2H), 3.55-3.43 (m, 1H).

[0673] Example 78 Preparation of 3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one (Compound 78) [ka]

[0674] Compound 78 of Example 78 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid was replaced with 3-hydroxy-2-(4-(trifluoromethyl)phenyl)propionic acid.

[0675] MS (ESI) m / z 468.1(M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 8.81-8.79 (d, J = 4.7 Hz, 1H), 8.18-8.13 (m, 1H), 7.99-7.97 (d, J = 8.0 Hz, 1H), 7.76-7.73 (m, 1H), 7.67-7.65 (d, J = 8.2 Hz, 2H), 7.52-7.50 (d, J = 8.2 Hz, 2H), 4.76-4.73 (d, J = 12.4 Hz, 1H), 4.54 (s, 4H), 4.43-4.39 (d, J = 13.2 Hz, 1H), 4.34-4.31 (d, J = 13.7 Hz, 1H), 4.24-4.21 (d, J = 12.9 Hz, 1H), 3.91-3.87 (m, 1H), 3.78-3.75 (m, 1H), 3.54-3.50(m, 1H), 2.67-2.65 (d, J = 7.4 Hz, 1H).

[0676] Example 79 Preparation of 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 79) [ka]

[0677] Step 1: Preparation of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (Compound 79B) [ka]

[0678] 2-(4-Hydroxy-3-nitrophenyl)acetic acid (5.0 g, 25.36 mmol) was dissolved in anhydrous methanol (100 mL), and then thionyl chloride (6.03 g, 50.72 mmol) was slowly added. The reaction solution was reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with water. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 79B.

[0679] MS (ESI) m / z 212.1 (M+H) +

[0680] Step 2: Preparation of methyl 2-(3-amino-4-hydroxyphenyl)acetate (Compound 79C) [ka]

[0681] Methyl 2-(4-hydroxy-3-nitrophenyl)acetate (4.7 g, 22.3 mmol) was dissolved in absolute ethanol (100 mL), and then palladium on carbon (470 mg, 2.23 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 79C.

[0682] MS (ESI) m / z 182.1 (M+H) + .

[0683] Step 3: Preparation of methyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetate (Compound 79D) [ka]

[0684] Methyl 2-(4-fluoro-2-methoxyphenyl)acrylate (3.5 g, 19.3 mmol) was dissolved in ethyl acetate (100 mL) and water (100 mL), followed by the addition of sodium carbonate (4.19 g, 38.6 mmol) and 2-chloroacetyl chloride (2.16 g, 19.3 mmol). The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the product was extracted three times with ethyl acetate (200 mL). The combined organic phases were purified using a silica gel column to obtain compound 79D.

[0685] MS (ESI) m / z 222.1 (M+H) + .

[0686] Step 4: Preparation of methyl 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetate (Compound 79E) [ka]

[0687] Methyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetate (2.4 g, 10.9 mmol) was dissolved in tetrahydrofuran (100 mL), followed by the addition of a tetrahydrofuran solution of borane (1.87 g, 21.7 mmol). The reaction solution was stirred at 60°C for 12 hours. After completion of the reaction, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 79E.

[0688] MS (ESI) m / z 208.1 (M+H) + .

[0689] Step 5: Preparation of tert-butyl 6-(2-methoxy-2-oxoethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 79F) [ka]

[0690] Methyl 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetate (1.2 g, 5.45 mmol) was dissolved in dichloromethane (100 mL), followed by the addition of triethylamine (1.18 g, 10.9 mmol) and 4-dimethylaminopyridine (662.7 mg, 5.45 mmol). The reaction mixture was cooled to 0 °C, and di-tert-butyl dicarbonate (1.77 g, 8.14 mmol) was slowly added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to dilute the reaction mixture. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 79F.

[0691] MS (ESI) m / z 308.1 (M+H) + .

[0692] Step 6: Preparation of tert-butyl 6-(3-hydroxy-1-methoxy-1-oxopropan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 79G) [ka]

[0693] 6-(2-Methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate tert-butyl (576 mg, 1.87 mmol) and paraformaldehyde (168.9 mg, 1.87 mmol) were dissolved in dimethyl sulfoxide (50.0 mL), followed by the addition of sodium methoxide (10.1 mg, 0.19 mmol). The reaction solution was reacted at room temperature for 4 hours. After completion of the reaction, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 79F.

[0694] MS (ESI) m / z 338.4 (M+H) + .

[0695] Step 7: Preparation of 2-(4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-hydroxypropionic acid (Compound 79H) [ka]

[0696] Methyl 3-hydroxy-2-(naphthalen-2-yl)propionate (235.0 mg, 0.69 mmol) was dissolved in anhydrous methanol (60.0 mL) and water (40.0 mL), followed by the addition of sodium hydroxide (27.8 mg, 0.69 mmol). The reaction solution was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was adjusted to pH 2 using 1N hydrochloric acid and extracted with dichloromethane (100 mL * 3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give a yellow oily compound, which was used directly in the next reaction step.

[0697] Compound 79 of Example 79 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0698] MS (ESI) m / z 457.2(M+H) + . 1H-NMR (400 MHz, DMSO-d6) δ 8.82-8.81 (m, 1H), 8.17-8.14(m, 1H), 8.00-7.98 (d, J = 8.0 Hz, 1H), 7.78-7.74 (m, 1H), 6.55-6.31 (m, 3H), 5.75 (s, 1H), 4.70-4.67 (m, 2H), 4.55 (s, 4H), 4.33-4.20 (m, 3H), 4.08-4.06 (m, 2H), 3.87-3.80 (m, 1H), 3.41-3.38 (m, 2H), 3.24 (s, 2H).

[0699] Example 80 Preparation of (S)-1-(1'-((5-(difluoromethoxy)pyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 80) [ka]

[0700] Step 1: Preparation of 2-(benzylthio)-5-(difluoromethoxy)pyridine (compound 80B) [ka]

[0701] 2-Bromo-5-difluoromethoxypyridine (2 g, 8.93 mmol) was dissolved in 1,4-dioxane, followed by the addition of benzyl mercaptan (1.11 g, 8.93 mmol), DIPEA (2.31 g, 17.86 mmol), Pd(dba)CHCl (913 mg, 0.89 mmol), and Xantphos (1.03 g, 1.79 mmol). After the addition was complete, the reaction mixture was purged under nitrogen three times and then heated to 80 °C and stirred for 16 h. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 80B.

[0702] MS (ESI) m / z 268.1 (M+H)+ .

[0703] Step 2: Preparation of 5-(difluoromethoxy)pyridine-2-sulfonyl chloride (compound 80C) [ka]

[0704] 2-(Benzylthio)-5-difluoromethoxypyridine (1.0 g, 3.74 mmol) was dissolved in acetonitrile, and acetic acid (1.12 g, 18.71 mmol), water (674 mg, 37.41 mmol), and 1,3-dichloro-5,5-dimethylhydantoin (1.47 g, 7.48 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 80C.

[0705] MS (ESI) m / z 244.0 (M+H)+.

[0706] Compound 80 of Example 80 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-(difluoromethoxy)pyridine-2-sulfonyl chloride.

[0707] MS (ESI) m / z 466.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 2.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.95 (dd, J = 8.7, 2.7 Hz, 1H), 7.50 (s, 1H), 7.34 - 7.19 (m, 5H), 4.80 (t, J = 5.3 Hz, 1H), 4.73 (d, J = 13.3 Hz, 1H), 4.53 (s, 4H), 4.42 - 4.27 (m, 2H), 4.22 (d, J = 15.0 Hz, 1H), 3.89 (m, 1H), 3.63 (dd, J = 8.8, 5.5 Hz, 1H), 3.46 (m, 1H).

