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WO2024230586A1 - New use of compound containing diazepine sulfonyl structure as pkm2 agonist - Google Patents

New use of compound containing diazepine sulfonyl structure as pkm2 agonist Download PDF

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Publication number
WO2024230586A1
WO2024230586A1 PCT/CN2024/090827 CN2024090827W WO2024230586A1 WO 2024230586 A1 WO2024230586 A1 WO 2024230586A1 CN 2024090827 W CN2024090827 W CN 2024090827W WO 2024230586 A1 WO2024230586 A1 WO 2024230586A1
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Prior art keywords
independently selected
cycloalkyl
alkyl
heteroatoms independently
membered
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PCT/CN2024/090827
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French (fr)
Chinese (zh)
Inventor
王早
赵树春
张凌
胡晓
李建宗
王静
张晓东
唐元清
唐军
Original Assignee
赛诺哈勃药业（成都）有限公司
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Publication of WO2024230586A1 publication Critical patent/WO2024230586A1/en

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  • the present invention belongs to the field of medical technology, and specifically relates to an application of a compound containing a diazasulfonyl structure as a PKM2 agonist and the treatment of related diseases.
  • PK Pyruvate kinase
  • PKM Pyruvate kinase
  • PKLR Pyruvate kinase
  • Differential splicing of PKM gene mRNA can encode two isozymes, PKM1 and PKM2.
  • PKM1 is mainly present in tissues such as skeletal muscle, heart and brain
  • PKM2 is mainly present in embryonic cells, stem cells, tumor cells, brain and liver tissues.
  • PKL and PKR encoded by PKLR gene are specifically expressed in liver and red blood cells, respectively (Semin Cell Dev Biol; 43:43-51 (2015)).
  • PKM2 is involved in regulating a variety of biological processes, including cell proliferation, differentiation, inflammation, signal transduction, and metabolic enzyme pathways. It is also involved in protein synthesis and interaction and is a transcriptional regulator and protein kinase. It is located in the cytoplasm, nucleus, and mitochondria and can aggregate into tetramers and dimers. Although composed of the same monomer, there are significant differences in the biological effects between tetramers and dimers. Studies have shown that the conversion between dimers and tetramers plays an important role in cell proliferation, energy supply of tumor cells, epithelial-mesenchymal transition, and signal transduction.
  • the low activity of dimeric PKM2 leads to the accumulation of metabolites in the glycolysis pathway, thereby promoting the biosynthesis of metabolites required for cell proliferation, such as cancer cells.
  • PKM2 in the dimeric state can enter the nucleus and regulate gene transcription and expression together with other transcription factors.
  • Tetrameric PKM2 exerts its metabolic enzyme function in the cytoplasm, mainly acting as pyruvate kinase to regulate glycolysis. Under physiological glucose concentrations, 30%-35% of PKM2 is a monomer, and most of the rest is a highly active tetramer (J Cell Physiol, 237(1), 128-148(2022)).
  • PKM2 When PKM2 is in a tetramer state, it has a higher affinity with the substrate phosphoenolpyruvate (PEP) and has higher PK enzyme activity, catalyzing phosphoenolpyruvate (PEP) to produce pyruvate and phosphorylating ADP into ATP.
  • PEP substrate phosphoenolpyruvate
  • PEP phosphoenolpyruvate
  • PKM2 dimers can promote lactate production, leading to the accumulation of upstream glycolytic metabolites, promoting macromolecular biosynthesis and inhibiting the production of intracellular reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • PKM2 can also translocate to the nucleus to stimulate the activity of transcription factors including HIF-1, HIF-2, ⁇ -catenin, STAT3 and Oct-4, thereby increasing the expression of gene products required for tumor growth (Trends Endocrin Met, 23, 11: 560-566 (2012)).
  • PKM2 agonists can promote the formation of PKM2 tetramers, reduce the transfer of PKM2 to the nucleus, interfere with cell anabolism and inhibit tumor growth (Nat Chem Biol, 8 (10), 839-847 (2012)).
  • Targeting the glycolytic enzyme PKM2 is a potential therapy for the treatment of breast cancer, lymphoma and pancreatic cancer.
  • DNX-3000 Small molecule PKM2 agonists currently under development include DNX-3000, ACT001, and TP-1454.
  • DNX-3000 was developed by Dynamix Pharmaceuticals Ltd. Its data showed that DNX-3000 had similar AC50 values, activation, and enzyme reaction kinetics to the natural PKM2 activator FBP.
  • DNX-3000 reduced the proliferation rate of various cancer cell lines by 80% in a dose-dependent manner, including liver cancer, lung cancer, and colorectal cancer. Its combination with chemotherapy drugs (such as 5-fluorouracil in HT29 colorectal cancer cells) had an additive effect on cancer cell proliferation, resulting in a 100% inhibition of cell growth.
  • ACT001 was developed by Nankai University.
  • ACT001 significantly inhibited the proliferation and metastasis of GBM (glioblastoma multiforme) cells such as U118, and induced their apoptosis. It inhibited tumor growth and reduced tumor weight in mouse model experiments.
  • TP-1454 was developed by Tolero Pharmaceuticals Inc., and data showed that in a colorectal cancer model, combination therapy with TP-1454 and anti-PD-1 resulted in tumor growth inhibition. In colorectal, breast, and renal cancer cell models, TP-1454 treatment reduced population size.
  • TCR T cell receptor
  • Th17 cells T helper cells
  • Tregs regulatory T cells
  • PKM2 acts on the STAT family in the differentiation of pro-inflammatory T cell subsets and has multiple regulatory functions: regulating STAT1/STAT4 to induce Th1 formation and participate in cellular immunity; regulating the phosphorylation of STAT6 and STAT3, regulating the differentiation of Th2 and Th17 cells, respectively, and participating in inflammatory-related diseases; regulating STAT5 binding to TGF- ⁇ , inducing Tregs formation and maintaining immune tolerance (Front Immunol, 13, 936967(2022), J Exp Med, 217(10), e20190613(2020)).
  • PKM2 agonists such as small molecule compounds TEPP-46 and sesquiterpene lactone derivatives can affect T cell activation by promoting PKM2 tetramerization and inhibiting PKM2 nuclear translocation, inhibiting the differentiation of Th17 and Th1 cells, inhibiting T cell-mediated inflammation in vivo, and improving inflammatory bowel diseases such as ulcerative colitis (J. Med. Chem. 2023, 66, 8, 5500–5523) (Bu Nan, Li Shanshan, et al. Changes in PKM2 expression in the intestinal mucosa of ulcerative colitis and its clinical significance.
  • ulcerative colitis J. Med. Chem. 2023, 66, 8, 5500–5523
  • Patent applications including WO2010118063A, WO2011002817A, WO2014074848A, WO2014139325A, WO2014139144A, CN104817490B, CN111170991A, WO2019035863A, etc. also disclose a series of small molecule compounds as PKM2 agonists. Combined with their clinical and preclinical activity data, these small molecule compounds have potential medical value in the treatment of PKM2-mediated tumors, autoimmune diseases, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc.
  • HFSCs hair follicle stem cells
  • the activation and regeneration of HFSCs require the participation of the glycolytic pathway, while the Wnt/ ⁇ -catenin signaling pathway contributes to the morphogenesis, maintenance and induction of hair follicle growth and development. Increased PKM2 expression and activation of the Wnt/ ⁇ -catenin signaling pathway can be observed in the growth phase of HFSCs.
  • TEPP-46 as a PKM2 agonist, can promote hair regeneration and proliferation by upregulating the Wnt/ ⁇ -catenin signaling pathway and activating PKM2 (Pharmaceutics, 14, 12: 2774 (2022)). Dual activation of PKM2 and Wnt/ ⁇ -catenin signaling pathways may be a potential therapeutic strategy for patients with hair loss.
  • the applicant of the present invention provides a novel compound containing a diazainyl sulfonyl structure in the prior international application PCT/CN2022/140731 (international application date December 21, 2022).
  • the novel compound provided in the application has excellent activity as a PKR agonist or USP9X inhibitor, which can be used to treat anemia, tumors and other related diseases mediated by PKR and USP9X.
  • the entire content of the prior international application PCT/CN2022/140731 is hereby introduced into the present invention as a part of the present invention.
  • novel compounds provided therein are also PKM2 agonists, which show good PKM2 agonist activity in in vitro enzymatic activity experiments. This agonist activity is further manifested at the cellular level, and still maintains good PKM2 agonist activity in human brain astroglioma cells (U118-MG). In addition, as confirmed in the mouse hair growth experiment, these compounds also have a significant promoting effect on hair growth.
  • the present invention provides use of a compound of the present invention as a PKM2 agonist.
  • the present invention provides compounds of the present invention for use as PKM2 agonists.
  • the present invention provides compounds of the present invention for use in treating diseases related to PKM2-mediated regulation.
  • the present invention provides compounds of the present invention for use in treating diseases selected from tumors, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc.; preferably, the disease is selected from liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, kidney cancer, inflammatory bowel disease, ulcerative colitis, alopecia, alopecia, hypotrichosis, etc.
  • the present invention provides use of the compound of the present invention in the preparation of a medicament for treating diseases related to PKM2-mediated regulation.
  • the present invention provides the use of the compounds of the present invention in the preparation of drugs for treating diseases that can exert therapeutic effects by promoting the generation of PKM2 tetramers, reducing the generation of PKM2 dimers, targeting PKM2 to affect glycolytic enzymes, or preventing PKM2 from entering the cell nucleus.
  • the present invention provides the use of the compounds of the present invention in the preparation of a medicament for treating a disease selected from tumors, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc.; preferably, the disease is selected from liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, kidney cancer, inflammatory bowel disease, ulcerative colitis, alopecia, alopecia, hypotrichosis, etc.
  • a disease selected from tumors, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc.
  • the disease is selected from liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, kidney cancer, inflammatory bowel disease, ulcerative colitis, alopecia, alopecia, hypotrichosis, etc.
  • the present invention provides a method for treating a disease related to PKM2-mediated regulation, the method comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof.
  • the present invention provides a method for treating diseases that can be treated by promoting the formation of PKM2 tetramers, reducing the production of PKM2 dimers, targeting PKM2 to affect glycolytic enzymes, or preventing PKM2 from entering the cell nucleus, the method comprising administering a therapeutically effective amount of a compound of the present invention to an individual in need thereof.
  • diseases that can be treated by the method of the present invention include tumors, inflammation, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc., such as liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, lymphoma, pancreatic cancer, renal cancer, inflammatory bowel disease, ulcerative colitis, hair loss, alopecia and hypotrichosis, etc.
  • Figure 2 shows the promoting effect of a representative compound of the present invention on hair growth in mice, wherein Figure 2a) shows the growth of the back of the animal after 4 weeks of administration; Figure 2b) shows a bar graph of the weight of new hair in different treatment groups.
  • the present invention provides a compound of formula I or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first, second, third and fourth aspects of the present invention:
  • R 1 , R 2 and R 3 are 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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -OR b , -SR b , -NR c R d , -S(O) 2R e ,
  • R1 and R2 , R1 and R3 , or R2 and R3, together with the atoms to which they are attached, may optionally combine to form -( C3 - C8 )cycloalkyl, 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, -( C5 - C8 )spirocyclyl, 5- to 8-membered spiroheterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, or 5-14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S;
  • R4 is -NH2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S , -ORb , -SRb , -NRcRd , -S(O ) 2Re , -S(O) 2NRcRd , -S(O )Re , -S ( O ) NR
  • t 0, 1, 2, or 3;
  • Ra , Rb , Rc , Rd , Re , Rf , Rg , Rh and Ri are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -SH, -S(O) 2
  • any two groups selected from Ra , Rb , Rc , Rd , Re , Rf , Rg, Rh and Ri on adjacent atoms together with the atoms to which they are attached may optionally combine to form a C6 - C14 aryl group optionally substituted with one or more Ra , a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, a ( C3 - C8 )cycloalkyl group, or a 3-14 membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S.
  • the present invention provides a specific isomeric compound of the above formula I for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, having the formula I-1 or I-2,
  • R 1 and R 2 can be independently further selected as follows:
  • R1 and R2 are independently -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -ORb or -NRcRd , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cyclo
  • R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
  • Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 -C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C6 -C6-alkyl, -( C2 - C6- alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl,
  • the invention also includes but is not limited to alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycl
  • R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
  • R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain 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 cyclic group containing 0-4 heteroatoms independently selected from O, N and S , -ORb or -NRcRd , wherein each alkyl, cycloalkyl, heterocyclyl, aryl , heteroaryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra
  • R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
  • Ra , Rb , Rc and Rd are independently, at each occurrence, -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C8 aryl, or a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
  • R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain alkyl, -( C3 - C6 ) cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra, -ORb , -NRcRd ;
  • R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
  • Ra , Rb , Rc and Rd are independently at each occurrence -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
  • R2 is -H, -F, -Cl or -Br;
  • R 1 is -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 , -(CH 2 ) q NH 2 , -(CH 2 ) q NH(CH 2 ) q CH 3 , -(CH 2 ) q N((CH 2 ) q CH 3 ) 2 , 3- 6-membered heterocycloalkyl, -(C 1 -C 6 )alkyl substituted by a 3-6-membered heterocycloalkyl containing 1 N atom;
  • q is 0, 1, 2, 3, or 4 independently at each occurrence
  • R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, tetrahydrofuran, tetrahydropyran, morpholine, dioxane or 2,3-dihydrobenzofuran ring;
  • R 1 and R 2 together with the atoms to which they are attached may optionally combine 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.
  • R2 is -H, -F, -Cl or -Br;
  • R 1 is -H, -F, -Cl, -Br, -OH, -NH 2 ,
  • R1 and R2 together with the atoms to which they are attached may optionally be combined to form
  • R1 and R2 together with the atoms to which they are attached may optionally be combined to form
  • R2 is -H, -F, -Cl or -Br;
  • R 1 is -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 , -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(
  • q is 1, 2, 3, or 4 independently at each occurrence
  • R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an oxetane, a tetrahydrofuran, a tetrahydropyran, a morpholine, a dioxane, a 2,3-dihydrobenzofuran ring or a tetrahydro-2H-pyran.
  • R2 is -H, -F, -Cl or -Br;
  • R 1 is -H, -F, -Cl, -Br, -OH, -NH 2 ,
  • R1 and R2 together with the atoms to which they are attached may optionally be combined to form
  • R1 and R2 together with the atoms to which they are attached may optionally be combined to form
  • the present invention provides compounds of the above formula I, formula I-1 or I-2 for use in the first, second, third and fourth aspects of the present invention, wherein R 1 and R 2 are independently selected from any of the above combinations, and R 3 can be independently further selected from the following:
  • Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 -C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C6 -C6-alkyl, -( C2 - C6- alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl,
  • the invention also includes but is not limited to alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycl
  • R3 is -H, -F, -Cl, -Br, -( C1 - C6 ) alkyl, -( C3 - C6 ) cycloalkyl, C6 - C8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or 7-14 membered bicyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, aryl, heteroaryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -R a and -OR b ;
  • Ra and Rb are independently -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from: -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
  • R3 is -H, -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl or benzopyrrolidinyl, wherein pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl are optionally substituted with one or more substituents selected from the following substituents: -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, -O-( C1 - C6 )alkyl, -O-( C3 - C6 )cycloalkyl, piperazinyl, piperazinyl substituted with any number of halogen or -( C1 -
  • R 3 is -H, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , pyridyl,
  • R 3 is -H, -F, -Cl, -Br, -(C 1 -C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, pyridyl, phenyl, naphthyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl or Among them, pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl, Optionally substituted with one or more substituents selected from the group consisting of -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,
  • ring is a 3-6 membered saturated or unsaturated heterocyclic group linked via a N atom, and the heterocyclic group optionally contains 1-2 heteroatoms independently selected from O, N and S in addition to the N atom.
  • R 3 is -H, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 ,
  • the present invention provides compounds of the above formula I, formula I-1 or I-2 for use in the first, second, third and fourth aspects of the present invention, wherein R 1 , R 2 and R 3 are independently selected from any combination as described above, and R 4 can be further selected from the following:
  • X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t - or -O-; wherein R c , R h , R i and t are optionally as defined anywhere in the present invention;
  • Y1 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 N at the same time;
  • Each Rj 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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -SH, -S(O)2H, -S(O)2NH2 , -S (O)
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2.
  • X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
  • Y1 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 N at the same time;
  • 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 and triazolyl;
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2.
  • X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
  • Y1 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 N at the same time;
  • 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 halogen, -(C 1 -C 6 )alkoxy substituted with any number of halogen, -(C 3 -C 6 )cycloalkyl substituted with any number of halogen, -O-(C 3 -C 6 )cycloalkyl substituted with any number of halogen, oxazolyl, thiazolyl and triazolyl;
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2.
  • X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t - or -O-; wherein R c , R h , R i and t are optionally as defined anywhere in the present invention;
  • Y1 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 N at the same time;
  • Each Rj 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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -SH, -S(O)2H, -S(O)2NH2 , -S (O)
  • n and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • Ring A is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, a 3-14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, a 5-14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
  • X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
  • Y1 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 N at the same time;
  • 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;
  • n and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine or triazine.
  • X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
  • Y1 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 N at the same time;
  • n and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxacyclohexane, piperazine, pyrazine, triazine, 4,5-dihydro-1H-imidazole or 1,3-dioxolane.
  • R4 can be further selected as
  • R4 can be further selected as
  • the present invention provides a compound represented by formula I, formula I-1 or I-2 or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention:
  • R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain alkyl, -( C3 - C6 ) cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra, -ORb , -NRcRd ;
  • R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
  • R3 is -H, -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, -( C6 - C8 )aryl, or a 7-14 membered bicyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, aryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -R a and -OR b ;
  • Ra , Rb , Rc and Rd are independently at each occurrence -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl;
  • X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
  • Y1 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 N at the same time;
  • n and p are independently 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxacyclohexane, piperazine, pyrazine or triazine; or, Ring A is 4,5-dihydro-1H-imidazole or 1,3-dioxolane.
  • the present invention provides a compound represented by Formula I, Formula I-1 or I-2 or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention:
  • R2 is -H, -F, -Cl or -Br;
  • R 1 is -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 , -(CH 2 ) q NH 2 , -(CH 2 ) q NH(CH 2 ) q CH 3 , -(CH 2 ) q N((CH 2 ) q CH 3 ) 2 , 3- 6-membered heterocycloalkyl, -(C 1 -C 6 )alkyl substituted by a 3-6-membered heterocycloalkyl containing 1 N atom; or, R 1 is -CH 2 F, -CHF 2 , -(CH 2 ) q CH 2 F, -(CH 2 ) q CHF 2 , -CH 2
  • q is 0, 1, 2, 3, or 4 independently at each occurrence
  • R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a tetrahydrofuran, a tetrahydropyran, a morpholine, a dioxane or a 2,3-dihydrobenzofuran ring; alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a tetrahydro-2H-pyran or an oxetane.
  • R3 is -H, -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl or benzopyrrolidinyl, wherein pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl, 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, piperazinyl substituted with any number of halogen or -( C1 - C6 )alkyl
  • X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
  • Y1 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 N at the same time;
  • n and p are independently 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxacyclohexane, piperazine, pyrazine or triazine; or, Ring A is 4,5-dihydro-1H-imidazole or 1,3-dioxolane.
  • the present invention provides a compound represented by Formula I, Formula I-1 or I-2 or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention:
  • R2 is -H, -F, -Cl or -Br;
  • R 1 is -H, -F, -Cl, -Br, -OH, -NH 2 , Alternatively, R1 is
  • R1 and R2 together with the atoms to which they are attached may optionally be combined to form
  • R1 and R2 together with the atoms to which they are attached may optionally be combined to form
  • R 3 is -H, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , pyridyl, Or R3 is
  • R4 is Or R 4 is
  • the present invention provides compounds of the present invention for use in the first, second, third and fourth aspects of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:
  • the present invention also provides compounds of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:
  • the present invention also provides compounds of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:
  • the present invention also provides a compound of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which is selected from the compound of the following formula II or its isomer, pharmaceutically acceptable salt or solvate:
  • R3 and R4 are as defined above for any corresponding R3 and R4 in the compounds of formula I, I-1 or I-2;
  • n is independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • v 0 or 1
  • Ring B is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, a 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a 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 cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
  • Ring B is (C 3 -C 8 )cycloalkyl, a 3-14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, a 5-14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14-membered bicyclic or tricyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
  • Ring B is a 3-7 membered oxacycloalkyl group or an 8-10 membered azabicyclic condensed heteroaryl group.
  • Ring B is oxepane, oxhexane, tetrahydrofuran, oxetane, oxirane, 1H-indole or isoindoline.
  • the present invention provides compounds of the present invention for use in the first, second, third and fourth aspects of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:
  • the present invention also provides a compound of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which is selected from the deuterated compound of the aforementioned formula I or II or an isomer, a pharmaceutically acceptable salt or a solvate thereof:
  • R 1 , R 2 , R 3 , R 4 , R j , m, v and ring B are as defined above for any corresponding R 1 , R 2 , R 3 , R 4 , R j , m, v and ring B in the compound of formula I or II;
  • R 1 , R 2 or R 3 is H, it is independently optionally substituted by D.
  • the present invention provides compounds of the present invention for use in the first, second, third and fourth aspects of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:
  • a later technical solution when a later technical solution further defines a previous technical solution, it may only further define some of the technical features.
  • the undefined technical features can be optionally defined in the previous technical solution or anywhere in the present invention.
  • the compounds of the present invention show good agonist activity in the PKM2 in vitro enzymatic activity experiment, and this agonist activity is further manifested at the cellular level, and still maintains good PKM2 agonist activity in human brain astrocytic glioblastoma cells (U118-MG).
  • the compounds of the present invention also have a significant promoting effect on hair growth.
  • the compounds of the present invention can be used in their own form, or can also be combined with pharmaceutically acceptable excipients to form a pharmaceutical composition, which can be presented in any pharmaceutically acceptable dosage form and route of administration.
  • Acceptable dosage forms include but are not limited to tablets, capsules, granules, pills, pastes, powders, tinctures, films, patches, coatings, implants, injections, lozenges, drops, sprays, aerosols, atomized inhalers, gels, suppositories, ointments, etc.
  • Acceptable routes of administration include but are not limited to: oral, intravenous, rectal, parenteral, topical, transdermal, ophthalmic, nasal, cheek or lung (inhalation) administration, etc.
  • Alkyl refers to an aliphatic hydrocarbon group, a saturated hydrocarbon group, which may be substituted or unsubstituted.
  • the alkyl portion may be a straight chain alkyl group or a branched chain alkyl group.
  • -(C 1 -C 6 )alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as an alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like.
  • the alkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
  • Alkenyl refers to an unsaturated hydrocarbon group containing a carbon-carbon double bond in the structure, which may be substituted or unsubstituted.
  • the alkenyl moiety may be a straight chain alkenyl or a branched chain alkenyl.
  • -(C 2 -C 6 )alkenyl or -(C 2 -C 4 )alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, such as an alkenyl group having 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • alkenyl groups include vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, n-hexenyl, and the like.
  • the alkenyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
  • Alkynyl refers to an unsaturated hydrocarbon group containing a carbon-carbon triple bond in its structure, which may be substituted or unsubstituted.
  • the alkynyl moiety may be a straight chain alkynyl or a branched chain alkynyl.
  • -(C 2 -C 6 )alkynyl or -(C 2 -C 4 )alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, such as alkynyl groups having 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.
  • alkynyl groups include ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, n-hexynyl, and the like.
  • the alkynyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
  • Ring refers to any covalently closed structure, including, for example, carbocyclic rings (e.g., aryl, cycloalkyl or cycloalkenyl), heterocyclic groups (e.g., heteroaryl, heterocycloalkyl or heterocycloalkenyl), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl), which may be substituted or unsubstituted.
  • the ring may be optionally substituted, and may be a monocyclic or polycyclic ring.
  • Typical polycyclic rings generally include bicyclic and tricyclic rings.
  • the ring of the present application generally has 3-20 ring atoms, for example, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms, 19 ring atoms or 20 ring atoms.
  • “Member” refers to the number of skeleton atoms constituting the ring.
  • Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene;
  • typical 6-membered rings include, for example, cyclohexyl, cyclohexenyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, etc.
  • a ring containing heteroatoms in the skeleton atoms is a heterocycle.
  • Heteroatom refers to an atom other than carbon or hydrogen.
  • One or more heteroatoms in the heterocycle of the present application may be independently selected from O, S, N, Si and P, but is not limited thereto.
  • Aromatic refers to a cyclic group with a conjugated ⁇ electron system, including aryl groups whose skeleton atoms constituting the ring are all carbon atoms and heteroaryl groups whose skeleton atoms constituting the ring contain heteroatoms.
  • Aryl preferably refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated ⁇ electron system having 6 to 14 carbon atoms (6 to 14 members), preferably having 6 to 10 atoms, such as phenyl and naphthyl, which may be substituted or unsubstituted. More preferably phenyl.
  • Heteroaryl preferably refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms, 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14), wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, which may be substituted or unsubstituted.
  • 1 to 4 e.g., 1, 2, 3 or 4
  • heteroatoms e.g., 1, 2, 3 or 4
  • 5 to 14 ring atoms e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
  • the heteroatoms are selected from oxygen, sulfur and nitrogen, which may be substituted or unsubstituted.
  • the heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably, pyrazolyl, such as 1H-pyrazol-4-yl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, a heterocycloalkyl, a cycloalkyl ring or another heteroaryl to form a fused heteroaryl.
  • the fused heteroaryl group is preferably an 8-10 membered fused heteroaryl group, including but 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]imidazolyl such as 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl-5-yl, or 1H-benzo[d]imidazolyl such as 1H-benzo[d]imidazolyl-6-yl.
  • Non-aromatic group refers to a cyclic group that does not have a conjugated ⁇ electron system and is not aromatic. It is also generally called an alicyclic group, including cycloalkyl and cycloalkenyl groups whose skeletal atoms constituting the ring are all carbon atoms and heterocycloalkyl and heterocycloalkenyl groups whose skeletal atoms constituting the ring contain heteroatoms.
  • fused refers to rings that share adjacent pairs of carbon atoms and are typically bi- or tri-ring fused.
  • “Fused cyclic group” includes “fused non-aromatic group”, “fused aromatic group”, “fused non-aromatic group” includes “fused cycloalkyl group”, “fused heterocycloalkyl group”, “fused cycloalkenyl group” and “fused heterocycloalkenyl group”, and “fused aromatic group” includes “fused aryl group” and “fused heteroaryl group”, all of which may be substituted or unsubstituted.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon substituent containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl, which contains 3 to 20 carbon atoms that can form a ring, preferably 3 to 10 carbon atoms (i.e., 3-10-membered cycloalkyl, also referred to as -(C 3 -C 10 )cycloalkyl), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms.
  • the cycloalkyl is selected from a monovalent cycloalkyl derived from the following rings:
  • cyclopropane cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane.
  • the cycloalkyl group may be substituted or unsubstituted.
  • the cycloalkyl when a cycloalkyl is connected to two groups according to the structure or context, the cycloalkyl is a divalent group, i.e., has two connection sites. In this case, it may also be referred to as a cycloalkylene group.
  • cycloalkylene groups include, but are not limited to, monocyclic structures such as cyclopropylene, cyclobutylene, cyclopentylene (e.g., cyclopentyl-1,2-diyl, cyclopentyl-1,3-diyl), cyclohexylene (e.g., cyclohexyl-1,2-diyl, cyclohexyl-1,3-diyl, cyclohexyl-1,4-diyl), cycloheptylene or cyclooctylene, etc.
  • monocyclic structures such as cyclopropylene, cyclobutylene, cyclopentylene (e.g., cyclopentyl-1,2-diyl, cyclopentyl-1,3-diyl), cyclohexylene (e.g., cyclohexyl-1,2-diyl, cyclohexyl-1
  • Heterocycloalkyl and “cycloheteroalkyl” are used interchangeably to refer to saturated non-aromatic monocyclic, fused, bridged, and spirocyclic rings containing one or more (e.g., 1, 2, 3, or 4) heteroatoms.
  • the heteroatoms may be N, O, S, or SO2 .
  • Heterocycloalkyl can be a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms) monocyclic or bicyclic or tricyclic group.
  • Typical heterocycloalkyl groups include, but are not limited to, monovalent groups derived from the following rings:
  • heterocycloalkyl groups can also be represented by commonly understood structural formulas, for example:
  • heterocycloalkyl group when a heterocycloalkyl group is connected to two groups according to the structure or context, the heterocycloalkyl group is a divalent group, i.e., there are two connection sites. In this case, it can also be referred to as a heterocycloalkylene group.
  • heterocycloalkylene groups include, but are not limited to, divalent groups formed by the above groups, such as:
  • Cycloalkenyl refers to a cyclic hydrocarbon substituent containing one to three rings, which contains one or more double bonds but none of which has a completely conjugated ⁇ electron system and is not aromatic, including monocyclic alkenyl, bicyclic alkenyl and tricyclic alkenyl, and contains 3-20 carbon atoms that can form a ring, preferably 3-10 carbon atoms (i.e., 3-10-membered cycloalkenyl, also referred to as -(C 3 -C 10 )cycloalkenyl), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms.
  • the cycloalkenyl is selected from a monovalent cycloalkenyl obtained from the following rings:
  • Cycloalkenyl may be substituted or unsubstituted. It should be understood that when, according to the structure or context, a cycloalkenyl is connected to two groups, the cycloalkenyl is a divalent group, i.e., has two connection sites. At this point, it may also be referred to as a cycloalkenylene.
  • Heterocycloalkenyl refers to an unsaturated non-aromatic monocyclic, fused, bridged, and spirocyclic ring containing one or more (e.g., 1, 2, 3, or 4) heteroatoms.
  • the heteroatoms may be N, O, S, or SO2 .
  • Heterocycloalkenyl may be a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms) monocyclic or bicyclic or tricyclic group.
  • Typical heterocycloalkenyl groups include, but are not limited to, monovalent groups derived from the following rings:
  • heterocyclic alkenyl groups can also be represented by commonly understood structural formulas, for example: It should be understood that when, according to the structure or context, the heterocycloalkenyl group is connected to two groups, the heterocycloalkenyl group is a divalent group, that is, there are two connection sites. In this case, it can also be called a heterocycloalkenylene group.
  • Halogen or halo refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom, such as CF3 .
  • Substituted means that one or more hydrogen atoms, preferably up to 5 (e.g. 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms in the group can be replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • Inhibitor refers to a substance that reduces the activity of an enzyme.
  • Antist refers to a substance that increases enzyme activity.
  • substituted or unsubstituted refers to any group being monosubstituted or polysubstituted by a specified substituent to the extent that such monosubstituted or polysubstituted (including multiple substitutions in the same moiety) is chemically permitted, and each substituent can be located at any available position on the group and can be connected through 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 methods taught herein and does not produce excessively unstable molecules. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and can therefore be the same or different.
  • Stepoisomerism "stereoisomer” as used herein means that when the compounds of the present invention contain one or more asymmetric centers, they can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers.
  • the compounds of the present invention may have asymmetric centers, which result in the existence of two optical isomers.
  • the scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefin double bonds, the scope of the present invention includes cis isomers and trans isomers unless otherwise specified.
  • the compounds of the present invention may exist in the form of tautomers (a type of functional group isomers), which have different hydrogen attachment points through one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are within the scope of the present invention. Enantiomers of all compounds. Diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof are all within the scope of the present invention.
  • pharmaceutically acceptable refers to molecular entities and compositions that are or are approvable by relevant agencies in various countries, or are listed in the generally recognized pharmacopoeia for use in animals, and more particularly in humans, or that do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.
  • such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts.
  • the term "individual” includes humans or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • non-human animals include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • composition refers to a composition comprising one or more compounds of Formula (I), Formula (I-1), Formula (I-2) or Formula (II) or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates and a carrier or excipient generally accepted in the art for delivering the biologically active compound to an organism (e.g., a human).
  • drug combination means that the compounds of the present invention can be combined with other active agents to achieve the purpose of the present invention.
  • the other active agents may be one or more additional compounds of the present invention, or may be a second or additional (e.g., a third) compound that is compatible with the compounds of the present invention, i.e., does not adversely affect each other, or has complementary activities.
  • Such active agents are suitably combined in an effective amount to achieve the intended purpose.
  • the other active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or may be administered separately from the compounds of the present invention in different discrete units, and when administered separately, may be performed simultaneously or sequentially. The sequential administration may be close or distant in time.
  • Grubb's 2 stands for Grubbs second generation catalyst
  • DMF stands for N,N-dimethylformamide
  • DMSO means dimethyl sulfoxide
  • HATU stands for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium
  • Xantphos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • -Cbz represents a benzyloxycarbonyl protecting group
  • -Boc represents a tert-butyloxycarbonyl 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 p-toluenesulfonyl protecting group
  • -Pht represents a phthaloyl protecting group
  • -Alloc represents an allyloxycarbonyl protecting group
  • Tris buffer means tris(hydroxymethyl)aminomethane buffer.
  • -TBS represents tert-butyldimethylsilyl
  • -TBDPS represents tert-butyldiphenylsilyl.
  • the present invention also provides a method for synthesizing the novel compound.
  • the method for synthesizing the novel compound is mainly based on the preparation method reported in chemical literature or using commercially available chemical reagents as starting materials for related synthesis.
  • RA refers to wherein R 4 is as defined in any place in the present invention
  • R C refers to Wherein R1 , R2 , R3 , Rj , m, v and ring B are as defined in the present invention at any time
  • RB refers to RC protected by a protecting group, and RB becomes RC after removing the protecting group, and the protecting group includes but is not limited to -TBS or -TBDPS.
  • the following steps involve compounds ZRA and ZRB , wherein "Z" is a compound capable of undergoing a condensation reaction with an amino group to connect RA or RB to
  • the condensation reaction is preferably a condensation reaction between sulfonyl chloride and an amino group or a condensation reaction between a carboxyl group and an amino group.
  • “Z” can be independently selected in different compounds and includes but is not limited to -Cl, -F, -Br, and -OH.
  • Compound ZRA is preferably Cl- RA
  • compound ZRB is preferably OH- RB .
  • Compound B is dissolved in trifluoroacetic acid, and the reaction is carried out at 60° C. After the reaction is completed, the product is concentrated to dryness and then separated and purified by a chromatography column to obtain compound C.
  • Example 1 The preparation and synthesis steps of (S)-1-(1'-((2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropane-1-one (Compound 1) are as follows:
  • Step 1 Preparation of 7-bromo-2,3-dihydro-[1,4]dioxo[2,3-b]pyridine (Compound 1A)
  • Benzyl 3-oxoazetidine-1-carboxylate (86.6 g, 268 mmol) and methyltriphenylphosphonium bromide (50 g, 243.5 mmol) were dissolved in tetrahydrofuran (500 mL), and potassium tert-butoxide (40.9 g, 365.5 mmol) was added, and the mixture was stirred overnight at 25° C. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 1E.
  • Step 6 Preparation of 1-benzyl 1'-(tert-butyl) 2H,2'H-[3,3'-diazetidinylidene]-1,1'(4H,4'H)-dicarboxylate (Compound 1F)
  • Step 7 Preparation of benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 1G)
  • Step 8 Preparation of benzyl 1'-((2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 1H)
  • Step 9 Preparation of 7-((1',4'-dihydro-2H,2'-H-[3,3'-diazetidinylidene]-1(4H)-ylsulfonyl)-2,3-dihydro-[1,4]dioxo[2.3-b]pyridine) (Compound 1I)
  • Step 10 Preparation of (S)-3-((tert-butyldiphenylsilyl)oxy)-1-(1'-((2,3-dihydro-[1,4]dioxo[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)
  • Step 11 Preparation of (S)-1-(1'-((2,3-dihydro-[1,4]dioxo[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)
  • step 8 of Example 1 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 2 of Example 2.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 3 of Example 3.
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 4 of Example 4.
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with p-methoxybenzenesulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 5 of Example 5.
  • Step 2 Preparation of benzyl 1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 6B)
  • Step 3 Preparation of 1-((4-(difluoromethoxy)phenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazetidine (Compound 6C)
  • 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)
  • 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)
  • step 4 of Example 6 (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 7 of Example 7.
  • 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-phenylethane-1-one (Compound 8):
  • step 4 of Example 6 2-hydroxy-2-phenylacetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid and the same preparation method as Example 6 was used to obtain Compound 8 of Example 8.
  • step 8 of Example 1 4-(trifluoromethoxy)benzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 9 of Example 9.
  • step 8 of Example 1 4-fluorobenzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 10 of Example 10.
  • step 8 of Example 1 3-fluoro-4-difluoromethoxybenzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 11 of Example 11.
  • 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-phenylpropane-1-one (Compound 12):
  • 6-Bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester 500 mg, 1.59 mmol
  • benzyl mercaptan 236.8 mg, 1.91 mmol
  • 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene 92 mg, 0.16 mmol
  • tris(dibenzylideneacetone)dipalladium 73 mg, 0.07 mmol
  • N,N-diisopropylethylamine (617 mg, 4.77 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction system was stirred at 40 ° C for 16 hours.
  • reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate (40 mL*3), and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After the organic phase was concentrated to dryness under reduced pressure, the residue was separated and purified by silica gel column to obtain compound 12C.
  • step 8 of Example 1 6-(chlorosulfonyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 12 of Example 12.
  • 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-hydroxyethane-1-one (Compound 13):
  • Step 1 Preparation of tert-butyl 6-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 13A)
  • 6-Bromo-2H-benzo[b][1,4]oxazine-4(3H)-carboxylic acid tert-butyl ester 500mg, 1.59mmol was added to dry tetrahydrofuran (10mL), the reaction system was replaced with nitrogen three times and then the nitrogen system was maintained, the temperature was lowered to -78°C, and n-butyl lithium (122mg, 1.91mmol) was slowly added dropwise under stirring, and the mixture was stirred at -78°C for 0.5 hours after completion, and diethyl oxalate (256mg, 1.75mmol) was added dropwise to the reaction solution, and the mixture was heated to room temperature and stirred for 1 hour after the addition was completed.
  • reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate (40mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness and separated and purified by silica gel column to obtain compound 13A.
  • 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)
  • Step 3 Preparation of 2-(4-(tert-Butyloxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-hydroxyacetic acid (Compound 13C)
  • 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (170 mg, crude product) and lithium hydroxide hydrate (106 mg, 2.52 mmol) were added to a mixed solution of tetrahydrofuran (3 mL) and water (3 mL) and stirred at room temperature for 16 hours.
  • reaction solution was adjusted to pH 4-5 with 2N hydrochloric acid solution under an ice bath, diluted with water and extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 13C.
  • step 4 of Example 6 2-(4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-hydroxyacetic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 13 of Example 13.
  • 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):
  • step 4 of Example 6 4-phenyltetrahydro-2H-pyran-4-carboxylic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 14 of Example 14.
  • 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)propane-1-one (Compound 15):
  • Methyl 2-(3-methoxyphenyl)acrylate (2.02 g, 10.5 mmol) was added to a solution of methylamine in tetrahydrofuran (20.0 mL) and reacted at room temperature for 4 hours.
  • Compound 15C was obtained by separation and purification on a silica gel column.
  • Step 3 Preparation of methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoate (Compound 15D)
  • Step 4 Preparation of 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoic acid (Compound 15E)
  • step 8 of Example 1 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 15 of Example 15.
  • 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-hydroxypropane-1-one (Compound 16):
  • step 4 of Example 6 2-(4-fluorophenyl)-3-hydroxypropionic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as Example 6 was used to obtain Compound 16 of Example 16.
  • 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-phenylbutane-1-one (Compound 17):
  • step 4 of Example 6 3-hydroxy-3-methyl-2-phenylbutyric acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as Example 6 was used to obtain Compound 17 of Example 17.
  • 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-hydroxypropane-1-one (Compound 18):
  • step 10 of Example 1 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 1 was used to obtain Compound 18 of Example 15.
  • 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-hydroxypropane-1-one (Compound 19):
  • step 10 of Example 1 2-(4-fluorophenyl)-3-hydroxypropionic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as Example 6 was used to obtain Compound 19 of Example 19.
  • step 8 of Example 1 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 20 of Example 20.
  • 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):
  • step 4 of Example 6 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 21 of Example 21.
  • 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):
  • step 4 of Example 6 2-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)acetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 22 of Example 22.
  • 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):
  • step 4 of Example 6 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)acetic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 23 of Example 23.
  • 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)ethane-1-one (Compound 24):
  • oxalyl chloride 70 mg, 551.50 ⁇ mol was slowly added dropwise to a solution of dimethyl sulfoxide (65 mg, 831.91 ⁇ mol) in dichloromethane (3 mL), and the resulting mixture was stirred at -78 ° C under nitrogen protection for 0.5 hours.
  • step 4 of Example 6 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 24 of Example 24.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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, and the same preparation method as in Example 1 was used to obtain compound 25 of Example 25.
  • 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):
  • step 10 of Example 1 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chlorophenyl)propanoic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 26 of Example 26.
  • step 8 of Example 1 3-fluoro-4-(oxazol-2-yl)benzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 27 of Example 27.
  • 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):
  • 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 solution was stirred at 60° C. for 1 hour. After the reaction was complete, the compound 28C was obtained by separation and purification on a silica gel column.
  • 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 the reaction was complete, the compound was separated and purified by silica gel column to obtain compound 28D.
  • Step 4 Preparation of methyl 3-(tert-butyloxycarbonyl)(methyl)amino)-2-(4-fluoro-2-methoxyphenyl)propanoate (Compound 28E):
  • Methyl 2-(4-fluoro-2-methoxyphenyl)-3-(methylamino)propanoate (406 mg, 1.68 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of triethylamine (340 mg, 3.37 mmol), the reaction system was cooled to 0°C, di-tert-butyl dicarbonate (440 mg, 2.02 mmol) was slowly added to the system, and the reaction solution was stirred at room temperature for 16 hours.
  • Step 5 Preparation of methyl 3-(tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propanoate (Compound 28F):
  • Step 6 Preparation of 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propanoic acid (Compound 28G):
  • step 8 of Example 1 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 28 of Example 28.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 29 of Example 29.
  • step 8 of Example 1 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, (S)-2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 30 of Example 30.
  • step 8 of Example 1 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, (R)-2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 31 of Example 31.
  • 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):
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(naphthalen-2-yl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 32 of Example 32.
  • 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):
  • 2-(3-bromophenyl)acetic acid methyl ester (5.0g, 21.83mmol), 1-methylpiperazine (3.3g, 32.74mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.3g, 2.18mmol) and cesium carbonate (10.7g, 32.74mmol) were dissolved in toluene (100.0mL), and then tri(dibenzylideneacetone)dipalladium (399.8mg, 0.44mmol) was added. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and heated to 110°C and stirred for 16 hours.
  • Methyl 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propanoate 90.0 mg, 0.32 mmol was dissolved in methanol (2.5 mL) and water (2.5 mL), followed by the addition of sodium hydroxide (25.9 mg, 0.64 mmol), and the reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, and then concentrated and used directly in the next step.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 33 of Example 33.
  • 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):
  • 2-(4-bromophenyl)acetic acid methyl ester (1.0g, 4.37mmol), (1-methyl-1H-pyrazol-4-yl)boric acid (604.7mg, 4.80mmol) and potassium carbonate (1.2g, 8.74mmol) were dissolved in a mixed solution of dioxane and water (4:1, 20.0mL), and then tetrakis(triphenylphosphine)palladium (504.5mg, 0.44mmol) was added. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and heated to 80°C and stirred for 16 hours.
  • Methyl 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoate (200.0 mg, 0.77 mmol) was dissolved in a mixed solution of methanol (6.0 mL) and water (4.0 mL), followed by the addition of sodium hydroxide (61.5 mg, 1.54 mmol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, and then concentrated and used directly in the next step.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 34 of Example 34.
  • 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
  • N,N-diisopropylethylamine 3.4 g, 26.30 mmol
  • 1,4-dioxane 50.0 mL
  • tris(dibenzylideneacetone)dipalladium 401.4 mg, 0.44 mmol
  • 6-(Benzylthio)-2-methylbenzo[d]thiazole (1.0 g, 3.68 mmol) was dissolved in a mixed solution of acetonitrile (40.0 mL), acetic acid (1.5 mL) and water (1.0 mL), and then dichlorobenzene (1.5 g, 7.37 mmol) was added to the reaction system at 0°C.
  • the reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate.
  • Compound 35C was obtained by separation and purification on a silica gel column.
  • step 8 of Example 1 2-methylbenzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 35 of Example 35.
  • 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-hydroxypropane-1-one (Compound 36):
  • 2,2-Difluoro-5-phenylthio-1,3-benzodioxolane (270 mg, 963.29 ⁇ mol) was dissolved in acetonitrile (20 mL), acetic acid (0.75 mL) and water (0.5 mL), and 5-dimethyl-imidazolidine-2,4-dione (380 mg, 1.93 mmol) was added at 0°C. After the addition, the reaction system was placed in a nitrogen atmosphere and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated and the pH value was adjusted to 6-7 with a saturated sodium bicarbonate aqueous solution.
  • aqueous phase was extracted with ethyl acetate (30.0 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Compound 36C was obtained by separation and purification on a silica gel column.
  • step 8 of Example 1 2,2-difluorobenzo[d][1,3]dioxolane-5-sulfonyl chloride was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 36 of Example 36.
  • 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):
  • Aryl magnesium 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 nitrogen atmosphere for 2 hours.
  • Compound 37B was obtained by separation and purification on a silica gel column.
  • step 4 of Example 6 3-phenyltetrahydrofuran-3-carboxylic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 37 of Example 37.
  • 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):
  • Methyl 2-(3-chloro-4-fluorophenyl)acrylate (395.0 mg, 1.84 mmol) was dissolved in a tetrahydrofuran solution of methylamine (8.0 mL). The reaction solution was reacted at room temperature for 16 hours. After the reaction was complete, the compound 38C was separated and purified by silica gel column.
  • Step 3 Preparation of methyl 3-(tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propanoate (Compound 38D)
  • Step 4 Preparation of 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propanoic acid (Compound 38E)
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propanoic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 38 of Example 38.
  • 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):
  • step 8 of Example 1 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 39 of Example 39.
  • step 8 of Example 1 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 40 of Example 40.
  • step 8 of Example 1 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 41 of Example 41.
  • 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):
  • Step 2 Preparation of ethyl 2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propanoate (Compound 42C)
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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, and the same preparation method as in Example 1 was used to obtain compound 42 of Example 42.
  • 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):
  • 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 1 drop of 1N tetrabutylammonium fluoride tetrahydrofuran solution was added. After the reaction solution was stirred at room temperature for 1 hour, the solvent was removed by rotary evaporation under reduced pressure. 6N hydrochloric acid aqueous solution (10 mL) was added to the residual oil and heated to reflux for 3 hours. The reaction mixture was cooled to 0 ° C and 10N sodium hydroxide solution was added dropwise to adjust the pH to 1.
  • Step 4 Preparation of methyl 2-((tert-butyldiphenylsilyl)oxy)-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (Compound 43E)
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 43 of Example 43.
  • 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):
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 44 of Example 44.
  • 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):
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(p-tolyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 45 of Example 45.
  • 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-hydroxypropane-1-one (Compound 46):
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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, and the same preparation method as in Example 1 was used to obtain compound 46 of Example 46.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, phenylacetic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 47 of Example 47.
  • 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):
  • aqueous phase was extracted with ethyl acetate (10.0 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Compound 48C was obtained by separation and purification on a silica gel column.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(pyridin-3-yl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 48 of Example 48.
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-6-sulfonyl chloride (the synthesis method is the same as that of Example 20D) is used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as that of Example 1 is used to obtain compound 49 of Example 49.
  • Methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (1.5 g, 7.47 mmol) was dissolved in a mixed solution of methanol (15.0 mL) and water (10.0 mL), and then sodium hydroxide (597.4 mg, 14.94 mmol) was added. The reaction solution was reacted at 50°C for 3 hours. TLC showed that the reaction was complete, and the pH of the reaction solution was adjusted to acidic with 1N hydrochloric acid.
  • aqueous phase was extracted with ethyl acetate (20 mL*3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and separated and purified by silica gel column to obtain compound 50C.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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.
  • the same preparation method as in Example 1 was used and chiral separation was performed to obtain compound 50 of Example 50.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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.
  • the same preparation method as in Example 1 was used and chiral separation was performed to obtain compound 51 of Example 51.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 52 of Example 52.
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 53 of Example 53.
  • 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):
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(4-fluorophenyl)-3-hydroxypropanoic acid.
  • the same preparation method as in Example 1 was used followed by chiral separation to give compound 54 of Example 54.
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(4-fluorophenyl)-3-hydroxypropanoic acid.
  • the same preparation method as in Example 1 was used followed by chiral separation to give Compound 55 of Example 55.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 56 of Example 56.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(p-tolyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 57 of Example 57.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 58 of Example 58.
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-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, and the same preparation method as in Example 1 was used to obtain compound 59 of Example 59.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(pyridin-3-yl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 60 of Example 60.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(3,4-difluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 61 of Example 61.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-3-methyl-2-phenylbutyric acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 62 of Example 62.
  • 6-Bromo-1-methyl-1H-benzo[d]imidazole (1 g, 4.74 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (588 mg, 4.74 mmol), DIPEA (1.22 g, 9.48 mmol), Pd 2 (dba) 3 CHCl 3 (485 mg, 0.47 mmol) and xantphos (548 mg, 0.95 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80°C and stirred for 16 hours. After the reaction was complete, the compound 63B was obtained by separation and purification by silica gel column.
  • 6-(Benzylthio)-1-methyl-1H-benzo[d]imidazole (560 mg, 2.20 mmol) was dissolved in acetonitrile.
  • 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 then added in sequence. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 63C was obtained by separation and purification by silica gel column.
  • step 8 of Example 1 1-methyl-1H-benzo[d]imidazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 63 of Example 63.
  • step 8 of Example 1 benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 64 of Example 64.
  • step 8 of Example 1 4-cyanobenzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 65 of Example 65.
  • 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-phenylpropane-1-one (Compound 66):
  • step 8 of Example 1 5-chloropyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 66 of Example 66.
  • step 8 of Example 1 5-methoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 67 of Example 67.
  • step 8 of Example 1 pyridine-3-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 68 of Example 68.
  • step 8 of Example 1 quinoline-8-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 69 of Example 69.
  • step 8 of Example 1 5-cyanopyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 70 of Example 70.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-(difluoromethyl)phenyl)-3-hydroxypropanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 71 of Example 71.
  • 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-phenylpropane-1-one (Compound 72):
  • step 8 of Example 1 5-ethoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 72 of Example 72.
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-fluoro-2-phenylpropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 73 of Example 73.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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 the same preparation method as in Example 1 was used to obtain compound 74 of Example 74.
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-chlorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 75 of Example 75.
  • 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):
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(3-chloro-4-fluorophenyl)-3-hydroxypropanoic acid.
  • the same preparation method as in Example 1 was used, followed by chiral separation to give Compound 76 of Example 76.
  • 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):
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(3-chloro-4-fluorophenyl)-3-hydroxypropanoic acid.
  • the same preparation method as in Example 1 was used, followed by chiral separation to give Compound 77 of Example 77.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-(trifluoromethyl)phenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 78 of Example 78.
  • Methyl 2-(4-fluoro-2-methoxyphenyl)acrylate (3.5 g, 19.3 mmol) was dissolved in ethyl acetate (100 mL) and water (100 mL), and then sodium carbonate (4.19 g, 38.6 mmol) and 2-chloroacetyl chloride (2.16 g, 19.3 mmol) were added, and the reaction solution was stirred at room temperature for 4 hours. After the reaction was complete, it was extracted with ethyl acetate (200 mL) for 3 times, and the organic phases were combined and separated and purified by silica gel column to obtain compound 79D.
  • Step 5 Preparation of tert-butyl 6-(2-methoxy-2-oxoethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 79F)
  • 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)
  • 6-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylic acid tert-butyl ester (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.
  • Step 7 Preparation of 2-(4-(tert-Butyloxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-hydroxypropanoic acid (Compound 79H)
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(4-(tert-butyloxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-hydroxypropanoic acid.
  • the same preparation method as in Example 1 was used to obtain Compound 79 of Example 79.
  • 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-phenylpropane-1-one (Compound 80):
  • step 8 of Example 1 5-(difluoromethoxy)pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 80 of Example 80.
  • step 8 of Example 1 5-isopropoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 81 of Example 81.
  • Example 82 Preparation of (S)-1-(1'-((5-cyclopropyloxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropane-1-one (Compound 82):
  • step 8 of Example 1 5-cyclopropyloxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 82 of Example 82.
  • 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):
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(2,4-difluorophenyl)-3-hydroxypropanoic acid.
  • the same preparation method as in Example 1 was used for separation and chiral separation to obtain compound 83 of Example 83.
  • 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):
  • step 8 of Example 1 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(2,4-difluorophenyl)-3-hydroxypropanoic acid.
  • the same preparation method as in Example 1 was used for separation and chiral separation to give compound 84 of Example 84.
  • 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):
  • step 8 of Example 1 pyridine-2-sulfonyl chloride is used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-cyanophenyl)-3-hydroxypropionic acid is used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the compound 85 of Example 85 is isolated using the same preparation method as in Example 1.
  • 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):

Abstract

The present disclosure relates to the technical field of medicine and health, and provides a use of a novel compound containing a diazepine sulfonyl structure as a PKM2 agonist. The compound can be used for treating related diseases mediated and regulated by PKM2, wherein the related diseases comprise, but not limited to, tumors, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom syndrome, pulmonary hypertension and the like. The specific diseases also relate to liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, kidney cancer, inflammatory bowel disease, ulcerative colitis, alopecia, atrichia, hypotrichosis and the like.

Description

含二氮杂亚基磺酰结构的化合物作为PKM2激动剂的新用途New use of compounds containing diazasulfonyl structure as PKM2 agonists 技术领域Technical Field
本发明属于医药技术领域，具体涉及一种含二氮杂亚基磺酰结构的化合物作为PKM2激动剂及治疗相关疾病的应用。The present invention belongs to the field of medical technology, and specifically relates to an application of a compound containing a diazasulfonyl structure as a PKM2 agonist and the treatment of related diseases.
背景技术Background Art
丙酮酸激酶(PK)是糖酵解过程中的限速酶之一。哺乳动物中有2个PK基因(PKM和PKLR)，通过对PKM基因mRNA的差异性剪接可编码PKM1和PKM2两种同工酶，PKM1主要存在于骨骼肌、心脏和大脑等组织中，PKM2主要存在于胚胎细胞、干细胞、肿瘤细胞以及脑、肝组织中；PKLR基因编码的PKL和PKR分别在肝脏和红细胞中特异性表达(Semin Cell Dev Biol；43:43-51(2015))。Pyruvate kinase (PK) is one of the rate-limiting enzymes in the glycolysis process. There are two PK genes (PKM and PKLR) in mammals. Differential splicing of PKM gene mRNA can encode two isozymes, PKM1 and PKM2. PKM1 is mainly present in tissues such as skeletal muscle, heart and brain, while PKM2 is mainly present in embryonic cells, stem cells, tumor cells, brain and liver tissues. PKL and PKR encoded by PKLR gene are specifically expressed in liver and red blood cells, respectively (Semin Cell Dev Biol; 43:43-51 (2015)).
PKM2参与调节多种生物过程，包括细胞增殖、分化、炎症、信号传导，以及代谢酶途径，同时也参与蛋白质合成和相互作用，是转录调节剂和蛋白激酶。其定位于细胞质、细胞核和线粒体，可聚集成四聚体和二聚体形式，虽然由同一单体组成，但四聚体与二聚体之间的生物学效应有显著差异。研究表明，二聚体和四聚体之间的转化在细胞增殖、肿瘤细胞能量供应、上皮间质转化、信号传导等方面发挥重要作用。在细胞质中，二聚体PKM2的低活性导致糖酵解途径中代谢物的积累，从而促进细胞增殖所需的代谢物生物合成，如癌细胞。此外，二聚体状态下的PKM2可进入细胞核与其他转录因子一起调控基因的转录和表达。四聚体PKM2在细胞质中发挥其代谢酶功能，主要起丙酮酸激酶作用，调节糖酵解。在生理葡萄糖浓度下，30％-35％的PKM2为单体，其余大部分为高活性四聚体形式(J Cell Physiol,237(1),128-148(2022))。当PKM2处于四聚体状态时，它与底物磷酸烯醇式丙酮酸酯(PEP)具有较高的亲和力，并且具有较高的PK酶活性，催化磷酸烯醇式丙酮酸酯(PEP)产生丙酮酸，将ADP磷酸化成ATP。PKM2 is involved in regulating a variety of biological processes, including cell proliferation, differentiation, inflammation, signal transduction, and metabolic enzyme pathways. It is also involved in protein synthesis and interaction and is a transcriptional regulator and protein kinase. It is located in the cytoplasm, nucleus, and mitochondria and can aggregate into tetramers and dimers. Although composed of the same monomer, there are significant differences in the biological effects between tetramers and dimers. Studies have shown that the conversion between dimers and tetramers plays an important role in cell proliferation, energy supply of tumor cells, epithelial-mesenchymal transition, and signal transduction. In the cytoplasm, the low activity of dimeric PKM2 leads to the accumulation of metabolites in the glycolysis pathway, thereby promoting the biosynthesis of metabolites required for cell proliferation, such as cancer cells. In addition, PKM2 in the dimeric state can enter the nucleus and regulate gene transcription and expression together with other transcription factors. Tetrameric PKM2 exerts its metabolic enzyme function in the cytoplasm, mainly acting as pyruvate kinase to regulate glycolysis. Under physiological glucose concentrations, 30%-35% of PKM2 is a monomer, and most of the rest is a highly active tetramer (J Cell Physiol, 237(1), 128-148(2022)). When PKM2 is in a tetramer state, it has a higher affinity with the substrate phosphoenolpyruvate (PEP) and has higher PK enzyme activity, catalyzing phosphoenolpyruvate (PEP) to produce pyruvate and phosphorylating ADP into ATP.
目前对PKM2的研究主要集中在肿瘤，免疫及毛发再生等方面。Currently, research on PKM2 mainly focuses on tumors, immunity and hair regeneration.
在肿瘤细胞代谢中，PKM2二聚体的增加可以促进乳酸生成，导致上游糖酵解代谢物的积累，促进大分子生物合成并抑制细胞内活性氧(ROS)的产生。PKM2还可易位到细胞核中以刺激包括HIF-1、HIF-2、β-连环蛋白、STAT3和Oct-4在内的转录因子的活性，从而增加肿瘤生长所需的基因产物的表达(Trends Endocrin Met,23,11:560-566(2012))。而PKM2激动剂可通过促进PKM2四聚体的形成，减少PKM2向核内的转移，干扰细胞合成代谢进而抑制肿瘤生长(Nat Chem Biol,8(10),839-847(2012))。靶向糖酵解酶PKM2，是治疗乳腺癌、淋巴瘤、胰腺癌的一种潜在疗法。In tumor cell metabolism, the increase of PKM2 dimers can promote lactate production, leading to the accumulation of upstream glycolytic metabolites, promoting macromolecular biosynthesis and inhibiting the production of intracellular reactive oxygen species (ROS). PKM2 can also translocate to the nucleus to stimulate the activity of transcription factors including HIF-1, HIF-2, β-catenin, STAT3 and Oct-4, thereby increasing the expression of gene products required for tumor growth (Trends Endocrin Met, 23, 11: 560-566 (2012)). PKM2 agonists can promote the formation of PKM2 tetramers, reduce the transfer of PKM2 to the nucleus, interfere with cell anabolism and inhibit tumor growth (Nat Chem Biol, 8 (10), 839-847 (2012)). Targeting the glycolytic enzyme PKM2 is a potential therapy for the treatment of breast cancer, lymphoma and pancreatic cancer.
当前在研的小分子PKM2激动剂如DNX-3000、ACT001、TP-1454等。DNX-3000由Dynamix Pharmaceuticals Ltd开发，其数据显示：DNX-3000与天然PKM2激活剂FBP具有相似的AC50值、活化和酶反应动力学，DNX-3000呈剂量依赖的降低80％的各种癌细胞系增殖率，包括肝癌、肺癌和结直肠癌，其与化疗药物(如HT29结直肠癌细胞中的5-氟尿嘧啶)联合使用，对癌细胞增殖具有累加效应，导致细胞生长的抑制率可达100％。ACT001由南开大学开发，其数据显示：ACT001显著抑制了U118等GBM(多形性胶质母细胞瘤)细胞的增殖和转移，并诱导其凋亡，作用于小鼠模型试验抑制了肿瘤生长并降低了肿瘤重量。TP-1454由Tolero Pharmaceuticals Inc开发，其数据显示：在结直肠癌模型中，TP-1454和抗PD-1联合治疗导致肿瘤生长抑制。在结直肠癌、乳腺癌和肾癌细胞模型中，TP-1454治疗减少了种群量。Small molecule PKM2 agonists currently under development include DNX-3000, ACT001, and TP-1454. DNX-3000 was developed by Dynamix Pharmaceuticals Ltd. Its data showed that DNX-3000 had similar AC50 values, activation, and enzyme reaction kinetics to the natural PKM2 activator FBP. DNX-3000 reduced the proliferation rate of various cancer cell lines by 80% in a dose-dependent manner, including liver cancer, lung cancer, and colorectal cancer. Its combination with chemotherapy drugs (such as 5-fluorouracil in HT29 colorectal cancer cells) had an additive effect on cancer cell proliferation, resulting in a 100% inhibition of cell growth. ACT001 was developed by Nankai University. Its data showed that ACT001 significantly inhibited the proliferation and metastasis of GBM (glioblastoma multiforme) cells such as U118, and induced their apoptosis. It inhibited tumor growth and reduced tumor weight in mouse model experiments. TP-1454 was developed by Tolero Pharmaceuticals Inc., and data showed that in a colorectal cancer model, combination therapy with TP-1454 and anti-PD-1 resulted in tumor growth inhibition. In colorectal, breast, and renal cancer cell models, TP-1454 treatment reduced population size.
在免疫系统中，T细胞受体(TCR)激活后，PKM2的表达上调(Cell metab,20(1),61-72(2014))。CD4+ T细胞根据细胞外因素和环境信号分化为多种T辅助(Th)细胞，包括Th17细胞和调节性T细胞(Tregs)。在辅助性T细胞亚群中，PKM2在促炎症T细胞亚群分化中作用于STAT家族，具有多方面的调节功能：调控STAT1/STAT4诱导Th1形成，参与细胞免疫；调控STAT6和STAT3的磷酸化，分别调控Th2和Th17细胞的分化，参与炎症相关疾病；调节STAT5与TGF-β结合，诱导Tregs形成并维持免疫耐受(Front Immunol,13,936967(2022)，J Exp Med,217(10),e20190613(2020))。有报道表明，小分子化合物TEPP-46、倍半萜内酯衍生物等PKM2激动剂，可通过促进PKM2四聚化和抑制PKM2核易位影响T细胞活化，抑制Th17和Th1细胞的分化，在体内抑制T细胞介导的炎症，改善如溃疡性结肠炎在内的炎症性肠病(J.Med.Chem.2023,66,8,5500–5523)(步楠,李姗姗等.溃疡性结肠炎肠黏膜内PKM2表达的变化及临床意义.重庆医学,2022,51(8),1315-1319)、实验性自身免疫性脑脊髓炎等疾病(Cell metab,31(2),391-405(2020))。因此，以PKM2为靶点，通过调节T细胞功能，是炎症和自身免疫性疾病的潜在治疗策略。In the immune system, PKM2 expression is upregulated after T cell receptor (TCR) activation (Cell Metab, 20(1), 61-72(2014)). CD4+ T cells differentiate into a variety of T helper (Th) cells, including Th17 cells and regulatory T cells (Tregs), according to extracellular factors and environmental signals. Among the helper T cell subsets, PKM2 acts on the STAT family in the differentiation of pro-inflammatory T cell subsets and has multiple regulatory functions: regulating STAT1/STAT4 to induce Th1 formation and participate in cellular immunity; regulating the phosphorylation of STAT6 and STAT3, regulating the differentiation of Th2 and Th17 cells, respectively, and participating in inflammatory-related diseases; regulating STAT5 binding to TGF-β, inducing Tregs formation and maintaining immune tolerance (Front Immunol, 13, 936967(2022), J Exp Med, 217(10), e20190613(2020)). It has been reported that PKM2 agonists such as small molecule compounds TEPP-46 and sesquiterpene lactone derivatives can affect T cell activation by promoting PKM2 tetramerization and inhibiting PKM2 nuclear translocation, inhibiting the differentiation of Th17 and Th1 cells, inhibiting T cell-mediated inflammation in vivo, and improving inflammatory bowel diseases such as ulcerative colitis (J. Med. Chem. 2023, 66, 8, 5500–5523) (Bu Nan, Li Shanshan, et al. Changes in PKM2 expression in the intestinal mucosa of ulcerative colitis and its clinical significance. Chongqing Medicine, 2022, 51(8), 1315-1319), experimental autoimmune encephalomyelitis and other diseases (Cell Metab, 31(2), 391-405(2020)). Therefore, targeting PKM2 and regulating T cell function is a potential therapeutic strategy for inflammatory and autoimmune diseases.
包括WO2010118063A、WO2011002817A、WO2014074848A、WO2014139325A、WO2014139144A、CN104817490B、CN111170991A、WO2019035863A等在内的专利申请中也披露了一系列的作为PKM2激动剂的小分子化合物，结合其临床及临床前活性数据，这些小分子化合物在治疗PKM2所调节介导的肿瘤、自身免疫性疾病、代谢性疾病、增殖依赖性疾病、冠状动脉疾病、布鲁姆综合征、肺动脉高压等中具有潜在的医疗价值。Patent applications including WO2010118063A, WO2011002817A, WO2014074848A, WO2014139325A, WO2014139144A, CN104817490B, CN111170991A, WO2019035863A, etc. also disclose a series of small molecule compounds as PKM2 agonists. Combined with their clinical and preclinical activity data, these small molecule compounds have potential medical value in the treatment of PKM2-mediated tumors, autoimmune diseases, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc.
在毛发再生中，毛囊干细胞(HFSCs)是参与毛发再生的重要细胞。在毛囊从休止期到生长期之间，HFSCs接收到来自真皮乳头细胞的毛发生长信号后进行增殖，并分化形成毛囊的多种细胞。脱发主要是由HFSC活性和毛囊再生能力下降引起的。HFSCs的激活和再生需要糖酵解途径参与，同时Wnt/β-catenin信号通路有助于毛囊形态发生、维持和毛发生长发育诱导。在HFSCs生长期可观察到PKM2表达增加和Wnt/β-catenin信号通路的激活。TEPP-46作为PKM2激动剂可通过上调Wnt/β-catenin信号通路激活PKM2促进毛发再生和增殖(Pharmaceutics,14,12:2774(2022))。PKM2和Wnt/β-catenin信号通路的双重激活可能是脱发患者潜在的治疗策略。In hair regeneration, hair follicle stem cells (HFSCs) are important cells involved in hair regeneration. Between the resting phase and the growing phase of hair follicles, HFSCs proliferate after receiving hair growth signals from dermal papilla cells, and differentiate into various cells of hair follicles. Hair loss is mainly caused by the decrease in HFSC activity and hair follicle regeneration ability. The activation and regeneration of HFSCs require the participation of the glycolytic pathway, while the Wnt/β-catenin signaling pathway contributes to the morphogenesis, maintenance and induction of hair follicle growth and development. Increased PKM2 expression and activation of the Wnt/β-catenin signaling pathway can be observed in the growth phase of HFSCs. TEPP-46, as a PKM2 agonist, can promote hair regeneration and proliferation by upregulating the Wnt/β-catenin signaling pathway and activating PKM2 (Pharmaceutics, 14, 12: 2774 (2022)). Dual activation of PKM2 and Wnt/β-catenin signaling pathways may be a potential therapeutic strategy for patients with hair loss.
发明内容Summary of the invention
本发明的申请人在先的国际申请PCT/CN2022/140731(国际申请日2022年12月21日)中提供了一种新颖的含二氮杂亚基磺酰结构的化合物。该申请中所提供的新颖化合物作为PKR激动剂或USP9X抑制剂具有优异的活性，其可用于治疗PKR和USP9X介导调节的贫血、肿瘤等相关疾病。该在先的国际申请PCT/CN2022/140731的全部内容在此引入本发明中，作为本发明的一部分。The applicant of the present invention provides a novel compound containing a diazainyl sulfonyl structure in the prior international application PCT/CN2022/140731 (international application date December 21, 2022). The novel compound provided in the application has excellent activity as a PKR agonist or USP9X inhibitor, which can be used to treat anemia, tumors and other related diseases mediated by PKR and USP9X. The entire content of the prior international application PCT/CN2022/140731 is hereby introduced into the present invention as a part of the present invention.
在PCT/CN2022/140731的基础上，本发明人进一步研究发现，其中所提供的新颖化合物还是PKM2激动剂，其在体外酶学活性实验中显示了对PKM2较好的激动活性，这种激动活性进一步表现在细胞层面，在人脑星形胶质母细胞瘤细胞(U118-MG)中依旧保持了良好的PKM2激动活性。此外，如在小鼠毛发生长实验中所证实的，这些化合物还对毛发生长具有明显的促进作用。On the basis of PCT/CN2022/140731, the inventors further discovered that the novel compounds provided therein are also PKM2 agonists, which show good PKM2 agonist activity in in vitro enzymatic activity experiments. This agonist activity is further manifested at the cellular level, and still maintains good PKM2 agonist activity in human brain astroglioma cells (U118-MG). In addition, as confirmed in the mouse hair growth experiment, these compounds also have a significant promoting effect on hair growth.
虽然在先的国际申请PCT/CN2022/140731已通过引述方式将全部内容纳入本发明，但出于更清楚完整的角度考虑，本发明中还通过下文结构描述以及后文具体实施例制备和表征对所述新颖化合物进行详细记载。所述国际申请PCT/CN2022/140731中所记载的通式化合物以及具体实施例的化合物在本申请中被称为“本发明的化合物”。Although the prior international application PCT/CN2022/140731 has been incorporated into the present invention in its entirety by reference, for the sake of clarity and completeness, the present invention also describes the novel compound in detail through the following structural description and the preparation and characterization of the specific examples below. The general formula compounds and the compounds of the specific examples described in the international application PCT/CN2022/140731 are referred to as "compounds of the present invention" in this application.
第一方面，本发明提供了本发明化合物作为PKM2激动剂的用途。In a first aspect, the present invention provides use of a compound of the present invention as a PKM2 agonist.
第二方面，本发明提供了用作PKM2激动剂的本发明化合物。特别地，本发明提供了用于治疗PKM2介导调节的相关疾病的本发明化合物。 In a second aspect, the present invention provides compounds of the present invention for use as PKM2 agonists. In particular, the present invention provides compounds of the present invention for use in treating diseases related to PKM2-mediated regulation.
特别地，本发明提供了用于治疗选自肿瘤、免疫性疾病、毛发缺失、代谢性疾病、增殖依赖性疾病、冠状动脉疾病、布鲁姆综合征、肺动脉高压等的疾病的本发明化合物；优选地，所述疾病选自肝癌、肺癌、结直肠癌、胶质母细胞瘤、乳腺癌、肾癌、炎症性肠病、溃疡性结肠炎、脱发、无毛症、少毛症等。In particular, the present invention provides compounds of the present invention for use in treating diseases selected from tumors, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc.; preferably, the disease is selected from liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, kidney cancer, inflammatory bowel disease, ulcerative colitis, alopecia, alopecia, hypotrichosis, etc.
第三方面，本发明提供了本发明化合物在制备用于治疗PKM2介导调节的相关疾病的药物中的用途。In a third aspect, the present invention provides use of the compound of the present invention in the preparation of a medicament for treating diseases related to PKM2-mediated regulation.
特别地，本发明提供了本发明化合物在制备用于治疗可通过促进PKM2四聚体的生成、减少PKM2二聚体的产生、靶向PKM2影响糖酵解酶、或者阻止PKM2进入细胞核等发挥治疗作用的疾病的药物中的用途。In particular, the present invention provides the use of the compounds of the present invention in the preparation of drugs for treating diseases that can exert therapeutic effects by promoting the generation of PKM2 tetramers, reducing the generation of PKM2 dimers, targeting PKM2 to affect glycolytic enzymes, or preventing PKM2 from entering the cell nucleus.
特别地，本发明提供了本发明化合物在制备用于治疗选自肿瘤、免疫性疾病、毛发缺失、代谢性疾病、增殖依赖性疾病、冠状动脉疾病、布鲁姆综合征、肺动脉高压等的疾病的药物中的用途；优选地，所述疾病选自肝癌、肺癌、结直肠癌、胶质母细胞瘤、乳腺癌、肾癌、炎症性肠病、溃疡性结肠炎、脱发、无毛症、少毛症等。In particular, the present invention provides the use of the compounds of the present invention in the preparation of a medicament for treating a disease selected from tumors, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc.; preferably, the disease is selected from liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, kidney cancer, inflammatory bowel disease, ulcerative colitis, alopecia, alopecia, hypotrichosis, etc.
第四方面，本发明提供了治疗PKM2介导调节的相关疾病的方法，所述方法包括向有需要的个体施用治疗有效量的本发明化合物。In a fourth aspect, the present invention provides a method for treating a disease related to PKM2-mediated regulation, the method comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof.
特别地，本发明提供了治疗可通过促进PKM2四聚体的生成、减少PKM2二聚体的产生、靶向PKM2影响糖酵解酶、或者阻止PKM2进入细胞核等发挥治疗作用的疾病的方法，所述方法包括向有需要的个体施用治疗有效量的本发明化合物。In particular, the present invention provides a method for treating diseases that can be treated by promoting the formation of PKM2 tetramers, reducing the production of PKM2 dimers, targeting PKM2 to affect glycolytic enzymes, or preventing PKM2 from entering the cell nucleus, the method comprising administering a therapeutically effective amount of a compound of the present invention to an individual in need thereof.
特别地，可通过本发明的方法治疗的疾病包括肿瘤、炎症、免疫性疾病、毛发缺失、代谢性疾病、增殖依赖性疾病、冠状动脉疾病、布鲁姆综合征、肺动脉高压等，例如肝癌、肺癌、结直肠癌、胶质母细胞瘤、乳腺癌、淋巴瘤、胰腺癌、肾癌、炎症性肠病、溃疡性结肠炎、脱发、无毛症和少毛症等。In particular, diseases that can be treated by the method of the present invention include tumors, inflammation, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome, pulmonary hypertension, etc., such as liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, lymphoma, pancreatic cancer, renal cancer, inflammatory bowel disease, ulcerative colitis, hair loss, alopecia and hypotrichosis, etc.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1显示了代表性的本发明化合物在体外条件下对小鼠毛囊生长的促进作用。其中，图1a)显示了不同处理组毛干生长情况；图1b)显示了不同处理组毛干长度柱状图(n＝15)。Figure 1 shows the promoting effect of a representative compound of the present invention on mouse hair follicle growth in vitro, wherein Figure 1a) shows the growth of hair shafts in different treatment groups; Figure 1b) shows a bar graph of hair shaft lengths in different treatment groups (n=15).
图2显示了代表性的本发明化合物对小鼠毛发生长的促进作用。其中，图2a)显示了给药4周后动物背部生长情况；图2b)显示了不同处理组新生毛发重量柱状图。Figure 2 shows the promoting effect of a representative compound of the present invention on hair growth in mice, wherein Figure 2a) shows the growth of the back of the animal after 4 weeks of administration; Figure 2b) shows a bar graph of the weight of new hair in different treatment groups.
发明详述：Detailed description of the invention:
在一个实施方案中，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的式Ⅰ的化合物或其异构体、药学上可接受盐或溶剂化物：
In one embodiment, the present invention provides a compound of formula I or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first, second, third and fourth aspects of the present invention:
其中：in:
R1、R2和R3独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb、-SRb、-NRcRd、 -S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf或-C(O)ORg，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-SRb、-NO2、-NRcRd、-S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf和-C(O)ORg；R 1 , R 2 and R 3 are 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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -OR b , -SR b , -NR c R d , -S(O) 2R e , -S(O) 2NR 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 , or -C(O)OR g , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from: =O, halogen, -CN, -R a , -OR b , -SR b , -NO 2 , -NR c R d , -S(O)2R e, -S(O)2NR 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 , or -C(O)OR g , wherein each alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from: =O, halogen, -CN , -R a , -OR b , -SR b , -NO 2 , -NR c R d , -S(O)2R e, -S(O)2NR 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 f and -C(O)OR g ;
或者，R1和R2、R1和R3或者R2和R3连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、-(C5-C8)螺环基、含有1-4个独立地选自O、N和S的杂原子的5至8元螺杂环基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基或含有1-4个独立地选自O、N和S的杂原子的5-14元的杂芳基；Alternatively, R1 and R2 , R1 and R3 , or R2 and R3, together with the atoms to which they are attached, may optionally combine to form -( C3 - C8 )cycloalkyl, 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, -( C5 - C8 )spirocyclyl, 5- to 8-membered spiroheterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, or 5-14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S;
R4为-NH2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb、-SRb、-NRcRd、-S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf、-C(O)ORg或-NRc(CRhRi)t-Ra，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-SRb、-NO2、-NRcRd、-S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf和-C(O)ORg； R4 is -NH2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S , -ORb , -SRb , -NRcRd , -S(O ) 2Re , -S(O) 2NRcRd , -S(O )Re , -S ( O ) NRcRd , -NRcS (O) 2Re -NRcS (O) Re , -C(O) Rf , -C(O) ORg , or -NRc ( CRhRi ) t - Ra , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from: =O, halogen, -CN, -R a , -ORb , -SRb , -NO2 , -NRcRd , -S( O ) 2Re , -S(O) 2NRcRd , -S (O) Re , -S (O)NRcRd, -NRcS(O)2Re, -NRcS(O)Re , -C ( O ) Rf , and -C(O) ORg ;
t为0、1、2或3；t is 0, 1, 2, or 3;
Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh和Ri在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-SH、-S(O)2H、-S(O)2NH2、-S(O)H、-S(O)NH2、-NHS(O)2H、-NHS(O)H、-C(O)H或-C(O)OH，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-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、-(C1-C6)烷基、-(C3-C8)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基，或者其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-S(O)2OH、-S(O)OH、-NHS(O)2OH或-NHS(O)OH；或者，Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh和Ri在每次出现时独立地为-S(O)2OH、-S(O)OH、-NHS(O)2OH或-NHS(O)OH； Ra , Rb , Rc , Rd , Re , Rf , Rg , Rh and Ri are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -SH, -S(O) 2H , -S(O) 2NH 2 , -S(O)H, -S(O) NH2 , -NHS(O) 2H , -NHS(O)H, -C(O)H, or -C(O)OH, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: =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, -( C1 - C6 )alkyl, -( C3 - C8) alkyl, ) cycloalkyl and 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, or wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: -S(O) 2OH , -S(O)OH, -NHS(O) 2OH or -NHS(O)OH; or, Ra , Rb, Rc , Rd , Re , Rf , Rg , Rh and Ri are independently -S(O) 2OH , -S(O)OH, -NHS(O) 2OH or -NHS(O)OH at each occurrence;
或者，在相邻原子上的任意两个选自Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh和Ri的基团连同它们所附接的原子任选的可结合形成任选地被一个或多个Ra取代的C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基。Alternatively, any two groups selected from Ra , Rb , Rc , Rd , Re , Rf , Rg, Rh and Ri on adjacent atoms together with the atoms to which they are attached may optionally combine to form a C6 - C14 aryl group optionally substituted with one or more Ra , a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, a ( C3 - C8 )cycloalkyl group, or a 3-14 membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S.
在一些实施方案中，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的上述式Ⅰ的特定异构体化合物，具有式Ⅰ-1或Ⅰ-2，
In some embodiments, the present invention provides a specific isomeric compound of the above formula I for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, having the formula I-1 or I-2,
在一些实施方案中，本发明所提供的前述式Ⅰ、式Ⅰ-1或Ⅰ-2所示的化合物中，R1和R2可独立的进一步作如下选择：In some embodiments, in the compounds of the aforementioned formula I, formula I-1 or I-2 provided by the present invention, R 1 and R 2 can be independently further selected as follows:
在一实施方案中，In one embodiment,
R1和R2独立的为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb或-NRcRd，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd； R1 and R2 are independently -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -ORb or -NRcRd , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: =0, halogen, -CN, -Ra , -ORb , -NO2 , -NRcRd ;
或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C8)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 -C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C6 -C6-alkyl, -( C2 - C6- alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, The invention also includes but is not limited to alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl is optionally substituted by one or more substituents selected from the group consisting of: =O, halogen, -CN, -OH, -NO2 , -NH2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl and a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S.
在另一实施方案中，In another embodiment,
R1和R2独立的为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb或-NRcRd，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd；R 1 and R 2 are 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, 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -OR b or -NR c R d , wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the following: =O, halogen, -CN, -R a , -OR b , -NO 2 , -NR c R d ;
或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C6)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C8 aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of =O, halogen, -CN, -OH, -NO2, -NH2, -(C1-C6)alkyl, -( C3 - C6) cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 -C8 aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S , or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S. )cycloalkyl and 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S.
在另一实施方案中，In another embodiment,
R1和R2独立的为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)直链烷基、-(C1-C6)支链烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元二环或三环稠合环基、-ORb或-NRcRd，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra、-ORb、-NRcRd； R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain 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 cyclic group containing 0-4 heteroatoms independently selected from O, N and S , -ORb or -NRcRd , wherein each alkyl, cycloalkyl, heterocyclyl, aryl , heteroaryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra, -ORb , -NRcRd ;
或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
Ra、Rb、Rc和Rd在每次出现时独立地为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基或含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-OH、-NO2、-NH2和-(C1-C6)烷基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C8 aryl, or a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
在另一实施方案中，In another embodiment,
R1和R2独立的为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)直链烷基、-(C1-C6)支链烷基、-(C3-C6)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra、-ORb、-NRcRd； R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain alkyl, -( C3 - C6 ) cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra, -ORb , -NRcRd ;
或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
Ra、Rb、Rc和Rd在每次出现时独立地为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-OH、-NO2、-NH2和-(C1-C6)烷基。 Ra , Rb , Rc and Rd are independently at each occurrence -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
在另一实施方案中，In another embodiment,
R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
R1为-H、-F、-Cl、-Br、-OH、-NH2、-(CH2)qCH3、-(CH2)qOH、-CH(OH)(CH2)qCH3、-C(OH)((CH2)qCH3)2、-(CH2)qNH2、-(CH2)qNH(CH2)qCH3、-(CH2)qN((CH2)qCH3)2、含有1个N原子的3-6元杂环烷基、被含有1个N原子的3-6元杂环烷基所取代的-(C1-C6)烷基；R 1 is -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 , -(CH 2 ) q NH 2 , -(CH 2 ) q NH(CH 2 ) q CH 3 , -(CH 2 ) q N((CH 2 ) q CH 3 ) 2 , 3- 6-membered heterocycloalkyl, -(C 1 -C 6 )alkyl substituted by a 3-6-membered heterocycloalkyl containing 1 N atom;
q在每次出现时独立的为0、1、2、3或4；q is 0, 1, 2, 3, or 4 independently at each occurrence;
或者，R1和R2连同它们所附接的原子任选的可结合以形成环丙烷环、环丁烷环、环戊烷环、环己烷环、四氢呋喃、四氢吡喃、吗啉、二噁烷或2,3-二氢苯并呋喃环；或者，R1和R2连同它们所附接的原子任选的可结合以形成环丙烷环、环丁烷环、环戊烷环、环己烷环、四氢呋喃、四氢吡喃、吗啉、二噁烷、2,3-二氢苯并呋喃环或四氢-2H-吡喃。Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, tetrahydrofuran, tetrahydropyran, morpholine, dioxane or 2,3-dihydrobenzofuran ring; Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine 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.
在另一实施方案中，In another embodiment,
R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
R1为-H、-F、-Cl、-Br、-OH、-NH2、 R 1 is -H, -F, -Cl, -Br, -OH, -NH 2 ,
或者，R1和R2连同它们所附接的原子任选的可结合以形成或者，R1和R2连同它们所附接的原子任选的可结合以形成 Alternatively, R1 and R2 together with the atoms to which they are attached may optionally be combined to form Alternatively, R1 and R2 together with the atoms to which they are attached may optionally be combined to form
在另一实施方案中，In another embodiment,
R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
R1为-H、-F、-Cl、-Br、-OH、-NH2、-CH3、-CH(OH)CH3、-(CH2)qCH3、-(CH2)qOH、-CH(OH)(CH2)qCH3、-C(OH)((CH2)qCH3)2、-C(OH)(CH2)qCH3)(CH3)、-C(OH)(CH3)2、 -CH2F、-CHF2、-(CH2)qCH2F、-(CH2)qCHF2、-CH2Cl、-CHCl2、-(CH2)qCH2Cl、-(CH2)qCHCl2、-(CH2)qNH2、-NHCH3、-NH(CH2)qCH3、-(CH2)qNHCH3、-(CH2)qNH(CH2)qCH3、-N(CH3)2、-N((CH2)qCH3)2、-(CH2)qN(CH3)((CH2)qCH3)、-(CH2)qN(CH3)2、-(CH2)qN((CH2)qCH3)2、含有1个N原子的3-6元杂环烷基、被含有1个N原子的3-6元杂环烷基所取代的-(C1-C6)烷基；R 1 is -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 , -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 , 3-6 membered heterocycloalkyl containing 1 N atom, -( C 1 -C 6 )alkyl;
q在每次出现时独立的为1、2、3或4；q is 1, 2, 3, or 4 independently at each occurrence;
或者，R1和R2连同它们所附接的原子任选的可结合以形成环丙烷环、环丁烷环、环戊烷环、环己烷环、氧杂环丁烷、四氢呋喃、四氢吡喃、吗啉、二噁烷、2,3-二氢苯并呋喃环或四氢-2H-吡喃。Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an oxetane, a tetrahydrofuran, a tetrahydropyran, a morpholine, a dioxane, a 2,3-dihydrobenzofuran ring or a tetrahydro-2H-pyran.
在另一实施方案中，In another embodiment,
R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
R1为-H、-F、-Cl、-Br、-OH、-NH2、 R 1 is -H, -F, -Cl, -Br, -OH, -NH 2 ,
或者，R1和R2连同它们所附接的原子任选的可结合以形成或者，R1和R2连同它们所附接的原子任选的可结合以形成 Alternatively, R1 and R2 together with the atoms to which they are attached may optionally be combined to form Alternatively, R1 and R2 together with the atoms to which they are attached may optionally be combined to form
在一些实施方案中，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的前述式Ⅰ、式Ⅰ-1或Ⅰ-2所示的化合物，其中，R1和R2独立的作前述任意选择组合的基础上，R3可独立的进一步作如下选择：In some embodiments, the present invention provides compounds of the above formula I, formula I-1 or I-2 for use in the first, second, third and fourth aspects of the present invention, wherein R 1 and R 2 are independently selected from any of the above combinations, and R 3 can be independently further selected from the following:
在一实施方案中，In one embodiment,
R3为-H、卤素、-(C1-C6)烷基、-(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd； R3 is -H, halogen, -( C1 - C6 ) alkyl, -( C3 - C8 ) cycloalkyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the following: =O, halogen, -CN, -R a , -OR b , -NO 2 , -NR c R d ;
Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C8)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 -C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C6 -C6-alkyl, -( C2 - C6- alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, The invention also includes but is not limited to alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl is optionally substituted by one or more substituents selected from the group consisting of: =O, halogen, -CN, -OH, -NO2 , -NH2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl and a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S.
在另一实施方案中，In another embodiment,
R3为-H、卤素、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳 基或含有0-4个独立地选自O、N和S的杂原子的7-14元二环或三环稠合环基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd； R3 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 cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: =O, halogen, -CN, -R a , -OR b , -NO 2 , -NR c R d ;
Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C6)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C8 aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: =O, halogen, -CN, -OH, -NO2, -NH2, -(C1-C6)alkyl, -( C3 - C8) cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6- C8 aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S , or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O , N and S )cycloalkyl and 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S.
在另一实施方案中，In another embodiment,
R3为-H、-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元二环稠合环基，其中各烷基、环烷基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra和-ORb； R3 is -H, -F, -Cl, -Br, -( C1 - C6 ) alkyl, -( C3 - C6 ) cycloalkyl, C6 - C8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or 7-14 membered bicyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, aryl, heteroaryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -R a and -OR b ;
Ra和Rb在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-OH、-NO2、-NH2和-(C1-C6)烷基。 Ra and Rb, at each occurrence, are independently -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from: -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
在另一实施方案中，In another embodiment,
R3为-H、-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、吡啶基、苯基、苯并噻唑基、苯并吗啉基或苯并吡咯烷基，其中吡啶基、苯基、苯并噻唑基、苯并吗啉基、苯并吡咯烷基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、-O-(C1-C6)烷基、-O-(C3-C6)环烷基、哌嗪基、被任意数量卤素或-(C1-C6)烷基取代的哌嗪基。 R3 is -H, -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl or benzopyrrolidinyl, wherein pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl are optionally substituted with one or more substituents selected from the following substituents: -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, -O-( C1 - C6 )alkyl, -O-( C3 - C6 )cycloalkyl, piperazinyl, piperazinyl substituted with any number of halogen or -( C1 - C6 )alkyl.
在另一实施方案中，In another embodiment,
R3为-H、-F、-Cl、-Br、-CH3、-CH2CH3、吡啶基、 R 3 is -H, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , pyridyl,
在另一实施方案中，In another embodiment,
R3为-H、-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、吡啶基、苯基、萘基、苯并噻唑基、苯并吗啉基、苯并吡咯烷基或其中吡啶基、苯基、苯并噻唑基、苯并吗啉基、苯并吡咯烷基、任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-(C1-C6)烷基、-(C3-C6)环烷基、-O-(C1-C6)烷基、-O-(C3-C6)环烷基、-(C1-C6)卤代烷基、-(C3-C6)卤代环烷基、-O-(C1-C6)卤代烷基、-O-(C3-C6)卤代环烷基、吡唑基、被任意数量卤素或-(C1-C6)烷基取代的吡唑基、哌嗪基、被任意数量卤素或-(C1-C6)烷基取代的哌嗪基；R 3 is -H, -F, -Cl, -Br, -(C 1 -C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, pyridyl, phenyl, naphthyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl or Among them, pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl, Optionally substituted with one or more substituents selected from the group consisting of -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, pyrazolyl substituted with any number of halogen or -(C 1 -C 6 )alkyl, piperazinyl, piperazinyl substituted with any number of halogen or -(C 1 -C 6 )alkyl;
环为通过N原子连接的3-6元饱和或不饱和杂环基，所述杂环基除N原子外还任选地包含1-2个独立地选自O、N和S的杂原子。ring is a 3-6 membered saturated or unsaturated heterocyclic group linked via a N atom, and the heterocyclic group optionally contains 1-2 heteroatoms independently selected from O, N and S in addition to the N atom.
在另一实施方案中，In another embodiment,
R3为-H、-F、-Cl、-Br、-CH3、-CH2CH3、 R 3 is -H, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 ,
在一些实施方案中，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的前述式Ⅰ、式Ⅰ-1或Ⅰ-2所示的化合物，其中，R1、R2和R3独立的作前述任意选择组合的基础上，R4可进一步作如下选择：In some embodiments, the present invention provides compounds of the above formula I, formula I-1 or I-2 for use in the first, second, third and fourth aspects of the present invention, wherein R 1 , R 2 and R 3 are independently selected from any combination as described above, and R 4 can be further selected from the following:
在第一类实施方案中：In the first type of implementation:
R4为 R4 is
X为化学键、-(CRhRi)t-、-NRc(CRhRi)t-或-O-；其中Rc、Rh、Ri和t任选如本发明中任意出现处所定义的；X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t - or -O-; wherein R c , R h , R i and t are optionally as defined anywhere in the present invention;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C1-C6)烷氧基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-SH、-S(O)2H、-S(O)2NH2、-S(O)H、-S(O)NH2、-NHS(O)2H、-NHS(O)H、-C(O)H或-C(O)OH，其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-H、＝O、卤素、-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、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基或含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基，或者其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-S(O)2OH、-S(O)OH、-NHS(O)2OH或-NHS(O)OH；或者，各个Rj独立的可选为-O-(C3-C6)环烷基、-S(O)2OH、-S(O)OH、-NHS(O)2OH或-NHS(O)OH；Each Rj 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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 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 alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of -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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, a C6 -C 1-4 membered aryl or a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the following: -S(O) 2OH , -S(O)OH, -NHS(O) 2OH or -NHS(O)OH; or, each Rj is independently selected from -O-( C3 - C6 )cycloalkyl, -S(O) 2OH , -S(O)OH, -NHS(O) 2OH or -NHS(O)OH;
m为选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2。n is 0, 1 or 2.
在第一类的一些实施方案中，In some embodiments of the first class,
R4为 R4 is
X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、-(C1-C6)烷基、-(C1-C6)烷氧基、任意数量卤素取代的-(C1-C6)烷基或-(C1-C6)烷氧基、噁唑基、噻唑基和三唑基；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 and triazolyl;
m为选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2。n is 0, 1 or 2.
在第一类的一些实施方案中，In some embodiments of the first class,
R4为 R4 is
X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj各自独立的为-H、卤素、-OH、-NH2、-CN、-(C1-C6)烷基、-(C3-C6)环烷基、-(C1-C6)烷氧基、-O-(C3-C6)环烷基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷氧基、任意数量卤素取代的-(C3-C6)环烷基、任意数量卤素取代的-O-(C3-C6)环烷基、噁唑基、噻唑基和三唑基；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 halogen, -(C 1 -C 6 )alkoxy substituted with any number of halogen, -(C 3 -C 6 )cycloalkyl substituted with any number of halogen, -O-(C 3 -C 6 )cycloalkyl substituted with any number of halogen, oxazolyl, thiazolyl and triazolyl;
m为选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2。n is 0, 1 or 2.
在第二类实施方案中，In a second embodiment,
R4为 R4 is
X为化学键、-(CRhRi)t-、-NRc(CRhRi)t-或-O-；其中Rc、Rh、Ri和t任选如本发明中任意出现处所定义的；X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t - or -O-; wherein R c , R h , R i and t are optionally as defined anywhere in the present invention;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C1-C6)烷氧基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-SH、-S(O)2H、-S(O)2NH2、-S(O)H、-S(O)NH2、-NHS(O)2H、-NHS(O)H、-C(O)H或-C(O)OH，其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-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、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基或含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基，或者其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-S(O)2OH、-S(O)OH、-NHS(O)2OH或-NHS(O)OH；或者，各个Rj独立的可选为＝O、-S(O)2OH、-S(O)OH、-NHS(O)2OH或-NHS(O)OH；Each Rj 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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 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 alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: =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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, a C6 -C 1-4 membered aryl or a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: -S(O) 2OH , -S(O)OH, -NHS(O) 2OH or -NHS(O)OH; or, each Rj is independently selected to be =O, -S(O) 2OH , -S(O)OH, -NHS(O) 2OH or -NHS(O)OH;
m、p独立的为选自0、1、2、3、4、5或6；m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2；n is 0, 1 or 2;
环A为(C3-C8)环烷基、(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基。Ring A is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, a 3-14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, a 5-14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
在第二类的一些实施方案中， In some embodiments of the second class,
R4为 R4 is
X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、-(C1-C6)烷基、-(C1-C6)烷氧基、任意数量卤素取代的-(C1-C6)烷基或-(C1-C6)烷氧基、噁唑基、噻唑基或三唑基；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、p独立的为选自0、1、2、3、4、5或6；m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2；n is 0, 1 or 2;
环A为呋喃、噻吩、噁唑、噻唑、三唑、哌啶、吡啶、吡喃、噻喃、吗啉、1,4-二氧环己烷、哌嗪、吡嗪或三嗪。Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxane, piperazine, pyrazine or triazine.
在第二类的一些实施方案中，In some embodiments of the second class,
R4为 R4 is
X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj各自独立的为-H、卤素、-OH、-NH2、-CN、＝O、-(C1-C6)烷基、-(C1-C6)烷氧基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷氧基、噁唑基、噻唑基或三唑基；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、p独立的为选自0、1、2、3、4、5或6；m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2；n is 0, 1 or 2;
环A为呋喃、噻吩、噁唑、噻唑、三唑、哌啶、吡啶、吡喃、噻喃、吗啉、1,4-二氧环己烷、哌嗪、吡嗪、三嗪、4,5-二氢-1H-咪唑或1,3-二氧戊环。 Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxacyclohexane, piperazine, pyrazine, triazine, 4,5-dihydro-1H-imidazole or 1,3-dioxolane.
在另一些具体实施方案中，R4可进一步选择为 In other specific embodiments, R4 can be further selected as
在另一些具体实施方案中，R4可进一步选择为 In other specific embodiments, R4 can be further selected as
作为优选之一，在一些实施方案中，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的式Ⅰ、式Ⅰ-1或Ⅰ-2所示的化合物或其异构体、药学上可接受盐或溶剂化物：
As one of the preferred embodiments, the present invention provides a compound represented by formula I, formula I-1 or I-2 or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention:
其中，in,
R1和R2独立的为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)直链烷基、-(C1-C6)支链烷基、-(C3-C6)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra、-ORb、-NRcRd； R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain alkyl, -( C3 - C6 ) cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra, -ORb , -NRcRd ;
或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基； Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
R3为-H、-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、-(C6-C8)芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元二环稠合环基，其中各烷基、环烷基、芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra和-ORb； R3 is -H, -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, -( C6 - C8 )aryl, or a 7-14 membered bicyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, aryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -R a and -OR b ;
Ra、Rb、Rc和Rd在每次出现时独立地为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-OH、-NO2、-NH2和-(C1-C6)烷基； Ra , Rb , Rc and Rd are independently at each occurrence -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl;
R4为 R4 is
X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、-(C1-C6)烷基、-O-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-O-(C1-C6)烷基、噁唑基、噻唑基或三唑基；或者，各个Rj还可以进一步独立地选自＝O、-(C3-C6)环烷基、-O-(C3-C6)环烷基、任意数量卤素取代的-(C3-C6)环烷基、任意数量卤素取代的-O-(C3-C6)环烷基；Each R j is independently -H, halogen, -OH, -NH 2 , -CN, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with any number of halogens, -O-(C 1 -C 6 )alkyl substituted with any number of halogens, oxazolyl, thiazolyl or triazolyl; or, each R j can be further independently selected from =O, -(C 3 -C 6 )cycloalkyl, -O-(C 3 -C 6 )cycloalkyl, -(C 3 -C 6 )cycloalkyl substituted with any number of halogens, -O-(C 3 -C 6 )cycloalkyl substituted with any number of halogens;
m、p独立的为0、1、2、3、4、5或6；m and p are independently 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2；n is 0, 1 or 2;
环A为呋喃、噻吩、噁唑、噻唑、三唑、哌啶、吡啶、吡喃、噻喃、吗啉、1,4-二氧环己烷、哌嗪、吡嗪或三嗪；或者，环A为4,5-二氢-1H-咪唑或1，3-二氧戊环。Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxacyclohexane, piperazine, pyrazine or triazine; or, Ring A is 4,5-dihydro-1H-imidazole or 1,3-dioxolane.
作为优选之二，在一些实施方案中，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的式Ⅰ、式Ⅰ-1或Ⅰ-2所示的化合物或其异构体、药学上可接受盐或溶剂化物：
As a second preferred embodiment, in some embodiments, the present invention provides a compound represented by Formula I, Formula I-1 or I-2 or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention:
其中，in,
R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
R1为-H、-F、-Cl、-Br、-OH、-NH2、-(CH2)qCH3、-(CH2)qOH、-CH(OH)(CH2)qCH3、-C(OH)((CH2)qCH3)2、-(CH2)qNH2、-(CH2)qNH(CH2)qCH3、-(CH2)qN((CH2)qCH3)2、含有1个N原子的3-6元杂环烷基、被含有1个N原子的3-6元杂环烷基所取代的-(C1-C6)烷基；或者，R1为-CH2F、-CHF2、-(CH2)qCH2F、-(CH2)qCHF2、-CH2Cl、-CHCl2、-(CH2)qCH2Cl或-(CH2)qCHCl2；R 1 is -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 , -(CH 2 ) q NH 2 , -(CH 2 ) q NH(CH 2 ) q CH 3 , -(CH 2 ) q N((CH 2 ) q CH 3 ) 2 , 3- 6-membered heterocycloalkyl, -(C 1 -C 6 )alkyl substituted by a 3-6-membered heterocycloalkyl containing 1 N atom; or, R 1 is -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 or -(CH 2 ) q CHCl 2 ;
q在每次出现时独立的为0、1、2、3或4；q is 0, 1, 2, 3, or 4 independently at each occurrence;
或者，R1和R2连同它们所附接的原子任选的可结合以形成环丙烷环、环丁烷环、环戊烷环、环己烷环、四氢呋喃、四氢吡喃、吗啉、二噁烷或2,3-二氢苯并呋喃环；或者，R1和R2连同它们所附接的原子任选的可结合以形成四氢-2H-吡喃或氧杂环丁烷。Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a tetrahydrofuran, a tetrahydropyran, a morpholine, a dioxane or a 2,3-dihydrobenzofuran ring; alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a tetrahydro-2H-pyran or an oxetane.
R3为-H、-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、吡啶基、苯基、苯并噻唑基、苯并吗啉基或苯并吡咯烷基，其中吡啶基、苯基、苯并噻唑基、苯并吗啉基、苯并吡咯烷基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、-O-(C1-C6)烷基、-O-(C3-C6)环烷基、哌嗪基、被任意数量卤素或-(C1-C6)烷基取代的哌嗪基；或者，R3为其中环为通过N原子连接的3-6元饱和或不饱和含N杂环基，所述杂环基除N原子外还任选地包含1-2个独立地选自O、N和S的杂原子，并且任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-(C1-C6)烷基、-(C3-C6)环烷基、-O-(C1-C6)烷基、-O-(C3-C6)环烷基、-(C1-C6)卤代烷基、-(C3-C6)卤代环烷基、-O-(C1-C6)卤代烷基、-O-(C3-C6)卤代环烷基、吡唑基、被任意数量卤素或-(C1-C6)烷基取代的吡唑基、哌嗪基、被任意数量卤素或-(C1-C6)烷基取代的哌嗪基。 R3 is -H, -F, -Cl, -Br, -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl or benzopyrrolidinyl, wherein pyridinyl, phenyl, benzothiazolyl, benzomorpholinyl, 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, piperazinyl substituted with any number of halogen or -( C1 - C6 )alkyl; or, R3 is Among them is a 3-6 membered saturated or unsaturated N-containing heterocyclic group connected via a N atom, the heterocyclic group optionally containing 1-2 heteroatoms independently selected from O, N and S in addition to the N atom, and Optionally substituted with one or more substituents selected from the group consisting of -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, pyrazolyl substituted with any number of halogen or -(C 1 -C 6 )alkyl, piperazinyl, piperazinyl substituted with any number of halogen or -(C 1 -C 6 )alkyl.
R4为 R4 is
X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
代表单键或双键； represents a single bond or a double bond;
Y1为N、C或CH； Y1 is N, C or CH;
Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、-(C1-C6)烷基、-O-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-O-(C1-C6)烷基、噁唑、噻唑和三唑；或者，各个Rj还可以进一步独立地选自＝O、(C3-C6)环烷基、-O-(C3-C6)环烷基、任意数量卤素取代的-(C3-C6)环烷基或任意数量卤素取代的-O-(C3-C6)环烷基；Each R j is independently -H, halogen, -OH, -NH 2 , -CN, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with any number of halogens, -O-(C 1 -C 6 )alkyl substituted with any number of halogens, oxazole, thiazole and triazole; or, each R j can be further independently selected from =O, (C 3 -C 6 )cycloalkyl, -O-(C 3 -C 6 )cycloalkyl, -(C 3 -C 6 )cycloalkyl substituted with any number of halogens or -O-(C 3 -C 6 )cycloalkyl substituted with any number of halogens;
m、p独立的为0、1、2、3、4、5或6；m and p are independently 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2；n is 0, 1 or 2;
环A为呋喃、噻吩、噁唑、噻唑、三唑、哌啶、吡啶、吡喃、噻喃、吗啉、1,4-二氧环己烷、哌嗪、吡嗪或三嗪；或者，环A为4,5-二氢-1H-咪唑或1,3-二氧戊环。 Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxacyclohexane, piperazine, pyrazine or triazine; or, Ring A is 4,5-dihydro-1H-imidazole or 1,3-dioxolane.
作为优选之三，在一些实施方案中，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的式Ⅰ、式Ⅰ-1或Ⅰ-2所示的化合物或其异构体、药学上可接受盐或溶剂化物：
As a third preferred embodiment, in some embodiments, the present invention provides a compound represented by Formula I, Formula I-1 or I-2 or an isomer, a pharmaceutically acceptable salt or a solvate thereof for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention:
其中，in,
R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
R1为-H、-F、-Cl、-Br、-OH、-NH2、 或者，R1为 R 1 is -H, -F, -Cl, -Br, -OH, -NH 2 , Alternatively, R1 is
或者，R1和R2连同它们所附接的原子任选的可结合以形成或者，R1和R2连同它们所附接的原子任选的可结合以形成 Alternatively, R1 and R2 together with the atoms to which they are attached may optionally be combined to form Alternatively, R1 and R2 together with the atoms to which they are attached may optionally be combined to form
R3为-H、-F、-Cl、-Br、-CH3、-CH2CH3、吡啶基、 或者R3为 R 3 is -H, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , pyridyl, Or R3 is
R4为 或者R4为 R4 is Or R 4 is
作为优选，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的本发明化合物，其选自如下表中所示的化合物或其异构体、药学上可接受盐或溶剂化物：