[0708] Example 81 Preparation of (S)-3-hydroxy-1-(1'-((5-isopropoxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 81) [ka]

[0709] Step 1: Preparation of 2-(benzylthio)-5-isopropoxypyridine (compound 81B) [ka]

[0710] 2-Bromo-5-isopropoxypyridine (2 g, 9.26 mmol) was dissolved in 1,4-dioxane, followed by the addition of benzyl mercaptan (1.15 g, 9.26 mmol), DIPEA (2.39 g, 18.51 mmol), Pd(dba)CHCl (947 mg, 0.93 mmol), and Xantphos (1.07 g, 1.85 mmol). After the addition was complete, the reaction mixture was purged under nitrogen three times and then heated to 80 °C and stirred for 16 h. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 81B.

[0711] MS (ESI) m / z 260.1(M+H) + .

[0712] Step 2: Preparation of 5-isopropoxypyridine-2-sulfonyl chloride (compound 81C) [ka]

[0713] 2-(Benzylthio)-5-isopropoxypyridine (1.0 g, 3.86 mmol) was dissolved in acetonitrile, and acetic acid (1.16 g, 19.28 mmol), water (695 mg, 38.56 mmol), and 1,3-dichloro-5,5-dimethylhydantoin (1.52 g, 7.71 mmol) were added sequentially. After the addition of the materials was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the product was purified using a silica gel column to obtain compound 81C.

[0714] MS (ESI) m / z 236.0(M+H) + .

[0715] Compound 81 of Example 81 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-isopropoxypyridine-2-sulfonyl chloride.

[0716] MS (ESI) m / z 458.2(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 8.8, 2.8 Hz, 1H), 7.26 (m, 5H), 4.82 (m, 2H), 4.72 (d, J = 13.3 Hz, 1H), 4.47 (s, 4H), 4.42 - 4.26 (m, 2H), 4.21 (d, J = 14.6 Hz, 1H), 3.89 (m, 1H), 3.62 (dd, J = 8.9, 5.5 Hz, 1H), 3.46 (m, 1H), 1.32 (d, J = 6.0 Hz, 6H).

[0717] Example 82 Preparation of (S)-1-(1'-((5-cyclopropoxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 82) [ka]

[0718] Step 1: Preparation of 2-(benzylthio)-5-cyclopropoxypyridine (compound 82B) [ka]

[0719] 2-Bromo-5-cyclopropoxypyridine (3.98 g, 18.59 mmol) was dissolved in 1,4-dioxane, followed by the addition of benzyl mercaptan (2.31 g, 18.59 mmol), DIPEA (7.21 g, 55.77 mmol), Pd(dba)CHCl (1.92 g, 1.86 mmol), and Xantphos (2.15 g, 3.72 mmol). After the addition was complete, the reaction was purged under nitrogen three times and then heated to 80 °C and stirred for 16 h. After completion of the reaction, the product was purified by silica gel column chromatography to give compound 82B.

[0720] MS (ESI) m / z 258.1 (M+H) + .

[0721] Step 2: Preparation of 5-cyclopropoxypyridine-2-sulfonyl chloride (compound 82C) [ka]

[0722] 2-(Benzylthio)-5-cyclopropoxypyridine (2.0 g, 7.78 mmol) was dissolved in acetonitrile, and acetic acid (2.33 g, 38.9 mmol), water (1.40 g, 77.8 mmol), and 1,3-dichloroimidazolidine-2,4-dione (3.06 g, 15.56 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 82C.

[0723] MS (ESI) m / z 233.9 (M+H) + .

[0724] Compound 82 of Example 82 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-cyclopropoxypyridine-2-sulfonyl chloride.

[0725] MS (ESI) m / z 456.2(M+H) + . 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 2.8 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.6, 2.9 Hz, 1H), 7.38 - 7.28 (m, 3H), 7.25 - 7.19 (m, 2H), 4.50 (d, J = 29.8 Hz, 7H), 4.19 - 3.92 (m, 2H), 3.86 (m, J = 6.4, 2.9 Hz, 1H), 3.71 (dd, J = 11.2, 4.4 Hz, 1H), 3.65 (dd, J = 8.8, 4.4 Hz, 1H), 0.97 ‐ 0.79 (m, 4H).

[0726] Example 83 Preparation of (S)-2-(2,4-difluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 83) [ka]

[0727] In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(2,4-difluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and separation was carried out using the same preparation method as in Example 1. The product was then subjected to chiral separation to obtain Compound 83 of Example 83.

[0728] MS (ESI) m / z 436.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.80 (d, J = 3.8 Hz, 1H), 8.18-8.13 (t, J = 7.7 Hz, 1H), 7.99-7.97 (d, J = 7.7 Hz, 1H), 7.77-7.74 (t, J = 5.9 Hz, 1H), 7.45-7.39 (q, J = 7.7 Hz, 1H), 7.23-7.17 (t, J = 9.8 Hz, 1H), 7.07-7.02 (t, J = 8.4 Hz, 1H), 4.92-4.89 (m, 1H), 4.74-4.71 (m, 1H), 4.60-4.48 (m, 4H), 4.40-4.19 (m, 3H), 3.92-3.82 (m, 2H), 3.55-3.48 (m, 1H).

[0729] Example 84 Preparation of (R)-2-(2,4-difluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 84) [ka]

[0730] In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(2,4-difluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and separation was carried out using the same preparation method as in Example 1. The product was then subjected to chiral separation to obtain compound 84 of Example 84.

[0731] MS (ESI) m / z 436.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.80 (d, J = 3.8 Hz, 1H), 8.18-8.13 (t, J = 7.7 Hz, 1H), 7.99-7.97 (d, J = 7.7 Hz, 1H), 7.77-7.74 (t, J = 5.9 Hz, 1H), 7.45-7.39 (q, J = 7.7 Hz, 1H), 7.23-7.17 (t, J = 9.8 Hz, 1H), 7.07-7.02 (t, J = 8.4 Hz, 1H), 4.92-4.89 (m, 1H), 4.74-4.71 (m, 1H), 4.60-4.48 (m, 4H), 4.40-4.19 (m, 3H), 3.92-3.82 (m, 2H), 3.55-3.48 (m, 1H)

[0732] Example 85 Preparation of 4-(3-hydroxy-1-oxo-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-2-yl)benzonitrile (Compound 85) [ka]

[0733] Step 1: Preparation of methyl 2-(4-cyanophenyl)-3-hydroxypropionate (Compound 85B) [ka]

[0734] Methyl 2-(4-cyanophenyl)acetate (1.0 g, 5.71 mmol), paraformaldehyde (257 mg, 2.85 mmol), and sodium bicarbonate (14 mg, 0.17 mmol) were dissolved in dimethyl sulfoxide (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the product was purified using a silica gel column to obtain compound 85B.

[0735] MS (ESI) m / z 206.1 (M+H)+ .

[0736] Step 2: Preparation of 2-(4-cyanophenyl)-3-hydroxypropionic acid (compound 85C) [ka]

[0737] Methyl 3-hydroxy-2-(4-cyanophenyl)propionate (0.2 g, 0.97 mmol) and lithium hydroxide monohydrate (82 mg, 1.95 mmol) were dissolved in a mixture of methanol (3.0 mL) and water (1 mL). After the addition was complete, the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the product was purified on a silica gel column to give compound 85C.

[0738] MS (ESI) m / z 192.2 (M+H) + .

[0739] Compound 85 of Example 85 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(4-cyanophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0740] MS (ESI) m / z 425.1(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.82-8.81 (m, 1H), 8.17-8.14 (t, J = 1.2 Hz, 1H), 8.00-7.98 (d, J = 0.8Hz, 1H), 7.79-7.77 (m, 3H), 7.51-7.48 (d, J = 1.2 Hz, 2H), 4.94-4.92 (d, J = 0.8 Hz, 1H), 4.75-4.72 (d, J = 1.2 Hz, 1H), 4.55-4.25 (m, 6H), 3.91-3.81 (m, 1H), 3.79-3.77 (t, J = 0.8 Hz, 1H), 3.56-3.38 (m, 2H).