Preferably, the present invention provides compounds of the present invention for use in the first, second, third and fourth aspects of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:



作为优选，本发明还提供用于本发明的第一方面、第二方面、第三方面和第四方面的本发明化合物，其选自如下表中所示的化合物或其异构体、药学上可接受盐或溶剂化物：
Preferably, the present invention also provides compounds of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:
作为优选，本发明还提供用于本发明的第一方面、第二方面、第三方面和第四方面的本发明化合物，其选自如下表中所示的化合物或其异构体、药学上可接受盐或溶剂化物：




Preferably, the present invention also provides compounds of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:




在一个实施方案中，本发明还提供用于本发明的第一方面、第二方面、第三方面和第四方面的本发明化合物，其选自下式Ⅱ的化合物或其异构体、药学上可接受盐或溶剂化物：
In one embodiment, the present invention also provides a compound of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which is selected from the compound of the following formula II or its isomer, pharmaceutically acceptable salt or solvate:
式Ⅱ中：In Formula II:
R3和R4如前述式Ⅰ、Ⅰ-1或Ⅰ-2化合物中任一相应R3和R4所涉及的定义； R3 and R4 are as defined above for any corresponding R3 and R4 in the compounds of formula Ⅰ, Ⅰ-1 or Ⅰ-2;
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、＝O、-NO2、-(C1-C6)烷基、-(C1-C6)烷氧基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-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或-NHS(O)OH、-C(O)H或-C(O)OH，其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-H、＝O、卤素、-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或-NHS(O)OH、-C(O)H、-C(O)OH、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基或含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基；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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic 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, or -NHS(O)OH, -C(O)H, or -C(O)OH, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: -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 or -NHS(O)OH, -C(O)H, -C(O)OH, a 3-14 membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, or a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S;
m独立的为选自0、1、2、3、4、5或6；m is independently selected from 0, 1, 2, 3, 4, 5 or 6;
v为0或1；v is 0 or 1;
环B为(C3-C8)环烷基、(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基。Ring B is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, a 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a 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 cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
在另一些具体实施方案中，In other specific embodiments,
各个Rj独立的为-H、卤素、-OH、-NH2、-CN、＝O、-(C1-C6)烷基、-(C1-C6)烷氧基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷氧基、噁唑基、噻唑基和三唑基； 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, and triazolyl;
环B为(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元二环或三环稠合环基。Ring B is (C 3 -C 8 )cycloalkyl, a 3-14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, a 5-14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14-membered bicyclic or tricyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
在另一些具体实施方案中，In other specific embodiments,
环B为3-7元氧杂环烷基或8-10元氮杂二环稠合杂芳基。或者，环B为氧杂环庚烷、氧杂环己烷、四氢呋喃、氧杂环丁烷、氧杂环丙烷、1H-吲哚或异吲哚啉。Ring B is a 3-7 membered oxacycloalkyl group or an 8-10 membered azabicyclic condensed heteroaryl group. Alternatively, Ring B is oxepane, oxhexane, tetrahydrofuran, oxetane, oxirane, 1H-indole or isoindoline.
在另一些具体实施方案中，In other specific embodiments,
环B为 Ring B is
作为优选，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的本发明化合物，其选自如下表中所示的化合物或其异构体、药学上可接受盐或溶剂化物：

Preferably, the present invention provides compounds of the present invention for use in the first, second, third and fourth aspects of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:

在一个实施方案中，本发明还提供用于本发明的第一方面、第二方面、第三方面和第四方面的本发明化合物，其选自前述式Ⅰ或Ⅱ的氘代化合物或其异构体、药学上可接受盐或溶剂化物：
In one embodiment, the present invention also provides a compound of the present invention for use in the first aspect, the second aspect, the third aspect and the fourth aspect of the present invention, which is selected from the deuterated compound of the aforementioned formula I or II or an isomer, a pharmaceutically acceptable salt or a solvate thereof:
其中，R1、R2、R3、R4、Rj、m、v和环B如前述式Ⅰ或Ⅱ化合物中任一相应R1、R2、R3、R4、Rj、m、v和环B所涉及的定义；wherein R 1 , R 2 , R 3 , R 4 , R j , m, v and ring B are as defined above for any corresponding R 1 , R 2 , R 3 , R 4 , R j , m, v and ring B in the compound of formula I or II;
式Ⅰ或Ⅱ的化合物中的任意1个以上的H被D所取代。In the compound of formula I or II, at least one H is replaced by D.
在另一些具体实施方案中，In other specific embodiments,
式Ⅰ或Ⅱ的化合物中的结构中的任意1个以上的H被D所取代，或者R4中的任意1个以上的H被D所取代。或者，式Ⅰ或Ⅱ的化合物中的结构中的所有H均被D所取代。The structure of the compound of formula I or II Any one or more H in R 4 is replaced by D. Alternatively, the compound of formula I or II has the structure All H in are replaced by D.
在另一些具体实施方案中，In other specific embodiments,
R1、R2或R3选择为H时，其独立的任选被D所取代。When R 1 , R 2 or R 3 is H, it is independently optionally substituted by D.
作为优选，本发明提供用于本发明的第一方面、第二方面、第三方面和第四方面的本发明化合物，其选自如下表中所示的化合物或其异构体、药学上可接受盐或溶剂化物：
Preferably, the present invention provides compounds of the present invention for use in the first, second, third and fourth aspects of the present invention, which are selected from the compounds shown in the following table or their isomers, pharmaceutically acceptable salts or solvates:
本发明中，在后的技术方案对在前的技术方案进一步限定时，可能仅对部分技术特征进行了进一步限定，此时未限定的技术特征可选具有在前技术方案或者本发明中任意出现处所定义。In the present invention, when a later technical solution further defines a previous technical solution, it may only further define some of the technical features. At this time, the undefined technical features can be optionally defined in the previous technical solution or anywhere in the present invention.
如本申请的实施例中所证实的，本发明化合物在PKM2体外酶学活性实验中显示了较好的激动活性，这种激动活性进一步表现在细胞层面，在人脑星形胶质母细胞瘤细胞(U118-MG)中依旧保持了良好的PKM2激动活性。此外，本发明化合物还对毛发生长具有明显的促进作用。As demonstrated in the examples of the present application, the compounds of the present invention show good agonist activity in the PKM2 in vitro enzymatic activity experiment, and this agonist activity is further manifested at the cellular level, and still maintains good PKM2 agonist activity in human brain astrocytic glioblastoma cells (U118-MG). In addition, the compounds of the present invention also have a significant promoting effect on hair growth.
在前述治疗方法或用途中，本发明化合物可以其自身的形式使用，或者还可组合药学上可接受的赋形剂形成药物组合物，所述药物组合物可以以药学上任意可接受的剂型和给药途径形式呈现。可接受的剂型包括但不限制于片剂、胶囊剂、颗粒剂、丸剂、糊剂、散剂、酊剂、膜剂、贴剂、涂剂、植入剂、注射剂、锭剂、滴剂、喷雾剂、气雾剂、雾化吸入剂、凝胶剂、栓剂、膏剂等。可接受的给药途径包括但不限制于：口服、静脉内、直肠、肠胃外、局部、经皮、眼、鼻、颊或肺(吸入)给药等。In the aforementioned treatment methods or uses, the compounds of the present invention can be used in their own form, or can also be combined with pharmaceutically acceptable excipients to form a pharmaceutical composition, which can be presented in any pharmaceutically acceptable dosage form and route of administration. Acceptable dosage forms include but are not limited to tablets, capsules, granules, pills, pastes, powders, tinctures, films, patches, coatings, implants, injections, lozenges, drops, sprays, aerosols, atomized inhalers, gels, suppositories, ointments, etc. Acceptable routes of administration include but are not limited to: oral, intravenous, rectal, parenteral, topical, transdermal, ophthalmic, nasal, cheek or lung (inhalation) administration, etc.
定义definition
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。Unless stated otherwise, the following terms used in the specification and claims have the following meanings.
“烷基”是指脂肪族烃基团，指饱和烃基，其可以是取代或非取代的。烷基部分可以是直链烷基，亦可以是支链烷基。例如，-(C1-C6)烷基或-(C1-C3)烷基。-(C1-C6)烷基指具有1至6个碳原子的烷基，例如具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子的烷基。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基、正己基等。所述烷基可以是非取代的或被一个或多个取代基所取代，所述取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、胺基、卤素、磺酰基、亚磺酰基、膦酰基等。"Alkyl" refers to an aliphatic hydrocarbon group, a saturated hydrocarbon group, which may be substituted or unsubstituted. The alkyl portion may be a straight chain alkyl group or a branched chain alkyl group. For example, -(C 1 -C 6 )alkyl or -(C 1 -C 3 )alkyl. -(C 1 -C 6 )alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as an alkyl group 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 groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like. The alkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
“烯基”是指结构中含有碳碳双键的不饱和烃基，其可以是取代或非取代的。烯基部分可以是直链烯基，亦可以是支链烯基。例如，-(C2-C6)烯基或-(C2-C4)烯基。-(C2-C6)烯基指具有2至6个碳原子的烯基，例如具有2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子的烯基。烯基的非限制性实例包括乙烯基、正丙烯基、异丙烯基、正丁烯基、异丁烯基、正己烯基等。所述烯基可以是非取代的或被一个或多个取代基所取代，所述取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、胺基、卤素、磺酰基、亚磺酰基、膦酰基等。"Alkenyl" refers to an unsaturated hydrocarbon group containing a carbon-carbon double bond in the structure, which may be substituted or unsubstituted. The alkenyl moiety may be a straight chain alkenyl or a branched chain alkenyl. For example, -(C 2 -C 6 )alkenyl or -(C 2 -C 4 )alkenyl. -(C 2 -C 6 )alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, such as an alkenyl group having 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, n-hexenyl, and the like. The alkenyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
“炔基”指结构中含有碳碳三键的不饱和烃基，其可以是取代或非取代的。炔基部分可以是直链炔基，亦可以是支链炔基。例如，-(C2-C6)炔基或-(C2-C4)炔基。-(C2-C6)炔基指具有2至6个碳原子的炔基，例如具有2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子的炔基。炔基的非限制性实例包括乙炔基、正丙炔基、异丙炔基、正丁炔基、异丁炔基、正己炔基等。所述炔基可以是非取代的或被一个或多个取代基所取代，所述取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、胺基、卤素、磺酰基、亚磺酰基、膦酰基等。"Alkynyl" refers to an unsaturated hydrocarbon group containing a carbon-carbon triple bond in its structure, which may be substituted or unsubstituted. The alkynyl moiety may be a straight chain alkynyl or a branched chain alkynyl. For example, -(C 2 -C 6 )alkynyl or -(C 2 -C 4 )alkynyl. -(C 2 -C 6 )alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, such as alkynyl groups having 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, n-hexynyl, and the like. The alkynyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
“环”是指任意的共价封闭结构，包括例如碳环(例如芳基、环烷基或环烯基)、杂环基(例如杂芳基、杂环烷基或杂环烯基)、芳香基(如芳基或杂芳基)、非芳香基(如环烷基、杂环烷基、环烯基、杂环烯基)，其可以是取代或非取代的。环可以是任选取代的，可以是单环或多环。典型的多环一般包括二环、三环。本申请的环通常具有3-20个环原子，例如3个环原子、4个环原子、5个环原子、6个环原子、7个环原子、8个环原子、9个环原子、10个环原子、11个环原子、12个环原子、13个环原子、14个环原子、15个环原子、16个环原子、17个环原子、18个环原子、19个环原子或20个环原子。"Ring" refers to any covalently closed structure, including, for example, carbocyclic rings (e.g., aryl, cycloalkyl or cycloalkenyl), heterocyclic groups (e.g., heteroaryl, heterocycloalkyl or heterocycloalkenyl), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl), which may be substituted or unsubstituted. The ring may be optionally substituted, and may be a monocyclic or polycyclic ring. Typical polycyclic rings generally include bicyclic and tricyclic rings. The ring of the present application generally has 3-20 ring atoms, for example, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms, 19 ring atoms or 20 ring atoms.
“元”是表示构成环的骨架原子的个数。典型的5元环包括例如环戊基、吡咯、咪唑、噻唑、呋喃和噻吩等；典型的6元环包括例如环己烷基、环己烯基、吡啶、吡喃、吡嗪、噻喃、哒嗪、嘧啶、苯等。其中，骨架原子中含有杂原子的环，即为杂环。"Member" refers to the number of skeleton atoms constituting the ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, for example, cyclohexyl, cyclohexenyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, etc. Among them, a ring containing heteroatoms in the skeleton atoms is a heterocycle.
“杂原子”是指除了碳或氢以外的原子。本申请的杂环中的一个或多个杂原子可独立地选自O、S、N、Si和P，但不限于此。"Heteroatom" refers to an atom other than carbon or hydrogen. One or more heteroatoms in the heterocycle of the present application may be independently selected from O, S, N, Si and P, but is not limited thereto.
“芳香基”指具有共轭的π电子体系的环状基团，包括构成环的骨架原子均为碳原子的芳基和构成环的骨架原子含有杂原子的杂芳基。“芳基”优选指具有共轭的π电子体系的具有6至14个碳原子(6至14元)的单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选具有6至10个原子，例如苯基和萘基，其可以是取代或非取代的。更优选苯基。“杂芳基”优选指包含1至4个(例如1、2、3或4个)杂原子、5至14个环原子(例如5、6、7、8、9、10、11、12、13、14个)的杂芳族体系，其中杂原子选自氧、硫和氮，其可以是取代或非取代的。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、吡喃基、噻喃基、嘧啶基、噻二唑、吡嗪基、三嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更优选吡唑基例如1H-吡唑-4-基或噻唑基。所述杂芳基环可以稠合于芳基、杂环烷基、环烷基环或另外的杂芳基上，从而形成稠杂芳基。稠杂芳基优选为8-10元稠杂芳基，包括但不限于：吲哚基例如1H-吲哚-5-基、2-氧代-2,3-二氢-1H-苯并[d]咪唑基例如2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基、或1H-苯并[d]咪唑基例如1H-苯并[d]咪唑-6-基。"Aromatic" refers to a cyclic group with a conjugated π electron system, including aryl groups whose skeleton atoms constituting the ring are all carbon atoms and heteroaryl groups whose skeleton atoms constituting the ring contain heteroatoms. "Aryl" preferably refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π electron system having 6 to 14 carbon atoms (6 to 14 members), preferably having 6 to 10 atoms, such as phenyl and naphthyl, which may be substituted or unsubstituted. More preferably phenyl. "Heteroaryl" preferably refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms, 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14), wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, which may be substituted or unsubstituted. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably, pyrazolyl, such as 1H-pyrazol-4-yl or thiazolyl. The heteroaryl ring may be fused to an aryl, a heterocycloalkyl, a cycloalkyl ring or another heteroaryl to form a fused heteroaryl. The fused heteroaryl group is preferably an 8-10 membered fused heteroaryl group, including but 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]imidazolyl such as 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl-5-yl, or 1H-benzo[d]imidazolyl such as 1H-benzo[d]imidazolyl-6-yl.
“非芳香基”指不具有共轭的π电子体系的环状基团，其不具有芳香性，一般也称为脂环族基团即脂环基，包括构成环的骨架原子均为碳原子的环烷基、环烯基和构成环的骨架原子含有杂原子的杂环烷基、杂环烯基。"Non-aromatic group" refers to a cyclic group that does not have a conjugated π electron system and is not aromatic. It is also generally called an alicyclic group, including cycloalkyl and cycloalkenyl groups whose skeletal atoms constituting the ring are all carbon atoms and heterocycloalkyl and heterocycloalkenyl groups whose skeletal atoms constituting the ring contain heteroatoms.
“稠合”指共享毗邻碳原子对的环，其一般为二环稠合或三环稠合。"Fused" refers to rings that share adjacent pairs of carbon atoms and are typically bi- or tri-ring fused.
“稠合环基”包括“稠合非芳香基”、“稠合芳香基”，“稠合非芳香基”包括“稠合环烷基”、“稠合杂环烷基”、“稠合环烯基”和“稠合杂环烯基”，“稠合芳香基”包括“稠合芳基”和“稠合杂芳基”，其均可以是取代或非取代的。 “Fused cyclic group” includes “fused non-aromatic group”, “fused aromatic group”, “fused non-aromatic group” includes “fused cycloalkyl group”, “fused heterocycloalkyl group”, “fused cycloalkenyl group” and “fused heterocycloalkenyl group”, and “fused aromatic group” includes “fused aryl group” and “fused heteroaryl group”, all of which may be substituted or unsubstituted.
“环烷基”是指饱和的包含1-3个环的环状烃取代基，其包括单环烷基、双环烷基以及三环烷基，其包含3-20个可形成环的碳原子，优选3-10个碳原子(即3-10元环烷基，也可称为-(C3-C10)环烷基)，例如3至8个，3至7个，3至6个，5至6个碳原子。优选地，环烷基选自由以下环得到的单价环烷基："Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl, which contains 3 to 20 carbon atoms that can form a ring, preferably 3 to 10 carbon atoms (i.e., 3-10-membered cycloalkyl, also referred to as -(C 3 -C 10 )cycloalkyl), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Preferably, the cycloalkyl is selected from a monovalent cycloalkyl derived from the following rings:
优选环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基或环辛烷基。环烷基其可以是取代或非取代的。 Preferred are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane. The cycloalkyl group may be substituted or unsubstituted.
应当理解，当根据结构或上下文，环烷基与两个基团进行连接时，该环烷基是二价基团，即有两个连接位点。此时，也可将其称为亚环烷基。优选的亚环烷基的实例包括但不限于单环结构，如亚环丙烷基、亚环丁烷基、亚环戊烷基(例如环戊-1,2-二基、环戊-1,3-二基)、亚环己烷基(例如环己-1,2-二基、环己-1,3-二基、环己-1,4-二基)、亚环庚烷基或亚环辛烷基等。It should be understood that when a cycloalkyl is connected to two groups according to the structure or context, the cycloalkyl is a divalent group, i.e., has two connection sites. In this case, it may also 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., cyclopentyl-1,2-diyl, cyclopentyl-1,3-diyl), cyclohexylene (e.g., cyclohexyl-1,2-diyl, cyclohexyl-1,3-diyl, cyclohexyl-1,4-diyl), cycloheptylene or cyclooctylene, etc.
“杂环烷基”和“环杂烷基”可互换使用，指饱和的非芳香性的含一个或多个(例如，1个、2个、3个或4个)杂原子的单环、稠合环、桥环和螺环。其中所述杂原子可为N、O、S或SO2 优选N、O和/或S。杂环烷基可为3元至10元(例如，3元、4元、5元、6元、7元、8元、9元、10元，即包含3个、4个、5个、6个、7个、8个、9个或10个环原子)的单环或双环或三环基团。典型的杂环烷基包括但不限于由以下环得到的单价基团："Heterocycloalkyl" and "cycloheteroalkyl" are used interchangeably to refer to saturated non-aromatic monocyclic, fused, bridged, and spirocyclic rings containing one or more (e.g., 1, 2, 3, or 4) heteroatoms. The heteroatoms may be N, O, S, or SO2 . Preferably N, O and/or S. Heterocycloalkyl can be a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms) monocyclic or bicyclic or tricyclic group. Typical heterocycloalkyl groups include, but are not limited to, monovalent groups derived from the following rings:
这些杂环烷基也可用通常理解的结构式方式表示，例如：
 These heterocycloalkyl groups can also be represented by commonly understood structural formulas, for example:
应当理解，当根据结构或上下文，杂环烷基与两个基团进行连接时，该杂环烷基是二价基团，即有两个连接位点。此时，也可将其称为亚杂环烷基。亚杂环烷基的实例包括但不限于由上述基团形成的二价基团，例如：
It should be understood that when a heterocycloalkyl group is connected to two groups according to the structure or context, the heterocycloalkyl group is a divalent group, i.e., there are two connection sites. In this case, it can also be referred to as a heterocycloalkylene group. Examples of heterocycloalkylene groups include, but are not limited to, divalent groups formed by the above groups, such as:
“环烯基”指包含一个或多个双键，但其没有一个环具有完全共轭的π电子体系，不具有芳香性的包含1～3个环的环状烃取代基，其包括单环烯基、双环烯基以及三环烯基，其包含3-20个可形成环的碳原子，优选3-10个碳原子(即3-10元环烯基，也可称为-(C3-C10)环烯基)，例如3至8个，3至7个，3至6个，5至6个碳原子。优选地，环烯基选自由以下环得到的单价环烯基："Cycloalkenyl" refers to a cyclic hydrocarbon substituent containing one to three rings, which contains one or more double bonds but none of which has a completely conjugated π electron system and is not aromatic, including monocyclic alkenyl, bicyclic alkenyl and tricyclic alkenyl, and contains 3-20 carbon atoms that can form a ring, preferably 3-10 carbon atoms (i.e., 3-10-membered cycloalkenyl, also referred to as -(C 3 -C 10 )cycloalkenyl), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Preferably, the cycloalkenyl is selected from a monovalent cycloalkenyl obtained from the following rings:
优选环丙烯基、环戊烯基、环己烯基。环烯基其可以是取代或非取代的。应当理解，当根据结构或上下文，环烯基与两个基团进行连接时，该环烯基是二价基团，即有两个连接位点。此时，也可将其称为亚环烯基。 Preferred are cyclopropenyl, cyclopentenyl and cyclohexenyl. Cycloalkenyl may be substituted or unsubstituted. It should be understood that when, according to the structure or context, a cycloalkenyl is connected to two groups, the cycloalkenyl is a divalent group, i.e., has two connection sites. At this point, it may also be referred to as a cycloalkenylene.
“杂环烯基”指不饱和的非芳香性的含一个或多个(例如，1个、2个、3个或4个)杂原子的单环、稠合环、桥环和螺环。其中所述杂原子可为N、O、S或SO2 优选N、O和/或S。杂环烯基可为3元至10元(例如，3元、4元、5元、6元、7元、8元、9元、10元，即包含3个、4个、5个、6个、7个、8个、9个或10个环原子)的单环或双环或三环基团。典型的杂环烯基包括但不限于由以下环得到的单价基团："Heterocycloalkenyl" refers to an unsaturated non-aromatic monocyclic, fused, bridged, and spirocyclic ring containing one or more (e.g., 1, 2, 3, or 4) heteroatoms. The heteroatoms may be N, O, S, or SO2 . Preferably N, O and/or S. Heterocycloalkenyl may be a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms) monocyclic or bicyclic or tricyclic group. Typical heterocycloalkenyl groups include, but are not limited to, monovalent groups derived from the following rings:
这些杂环烯基也可用通常理解的结构式方式表示，例如：应当理解，当根据结构或上下文，杂环烯基与两个基团进行连接时，该杂环烯基是二价基团，即有两个连接位点。此时，也可将其称为亚杂环烯基。 These heterocyclic alkenyl groups can also be represented by commonly understood structural formulas, for example: It should be understood that when, according to the structure or context, the heterocycloalkenyl group is connected to two groups, the heterocycloalkenyl group is a divalent group, that is, there are two connection sites. In this case, it can also be called a heterocycloalkenylene group.
“氧代”指碳上的氢被＝O取代。"Oxo" refers to the replacement of a hydrogen on a carbon with =0.
“卤素”或“卤”是指氟、氯、溴或碘。"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
“卤代烷基”是指烷基中至少一个氢被卤素原子置换，例如CF3。 "Haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom, such as CF3 .
“取代的”指基团中的一个或多个氢原子，优选为最多5个(例如1、2、3、4、5个)，更优选为1～3个氢原子可彼此独立地被相应数目的取代基所取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms, preferably up to 5 (e.g. 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms in the group can be replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
“抑制剂”，是指使酶活性下降的物质。"Inhibitor" refers to a substance that reduces the activity of an enzyme.
“激动剂”，是指使酶活性上升的物质。"Agonist" refers to a substance that increases enzyme activity.
“任选地”意味着随后所描述地事件或环境可以但不必然发生，该说明包括该事件或环境发生或不发生。"Optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes that the event or circumstance occurs or does not occur.
术语“取代或非取代的”在本文中是指任何基团由指定取代基单取代或多取代至这种单取代或多取代(包括在相同部分的多重取代)在化学上允许的程度，每个取代基可以位于该基团上任何可利用的位置，且可以通过所述取代基上任何可利用的原子连接。“任何可利用的位置”是指通过本领域已知的方法或本文教导的方法可化学得到，并且不产生过度不稳定的分子的所述基团上的任何位置。当在任何基团上有两个或多个取代基时，每个取代基独立于任何其它取代基而定义，因此可以是相同或不同的。The term "substituted or unsubstituted" herein refers to any group being monosubstituted or polysubstituted by a specified substituent to the extent that such monosubstituted or polysubstituted (including multiple substitutions in the same moiety) is chemically permitted, and each substituent can be located at any available position on the group and can be connected through 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 methods taught herein and does not produce excessively unstable molecules. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and can therefore be the same or different.
“立体异构”本发明所述的“立体异构体”是指当本发明的化合物含有一个或者多个不对称中心时，其可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体的形式存在。本发明的化合物可具有不对称中心，并由此导致存在两个光学异构体。本发明的范围包括所有可能的光学异构体和他们的混合物。本发明的化合物若含有烯烃双键，则除非特别说明，本发明的范围包括顺式异构体和反式异构体。本发明的化合物可以以互变异构体(官能团异构体的一种)形式存在，其通过一个或多个双键位移具有不同的氢的连接点，例如，酮和他的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都在本发明的范围内。所有化合物的对映异构体。非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等均在本发明的范围内。"Stereoisomerism" "stereoisomer" as used herein means that when the compounds of the present invention contain one or more asymmetric centers, they can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention may have asymmetric centers, which result in the existence of two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefin double bonds, the scope of the present invention includes cis isomers and trans isomers unless otherwise specified. The compounds of the present invention may exist in the form of tautomers (a type of functional group isomers), which have different hydrogen attachment points through one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are within the scope of the present invention. Enantiomers of all compounds. Diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof are all within the scope of the present invention.
本文所用的术语“本发明的化合物”意欲涵盖如本文所定义的通式(I)和(II)的化合物或其任一优选或具体的实施方案(包括式(I-1)、(I-2)等化合物及实施例化合物)、它们的立体异构体、药学上可接受的盐、互变异构体或溶剂合物。The term "compounds of the present invention" as used herein is intended to encompass compounds of the general formula (I) and (II) as defined herein or any preferred or specific embodiments thereof (including compounds of the formula (I-1), (I-2), etc. and example compounds), their stereoisomers, pharmaceutically acceptable salts, tautomers or solvates.
本文所用的术语“药学可接受的”意指由各个国家的相应机构批准的或可由其批准，或列于用于动物且更具体地人类的一般公认药典中，或当向动物例如人类适量施用时不会产生不利、过敏或其它不良反应的分子实体和组合物。The term "pharmaceutically acceptable" as used herein refers to molecular entities and compositions that are or are approvable by relevant agencies in various countries, or are listed in the generally recognized pharmacopoeia for use in animals, and more particularly in humans, or that do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans.
本文所用的术语“药学可接受的盐”意指药学上可接受且具有母体化合物所需药理学活性的本发明化合物的盐。具体地，此类盐无毒，可为无机酸加成盐或有机酸加成盐及碱加成盐。The term "pharmaceutically acceptable salt" used herein refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts.
如本文所使用的术语“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。As used herein, the term "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
本发明所述的“药物组合物”，指包含一种或多种式(I)、式(I-1)、式(I-2)或式(II)化合物或者其立体异构体、互变异构体、药学上可接受的盐或溶剂合物和在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体或赋形剂的组合物。The "pharmaceutical composition" described in the present invention refers to a composition comprising one or more compounds of Formula (I), Formula (I-1), Formula (I-2) or Formula (II) or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates and a carrier or excipient generally accepted in the art for delivering the biologically active compound to an organism (e.g., a human).
本文所用的术语“药物组合”是指本发明化合物可与其它活性剂组合用于实现本发明的目的。所述其他活性剂可以是一种或多种另外的本发明化合物，或可以是与本发明化合物相容即不会相互不利影响、或具有互补活性的第二种或另外的(例如第三种)化合物。这类活性剂以达到预期目的的有效量适宜地组合存在。所述其他活性剂可以与本发明化合物在单一药物组合物中共同施用，或与本发明化合物处于不同的离散单元中分别施用，当分别施用时可以同时或相继进行。所述相继施用在时间上可以是接近或隔远的。The term "drug combination" as used herein means that the compounds of the present invention can be combined with other active agents to achieve the purpose of the present invention. The other active agents may be one or more additional compounds of the present invention, or may be a second or additional (e.g., a third) compound that is compatible with the compounds of the present invention, i.e., does not adversely affect each other, or has complementary activities. Such active agents are suitably combined in an effective amount to achieve the intended purpose. The other active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or may be administered separately from the compounds of the present invention in different discrete units, and when administered separately, may be performed simultaneously or sequentially. The sequential administration may be close or distant in time.
应当理解，本发明的化合物结构中各基团进行选择时，相互之间具有连接、配合或影响的基团应在符合化学价键规则的前提下进行相应选择。It should be understood that when selecting the various groups in the compound structure of the present invention, the groups that are connected, coordinated or influenced by each other should be selected accordingly under the premise of complying with the chemical valence bond rules.
根据本发明的内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。According to the contents of the present invention, in accordance with common technical knowledge and means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.
具体实施方式DETAILED DESCRIPTION
为了进一步说明本发明，下面结合实施例对本发明提供的本发明化合物及其制备方法和应用进行详细描述。In order to further illustrate the present invention, the compounds of the present invention and their preparation methods and applications are described in detail below in conjunction with examples.
下面的缩写或术语具有如下所示的意义：The following abbreviations or terms have the following meanings:
Grubb's 2表示Grubbs二代催化剂Grubb's 2 stands for Grubbs second generation catalyst
DMF表示N,N-二甲基甲酰胺；DMF stands for N,N-dimethylformamide;
DMSO表示二甲基亚砜；DMSO means dimethyl sulfoxide;
HATU表示2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；HATU stands for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;
DIPEA表示N,N-二异丙基乙胺；DIPEA means N,N-diisopropylethylamine;
Pd2(dba)3表示三(二亚苄基丙酮)二钯；Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium;
Xantphos表示4,5-双二苯基膦-9,9-二甲基氧杂蒽；Xantphos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;
-Cbz表示苄氧基羰基保护基；-Cbz represents a benzyloxycarbonyl protecting group;
-Boc表示叔丁氧羰基保护基；-Boc represents a tert-butyloxycarbonyl protecting group;
-Fmoc表示9-芴基甲氧基羰基保护基；-Fmoc represents a 9-fluorenylmethoxycarbonyl protecting group;
-PMB表示对甲氧基苄基保护基；-PMB represents a p-methoxybenzyl protecting group;
-Bn表示苄基保护基；-Bn represents a benzyl protecting group;
-Trt表示三苯甲基保护基；-Trt represents a trityl protecting group;
-Tos表示对甲苯磺酰基保护基；-Tos represents a p-toluenesulfonyl protecting group;
-Pht表示邻苯二甲酰基保护基；-Pht represents a phthaloyl protecting group;
-Alloc表示烯丙氧羰基保护基；-Alloc represents an allyloxycarbonyl protecting group;
Tris缓冲液表示三羟甲基氨基甲烷缓冲液。Tris buffer means tris(hydroxymethyl)aminomethane buffer.
-TBS表示叔丁基二甲基硅基；-TBS represents tert-butyldimethylsilyl;
-TBDPS表示叔丁基二苯基硅基。-TBDPS represents tert-butyldiphenylsilyl.
本发明还提供了所述新颖化合物的合成方法，本发明的合成方法主要从化学文献中报道的制备方法或者以市售化学试剂为起始物料进行相关合成。 The present invention also provides a method for synthesizing the novel compound. The method for synthesizing the novel compound is mainly based on the preparation method reported in chemical literature or using commercially available chemical reagents as starting materials for related synthesis.
方法：
method:
上述反应式中，“RA”指其中R4如本发明中任意一处出现时所定义；“RC”指其中R1、R2、R3、Rj、m、v和环B如本发明中任意一处出现时所定义；“RB”指由保护基保护的RC，RB脱去保护基后即成为RC，所述保护基包括但不限制于-TBS或-TBDPS。In the above reaction formula, “ RA ” refers to wherein R 4 is as defined in any place in the present invention; "R C " refers to Wherein R1 , R2 , R3 , Rj , m, v and ring B are as defined in the present invention at any time; " RB " refers to RC protected by a protecting group, and RB becomes RC after removing the protecting group, and the protecting group includes but is not limited to -TBS or -TBDPS.
下述步骤涉及化合物Z-RA、化合物Z-RB，其中“Z”为能够与氨基发生缩合反应，以将RA或RB连接在上的基团，所述缩合反应优选为磺酰氯与氨基发生的缩合反应或羧基与氨基发生的缩合反应，“Z”在不同的化合物中可独立的选择实施基团包括但不限制于-Cl、-F、-Br、-OH，化合物Z-RA优选为Cl-RA，化合物Z-RB优选为OH-RB。The following steps involve compounds ZRA and ZRB , wherein "Z" is a compound capable of undergoing a condensation reaction with an amino group to connect RA or RB to The condensation reaction is preferably a condensation reaction between sulfonyl chloride and an amino group or a condensation reaction between a carboxyl group and an amino group. "Z" can be independently selected in different compounds and includes but is not limited to -Cl, -F, -Br, and -OH. Compound ZRA is preferably Cl- RA , and compound ZRB is preferably OH- RB .
步骤1：Step 1:
化合物A溶于四氢呋喃溶液中，然后加入三乙胺和化合物Z-RA，反应在25℃下进行。反应完全后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，浓缩后通过层析柱分离纯化得到化合物B。Compound A is dissolved in tetrahydrofuran solution, and then triethylamine and compound ZRA are added, and the reaction is carried out at 25° C. After the reaction is completed, it is extracted three times with ethyl acetate, and the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, and separated and purified by chromatography to obtain compound B.
步骤2：Step 2:
化合物B溶于三氟乙酸中，反应在60℃下进行，反应完毕后，浓缩干后通过层析柱分离纯化得到化合物C。Compound B is dissolved in trifluoroacetic acid, and the reaction is carried out at 60° C. After the reaction is completed, the product is concentrated to dryness and then separated and purified by a chromatography column to obtain compound C.
步骤3：Step 3:
化合物C溶于DMF溶液中，然后依次加入化合物Z-RB、HATU和DIPEA在25℃下进行缩合反应，反应完全后将反应液倒入水中，用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤浓缩后通过层析柱分离纯化得化合物D。Compound C was dissolved in DMF solution, and then compound ZRB , HATU and DIPEA were added in sequence to carry out condensation reaction at 25°C. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated and purified by chromatography to obtain compound D.
步骤4：Step 4:
化合物D溶于四氢呋喃溶液中，然后加入四丁基氟化铵，进行脱掉保护反应最终得到化合物E。Compound D is dissolved in tetrahydrofuran solution, and then tetrabutylammonium fluoride is added to perform a deprotection reaction to finally obtain compound E.
实施例1：(S)-1-(1'-((2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物1)的制备合成步骤如下所示：
Example 1: The preparation and synthesis steps of (S)-1-(1'-((2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropane-1-one (Compound 1) are as follows:
步骤1：7-溴-2,3-二氢-[1,4]二噁并[2,3-b]吡啶(化合物1A)的制备
Step 1: Preparation of 7-bromo-2,3-dihydro-[1,4]dioxo[2,3-b]pyridine (Compound 1A)
将5-溴吡啶-2,3-二醇(13.0g,68.4mmol)溶于DMF(130mL)中，然后加入1,2-二溴乙烷(19.3g,102.6mmol)和碳酸钾(28.3g,205mmol)，反应体系在100℃下搅拌过夜，反应完全后。反应液减压浓缩干，残余物通过硅胶柱分离纯化得化合物1A。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, and the reaction system was stirred at 100°C overnight. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 1A.
MS(ESI)m/z 216.0(M+H)+ MS (ESI) m/z 216.0 (M+H) +
步骤2：7-(苄硫基)-2,3-二氢-[1,4]二噁并[2,3-b]吡啶(化合物1B)的制备
Step 2: Preparation of 7-(benzylthio)-2,3-dihydro-[1,4]dioxo[2,3-b]pyridine (Compound 1B)
在氩气保护下，将7-溴-2,3-二氢-[1,4]二噁并[2,3-b]吡啶(1.0g,4.6mmol)溶于1,4-二氧六环溶液(20mL)中，随后加入苯甲硫醇(570mg,4.6mmol)、Pd2(dba)3(240mg,0.23mmol)、Xantphos(270mg,0.46mmol)和DIPEA(1190mg,9.3mmol)。反应体系在80℃下搅拌过夜。反应完全后，反应液减压浓缩干，残余物通过硅胶柱分离纯化得化合物1BUnder argon protection, 7-bromo-2,3-dihydro-[1,4]dioxo[2,3-b]pyridine (1.0 g, 4.6 mmol) was dissolved in 1,4-dioxane solution (20 mL), followed by the addition of benzyl mercaptan (570 mg, 4.6 mmol), Pd 2 (dba) 3 (240 mg, 0.23 mmol), Xantphos (270 mg, 0.46 mmol) and DIPEA (1190 mg, 9.3 mmol). The reaction system was stirred at 80 ° C overnight. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 1B
MS(ESI)m/z 260.1(M+H)+。MS (ESI) m/z 260.1 (M+H) + .
步骤3：2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯(化合物1C)的制备
Step 3: Preparation of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride (Compound 1C)
将7-(苄硫基)-2,3-二氢-[1,4]二噁并[2,3-b]吡啶(800mg,3mmol)，二氯海茵(820mg,6mmol)溶于乙腈(30mL),乙酸(0.75mL),水(0.5mL)的混合溶液中，反应体系在25℃下搅拌过夜。反应完全后，反应液减压浓缩干，残余物通过硅胶柱分离纯化得化合物1C。7-(Benzylthio)-2,3-dihydro-[1,4]dioxo[2,3-b]pyridine (800 mg, 3 mmol) and dichlorohydantoin (820 mg, 6 mmol) were dissolved in a mixed solution of acetonitrile (30 mL), acetic acid (0.75 mL) and water (0.5 mL), and the reaction system was stirred overnight at 25° C. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 1C.
MS(ESI)m/z 236.0(M+H)+。MS (ESI) m/z 236.0 (M+H) + .
步骤4：(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸(化合物1D)的制备
Step 4: Preparation of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid (Compound 1D)
将(S)-3-羟基-2-苯丙酸(900mg,5.4mmol),4-二甲氨基吡啶(1.32g,10.8mmol)溶于二氯甲烷(10mL)中，然后加入叔丁基二苯基氯硅烷(1.64g,6mmol)，反应体系25℃下搅拌过夜，反应完全后，将反应液浓缩干，粗品经C-18柱分离纯化得化合物1D。(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), and then tert-butyldiphenylsilyl chloride (1.64 g, 6 mmol) was added. The reaction system was stirred at 25°C overnight. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was separated and purified by C-18 column to obtain compound 1D.
MS(ESI)m/z 405.2(M+H)+。MS (ESI) m/z 405.2 (M+H) + .
步骤5：3-亚甲基氮杂环丁烷-1-羧酸苄酯(化合物1E)的制备
Step 5: Preparation of 3-methyleneazetidine-1-carboxylic acid benzyl ester (Compound 1E)
将3-氧代氮杂环丁烷-1-羧酸苄酯(86.6g,268mmol)和甲基三苯基溴化磷(50g,243.5mmol)溶于四氢呋喃(500mL)中，然后加入叔丁醇钾(40.9g,365.5mmol)，将混合物在25℃下搅拌过夜。反应完全后，将反应液浓缩干，残余物通过硅胶柱分离纯化得化合物1E。Benzyl 3-oxoazetidine-1-carboxylate (86.6 g, 268 mmol) and methyltriphenylphosphonium bromide (50 g, 243.5 mmol) were dissolved in tetrahydrofuran (500 mL), and potassium tert-butoxide (40.9 g, 365.5 mmol) was added, and the mixture was stirred overnight at 25° C. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 1E.
MS(ESI)m/z 204.1(M+H)+ MS (ESI) m/z 204.1 (M+H) +
步骤6：1-苄基1'-(叔丁基)2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1,1'(4H,4'H)-二羧酸酯(化合物1F)的制备
Step 6: Preparation of 1-benzyl 1'-(tert-butyl) 2H,2'H-[3,3'-diazetidinylidene]-1,1'(4H,4'H)-dicarboxylate (Compound 1F)
将3-亚甲基氮杂环丁烷-1-羧酸苄酯(39g,191.9mmol)、3-亚甲基氮杂环丁烷-1-羧酸叔丁酯(32.47g,191.9mmol)溶于二氯乙烷(2000mL)中，然后加入Grubb's 2(16.29g,19.19mmol)，将混合物在50℃下搅拌48小时。反应完全后，将反应液浓缩干，残余物通过硅胶柱分离纯化得化合物1F。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 Grubb's 2 (16.29 g, 19.19 mmol) was added, and the mixture was stirred at 50°C for 48 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 1F.
MS(ESI)m/z 345.2(M+H)+ MS (ESI) m/z 345.2 (M+H) +
步骤7：苄基1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-羧酸酯(化合物1G)的制备
Step 7: Preparation of benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 1G)
将1-苄基1'-(叔丁基)2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1,1'(4H,4'H)-二羧酸酯(3.2g，9.29mmol)溶于乙酸乙酯(32mL)中，然后加入对甲苯磺酸(1.6g,9.29mmol)，反应体系在50℃下搅拌6小时。反应完全后，将反应液浓缩干，残余物通过硅胶柱分离纯化得化合物1G。1-Benzyl 1'-(tert-butyl) 2H, 2'H-[3,3'-diazetidinylidene]-1, 1'(4H, 4'H)-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, and the reaction system was stirred at 50° C. for 6 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 1G.
MS(ESI)m/z 245.1(M+H)+ MS (ESI) m/z 245.1 (M+H) +
步骤8：苄基1'-((2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-羧酸酯(化合物1H)的制备
Step 8: Preparation of benzyl 1'-((2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-7-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 1H)
将苄基1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-羧酸酯(100mg,0.41mmol)和三乙胺(82.5mg,0.82mmol)溶于四氢呋喃(4mL)中，随后加入2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯(96.5mg,0.41mmol)将混合物在25℃下搅拌2小时。反应完全后，将反应液浓缩干，残余物通过硅胶柱分离纯化得化合物1H。Benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-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]dioxo[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 the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 1H.
MS(ESI)m/z 444.1(M+H)+ MS (ESI) m/z 444.1 (M+H) +
步骤9：7-((1',4'-二氢-2H,2'-H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基磺酰基)-2,3-二氢-[1,4]二噁并[2.3-b]吡啶)(化合物1I)的制备
Step 9: Preparation of 7-((1',4'-dihydro-2H,2'-H-[3,3'-diazetidinylidene]-1(4H)-ylsulfonyl)-2,3-dihydro-[1,4]dioxo[2.3-b]pyridine) (Compound 1I)
将苄基1'-((2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-羧酸酯(120mg,0.27mmol)溶于三氟乙酸(5mL)中，反应体系在60℃下搅拌过夜。反应完全后，将反应液浓缩干，残余物通过硅胶柱分离纯化得化合物1I。Benzyl 1'-((2,3-dihydro-[1,4]dioxo[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 system was stirred at 60° C. overnight. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 1I.
MS(ESI)m/z 310.1(M+H)+ MS (ESI) m/z 310.1 (M+H) +
步骤10：(S)-3-((叔丁基二苯基硅基)氧基)-1-(1'-((2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯丙烷-1-酮(化合物1J)的制备
Step 10: Preparation of (S)-3-((tert-butyldiphenylsilyl)oxy)-1-(1'-((2,3-dihydro-[1,4]dioxo[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)
将(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸(80mg，0.2mmol)和7-((1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基二联氮杂环丁烷亚基]-1(4H)-基磺酰基)-2,3-二氢-[1.4]二噁并[2.3-b]吡啶)(61mg,0.2mmol)溶DMF(5mL)中，再加入HATU(112mg,0.3mmol)和DIPEA(77mg,0.6mmol)，反应体系在25℃下搅拌3小时。反应完全后，将反应液浓缩干，通过反相高压液相制备得化合物1J。(S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid (80 mg, 0.2 mmol) and 7-((1',4'-dihydro-2H,2'H-[3,3'-diazotidinediazotidine]-1(4H)-ylsulfonyl)-2,3-dihydro-[1.4]dioxo[2.3-b]pyridine) (61 mg, 0.2 mmol) were dissolved in DMF (5 mL), and HATU (112 mg, 0.3 mmol) and DIPEA (77 mg, 0.6 mmol) were added, and the reaction system was stirred at 25° C. for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and compound 1J was prepared by reverse phase high pressure liquid chromatography.
MS(ESI)m/z 695.3(M+H)+ MS (ESI) m/z 695.3 (M+H) +
步骤11：(S)-1-(1'-((2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-基)磺酰基)-1',4'-二氢-2H，2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物1)的制备
Step 11: Preparation of (S)-1-(1'-((2,3-dihydro-[1,4]dioxo[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)
将(S)-3-((叔丁基二苯基硅基)氧基)-1-(1'-((2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯丙烷-1-酮(50mg,0.087mmol)溶于四氢呋喃(5mL)中，然后加入四丁基氟化铵(45.5mg,0.17mmol)，反应体系在25℃搅拌3小时。反应完全后，将反应液浓缩干，通过反相高压液相制备得实施例1的化合物1。(S)-3-((tert-butyldiphenylsilyl)oxy)-1-(1'-((2,3-dihydro-[1,4]dioxo[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, and the reaction system was stirred at 25° C. for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and compound 1 of Example 1 was prepared by reverse phase high pressure liquid chromatography.
MS(ESI)m/z 458.2(M+H)+ MS (ESI) m/z 458.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.23(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). 1 H NMR (400MHz, DMSO-d 6 )δ8.23(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).
实施例2：(S)-1-(1'-((2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物2)的制备：
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-phenylpropane-1-one (Compound 2):
在实施例1的步骤8中用2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例2的化合物2。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]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 2 of Example 2.
MS(ESI)m/z 457.1(M+H)+。MS (ESI) m/z 457.1 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.35-7.20(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). 1 H NMR (400MHz, DMSO-d 6 )δ7.35-7.20(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).
实施例3：(S)-1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物3)的制备：
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-phenylpropane-1-one (Compound 3):
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例3的化合物3。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 3 of Example 3.
MS(ESI)m/z 456.1(M+H)+ MS (ESI) m/z 456.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.77(s,1H),8.35-8.24(m,1H),7.90(d,J＝9.4Hz,1H),7.21(d,J＝14.2Hz,5H),4.64(d,J＝12.5Hz,2H),4.34-4.10(m,7H),3.81(d,J＝10.0Hz,1H),3.61-3.50(m,1H),3.40(d,J＝7.1Hz,1H). 1 H NMR (400MHz, DMSO-d 6 )δ9.64(s,1H),8.77(s,1H),8.35-8.24(m,1H),7.90(d,J＝9.4Hz,1H),7.21(d,J＝14.2Hz,5H), 4.64(d ,J＝12.5Hz,2H),4.34-4.10(m,7H),3.81(d,J＝10.0Hz,1H),3.61-3.50(m,1H),3.40(d,J＝7.1Hz,1H) .
实施例4：(S)-3-羟基-2-苯基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3.3'-二联氮杂环丁烷亚基]-1(4H)-基)丙烷-1-酮(化合物4)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例4的化合物4。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 4 of Example 4.
MS(ESI)m/z 400.0(M+H)+ MS (ESI) m/z 400.0 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.11(d,J＝11.6Hz,1H),7.95(d,J＝5.3Hz,1H),7.71(s,1H),7.28-7.19(m,5H),4.68(d,J＝13.2Hz,1H),4.50(s,4H),4.37-4.23(m,2H),4.17(d,J＝14.6Hz,1H),3.85(q,J＝9.0Hz,1H),3.58(d,J＝10.4Hz,1H),3.50-3.40(m,2H) 1 H NMR (400MHz, DMSO-d 6 )δ8.76(s,1H),8.11(d,J＝11.6Hz,1H),7.95(d,J＝5.3Hz,1H),7.71(s,1H),7.28-7.19(m,5H), 4.68(d,J=13.2Hz,1H),4 .50(s,4H),4.37-4.23(m,2H),4.17(d,J＝14.6Hz,1H),3.85(q,J＝9.0Hz,1H),3.58(d,J＝10.4Hz, 1H),3.50-3.40(m,2H)
实施例5：(S)-3-羟基-1-(1’-((4-甲氧基苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯丙烷-1-酮(化合物5)的制备：
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):
在实施例1的步骤8中用对甲氧基苯磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例5的化合物5。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with p-methoxybenzenesulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 5 of Example 5.
MS(ESI)m/z 429.5(M+H)+ MS (ESI) m/z 429.5 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.80-7.65(m,2H),7.20(m,7H),4.83-4.60(m,2H),4.24(d,J＝30.9Hz,7H),3.82(s,4H),3.60-3.54(m,1H),3.41(d,J＝10.1Hz,1H). 1 H NMR (400MHz, DMSO-d 6 )δ7.80-7.65(m,2H),7.20(m,7H),4.83-4.60(m,2H),4.24(d,J＝30.9Hz,7H),3.82(s,4H),3.60-3.54 (m,1H),3.41(d,J=10.1Hz,1H).
实施例6：1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物6)的制备：

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-phenylpropane-1-one (Compound 6):

步骤1：3-((叔丁基二苯基硅基)氧基)-2-苯丙酸(化合物6A)的制备
Step 1: Preparation of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid (Compound 6A)
将3-羟基-2-苯丙酸(1.0g,6.0mmol),4-二甲氨基吡啶(1.47g,12mmol)溶于二氯甲烷(10mL)中，然后加入叔丁基二苯基氯硅烷(1.54g,9mmol)，反应体系25℃下搅拌过夜。反应完全后，将反应液浓缩干，通过硅胶柱分离纯化得化合物6A。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-butyldiphenylsilyl chloride (1.54 g, 9 mmol) was added, and the reaction system was stirred overnight at 25° C. After the reaction was complete, the reaction solution was concentrated to dryness and separated and purified by silica gel column to obtain compound 6A.
MS(ESI)m/z 405.2(M+H)+。MS (ESI) m/z 405.2 (M+H) + .
步骤2：苄基1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-羧酸酯(化合物6B)的制备
Step 2: Preparation of benzyl 1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylate (Compound 6B)
将3-(氮杂环丁烷-3-亚基)氮杂环丁烷-1-羧酸苄酯(500mg,2.05mmol)和三乙胺(413mg,4.1mmol)溶于四氢呋喃溶液中(20mL)，随后加入4-(二氟甲氧基)苯磺酰氯(500mg,2.05mmol)，反应体系在25℃搅拌3小时。反应完全后，反应液减压浓缩干，残余物通过硅胶柱分离纯化得化合物6B。3-(Azetidine-3-ylidene)azetidine-1-carboxylic acid benzyl ester (500 mg, 2.05 mmol) and triethylamine (413 mg, 4.1 mmol) were dissolved in tetrahydrofuran solution (20 mL), followed by the addition of 4-(difluoromethoxy)benzenesulfonyl chloride (500 mg, 2.05 mmol), and the reaction system was stirred at 25° C. for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 6B.
MS(ESI)m/z 451.1(M+H)+。MS (ESI) m/z 451.1 (M+H) + .
步骤3：1-((4-(二氟甲氧基)苯基)磺酰基)-1,1',4,4'-四氢-2H,2'H-3,3'-二联氮杂环丁烷亚基(化合物6C)的制备
Step 3: Preparation of 1-((4-(difluoromethoxy)phenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazetidine (Compound 6C)
将苄基1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-羧酸酯(750mg,1.66mmol)溶于三氟乙酸(5mL)中，混合物在40℃搅拌16小时。反应完全后，反应液浓缩干，残余物通过硅胶柱分离纯化得化合物6C。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 the reaction was complete, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 6C.
MS(ESI)m/z 317.1(M+H)+ MS (ESI) m/z 317.1 (M+H) +
步骤4：3-((叔丁基二苯基硅基)氧基)-1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯丙烷-1-酮(化合物6D)的制备
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)
将3-((叔丁基二苯基硅基)氧基)-2-苯丙酸(109mg，0.3mmol)，1-((4-(二氟甲氧基)苯基)磺酰基)-1,1',4,4'-四氢-2H,2'H-3,3'-二联氮杂环丁烷亚基(85mg,0.3mmol)溶于DMF(5mL)中，再加入HATU(157mg,0.4mmol)和DIPEA(104mg,0.8mmol)，反应体系在25℃下搅拌3小时。反应完全后，将反应液浓缩干，通过反相高压液相制备得化合物6D。3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid (109 mg, 0.3 mmol), 1-((4-(difluoromethoxy)phenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazetidine (85 mg, 0.3 mmol) were dissolved in DMF (5 mL), and HATU (157 mg, 0.4 mmol) and DIPEA (104 mg, 0.8 mmol) were added, and the reaction system was stirred at 25° C. for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and compound 6D was prepared by reverse phase high pressure liquid chromatography.
MS(ESI)m/z 703.2(M+H)+ MS (ESI) m/z 703.2 (M+H) +
步骤5：1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'-H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物6)的制备
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)
将3-((叔丁基二苯基硅基)氧基)-1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯丙烷-1-酮(100mg,0.14mmol)，四丁基氟化铵(37mg,0.14mmol)溶于四氢呋喃(5mL)中，反应体系在25℃搅拌3小时。反应完全后，将反应液浓缩干，通过反相高压液相制备得实施例6的化合物6。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 system was stirred at 25° C. for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and compound 6 of Example 6 was prepared by reverse phase high pressure liquid chromatography.
MS(ESI)m/z 465.2(M+H)+ MS (ESI) m/z 465.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.91-7.88(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). 1 H NMR (400MHz, DMSO-d 6 )δ7.91-7.88(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).
实施例7：(S)-1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物7)的制备：
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-phenylpropane-1-one (Compound 7):
在实施例6的步骤4中用(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例7的化合物7。 In step 4 of Example 6, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 7 of Example 7.
MS(ESI)m/z 465.1(M+H)+ MS (ESI) m/z 465.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.91-7.88(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). 1 H NMR (400MHz, DMSO-d 6 )δ7.91-7.88(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).
实施例8：1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-羟基-2-苯基乙烷-1-酮(化合物8)的制备：
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-phenylethane-1-one (Compound 8):
在实施例6的步骤4中用2-羟基-2-苯乙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸采用与实施例6相同的制备方法得到实施例8的化合物8。In step 4 of Example 6, 2-hydroxy-2-phenylacetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid and the same preparation method as Example 6 was used to obtain Compound 8 of Example 8.
MS(ESI)m/z 451.1(M+H)+ MS (ESI) m/z 451.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.90(m,2H),7.45(s,2H),7.30(d,J＝21.5Hz,5H),5.85(s,1H),5.04(s,1H),4.65(d,J＝13.9Hz,1H),4.52(d,J＝14.1Hz,1H),4.29(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.47(s,1H),7.90(m,2H),7.45(s,2H),7.30(d,J＝21.5Hz,5H),5.85(s,1H ),5.04(s,1H),4.65(d,J＝13.9Hz,1H),4.52(d,J＝14.1Hz,1H),4.29(s,6H).
实施例9：(S)-3-羟基-2-苯基-1-(1'-((4-(三氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙烷-1-酮(化合物9)的制备：
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):
在实施例1的步骤8中用4-(三氟甲氧基)苯磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例9的化合物9。In step 8 of Example 1, 4-(trifluoromethoxy)benzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 9 of Example 9.
MS(ESI)m/z 483.1(M+H)+ MS (ESI) m/z 483.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.99-7.96(m,2H),7.67-7.65(d,J＝0.8Hz,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＝0.8Hz,1H),3.63-3.60(m,1H),3.47-3.43(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ7.99-7.96(m,2H),7.67-7.65(d,J＝0.8Hz,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＝0.8Hz,1H),3.63-3.60(m,1H),3.47-3.43(m,1H).
实施例10：(S)-1-(1'-(4-氟苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物10)的制备：
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-phenylpropane-1-one (Compound 10):
在实施例1的步骤8中用4-氟苯磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例10的化合物10。In step 8 of Example 1, 4-fluorobenzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 10 of Example 10.
MS(ESI)m/z 417.1(M+H)+ MS (ESI) m/z 417.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.99-7.96(m,2H),7.67-7.65(d,J＝0.8Hz,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＝0.8Hz,1H),3.63-3.60(m,1H),3.47-3.43(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ7.99-7.96(m,2H),7.67-7.65(d,J＝0.8Hz,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＝0.8Hz,1H),3.63-3.60(m,1H),3.47-3.43(m,1H).
实施例11：(S)-1-(1'-(3-氟-4-二氟甲氧基苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物11)的制备：
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-phenylpropane-1-one (Compound 11):
在实施例1的步骤8中用3-氟-4-二氟甲氧基苯磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例11的化合物11。In step 8 of Example 1, 3-fluoro-4-difluoromethoxybenzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 11 of Example 11.
MS(ESI)m/z 483.1(M+H)+ MS (ESI) m/z 483.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.92-7.89(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＝28.0Hz,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). 1 H NMR (400MHz, DMSO-d 6 )δ7.92-7.89(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＝28.0Hz,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).
实施例12：(S)-1-(1'-((3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物12)的制备：
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-phenylpropane-1-one (Compound 12):
步骤1：6-溴-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(化合物12B)的制备
Step 1: Preparation of tert-butyl 6-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 12B)
将6-溴-3,4-二氢-2H-1,4-苯并恶嗪(2g,9.34mmol),4-二甲氨基吡啶(114mg,0.93mmol)和三乙胺(1.42g,14mmol)溶于四氢呋喃(40mL)中，然后加入二碳酸二叔丁酯(2g,9.34mmol)，反应体系40℃下搅拌16小时。反应完全后，将反应液倒入水中，用乙酸乙酯(60mL*3)萃取，合并有机相并用饱和食盐水洗涤后通无水硫酸钠干燥。通过硅胶柱分离纯化得化合物12B。6-Bromo-3,4-dihydro-2H-1,4-benzoxazine (2g, 9.34mmol), 4-dimethylaminopyridine (114mg, 0.93mmol) and triethylamine (1.42g, 14mmol) were dissolved in tetrahydrofuran (40mL), and then di-tert-butyl dicarbonate (2g, 9.34mmol) was added. The reaction system was stirred at 40°C for 16 hours. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate (60mL*3). The organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. Compound 12B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 314.0(M+H)+。 MS (ESI) m/z 314.0 (M+H) + .
步骤2：6-(苄基硫基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(化合物12C)的制备
Step 2: Preparation of tert-butyl 6-(benzylthio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 12C)
将6-溴-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(500mg,1.59mmol)，苄硫醇(236.8mg,1.91mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(92mg,0.16mmol)，三(二亚苄基丙酮)二钯(73mg,0.07mmol)和N,N-二异丙基乙胺(617mg,4.77mmol)溶于1,4-二氧六环(10mL)中，将反应体系置于40℃搅拌16小时。反应完全后，将反应液倒入水中，水相用乙酸乙酯(40mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。有机相减压浓缩干后，残余物通过硅胶柱分离纯化得化合物12C。6-Bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (500 mg, 1.59 mmol), benzyl mercaptan (236.8 mg, 1.91 mmol), 4,5-bis(diphenylphosphine)-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 the reaction system was stirred at 40 ° C for 16 hours. After the reaction was complete, the reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate (40 mL*3), and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After the organic phase was concentrated to dryness under reduced pressure, the residue was separated and purified by silica gel column to obtain compound 12C.
MS(ESI)m/z 358.1(M+H)+。MS (ESI) m/z 358.1 (M+H) + .
步骤3：6-(氯磺酰基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(化合物12D)的制备
Step 3: Preparation of tert-butyl 6-(chlorosulfonyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 12D)
将6-(苄基硫基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(500mg,1.39mmol)溶于混合溶剂(乙腈:醋酸:水＝40:1.5:1,25mL)中，在0℃搅拌下加入1,3-二氯-5,5-二甲基乙内酰脲(547.6mg,2.78mmol)。然后在室温下搅拌3小时。反应完全后，将反应液倒入水中，用乙酸乙酯(60mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。有机相浓缩干，残余物通过硅胶柱分离纯化得化合物12D。Dissolve 6-(Benzylthio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (500mg, 1.39mmol) in a mixed solvent (acetonitrile: acetic acid: water = 40:1.5:1, 25mL), add 1,3-dichloro-5,5-dimethylhydantoin (547.6mg, 2.78mmol) under stirring at 0°C. Then stir at room temperature for 3 hours. After the reaction is complete, pour the reaction solution into water, extract with ethyl acetate (60mL*3), wash the combined organic phases with saturated brine and dry with anhydrous sodium sulfate. The organic phase is concentrated to dryness, and the residue is separated and purified by silica gel column to obtain compound 12D.
在实施例1的步骤8中用6-(氯磺酰基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例12的化合物12。In step 8 of Example 1, 6-(chlorosulfonyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 12 of Example 12.
MS(ESI)m/z 456.1(M+H)+ MS (ESI) m/z 456.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.34-7.21(m,6H),7.0(s,1H),6.89-6.84(m,2H),6.33(s,1H),4.82-4.79(t,J＝0.8Hz,1H),4.73-4.70(d,J＝1.2Hz,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). 1 H NMR (400MHz, DMSO-d 6 )δ7.34-7.21(m,6H),7.0(s,1H),6.89-6.84(m,2H),6.33(s,1H),4.82-4.79(t,J＝0.8Hz,1H),4.73 - 4.70(d,J=1.2Hz,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).
实施例13：1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)-2-羟基乙烷-1-酮(化合物13)的制备：