[0741] Example 86 Preparation of 2-(3-chloro-5-fluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 86) [ka]

[0742] Step 1: Preparation of methyl 2-(3-chloro-5-fluorophenyl)acetate (Compound 86B) [ka]

[0743] 2-(3-Chloro-5-fluorophenyl)acetic acid (1 g, 5.30 mmol) was dissolved in methanol (10 mL), and then thionyl chloride (1.25 g, 10.59 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was purified using a silica gel column to obtain compound 86B.

[0744] MS (ESI) m / z 201.2 (M−H) - .

[0745] Step 2: Preparation of methyl 2-(3-chloro-5-fluorophenyl)-3-hydroxypropionate (Compound 86C) [ka]

[0746] Methyl 2-(3-chloro-5-fluorophenyl)acetate (1.01 g, 4.98 mmol) was dissolved in dimethyl sulfoxide (10 mL), followed by the addition of sodium methoxide (90 mg, 500.00 μmol) and paraformaldehyde (220 mg, 2.44 mmol) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Water was added to dilute the reaction solution, and the aqueous phase was extracted with ethyl acetate (10.0 mL*3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. After the reaction was complete, the product was purified using a silica gel column to obtain compound 86C.

[0747] MS (ESI) m / z 233.1 (M+H) + .

[0748] Step 3: Preparation of 2-(3-chloro-5-fluorophenyl)-3-hydroxypropionic acid (compound 86D) [ka]

[0749] Methyl 2-(3-chloro-5-fluorophenyl)-3-hydroxypropionate (200 mg, 859.71 μmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide (72 mg, 1.71 mmol) was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was complete, the reaction mixture was concentrated and the pH was adjusted to 3-4 using 1N hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate (10.0 mL*3). The combined organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. After the reaction was complete, the mixture was purified using a silica gel column to obtain compound 86D.

[0750] MS (ESI) m / z 217.1 (M−H) - .

[0751] Compound 86 of Example 86 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in Step 10, 2-(3-chloro-5-fluorophenyl)-3-hydroxypropionic acid was replaced with (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid.

[0752] MS (ESI) m / z 452.1(M+H) + . 1 H-NMR (400 MHz, DMSO-d6) δ 8.82-8.81 (m, 1H), 8.16-8.14 (m, 1H), 8.00-7.98 (m, 1H), 7.77-7.74 (m, 1H), 7.34-7.30 (m, 1H), 7.24 (s, 1H), 7.17-7.14 (m, 1H), 4.94 (t, J = 5.2 Hz, 1H), 4.74-4.70 (m, 1H), 4.55-4.50 (m, 5H), 4.35-4.23 (m, 2H), 3.86- 3.80 (m, 1H), 3.73-3.70 (m, 1H), 3.54-3.49 (m, 1H).

[0753] Example 87 Preparation of (S)-2-(2,4-difluorophenyl)-3-hydroxy-1-(1'-((5-methoxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 87) [ka]

[0754] Step 1: Preparation of methyl 2-(2,4-difluorophenyl)-3-hydroxypropionate (Compound 87B) [ka]

[0755] Methyl 2-(2,4-difluorophenyl)acetate (820 mg, 4.40 mmol) was dissolved in dimethyl sulfoxide (8 mL), followed by the addition of sodium methoxide (80 mg, 444.44 μmol, 30% purity) and paraformaldehyde (200 mg, 2.22 mmol) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After the reaction was complete, water was added to dilute the reaction solution. The aqueous phase was extracted with ethyl acetate (30.0 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain compound 87B.

[0756] MS (ESI) m / z 217.1 (M+H) + .

[0757] Step 2: Preparation of 2-(2,4-difluorophenyl)-3-hydroxypropionic acid (compound 87C) [ka]

[0758] Methyl 2-(2,4-difluorophenyl)-3-hydroxypropionate (260 mg, 1.20 mmol) was dissolved in water (3 mL) and tetrahydrofuran (3 mL), and lithium hydroxide (100 mg, 2.38 mmol) was added at room temperature. After the addition was complete, the reaction mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 87C.

[0759] MS (ESI) m / z 201.0 (M−H) - .

[0760] Compound 87 of Example 87 was obtained by the same preparation method as in Example 1, except that in Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-methoxypyridine-2-sulfonyl chloride, and in Step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid was replaced with 2-(2,4-difluorophenyl)-3-hydroxypropionic acid.

[0761] MS (ESI) m / z 466.1(M+H) + . 1 H-NMR (400 MHz, DMSO- d6) δ 8.49-8.48 (d, J = 2.7 Hz, 1H), 7.96-7.34 (d, J = 8.8 Hz, 1H), 7.67-7.64 (m, 1H), 7.43-7.41 (m, 1H), 7.22-7.17 (m, 1H), 7.07-7.04 (m, 1H), 4.74-4.4.71 (d, J = 12.9 Hz, 1H), 4.48 (s, 4H), 4.36-4.21 (m, 3H), 3.94 (s, 3H), 3.89-3.83 (m, 2H), 3.55-3.48 (m, 1H).

[0762] Example 88 Preparation of (R)-2-(2,4-difluorophenyl)-3-hydroxy-1-(1'-((5-methoxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 88) [ka]

[0763] In step 8 of Example 1, 5-methoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(2,4-difluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid. Separation was carried out using the same preparation method as in Example 1, and then the product was subjected to chiral separation to obtain Compound 88 of Example 88.

[0764] MS (ESI) m / z 466.1(M+H) + . 1 H-NMR (400 MHz, DMSO- d6) δ 8.49-8.48 (d, J = 2.7 Hz, 1H), 7.96-7.34 (d, J = 8.8 Hz, 1H), 7.67-7.64 (m, 1H), 7.43-7.41 (m, 1H), 7.22-7.17 (m, 1H), 7.07-7.04 (m, 1H), 4.74-4.4.71 (d, J = 12.9 Hz, 1H), 4.48 (s, 4H), 4.36-4.21 (m, 3H), 3.94 (s, 3H), 3.89-3.83 (m, 2H), 3.55-3.48 (m, 1H).

[0765] Example 89 Preparation of (3-phenyloxetan-3-yl)(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)methanone (Compound 89) [ka]

[0766] Step 1: Preparation of ethyl 2-(3-phenyloxetan-3-yl)acetate (Compound 89B) [ka]

[0767] Ethyl 2-(oxetan-3-ylidene)acetate (5 g, 35.17 mmol) was dissolved in 1,4-dioxane, followed by the sequential addition of aqueous potassium hydroxide (2.57 g, 1.5 N, 45.72 mmol), phenylboronic acid (6.43 g, 52.76 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (1.73 g, 3.52 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the product was purified by silica gel column chromatography to obtain compound 89B.

[0768] MS (ESI) m / z 221.1 (M+H) + .

[0769] Step 2: Preparation of 2-(3-phenyloxetan-3-yl)ethan-1-ol (Compound 89C) [ka]

[0770] Ethyl 2-(3-phenyloxetan-3-yl)acetate (3 g, 13.62 mmol) was dissolved in tetrahydrofuran, and the reaction mixture was cooled to 0 °C. Lithium aluminum hydride (0.52 g, 13.62 mmol) was then slowly added. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction was complete, the product was purified using a silica gel column to give compound 89C.

[0771] MS (ESI) m / z 179.1 (M+H) + .

[0772] Step 3: Preparation of 2-(3-phenyloxetan-3-yl)ethyl methanesulfonate (Compound 89D) [ka]

[0773] 2-(3-Phenyloxetan-3-yl)ethan-1-ol (2.43 g, 13.63 mmol) was dissolved in dichloromethane. The reaction mixture was cooled to 0 °C, and then triethylamine (2.48 g, 24.54 mmol) was added, followed by the slow dropwise addition of methylsulfonyl chloride (2.81 g, 24.54 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction was complete, the product was purified using a silica gel column to obtain compound 89D.

[0774] Step 4: Preparation of 3-phenyl-3-vinyloxetane (compound 89E) [ka]

[0775] 2-(3-phenyloxetan-3-yl)ethyl methanesulfonate (3.4 g, 13.26 mmol) was dissolved in dimethyl sulfoxide, and potassium t-butoxide (1.64 g, 14.59 mmol) was added in several portions. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic phases were combined and purified using a silica gel column to obtain compound 89E.