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-hydroxyethane-1-one (Compound 13):

步骤1：6-(2-乙氧基-2-氧代乙酰基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(化合物13A)的制备
Step 1: Preparation of tert-butyl 6-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 13A)
将6-溴-2H-苯并[b][1,4]恶嗪-4(3H)-羧酸叔丁酯(500mg,1.59mmol)加入干燥的四氢呋喃(10mL)中，将反应体系置换氮气三次后保持氮气体系，降温至-78℃下，搅拌下缓慢滴加正丁基锂(122mg,1.91mmol)，完毕后-78℃搅拌0.5小时，将草酸二乙酯(256mg,1.75mmol)滴加至反应液中，滴加完毕后升温至室温搅拌1小时。反应完全后，将反应液倒入水中，水相用乙酸乙酯(40mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。有机相浓缩干后通过硅胶柱分离纯化得化合物13A。6-Bromo-2H-benzo[b][1,4]oxazine-4(3H)-carboxylic acid tert-butyl ester (500mg, 1.59mmol) was added to dry tetrahydrofuran (10mL), the reaction system was replaced with nitrogen three times and then the nitrogen system was maintained, the temperature was lowered to -78°C, and n-butyl lithium (122mg, 1.91mmol) was slowly added dropwise under stirring, and the mixture was stirred at -78°C for 0.5 hours after completion, and diethyl oxalate (256mg, 1.75mmol) was added dropwise to the reaction solution, and the mixture was heated to room temperature and stirred for 1 hour after the addition was completed. After the reaction was complete, the reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate (40mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness and separated and purified by silica gel column to obtain compound 13A.
MS(ESI)m/z 336.1(M+H)+。MS (ESI) m/z 336.1 (M+H) + .
步骤2：6-(2-乙氧基-1-羟基-2-氧代乙基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(化合物13B)的制备
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)
将6-(2-乙氧基-2-氧代乙酰基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(170mg,0.50mmol)加入四氢呋喃(8mL)中，在0℃搅拌下，加入硼氢化钠(29mg,0.76mmol)。然后在室温下搅拌0.5小时。反应完全后，将反应液倒入水中，用乙酸乙酯(30mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。有机相减压浓缩干后，残余物通过硅胶柱分离纯化得化合物13B。6-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (170 mg, 0.50 mmol) was added to tetrahydrofuran (8 mL), and sodium borohydride (29 mg, 0.76 mmol) was added under stirring at 0°C. Then, the mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the organic phase was concentrated to dryness under reduced pressure, the residue was separated and purified by silica gel column to obtain compound 13B.
MS(ESI)m/z 338.1(M+H)+。MS (ESI) m/z 338.1 (M+H) + .
步骤3：2-(4-(叔丁氧羰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)-2-羟基乙酸(化合物13C)的制备
Step 3: Preparation of 2-(4-(tert-Butyloxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-hydroxyacetic acid (Compound 13C)
将6-(2-乙氧基-1-羟基-2-氧代乙基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(170mg,粗品)和氢氧化锂水合物(106mg,2.52mmol)加入四氢呋喃(3mL)和水(3mL)的混合溶液中，室温下搅拌16小时。反应完全后，反应液在冰浴下用2N盐酸溶液调pH至4-5，加水稀释后用乙酸乙酯(20mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。有机相浓缩干，残余物通过硅胶柱分离纯化得化合物13C。6-(2-ethoxy-1-hydroxy-2-oxoethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (170 mg, crude product) and lithium hydroxide hydrate (106 mg, 2.52 mmol) were added to a mixed solution of tetrahydrofuran (3 mL) and water (3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was adjusted to pH 4-5 with 2N hydrochloric acid solution under an ice bath, diluted with water and extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the residue was separated and purified by silica gel column to obtain compound 13C.
MS(ESI)m/z 310.1(M+H)+。MS (ESI) m/z 310.1 (M+H) + .
在实施例6的步骤4中用2-(4-(叔丁氧羰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)-2-羟基乙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例13的化合物13。In step 4 of Example 6, 2-(4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-hydroxyacetic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 13 of Example 13.
MS(ESI)m/z 508.1(M+H)+ MS (ESI) m/z 508.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.95-7.88(d,J＝8Hz,2H),7.49-7.43(d,J＝8Hz,3H),6.56-6.51(m,2H),6.41-6.39(m,1H),5.76(s,1H),5.49-5.48(d,J＝4Hz,1H),4.81-4.79(d,J＝8Hz,1H),4.61-4.57(d,J＝16Hz,1H),4.42-4.38(d,J＝16Hz,1H),4.27(s,6H),4.07-4.05(m,2H),3.22(s,2H). 1 H NMR (400MHz, DMSO-d 6 )δ7.95-7.88(d,J＝8Hz,2H),7.49-7.43(d,J＝8Hz,3H),6.56-6.51(m,2H),6.41-6.39(m,1H),5.76(s ,1H),5.49-5.48(d,J＝4Hz,1 H),4.81-4.79(d,J＝8Hz,1H),4.61-4.57(d,J＝16Hz,1H),4.42-4.38(d,J＝16Hz,1H),4.27(s,6H),4.07 -4.05(m,2H),3.22(s,2H).
实施例14：(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)(4-苯基四氢-2H-吡喃-4-基)甲酮(化合物14)的制备：
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):
步骤1：4-苯基四氢-2H-吡喃-4-羧酸甲酯(化合物14B)的制备
Step 1: Preparation of methyl 4-phenyltetrahydro-2H-pyran-4-carboxylate (Compound 14B)
将2-苯乙酸甲酯(2.0g,13.32mmol)溶于四氢呋喃(40.0mL)中，将反应体系温度降至0℃，随后分批慢慢加入氢化钠(1.06g,26.64mmol)。反应液在0℃搅拌30分钟之后滴加2-碘乙醚(3.47g,10.65mmol)。滴加完毕后反应体系在0℃下搅拌10分钟后缓慢升至室温。随后将反应体系升温至50℃下搅拌18小时。反应完全后加水淬灭反应，水相用乙酸乙酯(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物14B。Dissolve methyl 2-phenylacetate (2.0 g, 13.32 mmol) in tetrahydrofuran (40.0 mL), lower the temperature of the reaction system to 0 ° C, and then slowly add sodium hydride (1.06 g, 26.64 mmol) in batches. After stirring the reaction solution at 0 ° C for 30 minutes, 2-iodoethyl ether (3.47 g, 10.65 mmol) was added dropwise. After the addition was completed, the reaction system was stirred at 0 ° C for 10 minutes and then slowly warmed to room temperature. The reaction system was then heated to 50 ° C and stirred for 18 hours. After the reaction was complete, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL * 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 14B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 221.1(M+H)+。MS (ESI) m/z 221.1 (M+H) + .
步骤2：4-苯基四氢-2H-吡喃-4-羧酸(化合物14C)的制备
Step 2: Preparation of 4-phenyltetrahydro-2H-pyran-4-carboxylic acid (Compound 14C)
将4-苯基四氢-2H-吡喃-4-羧酸甲酯(1.0g,4.54mmol)溶于甲醇(10.0mL)和水(10.0mL)中，随后加入氢氧化钠(544.8mg,13.62mmol)，反应液在50℃搅拌3小时。反应完全后，反应体系用1N盐酸调pH至2，用二氯甲烷(50mL*3)萃取，合并有机相用饱和食盐水洗涤后用无水硫酸钠干燥。有机相减压浓缩干后，残余物通过硅胶柱分离纯化得化合物14C。4-Phenyltetrahydro-2H-pyran-4-carboxylic acid methyl ester (1.0 g, 4.54 mmol) was dissolved in methanol (10.0 mL) and water (10.0 mL), followed by the addition of sodium hydroxide (544.8 mg, 13.62 mmol), and the reaction solution was stirred at 50°C for 3 hours. After the reaction was complete, the reaction system was adjusted to pH 2 with 1N hydrochloric acid, extracted with dichloromethane (50 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After the organic phase was concentrated under reduced pressure, the residue was separated and purified by silica gel column to obtain compound 14C.
MS(ESI)m/z 338.1(M+H)+。MS (ESI) m/z 338.1 (M+H) + .
在实施例6的步骤4中用4-苯基四氢-2H-吡喃-4-羧酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例14的化合物14。In step 4 of Example 6, 4-phenyltetrahydro-2H-pyran-4-carboxylic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 14 of Example 14.
MS(ESI)m/z 505.1(M+H)+ MS (ESI) m/z 505.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.88-7.84(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＝11.0Hz,2H),2.15(d,J＝13.5Hz,2H),1.91-1.72(m,2H). 1 H NMR(400MHz,DMSO-d6)δ7.88-7.84(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＝11.0Hz,2H),2.15(d,J＝13.5Hz,2H),1.91-1.72(m,2H).
实施例15：1-(1'-((2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(3-甲氧基苯基)-3-(甲氨基)丙烷-1-酮(化合物15)的制备：
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)propane-1-one (Compound 15):
步骤1：2-(3-甲氧基苯基)丙烯酸甲酯(化合物15B)的制备
Step 1: Preparation of methyl 2-(3-methoxyphenyl)acrylate (Compound 15B)
将2-(3-甲氧基苯基)乙酸甲酯(2.00g,11.10mmol)加入N,N-二甲基甲酰胺(20.0mL)中，随后依次加入碳酸钾(3.83g,27.75mmol)，三聚甲醛(1.19g,13.32mmol)以及四丁基碘化铵(410.0mg,1.11mmol)。反应液在80℃下反应半小时。反应完全后。通过硅胶柱分离纯化得化合物15B。2-(3-methoxyphenyl)acetic acid methyl ester (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 half an hour. After the reaction was complete, compound 15B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 193.1(M+H)+。MS (ESI) m/z 193.1 (M+H) + .
步骤2：2-(3-甲氧基苯基)-2-(甲氨基)乙酸甲酯(化合物15C)的制备
Step 2: Preparation of methyl 2-(3-methoxyphenyl)-2-(methylamino)acetate (Compound 15C)
将2-(3-甲氧基苯基)丙烯酸甲酯(2.02g,10.5mmol)加入甲氨四氢呋喃溶液(20.0mL)中，室温下反应4小时。通过硅胶柱分离纯化得化合物15C。Methyl 2-(3-methoxyphenyl)acrylate (2.02 g, 10.5 mmol) was added to a solution of methylamine in tetrahydrofuran (20.0 mL) and reacted at room temperature for 4 hours. Compound 15C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 224.1(M+H)+。MS (ESI) m/z 224.1 (M+H) + .
步骤3：3-((叔丁氧羰基)(甲基)氨基)-2-(3-甲氧基苯基)丙酸甲酯(化合物15D)的制备
Step 3: Preparation of methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoate (Compound 15D)
将2-(3-甲氧基苯基)-2-(甲氨基)乙酸甲酯(2.00g,8.96mmol)和4-二甲氨基吡啶溶于二氯甲烷(10.0mL)中，加入三乙胺(1.81g,17.92mmol)、二碳酸二叔丁酯(1.95g,8.96mmol)。常温下反应两小时，反应完全后，向反应体系中加水淬灭并用2N盐酸水溶液调节pH至5-6。然后用乙酸乙酯(20.0mL*3)萃取。合并有机层用饱和氯化钠(20.0mL)洗涤后用无水硫酸钠干燥。有机相减压浓缩干后，残余物通过硅胶柱分离纯化得化合物15D。2-(3-methoxyphenyl)-2-(methylamino)acetic acid methyl ester (2.00g, 8.96mmol) and 4-dimethylaminopyridine were dissolved in dichloromethane (10.0mL), and triethylamine (1.81g, 17.92mmol) and di-tert-butyl dicarbonate (1.95g, 8.96mmol) were added. The reaction was carried out at room temperature for two hours. After the reaction was complete, water was added to the reaction system to quench the reaction and the pH was adjusted to 5-6 with 2N hydrochloric acid aqueous solution. Then it was extracted with ethyl acetate (20.0mL*3). The combined organic layers were washed with saturated sodium chloride (20.0mL) and dried over anhydrous sodium sulfate. After the organic phase was concentrated under reduced pressure, the residue was separated and purified by silica gel column to obtain compound 15D.
MS(ESI)m/z 324.2(M+H)+。MS (ESI) m/z 324.2 (M+H) + .
步骤4：3-((叔丁氧羰基)(甲基)氨基)-2-(3-甲氧基苯基)丙酸(化合物15E)的制备
Step 4: Preparation of 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoic acid (Compound 15E)
将3-((叔丁氧羰基)(甲基)氨基)-2-(3-甲氧基苯基)丙酸甲酯(669.0mg,2.07mmol)溶于四氢呋喃(5.0mL)和水(5.0mL)中，加入氢氧化锂(99.1mg,4.14mmol)。常温下反应16小时，反应完全反应后，有机相减压浓缩干后，残余物通过硅胶柱分离纯化得化合物15E。Methyl 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoate (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 mixture was reacted at room temperature for 16 hours. After the reaction was complete, the organic phase was concentrated under reduced pressure and the residue was separated and purified by silica gel column to obtain compound 15E.
MS(ESI)m/z 310.2(M+H)+。MS (ESI) m/z 310.2 (M+H) + .
在实施例1的步骤8中用2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-((叔丁氧羰基)(甲基)氨基)-2-(3-甲氧基苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例15的化合物15。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]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 15 of Example 15.
MS(ESI)m/z 500.2(M+H)+。MS (ESI) m/z 500.2 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.28-7.22(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). 1 H NMR (400MHz, DMSO-d 6 )δ7.28-7.22(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).
实施例16：1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙烷-1-酮(化合物16)的制备：
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-hydroxypropane-1-one (Compound 16):
步骤1：2-(4-氟苯基)-3-羟基丙酸甲酯(化合物16B)的制备
Step 1: Preparation of methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (Compound 16B)
将4-氟苯基乙酸甲酯(1.0g,5.95mmol)和多聚甲醛(562.5mg,6.24mmol)溶于二甲基亚砜(40.0mL)，随后加入甲醇钠(16.1mg,0.30mmol)。反应液在室温下反应4小时。反应完全，向反应体系中加入水淬灭，水相用乙酸乙酯(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。有机相减压浓缩干后，残余物通过硅胶柱分离纯化得化合物16B。Methyl 4-fluorophenylacetate (1.0 g, 5.95 mmol) and paraformaldehyde (562.5 mg, 6.24 mmol) were dissolved in dimethyl sulfoxide (40.0 mL), followed by the addition of sodium methoxide (16.1 mg, 0.30 mmol). The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, water was added to the reaction system to quench, the aqueous phase was extracted with ethyl acetate (50 mL*3), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After the organic phase was concentrated under reduced pressure, the residue was separated and purified by silica gel column to obtain compound 16B.
MS(ESI)m/z 199.1(M+H)+。MS (ESI) m/z 199.1 (M+H) + .
步骤2：2-(4-氟苯基)-3-羟基丙酸(化合物16C)的制备
Step 2: Preparation of 2-(4-fluorophenyl)-3-hydroxypropanoic acid (Compound 16C)
将2-(4-氟苯基)-3-羟基丙酸甲酯(600.0mg,3.03mmol)溶于甲醇(9.0mL)和水(6.0mL)中，随后加入氢氧化钠(242.2mg,6.05mmol)，反应液在50℃搅拌3小时。反应完全后，反应液用1N的盐酸水溶液调pH＝2，用二氯甲烷(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩得白色固体化合物残余物通过硅胶柱分离纯化得化合物16C。2-(4-fluorophenyl)-3-hydroxypropionic acid methyl ester (600.0 mg, 3.03 mmol) was dissolved in methanol (9.0 mL) and water (6.0 mL), followed by the addition of sodium hydroxide (242.2 mg, 6.05 mmol), and the reaction solution was stirred at 50°C for 3 hours. After the reaction was complete, the reaction solution was adjusted to pH = 2 with 1N hydrochloric acid aqueous solution, extracted with dichloromethane (50 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The white solid compound residue was concentrated and separated and purified by silica gel column to obtain compound 16C.
MS(ESI)m/z 185.1(M+H)+。MS (ESI) m/z 185.1 (M+H) + .
在实施例6的步骤4中用2-(4-氟苯基)-3-羟基丙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例16的化合物16。In step 4 of Example 6, 2-(4-fluorophenyl)-3-hydroxypropionic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as Example 6 was used to obtain Compound 16 of Example 16.
MS(ESI)m/z 483.1(M+H)+。MS (ESI) m/z 483.1 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.91-7.89(d,J＝7.7Hz,2H),7.63-7.29(m,5H),7.12-7.09(m,2H),4.85(s,1H),4.70(d,J＝12.7Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ7.91-7.89 (d, J = 7.7Hz, 2H), 7.63-7.29 (m, 5H), 7.12-7.09 (m, 2H), 4.85 (s, 1H) ),4.70(d,J＝12.7Hz,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).
实施例17：1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-3-甲基-2-苯基丁烷-1-酮(化合物17)的制备：
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-phenylbutane-1-one (Compound 17):
步骤1：3-羟基-3-甲基-2-苯基丁酸(化合物17B)的制备
Step 1: Preparation of 3-hydroxy-3-methyl-2-phenylbutyric acid (Compound 17B)
将2-苯乙酸(0.7g,5.14mmol)溶于四氢呋喃(11.0mL)中，室温下滴加异丙基氯化镁(1.06g,10.28mmol,2M)，滴加完毕后将反应液在40℃下搅拌1小时。随后加入丙酮(328.5mg,5.66mmol)，反应液在40℃下继续搅拌1小时。用3N盐酸将反应液调至pH＝2，水相用二氯甲烷(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩得白色固体化合物残余物通过硅胶柱分离纯化得化合物17B。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 was complete, 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, the aqueous phase was extracted with dichloromethane (50 mL * 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The white solid compound residue was concentrated and separated and purified by silica gel column to obtain compound 17B.
MS(ESI)m/z 195.1(M+H)+。MS (ESI) m/z 195.1 (M+H) + .
在实施例6的步骤4中用3-羟基-3-甲基-2-苯基丁酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例17的化合物17。In step 4 of Example 6, 3-hydroxy-3-methyl-2-phenylbutyric acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as Example 6 was used to obtain Compound 17 of Example 17.
MS(ESI)m/z 493.2(M+H)+。MS (ESI) m/z 493.2 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.90-7.88(m,2H),7.63-7.19(m,8H),4.91(s,1H),4.75-4.72(d,J＝13.3Hz,1H),4.28-4.22(m,7H),3.50(s,1H),1.13(s,3H),0.98(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.90-7.88 (m, 2H), 7.63-7.19 (m, 8H), 4.91 (s, 1H), 4.75-4.72 (d, J = 13.3Hz, 1H ),4.28-4.22(m,7H),3.50(s,1H),1.13(s,3H),0.98(s,3H).
实施例18：1-(1'-((2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙烷-1-酮(化合物18)的制备：
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-hydroxypropane-1-one (Compound 18):
在实施例1的步骤10中用3-((叔丁氧羰基)(甲基)氨基)-2-(3-甲氧基苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例15的化合物18。In step 10 of Example 1, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-methoxyphenyl)propanoic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 1 was used to obtain Compound 18 of Example 15.
MS(ESI)m/z 475.1(M+H)+。 MS (ESI) m/z 475.1 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.34-7.24(m,4H),7.14-7.10(m,2H),7.06(d,J＝8.4Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ7.34-7.24 (m, 4H), 7.14-7.10 (m, 2H), 7.06 (d, J = 8.4Hz, 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).
实施例19：1-(1'-((2,3-二氢-[1,4]二氧戊环[2,3-b]吡啶-7-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙烷-1-酮(化合物19)的制备：
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-hydroxypropane-1-one (Compound 19):
在实施例1的步骤10中用2-(4-氟苯基)-3-羟基丙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例19的化合物19。In step 10 of Example 1, 2-(4-fluorophenyl)-3-hydroxypropionic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as Example 6 was used to obtain Compound 19 of Example 19.
MS(ESI)m/z 476.1(M+H)+。MS (ESI) m/z 476.1 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ8.28(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). 1 H NMR (400MHz, DMSO-d 6 ) δ8.28(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).
实施例20：(S)-1-(1'-((8-氟-2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物20)的制备：
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-phenylpropane-1-one (Compound 20):
步骤1：7-溴-5-氟-2,3-二氢苯并[b][1,4]二恶英(化合物20B)的制备
Step 1: Preparation of 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin (Compound 20B)
将5-溴-3-氟苯-1,2-二醇(500mg,2.42mmol)，1,2-二溴乙烷(680.67mg,3.62mmol)，碳酸钾(1.0g,7.25mmol)加入到N,N-二甲基甲酰胺(5mL)中，最后将反应体系在100℃下搅拌16小时。反应完全后，将反应液减压浓缩干，残余物通过硅胶柱分离纯化得化合物20B。5-Bromo-3-fluorobenzene-1,2-diol (500 mg, 2.42 mmol), 1,2-dibromoethane (680.67 mg, 3.62 mmol), potassium carbonate (1.0 g, 7.25 mmol) were added to N,N-dimethylformamide (5 mL), and the reaction system was stirred at 100° C. for 16 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 20B.
MS(ESI)m/z 233.0(M+H)+。MS (ESI) m/z 233.0 (M+H) + .
步骤2：7-(苄基硫基)-5-氟-2,3-二氢苯并[b][1,4]二恶英(化合物20C)的制备
Step 2: Preparation of 7-(benzylthio)-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin (Compound 20C)
将7-溴-5-氟-2,3-二氢苯并[b][1,4]二恶英(330mg,1.42mmol)，苯甲硫醇(175.88mg,1.42mmol)，N,N-二异丙基乙胺(365.35mg,2.83mmol)，三(二亚苄基丙酮)二钯-氯仿加合物(64.84mg,70.81μmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(81.94mg,141.61μmol)加入到1,4-二氧六环(6mL)中，最后将反应体系置于80℃搅拌16小时。反应完全后，将反应液减压浓缩干，残余物通过硅胶柱分离纯化得化合物20C。7-Bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin (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), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (81.94 mg, 141.61 μmol) were added to 1,4-dioxane (6 mL), and the reaction system was stirred at 80°C for 16 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 20C.
MS(ESI)m/z 277.1(M+H)+。MS (ESI) m/z 277.1 (M+H) + .
步骤3：8-氟-2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯(化合物20D)的制备
Step 3: Preparation of 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride (Compound 20D)
将7-(苄基硫基)-5-氟-2,3-二氢苯并[b][1,4]二恶英(200mg,723.78μmol)，二氯海茵(285.20mg,1.45mmol)加入到乙腈(7.5mL),乙酸(0.19mL)，水(0.13mL),加毕反应体系25℃下搅拌16小时，反应完全后。反应液减压浓缩干，残余物通过硅胶柱分离纯化得化合物20D。7-(Benzylthio)-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin (200 mg, 723.78 μmol) and dichlorobenzene (285.20 mg, 1.45 mmol) were added to acetonitrile (7.5 mL), acetic acid (0.19 mL) and water (0.13 mL). The reaction system was stirred at 25°C for 16 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 20D.
MS(ESI)m/z 253.0(M+H)+。MS (ESI) m/z 253.0 (M+H) + .
在实施例1的步骤8中用8-氟-2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例20的化合物20。In step 8 of Example 1, 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 20 of Example 20.
MS(ESI)m/z 475.1(M+H)+。MS (ESI) m/z 475.1 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.31-7.15(m,7H),4.73-4.70(d,J＝13.0Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ7.31-7.15 (m, 7H), 4.73-4.70 (d, J = 13.0Hz, 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).
实施例21：2-氨基-1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯基乙-1-酮(化合物21)的制备：
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):
在实施例6的步骤4中用2-((叔丁氧基羰基)氨基)-2-苯乙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例21的化合物21。In step 4 of Example 6, 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 21 of Example 21.
MS(ESI)m/z 450.1(M+H)+。MS (ESI) m/z 450.1 (M+H) + .
1H-NMR(400MHz,DMSO-d6)δ7.91-7.89(m,2H),7.45-7.43(m,3H),7.32-7.22(m,5H),4.72-4.69(d,J＝10.4Hz,1H),4.37-4.19(m,8H),2.12(s,2H). 1 H-NMR (400MHz, DMSO-d 6 ) δ7.91-7.89 (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).
实施例22：2-氨基-1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)乙-1-酮(化合物22)的制备：
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):
在实施例6的步骤4中用2-((叔丁氧基羰基)氨基)-2-(4-氟苯基)乙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例22的化合物22。In step 4 of Example 6, 2-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)acetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 22 of Example 22.
MS(ESI)m/z 468.1(M+H)+。MS (ESI) m/z 468.1 (M+H) + .
1H-NMR(400MHz,DMSO-d6)δ7.91-7.89(d,J＝8.8Hz,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). 1 H-NMR (400MHz, DMSO-d 6 ) δ7.91-7.89 (d, J = 8.8Hz, 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).
实施例23：2-氨基-1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(3-(三氟甲基)苯基)乙-1-酮(化合物23)的制备：
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):
在实施例6的步骤4中用2-((叔丁氧基羰基)氨基)-2-(3-(三氟甲基)苯基)乙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例23的化合物23。In step 4 of Example 6, 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)acetic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 23 of Example 23.
MS(ESI)m/z 518.1(M+H)+。MS (ESI) m/z 518.1 (M+H) + .
1H-NMR(400MHz,DMSO-d6)δ7.92-7.90(d,J＝8.8Hz,2H),7.67-7.51(m,4H),7.46-7.44(d,J＝8.5Hz,2H),4.80-4.75(d,J＝13.7Hz,1H),4.53-4.21(m,8H),2.33-2.27(d,J＝24.7Hz,2H). 1 H-NMR (400MHz, DMSO-d 6 ) δ7.92-7.90 (d, J＝8.8Hz, 2H), 7.67-7.51 (m, 4H), 7.46-7.44 (d, J＝8.5Hz, 2H) ,4.80-4.75(d,J＝13.7Hz,1H),4.53-4.21(m,8H),2.33-2.27(d,J＝24.7Hz,2H).
实施例24：1-(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-羟基-2-(2-甲基苯并[d]噻唑-4-基)乙烷-1-酮(化合物24)的制备：
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)ethane-1-one (Compound 24):
步骤1：2-甲基-4-羟甲基苯并[d]噻唑(化合物24B)的制备:
Step 1: Preparation of 2-methyl-4-hydroxymethylbenzo[d]thiazole (Compound 24B):
将4-溴-2-甲基-1,3-苯并噻唑(200mg,876.77μmol)和三丁基甲锡甲醇(430mg,1.34mmol)溶入1,4-二氧六环(5mL)中，在室温下加入四(三苯基膦)钯(100mg,86.58μmol),所得混合物在氮气保护下在100℃搅拌16小时。冷却至室温后，反应混合物用饱和氯化铵水溶液淬灭，水相用乙酸乙酯(10mL*3)萃取，合并有机相用饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物24B。4-Bromo-2-methyl-1,3-benzothiazole (200 mg, 876.77 μmol) and tributyltin carbinol (430 mg, 1.34 mmol) were dissolved in 1,4-dioxane (5 mL), and tetrakis(triphenylphosphine)palladium (100 mg, 86.58 μmol) was added at room temperature. The resulting mixture was stirred at 100 ° C for 16 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 24B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 180.0(M+H)+。MS (ESI) m/z 180.0 (M+H) + .
步骤2：2-甲基苯并[d]噻唑-4-甲醛(化合物24C)的制备:
Step 2: Preparation of 2-methylbenzo[d]thiazole-4-carbaldehyde (Compound 24C):
在-78℃下，向二甲基亚砜(65mg,831.91μmol)的二氯甲烷(3mL)溶液缓慢滴加草酰氯(70mg,551.50μmol)，所得混合物在-78℃在氮气保护下搅拌0.5小时。随后在相同温度下加入2-甲基-4-羟甲基苯并[d]噻唑(50mg,278.96μmol)的二氯甲烷(2mL)溶液，并将所得混合物在此温度下搅拌1小时，随后加入三乙胺(0.3mL)并将所得混合物继续搅拌0.5小时后升到室温再搅拌0.5小时。反应完全后。用10mL盐水淬灭反应混合物。水相用乙酸乙酯(10mL*3)萃取，合并有机相用饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物24C。At -78 ° C, 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), and the resulting mixture was stirred at -78 ° C under nitrogen protection for 0.5 hours. Subsequently, 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 hour, followed by the addition of triethylamine (0.3 mL) and the resulting mixture was continued to be stirred for 0.5 hours and then warmed to room temperature and stirred for another 0.5 hours. After the reaction was complete. The reaction mixture was quenched with 10 mL of brine. The aqueous phase was extracted with ethyl acetate (10 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 24C was separated and purified by silica gel column.
MS(ESI)m/z 178.0(M+H)+ MS (ESI) m/z 178.0 (M+H) +
步骤3：2-羟基-2-(2-甲基苯并[d]噻唑-4-基)乙腈(化合物24D)的制备:
Step 3: Preparation of 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetonitrile (Compound 24D):
将2-甲基-1,3-苯并噻唑-4-甲醛(110mg,620.69μmol)溶入二氯甲烷(3mL)中，室温下加入三甲基氰硅烷(180mg,1.82mmol)和碘化锌(100mg,313.48μmol)。所得混合物在氮气保护下室温搅拌2小时。用10mL盐水淬灭反应混合物。水相用乙酸乙酯(10mL*3)萃取,合并有机相用饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物24D。2-Methyl-1,3-benzothiazole-4-carboxaldehyde (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 for 2 hours under nitrogen protection. The reaction mixture was quenched with 10 mL of brine. The aqueous phase was extracted with ethyl acetate (10 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 24D was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 205.1(M+H)+ MS (ESI) m/z 205.1 (M+H) +
步骤4：2-羟基-2-(2-甲基苯并[d]噻唑-4-基)乙酸甲酯(化合物24E)的制备:
Step 4: Preparation of methyl 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetate (Compound 24E):
将2-羟基-2-(2-甲基-1,3-苯并噻唑-4-基)乙腈(110mg,538.56μmol)溶于甲醇(3mL)中，随后滴加浓盐酸(3mL)，将所得混合物在氮气保护下60℃搅拌2小时。反应结束将反应混合物浓缩并用饱和碳酸氢钠水溶液将溶液的pH值调节至7-8。水相用乙酸乙酯(10mL*3)萃取，合并有机相用饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物24E。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 then added dropwise. The resulting mixture was stirred at 60 ° C for 2 hours under nitrogen protection. After the reaction, the reaction mixture was concentrated and the pH value of the solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (10 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 24E was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 238.0(M+H)+ MS (ESI) m/z 238.0 (M+H) +
步骤5：2-羟基-2-(2-甲基苯并[d]噻唑-4-基)乙酸(化合物24F)的制备:
Step 5: Preparation of 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetic acid (Compound 24F):
将2-羟基-2-(2-甲基-1,3-苯并噻唑-4-基)乙酸甲酯(125mg,526.82μmol)溶于四氢呋喃(3mL)和水(3mL)的混合溶液中，随后加入氢氧化锂的一水合物(100mg,2.44mmol)，将所得混合物在室温下搅拌16小时。将反应混合物浓缩并用2N稀盐酸将溶液的pH值调节至5-6。水相用乙酸乙酯(10mL*3)萃取，合并有机相用饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物24F。2-Hydroxy-2-(2-methyl-1,3-benzothiazol-4-yl)acetic acid methyl ester (125mg, 526.82μmol) was dissolved in a mixed solution of tetrahydrofuran (3mL) and water (3mL), followed by the addition of lithium hydroxide monohydrate (100mg, 2.44mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the pH value of the solution was adjusted to 5-6 with 2N dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 24F was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 224.1(M+H)+ MS (ESI) m/z 224.1 (M+H) +
在实施例6的步骤4中用2-羟基-2-(2-甲基苯并[d]噻唑-4-基)乙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例24的化合物24。In step 4 of Example 6, 2-hydroxy-2-(2-methylbenzo[d]thiazol-4-yl)acetic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 24 of Example 24.
MS(ESI)m/z 522.1(M+H)+。MS (ESI) m/z 522.1 (M+H) + .
1H-NMR(400MHz,DMSO-d6)δ7.96-7.90(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). 1 H-NMR (400MHz, DMSO-d 6 ) δ7.96-7.90(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).
实施例25：(S)-1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙-1-酮(化合物25)的制备：
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):
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例25的化合物25。 In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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, and the same preparation method as in Example 1 was used to obtain compound 25 of Example 25.
MS(ESI)m/z 474.1(M+H)+。MS (ESI) m/z 474.1 (M+H) + .
1H-NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.82(s,1H),8.35-8.33(d,J＝8.0Hz,1H),7.96-7.94(d,J＝8.0Hz,1H),7.30-7.27(m,2H),7.13-7.08(m,2H),4.82(s,1H),4.69-4.66(d,J＝12.0Hz,1H),4.35-4.16(m,8H),3.83(s,1H),3.64-3.61(m,1H) 1 H-NMR (400MHz, DMSO-d 6 ) δ9.69 (s, 1H), 8.82 (s, 1H), 8.35-8.33 (d, J＝8.0Hz, 1H), 7.96-7.94 (d, J＝ 8.0Hz,1H),7.30-7.27(m,2H),7.13-7.08(m,2H),4.82(s,1H),4.69-4.66(d,J＝12.0Hz,1H),4.35-4.16(m ,8H),3.83(s,1H),3.64-3.61(m,1H)
实施例26：2-(3-氯苯基)-1-(1'-((2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-(甲氨基)丙-1-酮(化合物26)的制备：
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):
在实施例1的步骤10中用3-((叔丁氧羰基)(甲基)氨基)-2-(3-氯苯基)丙酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例26的化合物26。In step 10 of Example 1, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chlorophenyl)propanoic acid was used to replace 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 26 of Example 26.
MS(ESI)m/z 504.1(M+H)+。MS (ESI) m/z 504.1 (M+H) + .
1H-NMR(400MHz,DMSO-d6)δ7.36-7.24(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) 1 H-NMR (400MHz, DMSO-d 6 ) δ7.36-7.24 (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)
实施例27：(S)-1-(1'-((3-氟-4-(恶唑-2-基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯基丙烷-1-酮(化合物27)的制备：
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-phenylpropane-1-one (Compound 27):
步骤1：4-溴-N-(2,2-二甲氧基乙基)-2-氟苯甲酰胺(化合物27B)的制备:
Step 1: Preparation of 4-bromo-N-(2,2-dimethoxyethyl)-2-fluorobenzamide (Compound 27B):
将4-溴-2-氟-苯甲酸(3g,13.70mmol)溶于二氯甲烷(40mL)溶液中，随后添加加入N,N-二异丙基乙胺(3.53g,27.40mmol)、N,N-羰基二咪唑(2.17g,15.07mmol)。将反应在25℃搅拌30分钟。再向上述混合物中加入2,2-二甲氧基乙胺(1.58g,15.07mmol)并在25℃再搅拌4小时。反应完全后，通过硅胶柱分离纯化得化合物27B。4-Bromo-2-fluoro-benzoic acid (3 g, 13.70 mmol) was dissolved in dichloromethane (40 mL) solution, followed by addition of N,N-diisopropylethylamine (3.53 g, 27.40 mmol) and N,N-carbonyldiimidazole (2.17 g, 15.07 mmol). The reaction 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 another 4 hours. After the reaction was complete, the compound 27B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 306.1(M+H)+ MS (ESI) m/z 306.1 (M+H) +
步骤2：2-(4-溴-2-氟苯基)恶唑(化合物27C)的制备:
Step 2: Preparation of 2-(4-bromo-2-fluorophenyl)oxazole (Compound 27C):
将4-溴-N-(2,2-二甲氧基乙基)-2-氟-苯甲酰胺(2.1g,6.86mmol)加入多聚磷酸(20mL)中90℃反应5小时。反应完全后，通过硅胶柱分离纯化得化合物27C。4-Bromo-N-(2,2-dimethoxyethyl)-2-fluoro-benzamide (2.1 g, 6.86 mmol) was added to polyphosphoric acid (20 mL) and reacted at 90° C. for 5 hours. After the reaction was complete, the mixture was separated and purified by silica gel column to obtain compound 27C.
MS(ESI)m/z 243.0(M+H)+ MS (ESI) m/z 243.0 (M+H) +
步骤3：2-(4-(苄硫基)-2-氟苯基)恶唑(化合物27D)的制备:
Step 3: Preparation of 2-(4-(Benzylthio)-2-fluorophenyl)oxazole (Compound 27D):
向2-(4-溴-2-氟苯基)噁唑(0.8g,3.31mmol)的1,4-氧六环(10mL)溶液中加入苯甲硫醇(410.51mg,3.31mmol)、N,N-二异丙基乙胺(1.07g,8.26mmol)、三(二亚苄基丙酮)二钯(342.09mg,330.52μmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(382.74mg,661.04μmol)并在氮气保护下于90℃下搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物27D。To a solution of 2-(4-bromo-2-fluorophenyl)oxazole (0.8 g, 3.31 mmol) in 1,4-oxathane (10 mL) were added benzylmercaptan (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) and stirred at 90° C. for 3 hours under nitrogen protection. After the reaction was complete, the compound 27D was obtained by separation and purification by silica gel column.
MS(ESI)m/z 286.3(M+H)+ MS (ESI) m/z 286.3 (M+H) +
步骤4：3-氟-4-(恶唑-2-基)苯磺酰氯(化合物27E)的制备:
Step 4: Preparation of 3-fluoro-4-(oxazol-2-yl)benzenesulfonyl chloride (Compound 27E):
将2-(4-苄基硫烷基-2-氟-苯基)噁唑(0.7g,2.45mmol)溶于二氯甲烷(10mL)溶液、水(176.63mg,9.81mmol)和冰醋酸(735.98mg,12.27mmol)的混合溶液中，然后在0℃滴加磺酰氯(1.32g，9.81mmol)。将所得混合体系在20℃搅拌5小时。反应完全后，通过硅胶柱分离纯化得化合物27E。2-(4-Benzylsulfanyl-2-fluoro-phenyl)oxazole (0.7 g, 2.45 mmol) was dissolved in a mixed solution 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 the reaction was complete, the compound 27E was separated and purified by silica gel column.
MS(ESI)m/z 262.0(M+H)+ MS (ESI) m/z 262.0 (M+H) +
在实施例1的步骤8中用3-氟-4-(恶唑-2-基)苯磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例27的化合物27。In step 8 of Example 1, 3-fluoro-4-(oxazol-2-yl)benzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 27 of Example 27.
MS(ESI)m/z 484.1(M+H)+ MS (ESI) m/z 484.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.41(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＝0.8Hz,1H),4.71-4.68(d,J＝1.2Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ8.41(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＝0.8Hz,1H),4.71-4.68(d,J＝1.2Hz,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).
实施例28：2-(3-氯-4-氟-2-甲氧基苯基)-1-(1'-(2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-(甲氨基)丙-1-酮(化合物28)的制备：
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):
步骤1：2-(4-氟-2-甲氧基苯基)乙酸甲酯(化合物28B)的制备:
Step 1: Preparation of methyl 2-(4-fluoro-2-methoxyphenyl)acetate (Compound 28B):
将2-(4-氟-2-甲氧基苯基)乙酸(1.0g,5.43mmol)溶于无水甲醇(100mL)，随后缓慢加入氯化亚砜(1.29g,10.8mmol)。反应液在70℃下反应3小时。反应完全后，通过硅胶柱分离纯化得化合物28B。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 complete, the compound 28B was separated and purified by silica gel column.
MS(ESI)m/z 199.1(M+H)+ MS (ESI) m/z 199.1 (M+H) +
步骤2：2-(4-氟-2-甲氧基苯基)丙烯酸甲酯(化合物28C)的制备:
Step 2: Preparation of methyl 2-(4-fluoro-2-methoxyphenyl)acrylate (Compound 28C):
将2-(4-氟-2-甲氧基苯基)乙酸甲酯(900.0mg,4.54mmol)溶于N,N-二甲基甲酰胺(100.0mL)中，随后加入碳酸钾(1.57g,11.4mmol)，多聚甲醛(518.3mg,5.76mmol)，四丁基溴化铵(167.7mg,0.45mmol)反应液在60℃搅拌1小时。反应完全后，通过硅胶柱分离纯化得化合物28C。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 solution was stirred at 60° C. for 1 hour. After the reaction was complete, the compound 28C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 211.1(M+H)+ MS (ESI) m/z 211.1 (M+H) +
步骤3：2-(4-氟-2-甲氧基苯基)-3-(甲氨基)丙酸甲酯(化合物28D)的制备:
Step 3: Preparation of methyl 2-(4-fluoro-2-methoxyphenyl)-3-(methylamino)propanoate (Compound 28D):
将2-(4-氟-2-甲氧基苯基)丙烯酸甲酯(515.0mg,2.45mmol)溶于甲胺的四氢呋喃溶液中(20mL)中，反应液在室温搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物28D。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 the reaction was complete, the compound was separated and purified by silica gel column to obtain compound 28D.
MS(ESI)m/z 242.1(M+H)+ MS (ESI) m/z 242.1 (M+H) +
步骤4：3-(叔丁氧羰基)(甲基)氨基)-2-(4-氟-2-甲氧基苯基)丙酸甲酯(化合物28E)的制备:
Step 4: Preparation of methyl 3-(tert-butyloxycarbonyl)(methyl)amino)-2-(4-fluoro-2-methoxyphenyl)propanoate (Compound 28E):
将2-(4-氟-2-甲氧基苯基)-3-(甲氨基)丙酸甲酯(406mg,1.68mmol)溶于二氯甲烷中(50mL)，随后加入三乙胺(340mg,3.37mmol)，反应体系降至0℃，二碳酸二叔丁酯(440mg,2.02mmol)缓慢加入体系，反应液在室温搅拌16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物28E。Methyl 2-(4-fluoro-2-methoxyphenyl)-3-(methylamino)propanoate (406 mg, 1.68 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of triethylamine (340 mg, 3.37 mmol), the reaction system was cooled to 0°C, di-tert-butyl dicarbonate (440 mg, 2.02 mmol) was slowly added to the system, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (100 mL*3), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 28E was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 342.1(M+H)+ MS (ESI) m/z 342.1 (M+H) +
步骤5：3-(叔丁氧羰基)(甲基)氨基)-2-(3-氯-4-氟-2-甲氧基苯基)丙酸甲酯(化合物28F)的制备:
Step 5: Preparation of methyl 3-(tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propanoate (Compound 28F):
将3-((叔丁氧基羰基)(甲基)氨基)-2-(4-氟-2-甲氧基苯基)丙酸甲酯(393mg,1.15mmol)溶于N,N-二甲基甲酰胺(100.0mL)中，随后加入N-氯代丁二酰亚胺(461.3mg,3.45mmol)。，反应液室温下反应16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物28F。Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(4-fluoro-2-methoxyphenyl)propanoate (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 complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 28F was obtained by separation and purification by silica gel column.
MS(ESI)m/z 376.1(M+H)+ MS (ESI) m/z 376.1 (M+H) +
步骤6：3-((叔丁氧羰基)(甲基)氨基)-2-(3-氯-4-氟-2-甲氧基苯基)丙酸(化合物28G)的制备:
Step 6: Preparation of 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propanoic acid (Compound 28G):
将3-((叔丁氧基羰基)(甲基)氨基)-2-(3-氯-4-氟-2-甲氧基苯基)丙酸甲酯(302mg,0.81mmol)溶于四氢呋喃(50mL)和水(50mL)中，随后加入氢氧化锂(38.6g,1.61mmol)。反应液在室温下反应16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物28G。Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propanoate (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 complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 28G was obtained by separation and purification by silica gel column.
MS(ESI)m/z 362.1(M+H)+ MS (ESI) m/z 362.1 (M+H) +
在实施例1的步骤8中用2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-((叔丁氧羰基)(甲基)氨基)-2-(3-氯-4-氟-2-甲氧基苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例28的化合物28。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]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluoro-2-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 28 of Example 28.
MS(ESI)m/z 552.1(M+H)+ MS (ESI) m/z 552.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ7.25-7.21(m,3H),7.13-7.10(d,J＝8.0Hz,1H),7.04-7.02(d,J＝8.0Hz,1H),4.45-4.15(m,6H),3.98(s,6H),3.78(s,3H),2.96-2.94(d,J＝8.0Hz,1H),2.20(s,2H),1.41-0.82(m,4H) 1 H-NMR (400MHz, DMSO-d 6 ) δ7.25-7.21 (m, 3H), 7.13-7.10 (d, J＝8.0Hz, 1H), 7.04-7.02 (d, J＝8.0Hz, 1H) ,4.45-4.15(m,6H),3.98(s,6H),3.78(s,3H),2.96-2.94(d,J＝8.0Hz,1H),2.20(s,2H),1.41-0.82(m ,4H)
实施例29：(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3.3'-二联氮杂环丁烷亚基]-1(4H)-基)(4-苯基四氢-2H-吡喃-4-基)甲酮(化合物29)的制备：
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):
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用4-苯基四氢-2H-吡喃-4-羧酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例29的化合物29。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 29 of Example 29.
MS(ESI)m/z 496.2(M+H)+MS (ESI) m/z 496.2 (M+H)+
1H-NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.78-8.75(d,J＝1.9Hz,1H),8.32-8.29(d,J＝8.5Hz,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). 1 H-NMR (400MHz, DMSO-d 6 ) δ9.68 (s, 1H), 8.78-8.75 (d, J = 1.9Hz, 1H), 8.32-8.29 (d, J = 8.5Hz, 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).
实施例30：(S)-1-(1'-((2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙-1-酮(化合物30)的制备：
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):
在实施例1的步骤8中用2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用(S)-2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例30的化合物30。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]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, (S)-2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 30 of Example 30.
MS(ESI)m/z 475.1(M+H)+。MS (ESI) m/z 475.1 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.34-7.24(m,4H),7.14-7.10(m,2H),7.06(d,J＝8.4Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ7.34-7.24 (m, 4H), 7.14-7.10 (m, 2H), 7.06 (d, J = 8.4Hz, 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).
实施例31：(R)-1-(1'-((2,3-二氢苯并[b][1,4]二恶英-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙-1-酮(化合物31)的制备：
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):
在实施例1的步骤8中用2,3-二氢苯并[b][1,4]二恶英-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用(R)-2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例31的化合物31。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]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, (R)-2-(4-fluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 31 of Example 31.
MS(ESI)m/z 475.1(M+H)+。MS (ESI) m/z 475.1 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ7.34-7.24(m,4H),7.14-7.10(m,2H),7.06(d,J＝8.4Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ7.34-7.24 (m, 4H), 7.14-7.10 (m, 2H), 7.06 (d, J = 8.4Hz, 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).
实施例32：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-(萘-2-基)丙-1-酮(化合物32)的制备：
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):
步骤1：3-羟基-2-(萘-2-基)丙酸甲酯(化合物32B)的制备:
Step 1: Preparation of methyl 3-hydroxy-2-(naphthalen-2-yl)propanoate (Compound 32B):
将2-(萘-2-基)乙酸甲酯(1.0g,4.99mmol)和多聚甲醛(449.9mg,4.99mmol)溶于二甲基亚砜(40.0mL)，随后加入甲醇钠(27.0mg,0.50mmol)。反应液在室温下反应4小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(10mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物32B。2-(Naphthalene-2-yl)acetic acid methyl ester (1.0 g, 4.99 mmol) and paraformaldehyde (449.9 mg, 4.99 mmol) were dissolved in dimethyl sulfoxide (40.0 mL), followed by the addition of sodium methoxide (27.0 mg, 0.50 mmol). The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 32B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 231.1(M+H)+ MS (ESI) m/z 231.1 (M+H) +
步骤2：3-羟基-2-(萘-2-基)丙酸(化合物32C)的制备:
Step 2: Preparation of 3-hydroxy-2-(naphthalen-2-yl)propanoic acid (Compound 32C):
将3-羟基-2-(萘-2-基)丙酸甲酯(260.0mg,1.13mmol)溶于四氢呋喃(60.0mL)和水(40.0mL)的混合溶液中，随后加入氢氧化钠(45.2mg,1.13mmol)，反应液在室温搅拌5小时。反应完全后，反应液用1N盐酸调pH至2，用二氯甲烷(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩后直接用于下一步反应。Dissolve methyl 3-hydroxy-2-(naphthalene-2-yl)propanoate (260.0 mg, 1.13 mmol) in a mixed solution of tetrahydrofuran (60.0 mL) and water (40.0 mL), then add sodium hydroxide (45.2 mg, 1.13 mmol), and stir the reaction solution at room temperature for 5 hours. After the reaction is complete, adjust the pH of the reaction solution to 2 with 1N hydrochloric acid, extract with dichloromethane (100 mL*3), wash the combined organic phases with saturated brine, and dry with anhydrous sodium sulfate. After concentration, use it directly in the next reaction.
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(萘-2-基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例32的化合物32。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(naphthalen-2-yl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 32 of Example 32.
MS(ESI)m/z 506.1(M+H)+ MS (ESI) m/z 506.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.78-8.77(d,J＝4.0Hz,1H),8.31-8.29(d,J＝8.0Hz,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) 1 H-NMR (400MHz, DMSO-d 6 ) δ9.64 (s, 1H), 8.78-8.77 (d, J = 4.0Hz, 1H), 8.31-8.29 (d, J = 8.0Hz, 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)
实施例33：1-(1'-(苯并[d]噻唑-6-基磺酰基(-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)丙-1-酮(化合物33)的制备：

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):

步骤1：2-(3-(4-甲基哌嗪-1-基)苯基)乙酸甲酯(化合物33B)的制备
Step 1: Preparation of methyl 2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (Compound 33B)
将2-(3-溴苯基)乙酸甲酯(5.0g,21.83mmol)，1-甲基哌嗪(3.3g,32.74mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(1.3g,2.18mmol)和碳酸铯(10.7g,32.74mmol)溶于甲苯中(100.0mL)中，随后加入三(二亚苄基丙酮)二钯(399.8mg,0.44mmol)。加料完成后将反应体系置于氮气保护环境下升至110℃搅拌16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(150.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物33B。2-(3-bromophenyl)acetic acid methyl ester (5.0g, 21.83mmol), 1-methylpiperazine (3.3g, 32.74mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.3g, 2.18mmol) and cesium carbonate (10.7g, 32.74mmol) were dissolved in toluene (100.0mL), and then tri(dibenzylideneacetone)dipalladium (399.8mg, 0.44mmol) was added. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and heated to 110°C and stirred for 16 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (150.0mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 33B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 249.2(M+H)+ MS (ESI) m/z 249.2 (M+H) +
步骤2：3-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)丙酸甲酯(化合物33C)的制备
Step 2: Preparation of methyl 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propanoate (Compound 33C)
将2-(3-(4-甲基哌嗪-1-基)苯基)乙酸甲酯(1.8g,7.25mmol)和多聚甲醛(685.6mg,7.61mmol)溶于二甲基亚砜(90.0mL)，随后加入甲醇钠(39.2mg,0.72mmol)。反应液在50℃下反应4小时。反应液加水稀释，水相用二氯甲烷(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物33C。Methyl 2-(3-(4-methylpiperazine-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), followed by the addition of sodium methoxide (39.2 mg, 0.72 mmol). The reaction solution was reacted at 50°C for 4 hours. The reaction solution was diluted with water, the aqueous phase was extracted with dichloromethane (100 mL*3), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 33C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 279.2(M+H)+ MS (ESI) m/z 279.2 (M+H) +
步骤2：3-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)丙酸(化合物33D)的制备
Step 2: Preparation of 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propanoic acid (Compound 33D)
将3-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)丙酸甲酯(90.0mg,0.32mmol)溶于甲醇(2.5mL)和水(2.5mL)中，随后加入氢氧化钠(25.9mg,0.64mmol)，反应液在室温搅拌3小时。反应完全后，反应液用1N盐酸调pH至2，浓缩后直接用于下一步反应。Methyl 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propanoate (90.0 mg, 0.32 mmol) was dissolved in methanol (2.5 mL) and water (2.5 mL), followed by the addition of sodium hydroxide (25.9 mg, 0.64 mmol), and the reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, and then concentrated and used directly in the next step.
MS(ESI)m/z 265.2(M+H)+ MS (ESI) m/z 265.2 (M+H) +
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例33的化合物33。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 33 of Example 33.
MS(ESI)m/z 554.2(M+H)+。MS (ESI) m/z 554.2 (M+H) + .
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.81-8.80(d,J＝1.7Hz,1H),8.33-8.31(d,J＝8.6Hz,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＝7.6Hz,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). 1 H NMR (400 MHz, DMSO-d 6 )δ9.68(s,1H),8.81-8.80(d,J＝1.7Hz,1H),8.33-8.31(d,J＝8.6Hz,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. 6Hz,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).
实施例34：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-(4-(1-甲基-1H-吡唑-4-基)苯基)丙-1-酮(化合物34)的制备：
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):
步骤1：2-(4-(1-甲基-1H-吡唑-4-基)苯基)乙酸甲酯(化合物34B)的制备
Step 1: Preparation of methyl 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (Compound 34B)
将2-(4-溴苯基)乙酸甲酯(1.0g,4.37mmol)，(1-甲基-1H-吡唑-4-基)硼酸(604.7mg,4.80mmol)和碳酸钾(1.2g,8.74mmol)溶于二氧六环和水的混合溶液中(4:1,20.0mL)中，随后加入四(三苯基膦)钯(504.5mg,0.44mmol)。加料完成后将反应体系置于氮气保护环境下升至80℃搅拌16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(50.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物34B。2-(4-bromophenyl)acetic acid methyl ester (1.0g, 4.37mmol), (1-methyl-1H-pyrazol-4-yl)boric acid (604.7mg, 4.80mmol) and potassium carbonate (1.2g, 8.74mmol) were dissolved in a mixed solution of dioxane and water (4:1, 20.0mL), and then tetrakis(triphenylphosphine)palladium (504.5mg, 0.44mmol) was added. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and heated to 80°C and stirred for 16 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (50.0mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 34B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 231.2(M+H)+ MS (ESI) m/z 231.2 (M+H) +
步骤2：3-羟基-2-(4-(1-甲基-1H-吡唑-4-基)苯基)丙酸甲酯(化合物34C)的制备
Step 2: Preparation of methyl 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoate (Compound 34C)
将2-(4-(1-甲基-1H-吡唑-4-基)苯基)乙酸甲酯(800.0mg,3.47mmol)和多聚甲醛(313.0mg,3.47mmol)溶于二甲基亚砜(50.0mL)，随后加入甲醇钠(62.6mg,0.35mmol)。反应液在室温下反应4小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物34C。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 complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 34C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 261.2(M+H)+ MS (ESI) m/z 261.2 (M+H) +
步骤3：3-羟基-2-(4-(1-甲基-1H-吡唑-4-基)苯基)丙酸(化合物34D)的制备
Step 3: Preparation of 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoic acid (Compound 34D)
将3-羟基-2-(4-(1-甲基-1H-吡唑-4-基)苯基)丙酸甲酯(200.0mg,0.77mmol)溶于甲醇(6.0mL)和水(4.0mL)的混合溶液中，随后加入氢氧化钠(61.5mg,1.54mmol)，反应液在室温搅拌16小时。反应完全后，反应液用1N盐酸调pH至2，浓缩后直接用于下一步反应。Methyl 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoate (200.0 mg, 0.77 mmol) was dissolved in a mixed solution of methanol (6.0 mL) and water (4.0 mL), followed by the addition of sodium hydroxide (61.5 mg, 1.54 mmol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, and then concentrated and used directly in the next step.
MS(ESI)m/z 267.1(M+H)+ MS (ESI) m/z 267.1 (M+H) +
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(4-(1-甲基-1H-吡唑-4-基)苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例34的化合物34。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 34 of Example 34.
MS(ESI)m/z 536.1(M+H)+ MS (ESI) m/z 536.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.81-8.80(d,J＝1.6Hz,1H),8.32-8.31(d,J＝8.6Hz,1H),8.06(s,1H),7.95-7.92(d,J＝8.6,1H),7.79(s,1H),7.45-7.43(d,J＝8.2Hz,2H),7.20-7.18(d,J＝8.2Hz,2H),4.77-4.74(t,J＝5.3Hz,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). 1 H NMR (400 MHz, DMSO-d 6 )δ9.67(s,1H),8.81-8.80(d,J＝1.6Hz,1H),8.32-8.31(d,J＝8.6Hz,1H),8.06(s,1H),7.95-7.92(d,J＝8.6,1H),7.79(s,1H),7.45-7.43(d,J＝8.2Hz, 2H),7.20-7.18(d,J＝8.2Hz,2H),4.77-4.74(t,J＝5.3Hz,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).
实施例35：(S)-3-羟基-1-(1'-((2-甲基苯并[d]噻唑-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯基丙烷-1-酮(化合物35)的制备：
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-phenylpropane-1-one (Compound 35):
步骤1：6-(苄硫基)-2-甲基苯并[d]噻唑(化合物35B)的制备
Step 1: Preparation of 6-(benzylthio)-2-methylbenzo[d]thiazole (Compound 35B)
将6-溴-2-甲基苯并[d]噻唑(2.0g,8.77mmol)，苄硫醇(1.3g,10.52mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.5g,0.88mmol)和N,N-二异丙基乙胺(3.4g,26.30mmol)溶于1,4-二氧六环中(50.0mL)中，随后加入三(二亚苄基丙酮)二钯(401.4mg,0.44mmol)。加料完成后将反应体系置于氮气保护环境下升至100℃搅拌16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(150.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物35B。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 completed, the reaction system was placed under nitrogen protection and heated to 100 ° C and stirred for 16 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (150.0 mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 35B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 272.1(M+H)+ MS (ESI) m/z 272.1 (M+H) +
步骤2：2-甲基苯并[d]噻唑-6-磺酰氯(化合物35C)的制备
Step 2: Preparation of 2-methylbenzo[d]thiazole-6-sulfonyl chloride (Compound 35C)
将6-(苄硫基)-2-甲基苯并[d]噻唑(1.0g,3.68mmol)溶于乙腈(40.0mL)，醋酸(1.5mL)和水(1.0mL)的混合溶液中，随后反应体系在0℃下加入二氯海茵(1.5g,7.37mmol)。加毕反应液在室温下反应4小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物35C。6-(Benzylthio)-2-methylbenzo[d]thiazole (1.0 g, 3.68 mmol) was dissolved in a mixed solution of acetonitrile (40.0 mL), acetic acid (1.5 mL) and water (1.0 mL), and then dichlorobenzene (1.5 g, 7.37 mmol) was added to the reaction system at 0°C. The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 35C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 248.0(M+H)+ MS (ESI) m/z 248.0 (M+H) +
在实施例1的步骤8中用2-甲基苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例35的化合物35。In step 8 of Example 1, 2-methylbenzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 35 of Example 35.
MS(ESI)m/z 470.1(M+H)+ MS (ESI) m/z 470.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.66-8.65(d,J＝1.6Hz,1H),8.15-8.13(d,J＝8.5Hz,1H),7.89-7.86(d,J＝8.5,1H),7.29-7.19(m,5H),4.79-4.76(t,J＝5.2Hz,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) 1 H NMR (400MHz, DMSO-d 6 ) δ8.66-8.65 (d, J＝1.6Hz, 1H), 8.15-8.13 (d, J＝8.5Hz, 1H), 7.89-7.86 (d, J＝8.5 ,1H),7.29-7.19(m,5H),4.79-4.76(t,J＝5.2Hz,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)
实施例36：1-(1'-((2,2-二氟苯并[d][1,3]二氧戊环-5-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙烷-1-酮(化合物36)的制备：
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-hydroxypropane-1-one (Compound 36):
步骤1：5-(苄硫基)-2,2-二氟苯并[d][1,3]二氧戊环(化合物36B)的制备
Step 1: Preparation of 5-(benzylthio)-2,2-difluorobenzo[d][1,3]dioxolane (Compound 36B)
将5-溴-2,2-二氟-1,3-苯并二氧戊环(400mg,1.69mmol)和苯甲硫醇(280mg,2.25mmol)溶于二氧六环(10mL)中,随后加入叔丁醇钠(400.00mg,4.16mmol)和醋酸钯(40.00mg,178.57μmol),1,1'-联萘-2,2'-双二苯膦(100mg,160.60μmol),加料完成后将反应体系置于氮气氛围100℃搅拌16小时，反应结束冷却至室温后，反应液用加水稀释，水相用乙酸乙酯(30.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物36B。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) and palladium acetate (40.00 mg, 178.57 μmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (100 mg, 160.60 μmol), and the reaction system was placed in a nitrogen atmosphere and stirred at 100 ° C for 16 hours. After the reaction was completed and cooled to room temperature, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (30.0 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 36B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 280.1(M+H)+ MS (ESI) m/z 280.1 (M+H) +
步骤2：2,2-二氟苯并[d][1,3]二氧戊环-5-磺酰氯(化合物36C)的制备
Step 2: Preparation of 2,2-difluorobenzo[d][1,3]dioxolane-5-sulfonyl chloride (Compound 36C)
将2,2-二氟-5-苯硫基-1,3-苯并二氧戊环(270mg,963.29μmol)溶于乙腈(20mL),醋酸(0.75mL)和水(0.5mL)中，在0℃下加入5-二甲基-咪唑烷-2,4-二酮(380mg,1.93mmol),加料完成后将反应体系置于氮气氛围室温搅拌2小时,反应结束后，反应液浓缩并用饱和碳酸氢钠水溶液调节pH值至6-7，水相用乙酸乙酯(30.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物36C。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 5-dimethyl-imidazolidine-2,4-dione (380 mg, 1.93 mmol) was added at 0°C. After the addition, the reaction system was placed in a nitrogen atmosphere and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated and the pH value was adjusted to 6-7 with a saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (30.0 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 36C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 257.0(M+H)+ MS (ESI) m/z 257.0 (M+H) +
在实施例1的步骤8中用2,2-二氟苯并[d][1,3]二氧戊环-5-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例36的化合物36。In step 8 of Example 1, 2,2-difluorobenzo[d][1,3]dioxolane-5-sulfonyl chloride was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-fluorophenyl)-3-hydroxypropionic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 36 of Example 36.
MS(ESI)m/z 497.1(M+H)+。MS (ESI) m/z 497.1 (M+H) + .
1H-NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.74-7.68(m,2H),7.31-7.28(m,2H),7.11(t,J＝8.8Hz,2H),4.83-4.80(m,1H),4.70(d,J＝12.4Hz,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) 1 H-NMR (400MHz, DMSO-d 6 ) δ7.92 (s, 1H), 7.74-7.68 (m, 2H), 7.31-7.28 (m, 2H), 7.11 (t, J = 8.8Hz, 2H) ,4.83-4.80(m,1H),4.70(d,J＝12.4Hz,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)
实施例37：(1'-((4-(二氟甲氧基)苯基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)(3-苯基四氢呋喃-3-基)甲酮(化合物37)的制备：
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):
步骤1：4-苯基-3,6-二氢-2H-吡喃(化合物37B)的制备
Step 1: Preparation of 4-phenyl-3,6-dihydro-2H-pyran (Compound 37B)
将芳基溴化镁溶液(2.8N,12.86mL,36mmol)在-78℃下缓慢添加到四氢-4H-吡喃-4-酮(3.0g,29.97mmol)的四氢呋喃(300mL)溶液中。将反应混合物在室温氮气氛围搅拌2小时。通过硅胶柱分离纯化得化合物37B。Aryl magnesium 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 nitrogen atmosphere for 2 hours. Compound 37B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 161.1(M+H)+。MS (ESI) m/z 161.1 (M+H) + .
步骤2：3-苯基四氢呋喃-3-甲醛(化合物37C)的制备
Step 2: Preparation of 3-phenyltetrahydrofuran-3-carbaldehyde (Compound 37C)
将4-苯基-3,6-二氢-2H-吡喃(1g,6.24mmol)和碳酸钠(1.7g,16.04mmol)溶入二氯甲烷(150mL)，在0℃下加入间氯过氧苯甲酸(2.4g,13.95mmol)，随后在室温氮气氛围下搅拌3小时。反应完全后。向体系中加入饱和碳酸钠水溶液(50mL)，加入乙酸乙酯(50mL*3)至将反应混合物和有机层分离。有机萃取液经无水硫酸镁干燥。通过硅胶柱分离纯化得化合物37C。4-phenyl-3,6-dihydro-2H-pyran (1g, 6.24mmol) and sodium carbonate (1.7g, 16.04mmol) were dissolved in dichloromethane (150mL), and m-chloroperbenzoic acid (2.4g, 13.95mmol) was added at 0°C, followed by stirring for 3 hours under nitrogen atmosphere at room temperature. After the reaction was complete. Saturated sodium carbonate aqueous solution (50mL) was added to the system, and ethyl acetate (50mL*3) was added until the reaction mixture and the organic layer were separated. The organic extract was dried over anhydrous magnesium sulfate. Compound 37C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 177.1(M+H)+。MS (ESI) m/z 177.1 (M+H) + .
步骤3：3-苯基四氢呋喃-3-羧酸(化合物37D)的制备
Step 3: Preparation of 3-phenyltetrahydrofuran-3-carboxylic acid (Compound 37D)
将3-苯基四氢呋喃-3-甲醛(250mg,1.42mmol)和2-甲基丁-2-烯(2.25mL)溶于正丁醇(45mL)和2-甲基丁-2-烯(2.25mL)中，室温下加入亚氯酸钠(520mg,4.62mmol)和磷酸二氢钾(440mg,3.24mmol)，所得混合物室温氮气氛围下搅拌0.5小时。反应完全后，乙酸乙酯(10mL*3)萃取，合并有机相。通过硅胶柱分离纯化得化合物37D。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 for 0.5 hours under nitrogen atmosphere at room temperature. After the reaction was complete, ethyl acetate (10 mL*3) was used for extraction, and the organic phases were combined. Compound 37D was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 193.1(M+H)+。MS (ESI) m/z 193.1 (M+H) + .
在实施例6的步骤4中用3-苯基四氢呋喃-3-羧酸替代3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例6相同的制备方法得到实施例37的化合物37。In step 4 of Example 6, 3-phenyltetrahydrofuran-3-carboxylic acid was used instead of 3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as Example 6 was used to obtain Compound 37 of Example 37.
MS(ESI)m/z 491.1(M+H)+ MS (ESI) m/z 491.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ7.88-7.84(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) 1 H-NMR (400MHz, DMSO-d 6 )δ7.88-7.84(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)
实施例38：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(3-氯-4-氟苯基)-3-(甲氨基)丙-1-酮(化合物38)的制备：
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):
步骤1：2-(3-氯-4-氟苯基)丙烯酸甲酯(化合物38B)的制备
Step 1: Preparation of methyl 2-(3-chloro-4-fluorophenyl)acrylate (Compound 38B)
将(3-氯-4-氟苯基)硼酸(1.0g,5.74mmol)，2-溴丙烯酸甲酯(860.2mg,32.74mmol)，和磷酸钾(2.2g,10.43mmol)溶于二氧六环和水(4:1)的混合溶液中(25.0mL)中，随后加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(378.5mg,0.52mmol)。加料完成后将反应体系置于氮气保护环境下升至80℃搅拌16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(150.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物38B。(3-Chloro-4-fluorophenyl)boric acid (1.0g, 5.74mmol), methyl 2-bromoacrylate (860.2mg, 32.74mmol), and potassium phosphate (2.2g, 10.43mmol) were dissolved in a mixed solution of dioxane and water (4:1) (25.0mL), and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (378.5mg, 0.52mmol) was added. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and heated to 80°C and stirred for 16 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (150.0mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 38B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 215.2(M+H)+ MS (ESI) m/z 215.2 (M+H) +
步骤2：2-(3-氯-4-氟苯基)-3-(甲氨基)丙酸甲酯(化合物38C)的制备
Step 2: Preparation of methyl 2-(3-chloro-4-fluorophenyl)-3-(methylamino)propanoate (Compound 38C)
将2-(3-氯-4-氟苯基)丙烯酸甲酯(395.0mg,1.84mmol)溶于甲胺的四氢呋喃溶液(8.0mL)中。反应液在室温下反应16小时。反应完全后，通过硅胶柱分离纯化得化合物38C。Methyl 2-(3-chloro-4-fluorophenyl)acrylate (395.0 mg, 1.84 mmol) was dissolved in a tetrahydrofuran solution of methylamine (8.0 mL). The reaction solution was reacted at room temperature for 16 hours. After the reaction was complete, the compound 38C was separated and purified by silica gel column.
MS(ESI)m/z 246.1(M+H)+ MS (ESI) m/z 246.1 (M+H) +
步骤3：3-(叔丁氧羰基)(甲基)氨基)-2-(3-氯-4-氟苯基)丙酸甲酯(化合物38D)的制备
Step 3: Preparation of methyl 3-(tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propanoate (Compound 38D)
将2-(3-氯-4-氟苯基)-3-(甲氨基)丙酸酯(276.0mg,1.12mmol)，N,N-二甲胺基吡啶(13.7mg,0.11mmol)，三乙胺(227.4mg,2.25mmol)溶于二氯甲烷(5mL)中，随后加入二碳酸二叔丁酯(244.9mg,1.12mmol)，反应液在室温搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物38D。2-(3-chloro-4-fluorophenyl)-3-(methylamino)propanoate (276.0 mg, 1.12 mmol), N,N-dimethylaminopyridine (13.7 mg, 0.11 mmol), triethylamine (227.4 mg, 2.25 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of di-tert-butyl dicarbonate (244.9 mg, 1.12 mmol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the compound 38D was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 346.1(M+H)+ MS (ESI) m/z 346.1 (M+H) +
步骤4：3-((叔丁氧羰基)(甲基)氨基)-2-(3-氯-4-氟苯基)丙酸(化合物38E)的制备
Step 4: Preparation of 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propanoic acid (Compound 38E)
将3-(叔丁氧羰基)(甲基)氨基)-2-(3-氯-4-氟苯基)丙酸甲酯(245.0mg,0.71mmol)溶于甲醇(5.0mL)和水(5.0mL)的混合溶液中，随后加入一水合氢氧化锂(59.5mg,1.42mmol)。反应液在室温搅拌3小时，反应完全后，反应液用1N盐酸调pH至2，用二氯甲烷(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩得白色固体化合物直接用于下一步反应。Dissolve methyl 3-(tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propanoate (245.0 mg, 0.71 mmol) in a mixed solution of methanol (5.0 mL) and water (5.0 mL), and then add lithium hydroxide monohydrate (59.5 mg, 1.42 mmol). The reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid, extracted with dichloromethane (100 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated white solid compound was directly used in the next step.
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-((叔丁氧羰基)(甲基)氨基)-2-(3-氯-4-氟苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例38的化合物38。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-((tert-butyloxycarbonyl)(methyl)amino)-2-(3-chloro-4-fluorophenyl)propanoic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 38 of Example 38.
MS(ESI)m/z 521.1(M+H)+ MS (ESI) m/z 521.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.82(s,1H),8.37-8.31(d,J＝8.5Hz,1H),7.98-7.91(d,J＝8.5Hz,1H),7.49-7.42(d,J＝8.5Hz,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＝7.0Hz,1H),3.00-2.89(m,1H),2.64-2.55(m,2H),2.21(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.69(s,1H),8.82(s,1H),8.37-8.31(d,J＝8.5Hz,1H),7.98-7.91(d,J＝8.5Hz,1H),7.49-7.42(d ,J＝8.5Hz,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＝7.0Hz,1H),3.00-2.89(m,1H),2.64-2.55 (m,2H),2.21(s,3H).
实施例39：(S)-3-羟基-1-(1'-((4-甲基-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯基丙-1-酮(化合物39)的制备：

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):

步骤1：6-溴-4-甲基-3,4-二氢-2H-苯并[b][1,4]恶嗪(化合物39B)的制备
Step 1: Preparation of 6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound 39B)
将6-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪(0.5g,2.34mmol)、多聚甲醛(140.3mg,4.67mmol)和氰基硼氢化钠(234.8mg,3.74mmol)溶于乙腈溶液(30mL)中，加料完成后将反应体系置于室温下搅拌0.5小时后，加入冰醋酸(0.5mL)。反应完全后，反应液加水稀释，水相用乙酸乙酯(60mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物39B。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 solution (30 mL). After the addition was completed, the reaction system was stirred at room temperature for 0.5 hours, and glacial acetic acid (0.5 mL) was added. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (60 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 39B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 228.0(M+H)+ MS (ESI) m/z 228.0 (M+H) +
步骤2：6-(苄硫基)-4-甲基-3,4-二氢-2H-苯并[b][1,4]恶嗪(化合物39C)的制备
Step 2: Preparation of 6-(Benzylthio)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound 39C)
将6-溴-4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪(0.45g,1.77mmol)，苄硫醇(0.26g,3.54mmol)，三(二亚苄基丙酮)二钯(0.09g,0.09mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.1g,0.18mmol)和N,N-二异丙基乙胺(686mg,5.31mmol)溶于甲醇(7.0mL)和水(3.0mL)的混合溶液中，加毕反应体系置于室温下搅拌过夜。反应完全后，通过硅胶柱分离纯化得化合物39C。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 mixed solution of methanol (7.0 mL) and water (3.0 mL), and the reaction system was stirred at room temperature overnight. After the reaction was complete, compound 39C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 272.3(M+H)+ MS (ESI) m/z 272.3 (M+H) +
步骤3：4-甲基-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-磺酰氯(化合物39D)的制备
Step 3: Preparation of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride (Compound 39D)
将6-(苄硫基)-4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪(375mg,1.38mmol)加入混合溶剂(乙腈:醋酸:水＝40:1.5:1)(25mL)中，在0℃搅拌下，加入1,3-二氯-5,5-二甲基乙内酰脲(545mg,2.76mmol)。然后在室温下搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物39D。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. Then, the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was separated and purified by silica gel column to obtain compound 39D.
在实施例1的步骤8中用4-甲基-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例39的化合物39。In step 8 of Example 1, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 39 of Example 39.
MS(ESI)m/z 470.2(M+H)+ MS (ESI) m/z 470.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.29-7.21(m,5H),7.01-6.99(m,1H),6.92-6.87(m,2H),4.79-4.76(t,J＝10.8Hz,1H),4.73-4.70(t,J＝13.2Hz,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). 1 H NMR (400MHz, DMSO-d 6 )δ7.29-7.21(m,5H),7.01-6.99(m,1H),6.92-6.87(m,2H),4.79-4.76(t,J＝10.8Hz,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).
实施例40：(S)-6-((1'-(3-羟基-2-苯基丙酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)磺酰基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮(化合物40)的制备：
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]oxazine-3(4H)-one (Compound 40):
在实施例1的步骤8中用3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例40的化合物40。In step 8 of Example 1, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 40 of Example 40.
MS(ESI)m/z 470.1(M+H)+ MS (ESI) m/z 470.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ10.92(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). 1 H NMR (400MHz, DMSO-d 6 )δ10.92(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).
实施例41：(S)-6-((1'-(3-羟基-2-苯基丙酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)磺酰基)-4-甲基-2H-苯并[b][1,4]恶嗪-3(4H)-酮(化合物41)的制备：
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):
在实施例1的步骤8中用4-甲基-3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例41的化合物41。In step 8 of Example 1, 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 41 of Example 41.
MS(ESI)m/z 484.2(M+H)+ MS (ESI) m/z 484.2 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ7.48-7.46(d,2H),7.39(s,1H),7.30-7.23(m,6H),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). 1 H-NMR (400MHz, DMSO-d 6 )δ7.48-7.46(d,2H),7.39(s,1H),7.30-7.23(m,6H),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).
实施例42：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(3-氯-4-氟苯基)-3-(二甲氨基)丙-1-酮(化合物42)的制备：

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):