[0776] MS (ESI) m / z 161.1 (M+H) + .

[0777] Step 5: Preparation of 3-phenyloxetane-3-carboxylic acid (compound 89F) [ka]

[0778] 3-Phenyl-3-vinyloxetane (1.4 g, 8.74 mmol) was dissolved in a mixture of ethyl acetate, acetonitrile, and water. The reaction was cooled to 0°C, and ruthenium trichloride (91 mg, 0.43 mmol) was added. After the addition was complete, the reaction was stirred at 0°C for 10 minutes, and then sodium periodate (7.17 g, 33.21 mmol) was added slowly in several portions. After the addition was complete, the reaction was maintained at 0°C and stirred for 30 minutes. After the reaction was complete, the reaction was filtered through diatomaceous earth, and the aqueous phase was extracted with ethyl acetate (200 mL*3). The organic phases were combined and concentrated, followed by the addition of saturated aqueous sodium bicarbonate and one extraction with ethyl acetate. The aqueous phase was adjusted to pH 1 by the slow dropwise addition of 1N aqueous hydrochloric acid and spun dry to obtain compound 89F.

[0779] In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-phenyloxetane-3-carboxylic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and separation was carried out using the same preparation method as in Example 1. The product was then subjected to chiral separation to obtain Compound 89 of Example 89.

[0780] MS (ESI) m / z 412.1(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (m, 1H), 8.14 (m, 1H), 7.96 (dd, J = 7.9, 1.2 Hz, 1H), 7.75 (m, 1H), 7.43 (dd, J = 8.2, 6.8 Hz, 2H), 7.35 (m, 3H), 5.09 (d, J = 6.2 Hz, 2H), 4.69 (d, J = 6.2 Hz, 2H), 4.48 (m, 4H), 4.41 - 4.33 (m, 2H), 4.12 - 4.03 (m, 2H).

[0781] Example 90 Preparation of 2-cyclohexyl-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 90) [ka]

[0782] Step 1: Preparation of dimethyl 2-cyclohexylmalonate (compound 90B) [ka]

[0783] Sodium (1.6 g, 71.41 mmol) was slowly added in portions to anhydrous methanol (100.0 mL) in an ice bath. After the sodium wire was completely dissolved, dimethyl malonate (6.3 g, 47.61 mmol) and iodocyclohexane (10.0 g, 47.61 mmol) were added. The reaction solution was reacted at 70 °C for 18 hours. After the reaction was complete, the product was purified using a silica gel column to obtain compound 90B.

[0784] MS (ESI) m / z 215.3 (M+H) + .

[0785] Step 2: Preparation of 2-cyclohexyl-3-methoxy-3-oxopropionic acid (compound 90C) [ka]

[0786] Dimethyl 2-cyclohexylmalonate (100.0 mg, 0.47 mmol) was dissolved in methanol (3.0 mL) and water (1.0 mL), followed by the addition of potassium hydroxide (26.2 mg, 0.47 mmol) in water (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours. LCMS confirmed that the reaction was essentially complete. The reaction mixture was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give a yellow oily compound, which was used directly in the next reaction step.

[0787] Step 3: Preparation of methyl 2-cyclohexyl-3-oxo-3-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propionate (Compound 90D) [ka]

[0788] 2-Cyclohexyl-3-methoxy-3-oxopropionic acid (93.4 mg, 0.46 mmol), 1-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-3,3'-diazetidinylidene (94.78 mg, 0.26 mmol), HATU (197.3 mg, 0.52 mmol), and N,N-diisopropylethylamine (134.1 mg, 1.04 mmol) were dissolved in N,N-dimethylformamide (5.0 mL). The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the product was purified using a silica gel column to obtain compound 90D.

[0789] MS (ESI) m / z 434.2 (M+H) + .

[0790] Step 4: Preparation of 2-cyclohexyl-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propan-1-one (Compound 90) [ka]

[0791] Methyl 2-cyclohexyl-3-oxo-3-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propionate (60.0 mg, 0.14 mmol) was dissolved in methanol (6.0 mL) and tetrahydrofuran (6.0 mL), followed by the addition of sodium borohydride (52.4 mg, 1.38 mmol). The reaction solution was stirred at 80°C for 72 hours. After completion of the reaction, the product was purified by reverse-phase high-pressure liquid chromatography to obtain compound 90.

[0792] MS (ESI) m / z 406.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.83-8.82 (d, J = 4.4 Hz, 1H), 8.19-8.17 (m, 1H), 8.00-7.98 (d, J = 8.0 Hz, 1H), 7.78-7.75 (m, 1H), 4.63-4.46 (m, 8H), 4.30-4.25 (m, 2H), 3.52-3.36 (m, 2H), 2.16-2.14 (m, 1H), 1.65-1.58 (m, 4H), 1.52-1.32 (m, 2H), 1.10-1.03 (m, 2H), 1.00-0.81 (m, 2H).

[0793] Example 91 Preparation of (S)-3-hydroxy-1-(1'-((5-(methoxy-d3)pyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 91) [ka]

[0794] Step 1: Preparation of 2-bromo-5-(methoxy-d3)pyridine (Compound 91B) [ka]

[0795] 2-Bromo-5-hydroxypyridine (3 g, 17.24 mmol) was dissolved in 1,4-dioxane, followed by the addition of deuterated methanol (3.11 g, 86.20 mmol), triphenylphosphine (4.97 g, 18.96 mmol), and DIAD (3.83 g, 18.96 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the product was purified by silica gel column chromatography to give compound 91B.

[0796] MS (ESI) m / z 191.0 (M+H) + .

[0797] Step 2: Preparation of 2-(benzylthio)-5-(methoxy-d3)pyridine (compound 91C) [ka]

[0798] 2-Bromo-5-(methoxy-d3)pyridine (2.53 g, 13.24 mmol) was dissolved in 1,4-dioxane, followed by the addition of benzyl mercaptan (1.64 g, 13.24 mmol), DIPEA (3.42 g, 26.49 mmol), Pd2(dba)3CHCl3 (1.35 g, 1.32 mmol), and Xantphos (1.53 g, 2.65 mmol). After the addition was complete, the reaction was purged under nitrogen three times and then heated to 80 °C and stirred for 16 h. After completion of the reaction, the product was purified on a silica gel column to give compound 91C.

[0799] MS (ESI) m / z 235.1 (M+H) + .

[0800] Step 3: Preparation of 5-(methoxy-d3)pyridine-2-sulfonyl chloride (compound 91D) [ka]

[0801] 2-(Benzylthio)-5-(methoxy-d3)pyridine (1.1 g, 4.69 mmol) was dissolved in acetonitrile, and acetic acid (1.41 g, 23.47 mmol), water (846 mg, 46.94 mmol), and 1,3-dichloro-5,5-dimethylhydantoin (1.85 g, 9.39 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the product was purified by silica gel column chromatography to give compound 91D.

[0802] MS (ESI) m / z 211.0 (M+H) + .

[0803] In Step 8 of Example 1, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was replaced with 5-(methoxy-d3)pyridine-2-sulfonyl chloride, and separation was carried out using the same preparation method as in Example 1 to obtain Compound 91 of Example 91.

[0804] MS (ESI) m / z 433.2(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 8.8, 3.0 Hz, 1H), 7.27 (m, 5H), 4.80 (t, J = 5.2 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 4.48 (s, 4H), 4.41 - 4.27 (m, 2H), 4.21 (d, J = 14.7 Hz, 1H), 3.89 (m, 1H), 3.62 (dd, J = 8.9, 5.4 Hz, 1H), 3.46 (m, 1H).

[0805] Biological Test Data Unless otherwise noted, all experimental materials, reagents, procedures, and methods used in the following activity examples are either commercially available or readily known or can be prepared based on prior art.

[0806] Test Example 1: Pyruvate kinase (PKR) activity experiment

[0807] [Table 1]

[0808] [Table 2]

[0809] 1. Testing process

[0810] 1) A recombinant human PKR enzyme solution was prepared at a concentration of 60 ng / well (20 μL reaction system), and 5 μL of the solution was added to each well of a black, clear-bottom 384-well plate.