步骤1：3-氨基-2-(3-氯-4-氟苯基)丙酸乙酯(化合物42B)的制备
Step 1: Preparation of ethyl 3-amino-2-(3-chloro-4-fluorophenyl)propanoate (Compound 42B)
将3-(叔丁氧基羰基氨基)-2-(3-氯-4-氟苯基)丙酸乙酯(1g,2.89mmol)溶于盐酸-1,4-二氧六环(200mL)中，随后将反应体系置于氮气氛围室温搅拌6小时，反应完全后，通过硅胶柱分离纯化得化合物42B。Ethyl 3-(tert-butoxycarbonylamino)-2-(3-chloro-4-fluorophenyl)propanoate (1 g, 2.89 mmol) was dissolved in hydrochloric acid-1,4-dioxane (200 mL), and the reaction system was then placed in a nitrogen atmosphere and stirred at room temperature for 6 hours. After the reaction was complete, compound 42B was obtained by separation and purification using a silica gel column.
MS(ESI)m/z 246.1(M+H)+ MS (ESI) m/z 246.1 (M+H) +
步骤2：2-(3-氯-4-氟苯基)-3-(二甲氨基)丙酸乙酯(化合物42C)的制备
Step 2: Preparation of ethyl 2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propanoate (Compound 42C)
将3-氨基-2-(3-氯-4-氟-苯基)丙酸乙酯(801mg,3.26mmol)溶于甲醇(30mL)，在室温下加入N,N-二异丙基乙胺(842.74mg,6.52mmol)和多聚甲醛(587.39mg,6.52mmol),加料完成后将反应体系置于氮气氛围25℃搅拌6小时,反应结束后，通过硅胶柱分离纯化得化合物42C。Ethyl 3-amino-2-(3-chloro-4-fluoro-phenyl)propanoate (801 mg, 3.26 mmol) was dissolved in methanol (30 mL). 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 completed, the reaction system was placed in a nitrogen atmosphere and stirred at 25°C for 6 hours. After the reaction was completed, the compound 42C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 274.1(M+H)+ MS (ESI) m/z 274.1 (M+H) +
步骤3：2-(3-氯-4-氟苯基)-3-(二甲基氨基)丙酸(化合物42D)的制备
Step 3: Preparation of 2-(3-chloro-4-fluorophenyl)-3-(dimethylamino)propanoic acid (Compound 42D)
将2-(3-氯-4-氟-苯基)-3-(二甲基氨基)丙酸乙酯(391mg，1.43mmol)溶于乙醇(7mL)和水(7mL)中，在室温下加入氢氧化锂(119.99mg，2.86mmol),加料完成后将反应体系置于氮气氛围50℃搅拌16小时,反应结束后，通过硅胶柱分离纯化得化合物42D。Ethyl 2-(3-chloro-4-fluoro-phenyl)-3-(dimethylamino)propanoate (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 completed, the reaction system was placed in a nitrogen atmosphere and stirred at 50°C for 16 hours. After the reaction was completed, the mixture was separated and purified by silica gel column to obtain compound 42D.
MS(ESI)m/z 246.2(M+H)+ MS (ESI) m/z 246.2 (M+H) +
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(3-氯-4-氟苯基)-3-(二甲基氨基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例42的化合物42。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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, and the same preparation method as in Example 1 was used to obtain compound 42 of Example 42.
MS(ESI)m/z 535.1(M+H)+ MS (ESI) m/z 535.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.82(s,1H),8.35-8.33(d,J＝8.5Hz,1H),7.96-7.94(d,J＝8.5Hz,1H),7.49-7.47(d,J＝7.1Hz,1H),7.33-7.29(m,2H),4.68-4.65(d,J＝13.2Hz,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) 1 H-NMR (400MHz, DMSO-d 6 )δ9.68(s,1H),8.82(s,1H),8.35-8.33(d,J＝8.5Hz,1H),7.96-7.94(d,J＝8.5Hz,1H),7.49-7.47(d ,J＝7.1Hz,1H),7.33-7.29 (m,2H),4.68-4.65(d,J＝13.2Hz,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)
实施例43：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)乙-1-酮(化合物43)的制备：
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):
步骤1：2-(3-溴苯基)-2-羟基乙酸(化合物43B)的制备
Step 1: Preparation of 2-(3-bromophenyl)-2-hydroxyacetic acid (Compound 43B)
将3-溴苯甲醛(1.85g,10.0mmol)加入四氢呋喃(40mL)中，向溶液中加入三甲基甲硅烷基氰化物(1.1g,11.0mmol)，并滴入1滴1N的四丁基氟化铵四氢呋喃溶液。反应液在室温下搅拌1小时后，减压旋蒸除去溶剂。向残余油状物中加入6N盐酸水溶液(10mL)，加热回流3小时。将反应混合物冷却至0℃并滴加10N氢氧化钠溶液调节pH至1，反应完全后，用乙酸乙酯(60mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物43B。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 1 drop of 1N tetrabutylammonium fluoride tetrahydrofuran solution was added. After the reaction solution was stirred at room temperature for 1 hour, the solvent was removed by rotary evaporation under reduced pressure. 6N hydrochloric acid aqueous solution (10 mL) was added to the residual oil and heated to reflux for 3 hours. The reaction mixture was cooled to 0 ° C and 10N sodium hydroxide solution was added dropwise to adjust the pH to 1. After the reaction was complete, it was extracted with ethyl acetate (60 mL * 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 43B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 230.1(M-H)+ MS (ESI) m/z 230.1 (MH) +
步骤2：2-(3-溴苯基)-2-羟基乙酸甲酯(化合物43C)的制备
Step 2: Preparation of methyl 2-(3-bromophenyl)-2-hydroxyacetate (Compound 43C)
将(3-溴苯基)羟基乙酸(500mg,2.16mmol)加入甲醇(10mL)中，在室温下将二氯亚砜(773mg,6.49mmol)滴加至反应液中，滴加完毕后将反应体系置于60℃搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物43C。(3-Bromophenyl)hydroxyacetic 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, and after the addition was complete, the reaction system was stirred at 60° C. for 3 hours. After the reaction was complete, the compound 43C was separated and purified by silica gel column.
MS(ESI)m/z 268.1(M+Na)+ MS (ESI) m/z 268.1 (M+Na) +
步骤3：2-(3-溴苯基)-2-((叔丁基二苯基甲硅烷基)氧基)乙酸甲酯(化合物43D)的制备
Step 3: Preparation of methyl 2-(3-bromophenyl)-2-((tert-butyldiphenylsilyl)oxy)acetate (Compound 43D)
将2-(3-溴苯基)-2-羟基乙酸甲酯(400mg,1.63mmol)，叔丁基氯代二苯基硅烷(539mg,1.96mmol)，咪唑(278mg,4.08mmol)加入四氢呋喃(8mL)中，在40℃搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物43D。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 the reaction was complete, the mixture was separated and purified by silica gel column to obtain compound 43D.
MS(ESI)m/z 507.2(M+Na)+ MS (ESI) m/z 507.2 (M+Na) +
步骤4：2-((叔丁基二苯基甲硅基)氧基)-2-(3-(4-甲基哌嗪-1-基)苯基)乙酸甲酯(化合物43E)的制备
Step 4: Preparation of methyl 2-((tert-butyldiphenylsilyl)oxy)-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (Compound 43E)
将2-(3-溴苯基)-2-((叔丁基二苯基甲硅烷基)氧基)乙酸甲酯(400mg,0.83mmol)，1-甲基哌嗪(124mg,1.24mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(48mg,0.08mmol)，三(二亚苄基丙酮)二钯(43mg,0.04mmol)和碳酸铯(540mg,1.65mmol)加入1,4-二氧六环(10mL)中，置换氮气三次后，100℃下搅拌过夜。反应完全后，通过硅胶柱分离纯化得化合物43E。2-(3-bromophenyl)-2-((tert-butyldiphenylsilyl)oxy)acetic acid methyl ester (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), replaced nitrogen three times, and stirred at 100° C. overnight. After the reaction was complete, the compound 43E was obtained by separation and purification by silica gel column.
MS(ESI)m/z 542.6(M+Na)+ MS (ESI) m/z 542.6 (M+Na) +
步骤5：2-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)乙酸甲酯(化合物43F)的制备
Step 5: Preparation of methyl 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (Compound 43F)
将2-((叔丁基二苯基甲硅烷基)氧基)-2-(3-(4-甲基哌嗪-1-基)苯基)乙酸甲酯(350mg,0.74mmol)溶于四氢呋喃(10mL)中，加入四丁基氟化铵(386mg,1.48mmol)并将反应体系置于50℃搅拌过夜。反应完全后，加入50mL水稀释后，用乙酸乙酯(50mL*3)与水萃取，合并有机相用无水硫酸钠干燥，通过硅胶柱分离纯化得化合物43F。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 system was stirred at 50°C overnight. After the reaction was completed, 50 mL of water was added for dilution, and then the mixture was extracted with ethyl acetate (50 mL*3) and water. The organic phases were combined and dried over anhydrous sodium sulfate, and separated and purified by silica gel column to obtain compound 43F.
MS(ESI)m/z 256.3(M+H)+MS (ESI) m/z 256.3 (M+H)+
步骤6：2-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)乙酸(化合物43G)的制备
Step 6: Preparation of 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid (Compound 43G)
将2-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)乙酸甲酯(150mg,0.56mmol)、氢氧化钠(45mg,1.12mmol)溶于甲醇(3mL)和水(3mL)的混合溶液中，随后将反应体系置于25℃下搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物43G。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 mixed solution of methanol (3 mL) and water (3 mL), and the reaction system was stirred at 25° C. for 3 hours. After the reaction was completed, the compound 43G was obtained by separation and purification by silica gel column.
MS(ESI)m/z 249.2(M-H)+ MS (ESI) m/z 249.2 (MH) +
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-羟基-2-(3-(4-甲基哌嗪-1-基)苯基)乙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例43的化合物43。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-hydroxy-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid was used to replace (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 43 of Example 43.
MS(ESI)m/z 540.2(M+H)+ MS (ESI) m/z 540.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.80-8.79(d,J＝1.6Hz,1H),8.34-8.32(d,J＝8.4Hz,1H),7.95-7.92(m,1H),7.14-7.10(t,J＝15.6Hz,1H),6.86-6.69(m,3H),5.69-5.67(d,J＝5.2Hz,1H),4.93-4.92(d,J＝5.6Hz,1H),4.62-4.22(m,8H),3.09-3.06(t,J＝10Hz,4H),2.43-2.41(t,J＝9.6Hz,4H),2.21(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.68(s,1H),8.80-8.79(d,J＝1.6Hz,1H),8.34-8.32(d,J＝8.4Hz,1H) ,7.95-7.92(m,1H),7.14-7.10(t,J＝15.6Hz,1H),6.86-6.69(m,3H),5. 69-5.67(d,J＝5.2Hz,1H),4.93-4.92(d,J＝5.6Hz,1H),4.62-4.22(m,8H ),3.09-3.06(t,J＝10Hz,4H),2.43-2.41(t,J＝9.6Hz,4H),2.21(s,3H).
实施例44：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-(4-甲氧基苯基)丙-1-酮(化合物44)的制备：
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):
步骤1：3-羟基-2-(4-甲氧基苯基)丙酸甲酯(化合物44B)的制备
Step 1: Preparation of methyl 3-hydroxy-2-(4-methoxyphenyl)propanoate (Compound 44B)
将2-(4-甲氧基苯基)乙酸甲酯(1.0g,5.55mmol)，多聚甲醛(524.4mg,5.83mmol)和甲醇钠(15mg,0.28mmol)溶于二甲基亚砜溶液(10mL)中，加料完成后将反应体系置于室温下搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物44B。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 solution (10 mL). After the addition was completed, the reaction system was stirred at room temperature for 3 hours. After the reaction was complete, the compound 44B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 211.0(M+H)+ MS (ESI) m/z 211.0 (M+H) +
步骤2：3-羟基-2-(4-甲氧基苯基)丙酸(化合物44C)的制备
Step 2: Preparation of 3-hydroxy-2-(4-methoxyphenyl)propanoic acid (Compound 44C)
将3-羟基-2-(4-甲氧基苯基)丙酸甲酯(0.49g,2.33mmol)和氢氧化锂一水合物(0.2g,4.66mmol)溶于甲醇(7.0mL)和水(3.0mL)的混合溶液中，加料完毕后反应体系置于室温下搅拌过夜。反应完全后，通过硅胶柱分离纯化得化合物44C。Methyl 3-hydroxy-2-(4-methoxyphenyl)propanoate (0.49 g, 2.33 mmol) and lithium hydroxide monohydrate (0.2 g, 4.66 mmol) were dissolved in a mixed solution of methanol (7.0 mL) and water (3.0 mL). After the addition was completed, the reaction system was stirred at room temperature overnight. After the reaction was complete, the compound 44C was separated and purified by silica gel column.
MS(ESI)m/z 197.0(M+H)+ MS (ESI) m/z 197.0 (M+H) +
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(4-甲氧基苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例44的化合物44。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 44 of Example 44.
MS(ESI)m/z 486.1(M+H)+ MS (ESI) m/z 486.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.81-8.80(d,J＝2Hz,1H),8.34-8.32(d,J＝8.8Hz,1H),7.95-7.92(m,1H),7.14-7.12(d,J＝8.8Hz,2H),6.83-6.81(d,J＝8.8Hz,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). 1 H NMR (400MHz, DMSO-d 6 )δ9.67(s,1H),8.81-8.80(d,J＝2Hz,1H),8.34-8.32(d,J＝8.8Hz,1H),7. 95-7.92(m,1H),7.14-7.12(d,J＝8.8Hz,2H),6.83-6.81(d,J＝8.8Hz,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 ).
实施例45：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-(对甲苯基)丙-1-酮(化合物45)的制备：
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):
步骤1：3-羟基-2-(对甲苯基)丙酸甲酯(化合物45B)的制备
Step 1: Preparation of methyl 3-hydroxy-2-(p-tolyl)propanoate (Compound 45B)
将2-(对甲苯基)乙酸甲酯(0.5g,3.05mmol)和多聚甲醛(287.8mg,3.20mmol)溶于二甲基亚砜(2.0mL)，随后加入甲醇钠(8.2mg,0.31mmol)。反应液在室温下反应4小时。反应完全后，通过硅胶柱分离纯化得化合物45B。2-(p-Tolyl)acetic acid methyl ester (0.5 g, 3.05 mmol) and paraformaldehyde (287.8 mg, 3.20 mmol) were dissolved in dimethyl sulfoxide (2.0 mL), and then sodium methoxide (8.2 mg, 0.31 mmol) was added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the compound 45B was separated and purified by silica gel column.
MS(ESI)m/z 195.1(M+H)+ MS (ESI) m/z 195.1 (M+H) +
步骤2：3-羟基-2-(对甲苯基)丙酸(化合物45C)的制备
Step 2: Preparation of 3-hydroxy-2-(p-tolyl)propanoic acid (Compound 45C)
将2-(对甲苯基)乙酸甲酯(380.0mg,1.96mmol)溶于甲醇(9.0mL)和水(6.0mL)的混合溶液中，随后加入氢氧化钠(156.5mg,3.91mmol)，反应液在25℃搅拌16小时。反应完全后，反应液用1N盐酸调pH至2，用二氯甲烷(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩直接用于下一步反应。Dissolve methyl 2-(p-tolyl)acetate (380.0 mg, 1.96 mmol) in a mixed solution of methanol (9.0 mL) and water (6.0 mL), then add sodium hydroxide (156.5 mg, 3.91 mmol), and stir the reaction solution at 25°C for 16 hours. After the reaction is complete, adjust the pH of the reaction solution to 2 with 1N hydrochloric acid, extract with dichloromethane (50 mL*3), wash the combined organic phases with saturated brine, and dry with anhydrous sodium sulfate. Concentrate and use directly in the next reaction.
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(对甲苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例45的化合物45。 In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(p-tolyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 45 of Example 45.
MS(ESI)m/z 470.1(M+H)+ MS (ESI) m/z 470.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.81(s,1H),8.34-8.32(d,J＝9.1Hz,1H),7.95-7.93(d,J＝8.4Hz,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). 1 H NMR (400MHz, DMSO-d 6 )δ9.68(s,1H),8.81(s,1H),8.34-8.32(d,J＝9.1Hz,1H),7.95-7.93(d,J＝8.4Hz,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).
实施例46：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(3-氟苯基)-3-羟基丙烷-1-酮(化合物46)的制备：
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-hydroxypropane-1-one (Compound 46):
步骤1：2-(3-氟苯基)-3-羟基丙酸甲酯(化合物46B)的制备
Step 1: Preparation of methyl 2-(3-fluorophenyl)-3-hydroxypropanoate (Compound 46B)
将2-(3-氟苯基)乙酸甲酯(1.0g,5.95mmol)溶于二甲基亚砜(10mL)中,随后室温下加入甲醇钠(100mg,1.85mmol)和多聚甲醛(535mg,5.94mmol),加料完成后将反应体系置于氮气氛围室温搅拌3小时，反应液用加水稀释，水相用乙酸乙酯(10.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物46B。2-(3-fluorophenyl)acetic acid methyl ester (1.0 g, 5.95 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then sodium methoxide (100 mg, 1.85 mmol) and paraformaldehyde (535 mg, 5.94 mmol) were added at room temperature. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and stirred at room temperature for 3 hours. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate (10.0 mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 46B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 199.2(M+H)+ MS (ESI) m/z 199.2 (M+H) +
步骤2：2-(3-氟苯基)-3-羟基丙酸(化合物46C)的制备
Step 2: Preparation of 2-(3-fluorophenyl)-3-hydroxypropanoic acid (Compound 46C)
将2-(3-氟苯基)-3-羟基丙酸甲酯(610mg,3.08mmol)溶于甲醇(6mL)和水(6mL)中，在室温下加入氢氧化锂(650mg,27.14mmol),加料完成后将反应体系置于氮气氛围60℃搅拌3小时,反应结束后，反应液浓缩并用1N盐酸溶液调节pH值至3-4，水相用乙酸乙酯(10.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物46C。2-(3-Fluorophenyl)-3-hydroxypropionic acid methyl ester (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 completed, the reaction system was placed in a nitrogen atmosphere at 60°C and stirred for 3 hours. After the reaction was completed, the reaction solution was concentrated and the pH value was adjusted to 3-4 with 1N hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate (10.0 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 46C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 183.1(M-H)- MS (ESI) m/z 183.1 (MH) -
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(3-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例46的化合物46。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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, and the same preparation method as in Example 1 was used to obtain compound 46 of Example 46.
MS(ESI)m/z 474.1(M+H)+ MS (ESI) m/z 474.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ9.68(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) 1 H-NMR (400MHz, DMSO-d 6 )δ9.68(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)
实施例47：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯基乙-1-酮(化合物47)的制备：
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):
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用苯乙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例47的化合物47。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, phenylacetic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 47 of Example 47.
MS(ESI)m/z 426.1(M+H)+ MS (ESI) m/z 426.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.82(s,1H),8.35-8.33(d,J＝8.0Hz,1H),7.96-7.94(d,J＝8.0Hz,1H),7.27-7.15(m,5H),4.54-4.22(m,8H),3.44(s,2H).1H NMR (400MHz, DMSO-d 6 )δ9.69(s,1H),8.82(s,1H),8.35-8.33(d,J＝8.0Hz,1H),7.96-7.94(d,J＝8.0Hz,1H),7.27-7.15(m ,5H),4.54-4.22(m,8H),3.44(s,2H).
实施例48：1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-(吡啶-3-基)丙烷-1-酮(化合物48)的制备：
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):
步骤1：3-羟基-2-(吡啶-3-基)丙酸甲酯(化合物48B)的制备
Step 1: Preparation of methyl 3-hydroxy-2-(pyridin-3-yl)propanoate (Compound 48B)
将2-(3-吡啶基)乙酸甲酯(1.0g,6.62mmol)溶于二甲基亚砜(10mL)中，随后室温下加入甲醇钠(120mg,666.67μmol)和多聚甲醛(600mg,6.67mmol),加料完成后将反应体系置于氮气氛围室温搅拌3小时，反应液用加水稀释，水相用乙酸乙酯(30.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物48B。2-(3-pyridyl)acetic acid methyl ester (1.0 g, 6.62 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then sodium methoxide (120 mg, 666.67 μmol) and paraformaldehyde (600 mg, 6.67 mmol) were added at room temperature. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and stirred at room temperature for 3 hours. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate (30.0 mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 48B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 182.1(M+H)+ MS (ESI) m/z 182.1 (M+H) +
步骤2：3-羟基-2-(吡啶-3-基)丙酸(化合物48C)的制备
Step 2: Preparation of 3-hydroxy-2-(pyridin-3-yl)propanoic acid (Compound 48C)
将3-羟基-2-(2-吡啶基)丙酸甲酯(140mg,772.68μmol)溶于甲醇(2mL)、水(2mL)和四氢呋喃(2mL)的混合溶液中，在室温下加入氢氧化锂(350mg,8.33mmol),加料完成后将反应体系置于氮气氛围60℃搅拌3小时,反应结束后，反应液浓缩并用1N盐酸溶液调节pH至3-4，水相用乙酸乙酯(10.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物48C。3-Hydroxy-2-(2-pyridyl)propionic acid methyl ester (140 mg, 772.68 μmol) was dissolved in a mixed solution 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, the reaction system was placed in a nitrogen atmosphere at 60°C and stirred for 3 hours. After the reaction, the reaction solution 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), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 48C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 168.1(M+H)+ MS (ESI) m/z 168.1 (M+H) +
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(吡啶-3-基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例48的化合物48。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(pyridin-3-yl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 48 of Example 48.
MS(ESI)m/z 457.1(M+H)+ MS (ESI) m/z 457.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ9.67(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) 1 H-NMR (400MHz, DMSO-d 6 )δ9.67(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)
实施例49：(S)-1-(1'-((2,3-二氢-[1,4]二噁并[2,3-b]吡啶-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯基丙烷-1-酮(化合物49)的制备：
Example 49: Preparation of (S)-1-(1'-((2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-6-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropane-1-one (Compound 49):
在实施例1的步骤8中用2,3-二氢-[1,4]二噁并[2,3-b]吡啶-6-磺酰氯(合成方法同实施例20D)替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例49的化合物49。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-6-sulfonyl chloride (the synthesis method is the same as that of Example 20D) is used to replace 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as that of Example 1 is used to obtain compound 49 of Example 49.
MS(ESI)m/z 458.1(M+H)+ MS (ESI) m/z 458.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ7.54-7.50(t,J＝1.6Hz,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＝1.0Hz,1H),3.64-3.61(m,2H),3.48-3.44(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ7.54-7.50(t,J＝1.6Hz,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＝1.0Hz,1H),3.64-3.61(m,2H),3.48-3.44(m,1H).
实施例50：(S)-1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙烷-1-酮(化合物50)的制备：
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-hydroxypropane-1-one (Compound 50):
步骤1：2-(4-氟苯基)-3-羟基丙酸甲酯(化合物50B)的制备
Step 1: Preparation of methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (Compound 50B)
将2-(4-氟苯基)乙酸甲酯(2.0g,11.89mmol)溶于二甲基亚砜(20.0mL)，随后加入多聚甲醛(1.2g,12.49mmol)，后缓慢加入甲醇钠溶液(32.1mg,594.66μmol)。反应液在室温下反应4小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(50.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物50B。2-(4-fluorophenyl)acetic acid methyl ester (2.0g, 11.89mmol) was dissolved in dimethyl sulfoxide (20.0mL), followed by the addition of paraformaldehyde (1.2g, 12.49mmol), followed by the slow addition of sodium methoxide solution (32.1mg, 594.66μmol). The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (50.0mL*3), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 50B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 199.0(M+H)+ MS (ESI) m/z 199.0 (M+H) +
步骤2：2-(4-氟苯基)-3-羟基丙酸(化合物50C)的制备Step 2: Preparation of 2-(4-fluorophenyl)-3-hydroxypropanoic acid (Compound 50C)
将2-(4-氟苯基)-3-羟基丙酸甲酯(1.5g,7.47mmol)溶于甲醇(15.0mL)和水(10.0mL)的混合溶液中，随后加入氢氧化钠(597.4mg,14.94mmol)。反应液在50℃下反应3小时。TLC显示反应完全，反应液用1N盐酸调节pH至酸性，水相用乙酸乙酯(20mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥，通过硅胶柱分离纯化得化合物50C。Methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (1.5 g, 7.47 mmol) was dissolved in a mixed solution of methanol (15.0 mL) and water (10.0 mL), and then sodium hydroxide (597.4 mg, 14.94 mmol) was added. The reaction solution was reacted at 50°C for 3 hours. TLC showed that the reaction was complete, and the pH of the reaction solution was adjusted to acidic with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL*3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and separated and purified by silica gel column to obtain compound 50C.
MS(ESI)m/z 185.0(M+H)+ MS (ESI) m/z 185.0 (M+H) +
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法后通过手性分离得到实施例50的化合物50。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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. The same preparation method as in Example 1 was used and chiral separation was performed to obtain compound 50 of Example 50.
MS(ESI)m/z 474.1(M+H)+ MS (ESI) m/z 474.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.81-8.80(d,J＝4.0Hz,1H),8.34-8.32(d,J＝8.0Hz,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). 1 H NMR (400MHz, DMSO-d 6 )δ9.68(s,1H),8.81-8.80(d,J＝4.0Hz,1H),8.34-8.32(d,J＝8.0Hz,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).
实施例51：(R)-1-(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-氟苯基)-3-羟基丙烷-1-酮(化合物51)的制备：
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-hydroxypropane-1-one (Compound 51):
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法后通过手性分离得到实施例51的化合物51。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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. The same preparation method as in Example 1 was used and chiral separation was performed to obtain compound 51 of Example 51.
MS(ESI)m/z 474.1(M+H)+ MS (ESI) m/z 474.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.81-8.80(d,J＝4.0Hz,1H),8.34-8.32(d,J＝8.0Hz,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). 1 H NMR (400MHz, DMSO-d 6 )δ9.68(s,1H),8.81-8.80(d,J＝4.0Hz,1H),8.34-8.32(d,J＝8.0Hz,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).
实施例52：(1'-(苯并[d]噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)(1H-吲哚-3-基)甲酮(化合物52)的制备：
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):
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用1H-吲哚-3-羧酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例52的化合物52。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 52 of Example 52.
MS(ESI)m/z 451.1(M+H)+ MS (ESI) m/z 451.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.73-9.63(t,J＝4Hz,1H),8.85-8.84(d,J＝0.4Hz,1H),8.36-8.34(d,J＝0.8Hz,1H),8.05-8.03(d,J＝0.8Hz,1H),7.99-7.96(m,1H),7.69-7.68(d,J＝0.4Hz,1H),7.42-7.40(d,J＝0.8Hz,1H),7.16-7.06(m,2H),59-4.40(m,8H). 1 H NMR (400MHz, DMSO-d 6 )δ11.68(s,1H),9.73-9.63(t,J＝4Hz,1H),8.85-8.84(d,J＝0.4Hz,1H),8.36-8.34(d,J＝0.8Hz,1H) ,8.05-8.03(d,J=0.8 Hz,1H),7.99-7.96(m,1H),7.69-7.68(d,J＝0.4Hz,1H),7.42-7.40(d,J＝0.8Hz,1H),7.16-7.06(m,2H) ,59-4.40(m,8H).
实施例53：3-羟基-2-(4-甲氧基苯基)-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物53)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(4-甲氧基苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例53的化合物53。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-methoxyphenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 53 of Example 53.
MS(ESI)m/z 430.1(M+H)+ MS (ESI) m/z 430.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.81-8.79(m,1H),8.17-8.13(m,1H),7.99-7.97(d,J＝8.0Hz,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). 1 H-NMR (400MHz, DMSO-d 6 )δ8.81-8.79(m,1H),8.17-8.13(m,1H),7.99-7.97(d,J＝8.0Hz,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).
实施例54：(S)-2-(4-氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙烷-1-酮(化合物54)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法后用手性分离得到实施例54的化合物54。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(4-fluorophenyl)-3-hydroxypropanoic acid. The same preparation method as in Example 1 was used followed by chiral separation to give compound 54 of Example 54.
MS(ESI)m/z 418.1(M+H)+ MS (ESI) m/z 418.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.81-8.80(d,J＝4.7Hz,1H),8.17-8.13(m,1H),7.99-7.97(d,J＝7.7Hz,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). 1 H-NMR (400MHz, DMSO-d 6 )δ8.81-8.80(d,J＝4.7Hz,1H),8.17-8.13(m,1H),7.99-7.97(d,J＝7.7Hz,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).
实施例55：(R)-2-(4-氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙烷-1-酮(化合物55)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法后用手性分离得到实施例55的化合物55。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(4-fluorophenyl)-3-hydroxypropanoic acid. The same preparation method as in Example 1 was used followed by chiral separation to give Compound 55 of Example 55.
MS(ESI)m/z 418.1(M+H)+ MS (ESI) m/z 418.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.81-8.80(d,J＝4.7Hz,1H),8.17-8.13(m,1H),7.99-7.97(d,J＝7.7Hz,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). 1 H-NMR (400MHz, DMSO-d 6 )δ8.81-8.80(d,J＝4.7Hz,1H),8.17-8.13(m,1H),7.99-7.97(d,J＝7.7Hz,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).
实施例56：(1H-吲哚-3-基)(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)甲酮(化合物56)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用1H-吲哚--3-羧酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例56的化合物56。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 56 of Example 56.
MS(ESI)m/z 395.1(M+H)+ MS (ESI) m/z 395.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.84(s,1H),8.19-8.16(t,J＝1.2Hz,1H),8.08-8.06(d,J＝0.8Hz,1H),8.02-8.00(d,J＝0.8Hz,1H),7.77-7.73(d,J＝1.6Hz,2H),7.43-7.41(d,J＝0.8Hz,1H),7.17-7.08(m,2H),4.60(s,8H). 1 H NMR (400MHz, DMSO-d 6 )δ11.71(s,1H),8.84(s,1H),8.19-8.16(t,J＝1.2Hz,1H),8.08-8.06(d,J＝0.8Hz,1H),8.02-8.00(d ,J ＝0.8Hz,1H),7.77-7.73(d,J＝1.6Hz,2H),7.43-7.41(d,J＝0.8Hz,1H),7.17-7.08(m,2H),4.60(s,8H) .
实施例57：3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(对甲苯基)丙-1-酮(化合物57)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(对甲苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例57的化合物57。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(p-tolyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 57 of Example 57.
MS(ESI)m/z 414.1(M+H)+ MS (ESI) m/z 414.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.80-8.79(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). 1 H-NMR (400MHz, DMSO-d 6 )δ8.80-8.79(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).
实施例58：(4-苯基四氢-2H-吡喃-4-基)(1'-(吡啶-2-基磺酰基-(1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)甲酮(化合物58)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用4-苯基四氢-2H-吡喃-4-羧酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例58的化合物58。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 58 of Example 58.
MS(ESI)m/z 440.2(M+H)+ MS (ESI) m/z 440.2 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.78-8.76(m,1H),8.16-8.11(m,1H),7.95-7.93(d,J＝8.0Hz,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＝13.5Hz,2H),1.85-1.78(m,2H). 1 H-NMR (400MHz, DMSO-d 6 )δ8.78-8.76(m,1H),8.16-8.11(m,1H),7.95-7.93(d,J＝8.0Hz,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＝13.5Hz,2H),1.85-1.78(m,2H) .
实施例59：2-(3-氯-4-氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物59)的制备：
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):
步骤1：2-(3-氯-4-氟苯基)-3-羟基丙酸甲酯(化合物59B)的制备
Step 1: Preparation of methyl 2-(3-chloro-4-fluorophenyl)-3-hydroxypropanoate (Compound 59B)
将2-(3-氯-4-氟苯基)乙酸甲酯(2.2g,10.61mmol)和多聚甲醛(477.9mg,5.31mmol)溶于二甲基亚砜(40.0mL)，随后加入甲醇钠(191.1mg,1.06mmol,30％)。反应液在室温下反应4小时。反应完全后，通过硅胶柱分离纯化得化合物59B。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), and then sodium methoxide (191.1 mg, 1.06 mmol, 30%) was added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the compound 59B was separated and purified by silica gel column.
MS(ESI)m/z 233.0(M+H)+ MS (ESI) m/z 233.0 (M+H) +
步骤2：2-(3-氯-4-氟苯基)-3-羟基丙酸(化合物59C)的制备
Step 2: Preparation of 2-(3-chloro-4-fluorophenyl)-3-hydroxypropanoic acid (Compound 59C)
将2-(3-氯-4-氟苯基)-3-羟基丙酸甲酯(2.0g,8.60mmol)溶于四氢呋喃(60.0mL)和水(40.0mL)中，随后加入氢氧化钠(687.8mg,17.19mmol)，反应液在室温搅拌5小时。反应完全后，反应液用1N盐酸调pH至2，用二氯甲烷(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩得黄色油状化合物直接用于下一步反应。Dissolve methyl 2-(3-chloro-4-fluorophenyl)-3-hydroxypropionate (2.0g, 8.60mmol) in tetrahydrofuran (60.0mL) and water (40.0mL), then add sodium hydroxide (687.8mg, 17.19mmol), and stir the reaction solution at room temperature for 5 hours. After the reaction is complete, adjust the pH of the reaction solution to 2 with 1N hydrochloric acid, extract with dichloromethane (100mL*3), wash the combined organic phases with saturated brine, and dry with anhydrous sodium sulfate. Concentrate to obtain a yellow oily compound, which is directly used in the next step.
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(3-氯-4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例59的化合物59。 In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-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, and the same preparation method as in Example 1 was used to obtain compound 59 of Example 59.
MS(ESI)m/z 452.1(M+H)+ MS (ESI) m/z 452.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.82-8.81(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). 1 H NMR (400MHz, DMSO-d 6 )δ8.82-8.81(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 ).
实施例60：3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(吡啶-3-基)丙-1-酮(化合物60)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(吡啶-3-基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例60的化合物60。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(pyridin-3-yl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 60 of Example 60.
MS(ESI)m/z 401.1(M+H)+ MS (ESI) m/z 401.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.81-8.79(m,1H),8.47-8.44(m,2H),8.18-8.13(m,1H),7.99-7.97(d,J＝8.0Hz,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＝12.6Hz,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) 1 H-NMR (400MHz, DMSO-d 6 )δ8.81-8.79(m,1H),8.47-8.44(m,2H),8.18-8.13(m,1H),7.99-7.97(d,J＝8.0Hz,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＝12.6Hz,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)
实施例61：2-(3,4-二氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物61)的制备：
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):
步骤1：2-(3,4-二氟苯基)-3-羟基丙酸甲酯(化合物61B)的制备
Step 1: Preparation of methyl 2-(3,4-difluorophenyl)-3-hydroxypropanoate (Compound 61B)
将2-(3,4-二氟苯基)乙酸甲酯(0.5g,2.69mmol)和多聚甲醛(241.9mg,2.69mmol)溶于二甲基亚砜(10.0mL)，随后加入甲醇钠(48.4mg,0.27mmol,30％)。反应液在室温下反应4小时。反应完全后，通过硅胶柱分离纯化得化合物50C。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), and then sodium methoxide (48.4 mg, 0.27 mmol, 30%) was added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the compound 50C was separated and purified by silica gel column.
MS(ESI)m/z 217.2(M+H)+ MS (ESI) m/z 217.2 (M+H) +
步骤2：2-(3,4-二氟苯基)-3-羟基丙酸(化合物61C)的制备
Step 2: Preparation of 2-(3,4-difluorophenyl)-3-hydroxypropanoic acid (Compound 61C)
将2-(3,4-二氟苯基)-3-羟基丙酸甲酯(320.0mg,1.48mmol)溶于甲醇(15.0mL)和水(10.0mL)中，随后加入氢氧化钠(118.4mg,2.96mmol)，反应液在50℃搅拌3小时。反应完全后，反应液用1N盐酸调pH至2，用二氯甲烷(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩后直接用于下一步反应。Dissolve methyl 2-(3,4-difluorophenyl)-3-hydroxypropionate (320.0 mg, 1.48 mmol) in methanol (15.0 mL) and water (10.0 mL), then add sodium hydroxide (118.4 mg, 2.96 mmol), and stir the reaction solution at 50°C for 3 hours. After the reaction is complete, adjust the pH of the reaction solution to 2 with 1N hydrochloric acid, extract with dichloromethane (50 mL*3), and wash the combined organic phases with saturated brine and dry with anhydrous sodium sulfate. After concentration, use it directly in the next reaction.
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(3,4-二氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例61的化合物61。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(3,4-difluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 61 of Example 61.
MS(ESI)m/z 436.1(M+H)+ MS (ESI) m/z 436.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.82-8.78(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). 1 H NMR (400MHz, DMSO-d 6 ) δ8.82-8.78(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).
实施例62：3-羟基-3-甲基-2-苯基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丁-1-酮(化合物62)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-3-甲基-2-苯基丁酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例62的化合物62。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-3-methyl-2-phenylbutyric acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 62 of Example 62.
MS(ESI)m/z 428.2(M+H)+ MS (ESI) m/z 428.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.79-8.77(m,1H),8.17-8.12(m,1H),7.98-7.96(d,J＝7.7Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ8.79-8.77(m,1H),8.17-8.12(m,1H),7.98-7.96(d,J=7.7Hz,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).
实施例63：(S)-3-羟基-1-(1'-((1-甲基-1H-苯并咪唑-6-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯丙烷-1-酮(化合物63)的制备：
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):
步骤1：6-(苄硫基)-1-甲基-1H-苯并[d]咪唑(化合物63B)的制备
Step 1: Preparation of 6-(benzylthio)-1-methyl-1H-benzo[d]imidazole (Compound 63B)
将6-溴-1-甲基-1H-苯并[d]咪唑(1g，4.74mmol)溶于1,4-二氧六环溶液中，随后依次加入苄硫醇(588mg，4.74mmol)，DIPEA(1.22g，9.48mmol)，Pd2(dba)3CHCl3(485mg，0.47mmol)和xantphos(548mg，0.95mmol)。加料完毕后反应在氮气环境下置换3次后升温至80℃下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物63B。6-Bromo-1-methyl-1H-benzo[d]imidazole (1 g, 4.74 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (588 mg, 4.74 mmol), DIPEA (1.22 g, 9.48 mmol), Pd 2 (dba) 3 CHCl 3 (485 mg, 0.47 mmol) and xantphos (548 mg, 0.95 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80°C and stirred for 16 hours. After the reaction was complete, the compound 63B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 255.1(M+H)+ MS (ESI) m/z 255.1 (M+H) +
步骤2：1-甲基-1H-苯并[d]咪唑-6-磺酰氯(化合物63C)的制备
Step 2: Preparation of 1-methyl-1H-benzo[d]imidazole-6-sulfonyl chloride (Compound 63C)
将6-(苄硫基)-1-甲基-1H-苯并[d]咪唑(560mg,2.20mmol)溶于乙腈中。随后依次加入乙酸(661mg,11.01mmol)，水(397mg,22.02mmol)和1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮(868mg,4.40mmol)，加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物63C。6-(Benzylthio)-1-methyl-1H-benzo[d]imidazole (560 mg, 2.20 mmol) was dissolved in acetonitrile. 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 then added in sequence. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 63C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 231.0(M+H)+ MS (ESI) m/z 231.0 (M+H) +
在实施例1的步骤8中用1-甲基-1H-苯并[d]咪唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例63的化合物63。In step 8 of Example 1, 1-methyl-1H-benzo[d]imidazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 63 of Example 63.
MS(ESI)m/z 453.2(M+H)+ MS (ESI) m/z 453.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.17–8.04(m,1H),7.90(d,J＝8.5Hz,1H),7.70–7.59(m,1H),7.25(dt,J＝13.8,7.2Hz,5H),4.77(t,J＝5.2Hz,1H),4.67(d,J＝12.5Hz,1H),4.28(d,J＝21.7Hz,6H),4.17(d,J＝14.6Hz,1H),3.96(s,3H),3.86(td,J＝9.4,5.5Hz,1H),3.59(dd,J＝8.8,5.3Hz,1H),3.45(dd,J＝9.8,4.9Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.48 (s, 1H), 8.17–8.04 (m, 1H), 7.90 (d, J = 8.5Hz, 1H), 7.70–7.59 (m, 1H), 7.25(dt,J＝13.8,7.2Hz,5H),4.77(t,J＝5.2Hz,1H),4.67(d,J＝12.5Hz,1H),4.28(d,J＝21.7Hz,6H), 4.17(d,J＝14.6Hz,1H),3.96(s,3H),3.86(td,J＝9.4,5.5Hz,1H),3.59(dd,J＝8.8,5.3Hz,1H),3.45(dd ,J=9.8,4.9Hz,1H).
实施例64：(1'-(苯并噻唑-6-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)(异二氢吲哚-1-基)甲酮(化合物64)的制备：
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):
在实施例1的步骤8中用苯并[d]噻唑-6-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(叔丁氧基羰基)异二氢吲哚-1-羧酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例64的化合物64。In step 8 of Example 1, benzo[d]thiazole-6-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 64 of Example 64.
MS(ESI)m/z 453.1(M+H)+ MS (ESI) m/z 453.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.82(d,J＝1.8Hz,1H),8.35(d,J＝8.6Hz,1H),7.96(dd,J＝8.6,1.9Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ9.69 (s, 1H), 8.82 (d, J = 1.8Hz, 1H), 8.35 (d, J = 8.6Hz, 1H), 7.96 (dd, J = 8.6,1.9Hz,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).
实施例65：(S)-4-(1'-(3-羟基-2-苯丙酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基磺酰基)苯甲腈(化合物65)的制备：
Example 65: Preparation of (S)-4-(1'-(3-hydroxy-2-phenylpropanoyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-ylsulfonyl)benzonitrile (Compound 65):
在实施例1的步骤8中用4-氰基苯磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例65的化合物65。In step 8 of Example 1, 4-cyanobenzenesulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 65 of Example 65.
MS(ESI)m/z 424.1(M+H)+ MS (ESI) m/z 424.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.19–8.13(m,2H),8.03–7.98(m,2H),7.32–7.18(m,5H),4.79(t,J＝5.3Hz,1H),4.70(d,J＝12.5Hz,1H),4.33(d,J＝15.0Hz,6H),4.19(d,J＝14.4Hz,1H),3.88(m,1H),3.61(dd,J＝8.8,5.5Hz,1H),3.45(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.19–8.13(m,2H),8.03–7.98(m,2H),7.32–7.18(m,5H),4.79(t,J＝5.3Hz,1H ),4.70(d,J＝12.5Hz,1H),4.33(d,J＝15.0Hz,6H),4.19(d,J＝14.4Hz,1H),3.88(m,1H),3.61(dd,J =8.8,5.5Hz,1H),3.45(m,1H).
实施例66：(S)-1-(1'-(5-氯吡啶-2-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯丙烷-1-酮(化合物66)的制备：
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-phenylpropane-1-one (Compound 66):
在实施例1的步骤8中用5-氯吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例66的化合物66。In step 8 of Example 1, 5-chloropyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 66 of Example 66.
MS(ESI)m/z 434.1(M+H)+ MS (ESI) m/z 434.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.93–8.84(m,1H),8.28(dd,J＝8.4,2.4Hz,1H),7.99(dd,J＝8.4,0.7Hz,1H),7.31–7.23(m,5H),4.82–4.67(m,2H),4.54(d,J＝2.8Hz,4H),4.39–4.21(m,3H),3.89(m,1H),3.63(dd,J＝8.9,5.4Hz,1H),3.46(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.93–8.84 (m, 1H), 8.28 (dd, J＝8.4, 2.4Hz, 1H), 7.99 (dd, J＝8.4, 0.7Hz, 1H), 7.31–7.23(m,5H),4.82–4.67(m,2H),4.54(d,J＝2.8Hz,4H),4.39–4.21(m,3H),3.89(m,1H),3.63(dd, J＝8.9,5.4Hz,1H),3.46(m,1H).
实施例67：(S)-3-羟基-1-(1'-((5-甲氧基吡啶-2-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯基丙烷-1-酮(化合物67)的制备：
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-phenylpropane-1-one (Compound 67):
步骤1：2-(苄基硫基)-5-甲氧基吡啶(化合物67B)的制备
Step 1: Preparation of 2-(benzylthio)-5-methoxypyridine (Compound 67B)
将2-溴-5-甲氧基吡啶(1g，5.32mmol)溶于1,4-二氧六环溶液中，随后依次加入苄硫醇(660mg，5.32mmol)，DIPEA(1.37g，10.64mmol)，Pd2(dba)3CHCl3(544mg，0.53mmol)和xantphos(615mg，1.06mmol)。加料完毕后反应在氮气环境下置换3次后升温至80℃下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物67B。2-Bromo-5-methoxypyridine (1 g, 5.32 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (660 mg, 5.32 mmol), DIPEA (1.37 g, 10.64 mmol), Pd 2 (dba) 3 CHCl 3 (544 mg, 0.53 mmol) and xantphos (615 mg, 1.06 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80° C. and stirred for 16 hours. After the reaction was complete, the compound 67B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 232.1(M+H)+ MS (ESI) m/z 232.1 (M+H) +
步骤2：5-甲氧基吡啶-2-磺酰氯(化合物67C)的制备
Step 2: Preparation of 5-methoxypyridine-2-sulfonyl chloride (Compound 67C)
将2-(苄基硫基)-5-甲氧基吡啶(1.3g,5.62mmol)溶于乙腈中。随后依次加入乙酸(1.69g,28.1mmol)，水(1.01g,56.2mmol)和NCS(1.5g,11.24mmol)，加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物67C。2-(Benzylthio)-5-methoxypyridine (1.3 g, 5.62 mmol) was dissolved in acetonitrile. Acetic acid (1.69 g, 28.1 mmol), water (1.01 g, 56.2 mmol) and NCS (1.5 g, 11.24 mmol) were then added in sequence. After the addition was complete, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 67C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 208.0(M+H)+ MS (ESI) m/z 208.0 (M+H) +
在实施例1的步骤8中用5-甲氧基吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例67的化合物67。In step 8 of Example 1, 5-methoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 67 of Example 67.
MS(ESI)m/z 430.1(M+H)+ MS (ESI) m/z 430.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝2.9Hz,1H),7.94(d,J＝8.7Hz,1H),7.65(m,1H),7.33–7.20(m,5H),4.80(t,J＝5.3Hz,1H),4.72(d,J＝12.8Hz,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). 1 H NMR (400MHz, DMSO-d 6 ) δ8.48(d,J＝2.9Hz,1H),7.94(d,J＝8.7Hz,1H),7.65(m,1H),7.33–7.20(m, 5H),4.80(t,J＝5.3Hz,1H),4.72(d,J＝12.8Hz,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).
实施例68：(S)-3-羟基-2-苯基-1-(1'-(吡啶-3-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙烷-1-酮(化合物68)的制备：
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):
在实施例1的步骤8中用吡啶-3-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例68的化合物68。In step 8 of Example 1, pyridine-3-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 68 of Example 68.
MS(ESI)m/z 400.1(M+H)+ MS (ESI) m/z 400.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝2.3Hz,1H),8.92(dd,J＝4.8,1.6Hz,1H),8.26(m,1H),7.72(dd,J＝8.0,4.9Hz,1H),7.33–7.18(m,5H),4.76–4.64(m,1H),4.44–4.25(m,6H),4.19(d,J＝13.4Hz,1H),3.88(t,J＝9.5Hz,1H),3.61(dd,J＝8.8,5.5Hz,1H),3.45(dd,J＝10.1,5.5Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.99 (d, J = 2.3 Hz, 1H), 8.92 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (m, 1H), 7.72 (dd, J＝8.0,4.9Hz,1H),7.33–7.18(m,5H),4.76–4.64(m,1H),4.44–4.25(m,6H),4.19(d,J＝13.4Hz,1H),3.88 (t,J＝9.5Hz,1H),3.61(dd,J＝8.8,5.5Hz,1H),3.45(dd,J＝10.1,5.5Hz,2H).
实施例69：(S)-3-羟基-2-苯基-1-(1'-(喹啉-8-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物69)的制备：
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):
在实施例1的步骤8中用喹啉-8-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例69的化合物69。In step 8 of Example 1, quinoline-8-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 69 of Example 69.
MS(ESI)m/z 450.1(M+H)+ MS (ESI) m/z 450.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.08(dd,J＝4.2,1.8Hz,1H),8.56(dd,J＝8.4,1.8Hz,1H),8.35(m,2H),7.78(t,J＝7.8Hz,1H),7.71(dd,J＝8.3,4.2Hz,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＝9.5Hz,1H),3.62(dd,J＝8.8,5.5Hz,1H),3.46(dd,J＝10.1,5.5Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.08 (dd, J＝4.2, 1.8Hz, 1H), 8.56 (dd, J＝8.4, 1.8Hz, 1H), 8.35 (m, 2H), 7.78 ( t,J＝7.8Hz,1H),7.71(dd,J＝8.3,4.2Hz,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＝9.5Hz,1H),3.62(dd,J＝8.8,5.5Hz,1H),3.46(dd,J＝10.1,5.5Hz,1H).
实施例70：(S)-6-((1'-(3-羟基-2-苯基丙酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)磺酰基)烟腈(化合物70)的制备：
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):
步骤1：6-(苄硫基)烟腈(化合物70B)的制备
Step 1: Preparation of 6-(benzylthio)nicotinonitrile (Compound 70B)
将2-溴-5-氰基吡啶(2g，14.44mmol)溶于DMF中，随后依次加入苄硫醇(1.79g，14.44mmol)和碳酸铯(5.65g，17.33mmol)。加料完毕后反应升温至60℃下搅拌6小时。反应完全后，通过硅胶柱分离纯化得化合物70B。2-Bromo-5-cyanopyridine (2 g, 14.44 mmol) was dissolved in DMF, followed by the addition of benzyl mercaptan (1.79 g, 14.44 mmol) and cesium carbonate (5.65 g, 17.33 mmol). After the addition was completed, the reaction temperature was raised to 60°C and stirred for 6 hours. After the reaction was complete, the compound 70B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 227.1(M+H)+ MS (ESI) m/z 227.1 (M+H) +
步骤2：5-氰基吡啶-2-磺酰氯(化合物70C)的制备
Step 2: Preparation of 5-cyanopyridine-2-sulfonyl chloride (Compound 70C)
将6-(苄硫基)烟腈(1g,4.42mmol)溶于二氯甲烷和水的混合溶液中。将反应体系降温至0℃后缓慢滴加浓盐酸，滴加完毕后反应在0℃下搅拌10分钟后缓慢滴加次氯酸钠水溶液。滴加完毕后保持反应体系在0℃下搅拌10分钟后快速的分液。有机相直接进行下一步反应。Dissolve 6-(Benzylthio)nicotinonitrile (1g, 4.42mmol) in a mixed solution of dichloromethane and water. Cool the reaction system to 0°C and slowly add concentrated hydrochloric acid. After the addition is complete, stir the reaction at 0°C for 10 minutes and then slowly add sodium hypochlorite aqueous solution. After the addition is complete, keep the reaction system at 0°C and stir for 10 minutes before rapid separation. The organic phase is directly used for the next step.
在实施例1的步骤8中用5-氰基吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例70的化合物70。In step 8 of Example 1, 5-cyanopyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 70 of Example 70.
MS(ESI)m/z 425.1(M+H)+ MS (ESI) m/z 425.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ9.25(dd,J＝2.1,0.9Hz,1H),8.67(dd,J＝8.2,2.1Hz,1H),8.14(dd,J＝8.1,0.9Hz,1H),7.33–7.20(m,5H),4.80(t,J＝5.3Hz,1H),4.73(m,1H),4.63–4.52(m,4H),4.34(dd,J＝21.7,8.2Hz,2H),4.27–4.18(m,1H),3.90(m,1H),3.63(dd,J＝8.9,5.5Hz,1H),3.47(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.25 (dd, J＝2.1, 0.9Hz, 1H), 8.67 (dd, J＝8.2, 2.1Hz, 1H), 8.14 (dd, J＝8.1, 0.9 Hz,1H),7.33–7.20(m,5H),4.80(t,J＝5.3Hz,1H),4.73(m,1H),4.63–4.52(m,4H),4.34(dd,J＝21.7, 8.2Hz,2H),4.27–4.18(m,1H),3.90(m,1H),3.63(dd,J=8.9,5.5Hz,1H),3.47(m,1H).
实施例71：2-(4-(二氟甲基)苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物71)的制备：
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):
步骤1：2-(4-(二氟甲基)苯基)乙酸甲酯(化合物71B)的制备
Step 1: Preparation of methyl 2-(4-(difluoromethyl)phenyl)acetate (Compound 71B)
向二氯甲烷(10.0mL)中的2-(4-甲酰基苯基)乙酸甲酯(2.0g，11.22mmol)溶液中添加二乙胺基三氟化硫(3.62g，22.45mmol)，将混合物在氮气保护下50℃搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物71B。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), and the mixture was stirred at 50° C. for 3 hours under nitrogen protection. After the reaction was completed, the compound was separated and purified by silica gel column to obtain compound 71B.
MS(ESI)m/z 201.0(M+H)+ MS (ESI) m/z 201.0 (M+H) +
步骤2：2-(4-(二氟甲基)苯基)-3-羟基丙酸甲酯(化合物71C)的制备
Step 2: Preparation of methyl 2-(4-(difluoromethyl)phenyl)-3-hydroxypropanoate (Compound 71C)
将2-(4-(二氟甲基)苯基)乙酸甲酯(1.5g,7.49mmol)溶于二甲基亚砜(10.0mL)，随后加入多聚甲醛(681.13mg,7.57mmol)，后缓慢加入甲醇钠溶液(136.23mg,756.81μmol,30％纯度)。反应液在室温下反应3小时。反应完全后，通过硅胶柱分离纯化得化合物71C。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 reacted at room temperature for 3 hours. After the reaction was complete, the compound 71C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 231.0(M+H)+ MS (ESI) m/z 231.0 (M+H) +
步骤3：2-(4-(二氟甲基)苯基)-3-羟基丙酸(化合物71D)的制备
Step 3: Preparation of 2-(4-(difluoromethyl)phenyl)-3-hydroxypropanoic acid (Compound 71D)
将2-[4-(二氟甲基)苯基]-3-羟基-丙酸甲酯(300mg,1.30mmol)溶于水(3.0mL)、甲醇(3.0mL)和四氢呋喃(3.0mL)的混合溶液中，随后加入氢氧化锂(156.05mg,6.52mmol)。将混合物在50℃搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物71D。2-[4-(Difluoromethyl)phenyl]-3-hydroxy-propionic acid methyl ester (300 mg, 1.30 mmol) was dissolved in a mixed solution of water (3.0 mL), methanol (3.0 mL) and tetrahydrofuran (3.0 mL), and then lithium hydroxide (156.05 mg, 6.52 mmol) was added. The mixture was stirred at 50° C. for 3 hours. After the reaction was complete, the compound 71D was obtained by separation and purification by silica gel column.
MS(ESI)m/z 217.0(M+H)+ MS (ESI) m/z 217.0 (M+H) +
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-(二氟甲基)苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例71的化合物71。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-(difluoromethyl)phenyl)-3-hydroxypropanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 71 of Example 71.
MS(ESI)m/z 450.0(M+H)+ MS (ESI) m/z 450.0 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.80(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＝6.8Hz,2H),7.42-7.40(m,J＝6.8Hz,2H),7.113-6.85(t,1H),4.87(s,1H),4.75-4.72(d,J＝12.0Hz,1H),4.54(s,4H),4.40-4.19(m,3H),3.88(s,1H),3.71(s,1H),3.49(s,1H). 1 H NMR(400MHz, DMSO-d 6 )δ8.80(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＝6.8Hz,2H),7.42-7.40(m,J＝6.8Hz,2H),7.113-6.85(t,1H),4.87(s,1H),4.75-4.72(d,J＝12.0 Hz,1H),4.54(s,4H),4.40-4.19(m,3H),3.88(s,1H),3.71(s,1H),3.49(s,1H).
实施例72：(S)-1-(1'-((5-乙氧基吡啶-2-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯基丙烷-1-酮(化合物72)的制备：
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-phenylpropane-1-one (Compound 72):
步骤1：2-(苄基硫基)-5-乙氧基吡啶(化合物72B)的制备
Step 1: Preparation of 2-(benzylthio)-5-ethoxypyridine (Compound 72B)
将2-溴-5乙氧基吡啶(2g,9.9mmol)溶于1,4-二氧六环溶液中，随后依次加入苄硫醇(1.23g,9.9mmol)，DIPEA(3.28ml,19.8mmol)，Pd2(dba)3CHCl3(1.02g,0.99mmol)和xantphos(1.15g,1.98mmol)。加料完毕后反应在氮气环境下置换3次后升温至80℃下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物72B。2-Bromo-5-ethoxypyridine (2 g, 9.9 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (1.23 g, 9.9 mmol), DIPEA (3.28 ml, 19.8 mmol), Pd 2 (dba) 3 CHCl 3 (1.02 g, 0.99 mmol) and xantphos (1.15 g, 1.98 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80°C and stirred for 16 hours. After the reaction was complete, the compound 72B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 246.1(M+H)+ MS (ESI) m/z 246.1 (M+H) +
步骤2：5-乙氧基吡啶-2-磺酰氯(化合物72C)的制备
Step 2: Preparation of 5-ethoxypyridine-2-sulfonyl chloride (Compound 72C)
将2-(苄基硫基)-5-乙氧基吡啶(2.3g,9.37mmol)溶于乙腈中。随后依次加入乙酸(2.81g,46.85mmol)，水(1.69g,93.7mmol)和1,3-二氯咪唑烷-2,4-二酮(3.69g,18.74mmol)，加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物72C。2-(Benzylthio)-5-ethoxypyridine (2.3 g, 9.37 mmol) was dissolved in acetonitrile. 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 then added in sequence. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 72C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 221.9(M+H)+ MS (ESI) m/z 221.9 (M+H) +
在实施例1的步骤8中用5-乙氧基吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例72的化合物72。In step 8 of Example 1, 5-ethoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 72 of Example 72.
MS(ESI)m/z 444.1(M+H)+ MS (ESI) m/z 444.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝2.8Hz,1H),7.92(d,J＝8.7Hz,1H),7.63(dd,J＝8.8,2.9Hz,1H),7.39–7.11(m,5H),4.80(t,J＝5.3Hz,1H),4.72(d,J＝13.4Hz,1H),4.47(s,4H),4.40–4.26(m,2H),4.22(q,J＝7.0Hz,3H),3.89(m,1H),3.62(dd,J＝8.9,5.5Hz,1H),3.46(m,1H),1.37(t,J＝6.9Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.46 (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＝5.3Hz,1H),4.72(d,J＝13.4Hz,1H),4.47(s,4H),4.40–4.26(m,2H), 4.22(q,J＝7.0Hz,3H),3.89(m,1H),3.62(dd,J＝8.9,5.5Hz,1H),3.46(m,1H),1.37(t,J＝6.9Hz,3H ).
实施例73：3-氟-2-苯基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物73)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-氟-2-苯基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例73的化合物73。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-fluoro-2-phenylpropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 73 of Example 73.
MS(ESI)m/z 402.1(M+H)+ MS (ESI) m/z 402.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.79-8.78(d,J＝8.0Hz,1H),8.17-8.12(m,1H),7.98-7.96(d,J＝8.0Hz,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) 1 H-NMR (400MHz, DMSO-d 6 ) δ8.79-8.78 (d, J＝8.0Hz, 1H), 8.17-8.12 (m, 1H), 7.98-7.96 (d, J＝8.0Hz, 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)
实施例74：2-(2,4-二氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物74)的制备：
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):
步骤1：2-(2,4-二氟苯基)-3-羟基丙酸甲酯(化合物74B)的制备
Step 1: Preparation of methyl 2-(2,4-difluorophenyl)-3-hydroxypropanoate (Compound 74B)
将2-(2,4-二氟苯基)乙酸甲酯(0.8g,4.30mmol)和多聚甲醛(387.1mg,4.30mmol)溶于二甲基亚砜(5.0mL)，随后加入甲醇钠(77.4mg,0.43mmol,30％)。反应液在室温下反应4小时。反应完全后，通过硅胶柱分离纯化得化合物74B。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), and then sodium methoxide (77.4 mg, 0.43 mmol, 30%) was added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the compound 74B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 217.2(M+H)+ MS (ESI) m/z 217.2 (M+H) +
步骤2：2-(2,4-二氟苯基)-3-羟基丙酸(化合物74C)的制备
Step 2: Preparation of 2-(2,4-difluorophenyl)-3-hydroxypropanoic acid (Compound 74C)
将2-(2,4-二氟苯基)-3-羟基丙酸甲酯(440.0mg,2.04mmol)溶于甲醇(15.0mL)和水(10.0mL)中，随后加入氢氧化钠(162.8mg,4.07mmol)，反应液在50℃搅拌3小时。反应完全后，反应液用1N盐酸调pH至2，用二氯甲烷(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩后直接用于下一步反应。Dissolve methyl 2-(2,4-difluorophenyl)-3-hydroxypropionate (440.0 mg, 2.04 mmol) in methanol (15.0 mL) and water (10.0 mL), then add sodium hydroxide (162.8 mg, 4.07 mmol), and stir the reaction solution at 50°C for 3 hours. After the reaction is complete, adjust the pH of the reaction solution to 2 with 1N hydrochloric acid, extract with dichloromethane (50 mL*3), and wash the combined organic phases with saturated brine and dry with anhydrous sodium sulfate. After concentration, use it directly in the next reaction.
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(2,4-二氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例74的化合物74。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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 the same preparation method as in Example 1 was used to obtain compound 74 of Example 74.
MS(ESI)m/z 436.1(M+H)+ MS (ESI) m/z 436.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.81-8.80(d,J＝3.8Hz,1H),8.18-8.13(t,J＝7.7Hz,1H),7.99-7.97(d,J＝7.7Hz,1H),7.77-7.74(t,J＝5.9Hz,1H),7.45-7.39(q,J＝7.7Hz,1H),7.23-7.17(t,J＝9.8Hz,1H),7.07-7.02(t,J＝8.4Hz,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) 1 H NMR (400MHz, DMSO-d 6 ) δ8.81-8.80 (d, J = 3.8Hz, 1H), 8.18-8.13 (t, J = 7.7Hz, 1H), 7.99-7.97 (d, J = 7.7 Hz,1H),7.77-7.74(t,J＝5.9Hz,1H),7.45-7.39(q,J＝7.7Hz,1H),7.23-7.17( t,J＝9.8Hz,1H),7.07-7.02(t,J＝8.4Hz,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)
实施例75：2-(4-氯苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物75)的制备：