[0811] 2) Compound solutions were prepared at various concentrations, with final concentrations of 1000 / 300 / 100 nM (containing 1% DMSO). 5 μL of each compound solution was added to the plate prepared in section 3.1 and mixed thoroughly. The plate was incubated at room temperature for 10 minutes.

[0812] 3) Prepare the reaction mixture according to the kit's instructions (see the table below), add 10 μL of the reaction mixture to each well of a 384-well plate, and mix thoroughly with the solution from section 3.2.

[0813] [Table 3]

[0814] 4) The 384-well plate was placed in a microplate reader to detect fluorescence at 540 / 590 nm, with readings taken every 2 minutes for 1 hour.

[0815] 5) The slope value within the detection time was calculated, and the compound activation rate was calculated using 0.1% DMSO wells as control wells.

[0816] Activation % = (slope of compound wells / slope of control wells) x 100%

[0817] 6) Dose-effect curve fitting Dose-effect curves were fitted using log(agonist) vs. response-variable slope in the analytical software GraphPad Prism 5, with the logarithm of compound concentration on the X-axis and the percentage activation rate on the Y-axis, to calculate the AC of each compound's activity against PKR. 50 got the value.

[0818] Calculation formula: Y=min+(max-min) / (1+10^((LogAC 50 -X)×Hillslope))

[0819] 2. Test Results

[0820] The activation effect of the compounds of the present invention on the PKR enzyme was measured by the above-mentioned test. 50 The values ​​were as follows (A represents 0 to 100 nM, B represents 101 to 300 nM, and C represents 300 to 1,000 nM). [Table 4]

[0821] Test Example 2: USP9X enzyme activity experiment

[0822] [Table 5]

[0823] [Table 6]

[0824] 1. Testing process

[0825] 1) A 1x assay buffer was prepared consisting of modified Tris buffer (pH 7.5).

[0826] 2) Compound solutions were prepared at various concentrations, with final concentrations of 3,000 / 1,000 / 300 / 100 / 30 / 10 / 3 / 1 nM (containing 1% DMSO), and added to a 384-well plate.

[0827] 3) USP9X enzyme solution was prepared using 1x assay buffer.

[0828] 4) 10 μL of USP9X enzyme solution was added to a 384-well plate and incubated with the compound at room temperature for 1 hour.

[0829] 5) Rhodamine 110 protein was added to 1x assay buffer to prepare a substrate working solution.

[0830] 6) 10 μL of substrate solution was added to each reaction well, centrifuged for 30 seconds, and mixed evenly for 30 seconds.

[0831] 7) The 384-well plate was placed in a microplate reader and detected at an excitation wavelength of 480 nm and an emission wavelength of 540 nm. The test was run for 30 minutes and data was collected.

[0832] 8) Dose-effect curve fitting

[0833] Inhibition percentage Inh% = (Max-Signal) / (Max-Min)*100

[0834] Dose-effect curves were fitted using log(inhibitor) vs. response-variable slope in the analytical software GraphPad Prism 5, with the logarithm of compound concentration on the X-axis and the percentage of inhibition on the Y-axis, to calculate the IC of activity of each compound against USP9X. 50 got the value.

[0835] Calculation formula: Y=min+(max-min) / (1+10^((LogIC 50 -X)×Hillslope))

[0836] 2. Test Results

[0837] The inhibitory effect of the compounds of the present invention on the USP9X enzyme was measured by the above test. 50 The values ​​were as follows (A represents 0 to 100 nM, B represents 101 to 300 nM, and C represents 300 to 1,000 nM).

[0838] [Table 7]

[0839] The present invention is not limited to the above-described optional embodiments, and anyone can derive various other forms of products under the motivation of the present invention. The above-described specific embodiments should not be understood as limiting the scope of the present invention. The protection scope of the present invention should be according to the definition of the claims, and the specification can be used to interpret the claims.

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ , R ２ , and R ３ are independently —H, halogen, —OH, or —NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR ｂ , -SR ｂ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , or —C(O)OR ｇ wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R ａ , -OR ｂ , -SR ｂ , -NO ２ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , and —C(O)OR ｇ or optionally substituted with one or more substituents selected from Or, R １ and R ２ , R １ and R ３ , or R ２ and R ３ are optionally bonded together with the atoms to which they are attached to form -(C ３ -C ８ )cycloalkyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, -(C ５ -C ８ ) form a spirocyclyl, a 5-8 membered spiroheterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, a 7-14 membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, or a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; R ４ is -NH ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR ｂ , -SR ｂ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , -C(O)OR ｇ , or -NR ｃ (CR ｈ R ｉ ) ｔ -R ａ wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R ａ , -OR ｂ , -SR ｂ , -NO ２ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , and —C(O)OR ｇ optionally substituted with one or more substituents selected from t is 0, 1, 2, or 3; R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ is, in each occurrence, independently -H, halogen, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; —SH, —S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, —NHS(O)H, —C(O)H, or —C(O)OH, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is ═O, halogen, —CN, —OH, —SH, —NO ２ , -NH ２ , -S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, -NHS(O)H, -C(O)H, -C(O)OH, -(C １ -C ６ ) alkyl, -(C ３ -C ８ ) optionally substituted with one or more substituents selected from cycloalkyl and 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; Or, R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ Any two groups on adjacent atoms selected from, optionally joined together with the atoms to which they are attached, may be C ６ -C １４ aryl, 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; (C ３ -C ８ ) cycloalkyl, or 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, and one or more R ａ (optionally replaced by or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

2. Formula I: 【Chemistry 2】 (In the formula, R １ , R ２ , and R ３ are independently —H, halogen, —OH, or —NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR ｂ , -SR ｂ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , or —C(O)OR ｇ wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R ａ , -OR ｂ , -SR ｂ , -NO ２ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , and —C(O)OR ｇ or optionally substituted with one or more substituents selected from Or, R １ and R ２ , R １ and R ３ , or R ２ and R ３ are optionally bonded together with the atoms to which they are attached to form -(C ３ -C ８ )cycloalkyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, -(C ５ -C ８ ) form a spirocyclyl, a 5-8 membered spiroheterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, a 7-14 membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, or a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; R ４ is -NH ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR ｂ , -SR ｂ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , -C(O)OR ｇ , or -NR ｃ (CR ｈ R ｉ ) ｔ -R ａ wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R ａ , -OR ｂ , -SR ｂ , -NO ２ , -NR ｃ R ｄ , -S(O) ２ R ｅ , -S(O) ２ NR ｃ R ｄ , -S(O)R ｅ , -S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ R ｅ , -NR ｃ S(O)R ｅ , -C(O)R ｆ , and —C(O)OR ｇ optionally substituted with one or more substituents selected from t is 0, 1, 2, or 3; R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ is, in each occurrence, independently -H, halogen, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; —SH, —S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, -NHS(O)H, -S(O) ２ OH, -S(O)OH, -NHS(O) ２ -OH, -NHS(O)OH, -C(O)H, or -C(O)OH, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is ═O, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, -NHS(O)H, -C(O)H, -C(O)OH, -(C １ -C ６ ) alkyl, -(C ３ -C ８ ) optionally substituted with one or more substituents selected from cycloalkyl and 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; Or, R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ Any two groups on adjacent atoms selected from, optionally joined together with the atoms to which they are attached, may be C ６ -C １４ aryl, 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; (C ３ -C ８ ) cycloalkyl, or 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, and one or more R ａ (optionally replaced by or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

3. Formula I-1 or I-2: 【Transformation 3】 10. The compound of claim 1, having the formula: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

4. R １ and R ２ are independently —H, halogen, —OH, or —NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR ｂ , or -NR ｃ R ｄ wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R ａ , -OR ｂ , -NO ２ , and -NR ｃ R ｄ or optionally substituted with one or more substituents selected from Or, R １ and R ２ are optionally bonded together with the atoms to which they are attached to form -(C ３ -C ８ ) forming a cycloalkyl, or a 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R ａ , R ｂ , R ｃ , and R ｄ is, in each occurrence, independently -H, halogen, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is independently selected from ═O, halogen, —CN, —OH, —NO ２ , -NH ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ８ ) optionally substituted with one or more substituents selected from cycloalkyl and 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; 4. A compound according to claim 1 or 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

5. R １ and R ２ are independently —H, halogen, —OH, or —NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ６ cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C ６ -C ８ aryl, a 5- to 8-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; -OR ｂ , or -NR ｃ R ｄ wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from the group consisting of ═O, halogen, —CN, —R ａ , -OR ｂ , -NO ２ , and -NR ｃ R ｄ or optionally substituted with one or more substituents selected from Or, R １ and R ２ are optionally bonded together with the atoms to which they are attached to form -(C ３ -C ８ ) forming a cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R ａ , R ｂ , R ｃ , and R ｄ is, in each occurrence, independently -H, halogen, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ６ cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C ６ -C ８ aryl, a 5-8 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7-14 membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is independently selected from ═O, halogen, —CN, —OH, —NO ２ , -NH ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ６ ) optionally substituted with one or more substituents selected from cycloalkyl and 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; 5. The compound of claim 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

6. R １ and R ２ are independently —H, —F, —Cl, —Br, —OH, or —NH ２ , -CN, -NO ２ , -(C １ -C ６ ) straight chain alkyl, -(C １ -C ６ ) branched alkyl, -(C ３ -C ６ cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C ６ -C ８ a 7-14 membered bicyclic or tricyclic fused ring group containing 0-4 heteroatoms independently selected from aryl, O, N, and S; -OR ｂ , or -NR ｃ R ｄ wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is —F, —Cl, —Br, —CN, —R ａ , -OR ｂ , and -NR ｃ R ｄ or optionally substituted with one or more substituents selected from Or, R １ and R ２ are optionally bonded together with the atoms to which they are attached to form -(C ３ -C ８ ) forming a cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R ａ , R ｂ , R ｃ , and R ｄ is, in each occurrence, independently -H, -F, -Cl, -Br, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ６ cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C ６ -C ８ aryl, or a 5-8 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is selected from -F, -Cl, -Br, -CN, -OH, -NO ２ , -NH ２ , and -(C １ -C ６ ) alkyl, 6. The compound of claim 5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

7. R １ and R ２ are independently —H, —F, —Cl, —Br, —OH, or —NH ２ , -CN, -NO ２ , -(C １ -C ６ ) straight chain alkyl, -(C １ -C ６ ) branched alkyl, -(C ３ -C ６ ) cycloalkyl, or 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein each of said alkyl, cycloalkyl, or heterocyclyl is —F, —Cl, —Br, —CN, —R ａ , -OR ｂ , and -NR ｃ R ｄ or optionally substituted with one or more substituents selected from Or, R １ and R ２ are optionally bonded together with the atoms to which they are attached to form -(C ３ -C ８ ) forming a cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; R ａ , R ｂ , R ｃ , and R ｄ is, in each occurrence, independently -H, -F, -Cl, -Br, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ６ ) cycloalkyl, or 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein each of said alkyl, cycloalkyl, or heterocyclyl is —F, —Cl, —Br, —CN, —OH, —NO ２ , -NH ２ , and -(C １ -C ６ ) alkyl, 7. The compound of claim 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

8. R ２ is —H, —F, —Cl, or —Br; R １ は、-H、-F、-Cl、-Br、-OH、-NH ２ 、-(CH ２ ) ｑ CH ３ 、-(CH ２ ) ｑ OH、-CH(OH)(CH ２ ) ｑ CH ３ 、-C(OH)((CH ２ ) ｑ CH ３ ) ２ 、 【Chemistry 4】 - (CH ２ ) ｑ NH ２ , -(CH ２ ) ｑ NH (CH ２ ) ｑ CH ３ , -(CH ２ ) ｑ N ((CH ２ ) ｑ CH ３ ) ２ , a 3- to 6-membered heterocycloalkyl containing one N atom, or a -(C １ -C ６ ) alkyl; q in each occurrence is independently 0, 1, 2, 3, or 4; Or, R １ and R ２ are optionally joined together with the atoms to which they are attached to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, 2,3-dihydrobenzofuran ring, or tetrahydro-2H-pyran; 8. The compound of claim 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

9. R ２ is —H, —F, —Cl, or —Br; R １ is -H, -F, -Cl, -Br, -OH, -NH ２ , 【Transformation 5】 Is it; Or, R １ and R ２ are optionally bonded together with the atoms to which they are attached, 【Transformation 6】 Forming 5. The compound of claim 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

10. R ２ is —H, —F, —Cl, or —Br; R １ は、-H、-F、-Cl、-Br、-OH、-NH ２ 、-CH ３ 、-CH(OH)CH ３ 、-(CH ２ ) ｑ CH ３ 、-(CH ２ ) ｑ OH、-CH(OH)(CH ２ ) ｑ CH ３ 、-C(OH)((CH ２ ) ｑ CH ３ ) ２ 、-C(OH)((CH ２ ) ｑ CH ３ )(CH ３ )、-C(OH)(CH ３ ) ２ 、 【Transformation 7】 -CH ２ F, -CHF ２ , -(CH ２ ) ｑ CH ２ F, -(CH ２ ) ｑ CHF ２ , -CH ２ Cl, -CHCl ２ , -(CH ２ ) ｑ CH ２ Cl, -(CH ２ ) ｑ CHCl ２ , -(CH ２ ) ｑ NH ２ , -NHCH ３ , -NH(CH ２ ) ｑ CH ３ , -(CH ２ ) ｑ NHCH ３ , -(CH ２ ) ｑ NH (CH ２ ) ｑ CH ３ , -N(CH ３ ) ２ , -N((CH ２ ) ｑ CH ３ ) ２ , -(CH ２ ) ｑ N (CH ３ ) ((CH ２ ) ｑ CH ３ ), -(CH ２ ) ｑ N (CH ３ ) ２ , -(CH ２ ) ｑ N ((CH ２ ) ｑ CH ３ ) ２ , a 3- to 6-membered heterocycloalkyl containing one N atom, or a -(C １ -C ６ ) alkyl; q in each occurrence is independently 1, 2, 3, or 4; Or, R １ and R ２ are optionally joined together with the atoms to which they are attached to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, oxetane, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, 2,3-dihydrobenzofuran ring, or tetrahydro-2H-pyran; 7. The compound of claim 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

11. R ２ is —H, —F, —Cl, or —Br; R １ is -H, -F, -Cl, -Br, -OH, -NH ２ , 【Transformation 8】 Is it; Or, R １ and R ２ are optionally bonded together with the atoms to which they are attached, 【Chemistry 9】 Forming 5. The compound of claim 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

12. R ３ is -H, halogen, -(C １ -C ６ ) alkyl, -(C ３ -C ８ cycloalkyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is independently selected from ═O, halogen, —CN, —R ａ , -OR ｂ , -NO ２ , and -NR ｃ R ｄ optionally substituted with one or more substituents selected from R ａ , R ｂ , R ｃ , and R ｄ is, in each occurrence, independently -H, halogen, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is independently selected from ═O, halogen, —CN, —OH, —NO ２ , -NH ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ８ ) optionally substituted with one or more substituents selected from cycloalkyl and 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; 10. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

13. R ３ is -H, halogen, -(C １ -C ６ ) alkyl, -(C ３ -C ６ cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C ６ -C ８ aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered bicyclic or tricyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is independently selected from ═O, halogen, —CN, —R ａ , -OR ｂ , -NO ２ , and -NR ｃ R ｄ optionally substituted with one or more substituents selected from R ａ , R ｂ , R ｃ , and R ｄ is, in each occurrence, independently -H, halogen, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ８ cycloalkyl, 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C ６ -C ８ aryl, a 5-8 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, or a 7-14 membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is independently selected from ═O, halogen, —CN, —OH, —NO ２ , -NH ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ６ ) optionally substituted with one or more substituents selected from cycloalkyl and 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S; 13. The compound of claim 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

14. R ３ is -H, -F, -Cl, -Br, -(C １ -C ６ ) alkyl, -(C ３ -C ６ ) cycloalkyl, C ６ -C ８ aryl, or a 7-14 membered bicyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, wherein each of the alkyl, cycloalkyl, aryl, or fused ring groups is selected from -F, -Cl, -Br, -CN, -R ａ , and -OR ｂ optionally substituted with one or more substituents selected from R ａ and R ｂ is, in each occurrence, independently -H, halogen, -OH, -NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C ３ -C ８ ) cycloalkyl, or 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, wherein each of said alkyl, cycloalkyl, or heterocyclyl is —F, —Cl, —Br, —CN, —OH, —NO ２ , -NH ２ , and -(C １ -C ６ ) alkyl, 14. The compound of claim 13, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

15. R ３ is -H, -F, -Cl, -Br, -(C １ -C ６ ) alkyl, -(C ３ -C ６ ) cycloalkyl, pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, or benzopyrrolidinyl, wherein the pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, or benzopyrrolidinyl is selected from the group consisting of —F, —Cl, —Br, —(C １ -C ６ ) alkyl, -(C ３ -C ６ ) cycloalkyl, —O—(C １ -C ６ ) alkyl, —O—(C ３ -C ６ ) cycloalkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ６ ) halocycloalkyl, —O—(C １ -C ６ ) haloalkyl, —O—(C ３ -C ６ ) halocycloalkyl, piperazinyl, and any number of halogens or -(C １ -C ６ ) alkyl-substituted piperazinyl; 13. The compound of claim 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

16. R ３ is -H, -F, -Cl, -Br, -CH ３ , -CH ２ CH ３ , pyridyl, 【Chemistry 10】 That is, 13. The compound of claim 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

17. R ３ is -H, -F, -Cl, -Br, -(C １ -C ６ ) alkyl, -(C ３ -C ６ ) cycloalkyl, pyridyl, phenyl, naphthyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl, or 【Chemistry 11】 wherein the pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl, or 【Chemistry 12】 is -F, -Cl, -Br, -CN, -(C １ -C ６ ) alkyl, -(C ３ -C ６ ) cycloalkyl, —O—(C １ -C ６ ) alkyl, —O—(C ３ -C ６ ) cycloalkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ６ ) halocycloalkyl, —O—(C １ -C ６ ) haloalkyl, —O—(C ３ -C ６ ) halocycloalkyl, pyrazolyl, any number of halogens or -(C １ -C ６ ) alkyl-substituted pyrazolyl, piperazinyl, any number of halogens or -(C １ -C ６ ) alkyl-substituted piperazinyl; The above ring 【Chemistry 13】 is a 3-6 membered saturated or unsaturated N-containing heterocyclyl linked via an N atom, said heterocyclyl optionally containing, in addition to said N atom, 1-2 heteroatoms independently selected from O, N, and S; 13. The compound of claim 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

18. R ３ is -H, -F, -Cl, -Br, -CH ３ , -CH ２ CH ３ , 【Chemistry 14】 That is, 13. The compound of claim 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

19. Formula I, I-1, or I-2: 【Chemistry 15】 and any one of the following (1) to (4): (1) (in the formula, R ４ teeth, 【Chemistry 16】 and X is a chemical bond, -(CR ｈ R ｉ ) ｔ -, -NR ｃ (CR ｈ R ｉ ) ｔ - or -O-; 【Chemistry 17】 represents a single or double bond; Y １ is N, C, or CH; Y ２ and Y ３ are each independently N, CH ２ or CH, and Y ２ and Y ３ are not simultaneously both N; Each R ｊ are independently —H, halogen, —OH, or —NH ２ , -CN, -NO ２ , -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; —SH, —S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, —NHS(O)H, —C(O)H, or —C(O)OH, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each —H, ═O, halogen, —CN, —OH, —SH, —NO ２ , -NH ２ , -S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, —NHS(O)H, —C(O)H, —C(O)OH, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C ６ -C １４ optionally substituted with one or more substituents selected from aryl or 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; m is an integer selected from 0 to 6; n is 0, 1, or 2; R １ , R ２ , R ３ , R ｃ , R ｈ , R ｉ and t is as defined in any one of claims 1, 3 to 9, or 12 to 16, (2) (in the formula, R 4 is [Chemistry 18] and X is a chemical bond, —(CR h R i ) t —, —NR c (CR h R i ) t —, or —O—; 【Chemistry 19】 represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH 2 , or CH, provided that both Y 2 and Y 3 are not simultaneously N; Each R j is independently —H, halogen, —OH, —NH 2 , —CN, —NO 2 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —O—(C 3 -C 6 )cycloalkyl, —(C 4 -C 8 )cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S, —SH, —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 H, —NHS(O)H, —S(O) 2 OH, —S(O)OH, —NHS(O) 2 OH, —NHS(O)OH, —C(O)H, or —C(O)OH, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each —H, ═O, halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 optionally substituted with one or more substituents selected from H, —NHS(O)H, —S(O) 2 OH, —S(O)OH, —NHS(O) 2 OH, —NHS(O)OH, —C(O)H, —C(O)OH, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, or 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; m is an integer selected from 0 to 6; n is 0, 1, or 2; R 1 , R 2 , R 3 , R c , R h , R i and t are as defined in any one of claims 1 to 18), or (3) (in the formula, R 4 is 【Chemistry 20】 and X is a chemical bond, —(CR h R i ) t —, —NR c (CR h R i ) t —, or —O—; 【Chemistry 21】 represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH 2 , or CH, provided that both Y 2 and Y 3 are not simultaneously N; Each R j is independently —H, halogen, —OH, —NH 2 , —CN, —NO 2 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 4 -C 8 )cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, 7- to 14-membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, —SH, —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 H, —NHS(O)H, —C(O)H, or —C(O)OH, wherein each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is ═O, halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 H, —NHS(O)H, —C(O)H, —C(O)OH, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S, C 6 -C 14 optionally substituted with one or more substituents selected from aryl or 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; m and p are independently integers selected from 0 to 6; n is 0, 1, or 2; Ring A is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S; R 1 , R 2 , R 3 , R c , R h , R i and t are as defined in any one of claims 1, 3 to 9 or 12 to 16, or (4) (in the formula, R 4 is 【Chemistry 22】 and X is a chemical bond, —(CR h R i ) t —, —NR c (CR h R i ) t —, or —O—; 【Chemistry 23】 represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH 2 , or CH, provided that both Y 2 and Y 3 are not simultaneously N; Each R j is independently —H, halogen, —OH, ═O, —NH 2 , —CN, —NO 2 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 4 -C 8 )cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, 7- to 14-membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, —SH, —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 H, —NHS(O)H, —S(O) 2 OH, —S(O)OH, —NHS(O) 2 OH, —NHS(O)OH, —C(O)H, or —C(O)OH, wherein each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is ═O, halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 optionally substituted with one or more substituents selected from H, —NHS(O)H, —C(O)H, —C(O)OH, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, or 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; m and p are independently integers selected from 0 to 6; n is 0, 1, or 2; Ring A is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S; R 1 , R 2 , R 3 , R c , R h , R i and t are as defined in any one of claims 1 to 18, The compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

20. Any of the following (1) to (4): (1) X is a chemical bond, -CH ２ -, -CH ２ CH ２ --NHCH ２ --NHCH ２ CH ２ - or -O-; 【Chemistry 24】 represents a single or double bond; Y １ is N, C, or CH; Y ２ and Y ３ are each independently N, CH ２ or CH, and Y ２ and Y ３ are not simultaneously both N; Each R ｊ are independently —H, halogen, —OH, or —NH ２ , -CN, -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C １ -C ６ ) alkyl or -(C １ -C ６ ) alkoxy, oxazolyl, thiazolyl, and triazolyl; m is an integer selected from 0 to 6; n is 0, 1, or 2; (2) X is a chemical bond, —CH 2 —, —CH 2 CH 2 —, —NHCH 2 —, —NHCH 2 CH 2 —, or —O—; 【Chemistry 25】 represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH 2 , or CH, provided that both Y 2 and Y 3 are not simultaneously N; each R j is independently —H, halogen, —OH, —NH 2 , —CN, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 1 -C 6 )alkoxy, —O—(C 3 -C 6 )cycloalkyl, —(C 1 -C 6 )alkyl substituted with any number of halogens, —(C 1 -C 6 )alkoxy substituted with any number of halogens, —(C 3 -C 6 )cycloalkyl substituted with any number of halogens, —O—(C 3 -C 6 )cycloalkyl substituted with any number of halogens, oxazolyl, thiazolyl, and triazolyl; m is an integer selected from 0 to 6; n is 0, 1, or 2; (3) X is a chemical bond, —CH 2 —, —CH 2 CH 2 —, —NHCH 2 —, —NHCH 2 CH 2 —, or —O—; 【Chemistry 26】 represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH 2 , or CH, provided that both Y 2 and Y 3 are not simultaneously N; each R j is independently —H, halogen, —OH, —NH 2 , —CN, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 1 -C 6 )alkyl or —(C 1 -C 6 )alkoxy substituted with any number of halogens, oxazolyl, thiazolyl, or triazolyl; m and p are independently integers selected from 0 to 6; n is 0, 1, or 2; The ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine, or triazine; (4) X is a chemical bond, —CH 2 —, —CH 2 CH 2 —, —NHCH 2 —, —NHCH 2 CH 2 —, or —O—; 【Chemistry 27】 represents a single or double bond; Y 1 is N, C, or CH; Y 2 and Y 3 are each independently N, CH 2 , or CH, provided that both Y 2 and Y 3 are not simultaneously N; each R j is independently —H, halogen, —OH, —NH 2 , —CN, ═O, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 1 -C 6 )alkyl substituted with any number of halogens, —(C 1 -C 6 )alkoxy substituted with any number of halogens, oxazolyl, thiazolyl, or triazolyl; m and p are independently integers selected from 0 to 6; n is 0, 1, or 2; The ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine, triazine, 4,5-dihydro-1H-imidazole, or 1,3-dioxolane.

20. The compound of claim 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

21. R ４ teeth, 【Chemistry 28】 That is, 10. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

22. R ４ teeth, 【Chemistry 29】 That is, 10. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

23. Formula II: 【Transformation 30】 (In the formula, R ３ and R ４ is as defined in claim 1; Each R ｊ are independently —H, halogen, —OH, or —NH ２ , -CN, =O, -NO ２ , -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C ２ -C ６ ) alkenyl, -(C ２ -C ６ ) alkynyl, -(C ３ -C ８ ) cycloalkyl, -(C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S; a 7- to 14-membered fused ring group containing 0 to 4 heteroatoms independently selected from O, N, and S; —SH, —S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, -NHS(O)H, -S(O) ２ OH, -S(O)OH, -NHS(O) ２ -OH, -NHS(O)OH, -C(O)H, or -C(O)OH, wherein each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring groups is -H, ═O, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -S(O) ２ H, -S(O) ２ NH ２ , -S(O)H, -S(O)NH ２ , -NHS(O) ２ H, -NHS(O)H, -S(O) ２ OH, -S(O)OH, -NHS(O) ２ OH, —NHS(O)OH, —C(O)H, —C(O)OH, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ optionally substituted with one or more substituents selected from aryl or 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; m is independently an integer selected from 0 to 6; v is 0 or 1; Ring B is (C ３ -C ８ ) cycloalkyl, (C ４ -C ８ cycloalkenyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S. or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

24. Each R ｊ are independently —H, halogen, —OH, or —NH ２ , -CN, =O, -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, oxazolyl, thiazolyl, or triazolyl; The ring B is (C ３ -C ８ cycloalkyl, 3- to 14-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N, and S; C ６ -C １４ aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered bicyclic or tricyclic fused ring group containing 0-4 heteroatoms independently selected from O, N, and S; 24. The compound of claim 23, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

25. Ring B is a 3- to 7-membered oxacycloalkyl or an 8- to 10-membered azabicyclic fused heteroaryl; 25. The compound of claim 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

26. The ring B is oxacycloheptane, oxacyclohexane, tetrahydrofuran, oxetane, oxacyclopropane, 1H-indole, or isoindoline.

26. The compound of claim 25, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

27. The ring B is 【Chemistry 31】 That is, 27. The compound of claim 26, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

28. Formula I or II: 【Chemistry 32】 (In the formula, R 3 and R 4 are as defined in claim 1 ; Each R j is independently —H, halogen, —OH, —NH 2 , —CN, ═O, —NO 2 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 4 -C 8 )cycloalkenyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, 7- to 14-membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S, —SH, —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 H, —NHS(O)H, —S(O) 2 OH, —S(O)OH, —NHS(O) 2 OH, —NHS(O)OH, —C(O)H, or —C(O)OH, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused ring group is each —H, ═O, halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , —S(O) 2 H, —S(O) 2 NH 2 , —S(O)H, —S(O)NH 2 , —NHS(O) 2 H, —NHS(O)H, —S(O) 2 optionally substituted with one or more substituents selected from OH, —S(O)OH, —NHS(O) 2 OH, —NHS(O)OH, —C(O)H, —C(O)OH, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, or 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S; m is independently an integer selected from 0 to 6; v is 0 or 1; Ring B is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, C 6 -C 14 aryl, 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a 7-14 membered fused ring group containing 0-4 heteroatoms independently selected from O, N, and S; Any one or more H in the compound of formula I or II is replaced with D. or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

29. In compounds of formula I or II, the structure " 【Transformation 33】 ", any one or more H's are replaced by D, or R ４ wherein any one or more H's are replaced with D; 29. The compound of claim 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

30. In compounds of formula I or II, the structure " 【Transformation 34】 " in which all H is replaced by D, 30. The compound of claim 29, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

31. If selected as H, R １ , R ２ , or R ３ are independently optionally substituted with D; 29. The compound of claim 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof. 【Request Item 32】 【Chemistry 35-1】 【Chemistry 35-2】 【Chemistry 35-3】 【Chemistry 35-4】 【Transformation 35-5】 【Chemistry 35-6】 【Chemistry 35-7】 【Transformation 35-8】 【Chemistry 35-9】 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

33. 33. Use of a compound according to any one of claims 1 to 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, as a PKR agonist or USP9X inhibitor.

34. 36. Use of a compound of any one of claims 1 to 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, in the preparation of a medicament for treating a PKR or USP9X mediated disease.

35. 35. The use of claim 34, wherein the disease is pyruvate kinase deficiency, hemoglobinopathy, cancer, or tumor.

36. 35. The use of claim 34, wherein the disease comprises sickle cell anemia, beta-thalassemia, hereditary non-spherocytic anemia, hemolytic anemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia, congenital anemia, anemia of chronic disease, colon cancer, kidney cancer, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, melanoma, lymphoma, glioblastoma, or multiple myeloma.

37. The following formula III: 【Transformation 36】 (In the formula, R １０ is —H or an amino protecting group, and R ２０ is —H, an amino protecting group, or 【Chemistry 37】 and R ４ is as defined in any one of claims 1 to 31; Or, R １０ is —H, an amino protecting group, 【Transformation 38】 where R １ , R ２ , and R ３ is as defined in any one of claims 1 to 18 or 28 to 31, and m, v, R ｊ and ring B is as defined in any one of claims 23 to 27, R ２０ is —H or an amino protecting group) An intermediate compound represented by the formula:

38. each amino protecting group is independently selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, or -Alloc; and / or Any one or more H in the compound of formula III is replaced with D; 38. The compound of claim 37. 【Request Item 39】 【Chemistry 39】 38. The compound of claim 37 selected from:

40. 33. A pharmaceutical composition comprising the compound of any one of claims 1 to 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable excipient.

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