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):

步骤1：2-(4-氯苯基)-3-羟基丙酸甲酯(化合物75B)的制备
Step 1: Preparation of methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (Compound 75B)
将2-(4-氯苯基)乙酸甲酯(2.0g,10.83mmol)和多聚甲醛(975.9mg,10.83mmol)溶于二甲基亚砜(50.0mL)，随后加入甲醇钠(195.1mg,1.08mmol,30％)。反应液在室温下反应4小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。反应完全后，通过硅胶柱分离纯化得化合物75B。2-(4-chlorophenyl)acetic acid methyl ester (2.0g, 10.83mmol) and paraformaldehyde (975.9mg, 10.83mmol) were dissolved in dimethyl sulfoxide (50.0mL), and then sodium methoxide (195.1mg, 1.08mmol, 30%) was added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (50mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After the reaction was complete, the compound 75B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 215.1(M+H)+ MS (ESI) m/z 215.1 (M+H) +
步骤2：2-(4-氯苯基)-3-羟基丙酸(化合物75C)的制备
Step 2: Preparation of 2-(4-chlorophenyl)-3-hydroxypropanoic acid (Compound 75C)
将2-(4-氯苯基)-3-羟基丙酸甲酯(1.3g,6.06mmol)溶于甲醇(45.0mL)和水(30.0mL)中，随后加入氢氧化钠(484.5mg,12.11mmol)，反应液在50℃搅拌3小时。反应完全后，反应液用1N盐酸调pH至2，用乙酸乙酯(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩后直接用于下一步反应。Dissolve methyl 2-(4-chlorophenyl)-3-hydroxypropionate (1.3g, 6.06mmol) in methanol (45.0mL) and water (30.0mL), then add sodium hydroxide (484.5mg, 12.11mmol), and stir the reaction solution at 50℃ for 3 hours. After the reaction is complete, adjust the pH of the reaction solution to 2 with 1N hydrochloric acid, extract with ethyl acetate (50mL*3), wash the combined organic phase with saturated brine, and dry with anhydrous sodium sulfate. After concentration, use it directly in the next reaction.
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氯苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例75的化合物75。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-chlorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the same preparation method as in Example 1 was used to obtain compound 75 of Example 75.
MS(ESI)m/z 434.1(M+H)+ MS (ESI) m/z 434.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.81-8.80(m,1H),8.17-8.12(m,1H),7.99-7.97(d,J＝7.7Hz,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＝5.2Hz,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) 1 H NMR (400MHz, DMSO-d 6 ) δ8.81-8.80 (m, 1H), 8.17-8.12 (m, 1H), 7.99-7.97 (d, J = 7.7Hz, 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＝5.2Hz,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)
实施例76：(R)-2-(3-氯-4-氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物76)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(3-氯-4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法后用手性分离得到实施例76的化合物76。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(3-chloro-4-fluorophenyl)-3-hydroxypropanoic acid. The same preparation method as in Example 1 was used, followed by chiral separation to give Compound 76 of Example 76.
MS(ESI)m/z 452.1(M+H)+ MS (ESI) m/z 452.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.82-8.81(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). 1 H NMR (400MHz, DMSO-d 6 ) δ8.82-8.81(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).
实施例77：(S)-2-(3-氯-4-氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物77)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(3-氯-4-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法后用手性分离得到实施例77的化合物77。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(3-chloro-4-fluorophenyl)-3-hydroxypropanoic acid. The same preparation method as in Example 1 was used, followed by chiral separation to give Compound 77 of Example 77.
MS(ESI)m/z 452.1(M+H)+ MS (ESI) m/z 452.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.82-8.81(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). 1 H NMR (400MHz, DMSO-d 6 ) δ8.82-8.81(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).
实施例78：3-羟基-1-(1'-(吡啶-2-基磺酰基)-1'，4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-(4-(三氟甲基)苯基)丙-1-酮(化合物78)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-羟基-2-(4-(三氟甲基)苯基)丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例78的化合物78。In step 8 of Example 1, pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 3-hydroxy-2-(4-(trifluoromethyl)phenyl)propanoic acid was used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid, and the same preparation method as in Example 1 was used to obtain compound 78 of Example 78.
MS(ESI)m/z 468.1(M+H)+ MS (ESI) m/z 468.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.81-8.79(d,J＝4.7Hz,1H),8.18-8.13(m,1H),7.99-7.97(d,J＝8.0Hz,1H),7.76-7.73(m,1H),7.67-7.65(d,J＝8.2Hz,2H),7.52-7.50(d,J＝8.2Hz,2H),4.76-4.73(d,J＝12.4Hz,1H),4.54(s,4H),4.43-4.39(d,J＝13.2Hz,1H),4.34-4.31(d,J＝13.7Hz,1H),4.24-4.21(d,J＝12.9Hz,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＝7.4Hz,1H) 1 H-NMR (400MHz, DMSO-d 6 ) δ8.81-8.79 (d, J＝4.7Hz, 1H), 8.18-8.13 (m, 1H), 7.99-7.97 (d, J＝8.0Hz, 1H) ,7.76-7.73(m,1H),7.67-7.65(d,J＝8.2Hz,2H),7.52-7.50(d,J＝8.2Hz,2H),4.76-4.73(d,J＝12.4Hz,1H ),4 .54(s,4H),4.43-4.39(d,J＝13.2Hz,1H),4.34-4.31(d,J＝13.7Hz,1H),4.24-4.21(d,J＝12.9Hz,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＝7.4Hz,1H)
实施例79：2-(3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物79)的制备：
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):
步骤1：2-(4-羟基-3-硝基苯基)乙酸甲酯(化合物79B)的制备
Step 1: Preparation of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (Compound 79B)
将2-(4-羟基-3-硝基苯基)乙酸(5.0g,25.36mmol)溶于无水甲醇(100mL)，随后缓慢加入氯化亚砜(6.03g,50.72mmol)。反应液在室温下反应3小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物79B。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 complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 79B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 212.1(M+H)+ MS (ESI) m/z 212.1 (M+H) +
步骤2：2-(3-氨基-4-羟基苯基)乙酸甲酯(化合物79C)的制备
Step 2: Preparation of methyl 2-(3-amino-4-hydroxyphenyl)acetate (Compound 79C)
将2-(4-羟基-3-硝基苯基)乙酸甲酯(4.7g,22.3mmol)溶于无水乙醇(100.0mL)中，随后加入钯碳(470mg,2.23mmol)，反应液在室温下搅拌16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物79C。2-(4-Hydroxy-3-nitrophenyl)acetic acid methyl ester (4.7 g, 22.3 mmol) was dissolved in anhydrous ethanol (100.0 mL), and palladium carbon (470 mg, 2.23 mmol) was then added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 79C was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 182.1(M+H)+ MS (ESI) m/z 182.1 (M+H) +
步骤3：2-(3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)乙酸甲酯(化合物79D)的制备
Step 3: Preparation of methyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetate (Compound 79D)
将2-(4-氟-2-甲氧基苯基)丙烯酸甲酯(3.5g,19.3mmol)溶于乙酸乙酯(100mL)和水(100mL)中，随后加入碳酸钠(4.19g,38.6mmol)，2-氯乙酰氯(2.16g,19.3mmol)反应液在室温搅拌4小时。反应完全后，用乙酸乙酯(200mL)萃取3次，合并有机相，通过硅胶柱分离纯化得化合物79D。Methyl 2-(4-fluoro-2-methoxyphenyl)acrylate (3.5 g, 19.3 mmol) was dissolved in ethyl acetate (100 mL) and water (100 mL), and then sodium carbonate (4.19 g, 38.6 mmol) and 2-chloroacetyl chloride (2.16 g, 19.3 mmol) were added, and the reaction solution was stirred at room temperature for 4 hours. After the reaction was complete, it was extracted with ethyl acetate (200 mL) for 3 times, and the organic phases were combined and separated and purified by silica gel column to obtain compound 79D.
MS(ESI)m/z 222.1(M+H)+ MS (ESI) m/z 222.1 (M+H) +
步骤4：2-(3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)乙酸甲酯(化合物79E)的制备
Step 4: Preparation of methyl 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetate (Compound 79E)
将2-(3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)乙酸甲酯(2.4g,10.9mmol)溶于四氢呋喃(100.0mL)中，随后加入硼烷的四氢呋喃溶液(1.87g,21.7mmol)，反应液在60℃搅拌12小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物79E。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 (100.0 mL), and then a tetrahydrofuran solution of borane (1.87 g, 21.7 mmol) was added, and the reaction solution was stirred at 60°C for 12 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 79E was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 208.1(M+H)+ MS (ESI) m/z 208.1 (M+H) +
步骤5：6-(2-甲氧基-2-氧代乙基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(化合物79F)的制备
Step 5: Preparation of tert-butyl 6-(2-methoxy-2-oxoethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Compound 79F)
将2-(3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)乙酸甲酯(1.2g,5.45mmol)溶于二氯甲烷中(100mL)，随后加入三乙胺(1.18g,10.9mmol)，4-二甲氨基吡啶(662.7mg,5.45mmol)，反应体系降至0℃，二碳酸二叔丁酯(1.77g,8.14mmol)缓慢加入体系，反应液在室温搅拌16小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物79F。2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetic acid methyl ester (1.2g, 5.45mmol) was dissolved in dichloromethane (100mL), followed by the addition of triethylamine (1.18g, 10.9mmol) and 4-dimethylaminopyridine (662.7mg, 5.45mmol). The reaction system was cooled to 0°C, di-tert-butyl dicarbonate (1.77g, 8.14mmol) was slowly added to the system, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (100mL*3), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 79F was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 308.1(M+H)+ MS (ESI) m/z 308.1 (M+H) +
步骤6：6-(3-羟基-1-甲氧基-1-氧代丙烷-2-基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯(化合物79G)的制备
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)
将6-(2-甲氧基-2-氧代乙基)-2H-苯并[b][1,4]噁嗪-4(3H)-羧酸叔丁酯(576mg,1.87mmol)和多聚甲醛(168.9mg,1.87mmol)溶于二甲基亚砜(50.0mL)，随后加入甲醇钠(10.1mg,0.19mmol)。反应液在室温下反应4小时。反应完全后，反应液加水稀释，水相用乙酸乙酯(10mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物79F。6-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylic acid tert-butyl ester (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 the reaction was complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Compound 79F was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 338.4(M+H)+ MS (ESI) m/z 338.4 (M+H) +
步骤7：2-(4-(叔丁氧羰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)-3-羟基丙酸(化合物79H)的制备
Step 7: Preparation of 2-(4-(tert-Butyloxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-hydroxypropanoic acid (Compound 79H)
将3-羟基-2-(萘-2-基)丙酸甲酯(235.0mg,0.69mmol)溶于无水甲醇(60.0mL)和水(40.0mL)中，随后加入氢氧化钠(27.8mg,0.69mmol)，反应液在室温搅拌5小时。反应完全后，反应液用1N盐酸调pH至2，用二氯甲烷(100mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩得黄色油状化合物直接用于下一步反应。Dissolve methyl 3-hydroxy-2-(naphthalene-2-yl)propionate (235.0 mg, 0.69 mmol) in anhydrous methanol (60.0 mL) and water (40.0 mL), then add sodium hydroxide (27.8 mg, 0.69 mmol), and stir the reaction solution at room temperature for 5 hours. After the reaction is complete, adjust the pH of the reaction solution to 2 with 1N hydrochloric acid, extract with dichloromethane (100 mL*3), wash the combined organic phases with saturated brine, and dry with anhydrous sodium sulfate. Concentrate to obtain a yellow oily compound that is directly used in the next step.
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-(叔丁氧羰基)-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法得到实施例79的化合物79。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(4-(tert-butyloxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-hydroxypropanoic acid. The same preparation method as in Example 1 was used to obtain Compound 79 of Example 79.
MS(ESI)m/z 457.2(M+H)+ MS (ESI) m/z 457.2 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.82-8.81(m,1H),8.17-8.14(m,1H),8.00-7.98(d,J＝8.0Hz,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) 1 H-NMR (400MHz, DMSO-d 6 ) δ8.82-8.81(m,1H),8.17-8.14(m,1H),8.00-7.98(d,J＝8.0Hz,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)
实施例80：(S)-1-(1'-((5-(二氟甲氧基)吡啶-2-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯基丙烷-1-酮(化合物80)的制备：
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-phenylpropane-1-one (Compound 80):
步骤1：2-(苄硫基)-5-(二氟甲氧基)吡啶(化合物80B)的制备
Step 1: Preparation of 2-(benzylthio)-5-(difluoromethoxy)pyridine (Compound 80B)
将2-溴-5-二氟甲氧基吡啶(2g，8.93mmol)溶于1,4-二氧六环溶液中，随后依次加入苄硫醇(1.11g，8.93mmol)，DIPEA(2.31g，17.86mmol)，Pd2(dba)3CHCl3(913mg，0.89mmol)和xantphos(1.03g，1.79mmol)。加料完毕后反应在氮气环境下置换3次后升温至80℃下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物80B。2-Bromo-5-difluoromethoxypyridine (2 g, 8.93 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (1.11 g, 8.93 mmol), DIPEA (2.31 g, 17.86 mmol), Pd 2 (dba) 3 CHCl 3 (913 mg, 0.89 mmol) and xantphos (1.03 g, 1.79 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80° C. and stirred for 16 hours. After the reaction was complete, the compound 80B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 268.1(M+H)+ MS (ESI) m/z 268.1 (M+H) +
步骤2：5-(二氟甲氧基)吡啶-2-磺酰氯(化合物80C)的制备
Step 2: Preparation of 5-(difluoromethoxy)pyridine-2-sulfonyl chloride (Compound 80C)
将2-(苄基硫基)-5-二氟甲氧基吡啶(1.0g,3.74mmol)溶于乙腈中。随后依次加入乙酸(1.12g,18.71mmol)，水(674mg,37.41mmol)和1,3-二氯-5,5-二甲基海因(1.47g,7.48mmol)，加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物80C。2-(Benzylthio)-5-difluoromethoxypyridine (1.0 g, 3.74 mmol) was dissolved in acetonitrile. 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 then added in sequence. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 80C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 244.0(M+H)+ MS (ESI) m/z 244.0 (M+H)+
在实施例1的步骤8中用5-(二氟甲氧基)吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例80的化合物80。In step 8 of Example 1, 5-(difluoromethoxy)pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 80 of Example 80.
MS(ESI)m/z 466.1(M+H)+ MS (ESI) m/z 466.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.71(d,J＝2.7Hz,1H),8.07(d,J＝8.7Hz,1H),7.95(dd,J＝8.7,2.7Hz,1H),7.50(s,1H),7.34–7.19(m,5H),4.80(t,J＝5.3Hz,1H),4.73(d,J＝13.3Hz,1H),4.53(s,4H),4.42–4.27(m,2H),4.22(d,J＝15.0Hz,1H),3.89(m,1H),3.63(dd,J＝8.8,5.5Hz,1H),3.46(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.71(d,J＝2.7Hz,1H),8.07(d,J＝8.7Hz,1H),7.95(dd,J＝8.7,2.7Hz,1H) ,7.50(s,1H),7.34–7.19(m,5H),4.80(t,J＝5.3Hz,1H),4.73(d,J＝13.3Hz,1H),4.53(s,4H),4.42– 4.27(m,2H),4.22(d,J＝15.0Hz,1H),3.89(m,1H),3.63(dd,J＝8.8,5.5Hz,1H),3.46(m,1H).
实施例81：(S)-3-羟基-1-(1'-((5-异丙氧基吡啶-2-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯基丙烷-1-酮(化合物81)的制备：
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-phenylpropane-1-one (Compound 81):
步骤1：2-(苄硫基)-5-异丙氧基吡啶(化合物81B)的制备
Step 1: Preparation of 2-(benzylthio)-5-isopropoxypyridine (Compound 81B)
将2-溴-5-异丙氧基吡啶(2g，9.26mmol)溶于1,4-二氧六环溶液中，随后依次加入苄硫醇(1.15g，9.26mmol)，DIPEA(2.39g，18.51mmol)，Pd2(dba)3CHCl3(947mg，0.93mmol)和xantphos(1.07g，1.85mmol)。加料完毕后反应在氮气环境下置换3次后升温至80℃下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物81B。2-Bromo-5-isopropoxypyridine (2 g, 9.26 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (1.15 g, 9.26 mmol), DIPEA (2.39 g, 18.51 mmol), Pd 2 (dba) 3 CHCl 3 (947 mg, 0.93 mmol) and xantphos (1.07 g, 1.85 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80° C. and stirred for 16 hours. After the reaction was complete, the compound 81B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 260.1(M+H)+ MS (ESI) m/z 260.1 (M+H) +
步骤2：5-异丙氧基吡啶-2-磺酰氯(化合物81C)的制备
Step 2: Preparation of 5-isopropoxypyridine-2-sulfonyl chloride (Compound 81C)
将2-(苄基硫基)-5-异丙氧基吡啶(1.0g,3.86mmol)溶于乙腈中。随后依次加入乙酸(1.16g,19.28mmol)，水(695mg,38.56mmol)和1,3-二氯-5,5-二甲基海因(1.52g,7.71mmol)，加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物81C。2-(Benzylthio)-5-isopropoxypyridine (1.0 g, 3.86 mmol) was dissolved in acetonitrile. 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 then added in sequence. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 81C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 236.0(M+H)+ MS (ESI) m/z 236.0 (M+H) +
在实施例1的步骤8中用5-异丙氧基吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例81的化合物81。In step 8 of Example 1, 5-isopropoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 81 of Example 81.
MS(ESI)m/z 458.2(M+H)+ MS (ESI) m/z 458.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.42(d,J＝2.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.64(dd,J＝8.8,2.8Hz,1H),7.26(m,5H),4.82(m,2H),4.72(d,J＝13.3Hz,1H),4.47(s,4H),4.42–4.26(m,2H),4.21(d,J＝14.6Hz,1H),3.89(m,1H),3.62(dd,J＝8.9,5.5Hz,1H),3.46(m,1H),1.32(d,J＝6.0Hz,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.42(d,J＝2.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.64(dd,J＝8.8,2.8Hz,1H) ,7.26(m,5H),4.82(m,2H),4.72(d,J＝13.3Hz,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＝8.9,5.5Hz,1H),3.46(m,1H),1.32(d,J＝6.0Hz,6H).
实施例82：(S)-1-(1'-((5-环丙氧基吡啶-2-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-3-羟基-2-苯基丙烷-1-酮(化合物82)的制备：
Example 82: Preparation of (S)-1-(1'-((5-cyclopropyloxypyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropane-1-one (Compound 82):
步骤1：2-(苄基硫基)-5-环丙氧基吡啶(化合物82B)的制备
Step 1: Preparation of 2-(benzylthio)-5-cyclopropyloxypyridine (Compound 82B)
将2-溴-5-环丙氧基吡啶(3.98g，18.59mmol)溶于1,4-二氧六环溶液中，随后依次加入苄硫醇(2.31g，18.59mmol)，DIPEA(7.21g,55.77mmol)，Pd2(dba)3CHCl3(1.92g，1.86mmol)和xantphos(2.15g，3.72mmol)。加料完毕后反应在氮气环境下置换3次后升温至80℃下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物82B。2-Bromo-5-cyclopropyloxypyridine (3.98 g, 18.59 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (2.31 g, 18.59 mmol), DIPEA (7.21 g, 55.77 mmol), Pd 2 (dba) 3 CHCl 3 (1.92 g, 1.86 mmol) and xantphos (2.15 g, 3.72 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80° C. and stirred for 16 hours. After the reaction was complete, the compound 82B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 258.1(M+H)+ MS (ESI) m/z 258.1 (M+H) +
步骤2：5-环丙氧基吡啶-2-磺酰氯(化合物82C)的制备
Step 2: Preparation of 5-cyclopropyloxypyridine-2-sulfonyl chloride (Compound 82C)
将2-(苄基硫基)-5-环丙氧基吡啶(2.0g,7.78mmol)溶于乙腈中。随后依次加入乙酸(2.33g,38.9mmol)，水(1.40g,77.8mmol)和1,3-二氯咪唑烷-2,4-二酮(3.06g,15.56mmol)，加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物82C。2-(Benzylthio)-5-cyclopropyloxypyridine (2.0 g, 7.78 mmol) was dissolved in acetonitrile. 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 then added in sequence. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 82C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 233.9(M+H)+ MS (ESI) m/z 233.9 (M+H) +
在实施例1的步骤8中用5-环丙氧基吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法得到实施例82的化合物82。In step 8 of Example 1, 5-cyclopropyloxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the same preparation method as Example 1 was used to obtain Compound 82 of Example 82.
MS(ESI)m/z 456.2(M+H)+ MS (ESI) m/z 456.2 (M+H) +
1H NMR(400MHz,Chloroform-d)δ8.46(d,J＝2.8Hz,1H),7.93(d,J＝8.7Hz,1H),7.53(dd,J＝8.6,2.9Hz,1H),7.38–7.28(m,3H),7.25–7.19(m,2H),4.50(d,J＝29.8Hz,7H),4.19–3.92(m,2H),3.86(m,J＝6.4,2.9Hz,1H),3.71(dd,J＝11.2,4.4Hz,1H),3.65(dd,J＝8.8,4.4Hz,1H),0.97–0.79(m,4H). 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J＝2.8Hz,1H),7.93(d,J＝8.7Hz,1H),7.53(dd,J＝8.6,2.9Hz,1H), 7.38–7.28(m,3H),7.25–7.19(m,2H),4.50(d,J＝29.8Hz,7H),4.19–3.92(m,2H),3.86(m,J＝6.4,2.9Hz, 1H), 3.71 (dd, J＝11.2, 4.4Hz, 1H), 3.65 (dd, J＝8.8, 4.4Hz, 1H), 0.97–0.79 (m, 4H).
实施例83：(S)-2-(2,4-二氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物83)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(2,4-二氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法分离后通过手性分离得到实施例83的化合物83。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(2,4-difluorophenyl)-3-hydroxypropanoic acid. The same preparation method as in Example 1 was used for separation and chiral separation to obtain compound 83 of Example 83.
MS(ESI)m/z 436.1(M+H)+ MS (ESI) m/z 436.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.81-8.80(d,J＝3.8Hz,1H),8.18-8.13(t,J＝7.7Hz,1H),7.99-7.97(d,J＝7.7Hz,1H),7.77-7.74(t,J＝5.9Hz,1H),7.45-7.39(q,J＝7.7Hz,1H),7.23-7.17(t,J＝9.8Hz,1H),7.07-7.02(t,J＝8.4Hz,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) 1 H NMR (400MHz, DMSO-d 6 )δ8.81-8.80(d,J＝3.8Hz,1H),8.18-8.13(t,J＝7.7Hz,1H),7.99-7.97(d,J＝7. 7Hz,1H),7.77-7.74(t,J＝5.9Hz,1H),7.45-7.39(q,J＝7.7Hz,1H),7.23-7.17( t,J＝9.8Hz,1H),7.07-7.02(t,J＝8.4Hz,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)
实施例84：(R)-2-(2,4-二氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物84)的制备：
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):
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(2,4-二氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法分离后通过手性分离得到实施例84的化合物84。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 2-(2,4-difluorophenyl)-3-hydroxypropanoic acid. The same preparation method as in Example 1 was used for separation and chiral separation to give compound 84 of Example 84.
MS(ESI)m/z 436.1(M+H)+ MS (ESI) m/z 436.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.81-8.80(d,J＝3.8Hz,1H),8.18-8.13(t,J＝7.7Hz,1H),7.99-7.97(d,J＝7.7Hz,1H),7.77-7.74(t,J＝5.9Hz,1H),7.45-7.39(q,J＝7.7Hz,1H),7.23-7.17(t,J＝9.8Hz,1H),7.07-7.02(t,J＝8.4Hz,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) 1 H NMR (400MHz, DMSO-d 6 )δ8.81-8.80(d,J＝3.8Hz,1H),8.18-8.13(t,J＝7.7Hz,1H),7.99-7.97(d,J＝7. 7Hz,1H),7.77-7.74(t,J＝5.9Hz,1H),7.45-7.39(q,J＝7.7Hz,1H),7.23-7.17( t,J＝9.8Hz,1H),7.07-7.02(t,J＝8.4Hz,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)
实施例85：4-(3-羟基-1-氧代-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-2-基)苯甲腈(化合物85)的制备：
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):
步骤1：2-(4-氰基苯基)-3-羟基丙酸甲酯(化合物85B)的制备
Step 1: Preparation of methyl 2-(4-cyanophenyl)-3-hydroxypropanoate (Compound 85B)
将2-(4-氰基苯基)乙酸甲酯(1.0g,5.71mmol)，多聚甲醛(257mg,2.85mmol)和碳酸氢钠(14mg,0.17mmol)溶于二甲基亚砜溶液(10mL)中，加料完成后将反应体系置于室温下搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物85B。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 solution (10 mL). After the addition was completed, the reaction system was stirred at room temperature for 3 hours. After the reaction was complete, the compound 85B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 206.1(M+H)+ MS (ESI) m/z 206.1 (M+H) +
步骤2：2-(4-氰基苯基)-3-羟基丙酸(化合物85C)的制备
Step 2: Preparation of 2-(4-cyanophenyl)-3-hydroxypropionic acid (Compound 85C)
将3-羟基-2-(4-氰基苯基)丙酸甲酯(0.2g,0.97mmol)和氢氧化锂一水合物(82mg,1.95mmol)溶于甲醇(3.0mL)和水(1mL)的混合溶液中，加毕反应体系置于室温下搅拌过夜。反应完全后，通过硅胶柱分离纯化得化合物85C。Methyl 3-hydroxy-2-(4-cyanophenyl)propanoate (0.2 g, 0.97 mmol) and lithium hydroxide monohydrate (82 mg, 1.95 mmol) were dissolved in a mixed solution of methanol (3.0 mL) and water (1 mL). After the addition, the reaction system was stirred at room temperature overnight. After the reaction was complete, the compound 85C was separated and purified by silica gel column.
MS(ESI)m/z 192.2(M+H)+ MS (ESI) m/z 192.2 (M+H) +
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(4-氰基苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法分离得到实施例85的化合物85。In step 8 of Example 1, pyridine-2-sulfonyl chloride is used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(4-cyanophenyl)-3-hydroxypropionic acid is used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the compound 85 of Example 85 is isolated using the same preparation method as in Example 1.
MS(ESI)m/z 425.1(M+H)+ MS (ESI) m/z 425.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.82-8.81(m,1H),8.17-8.14(t,J＝1.2Hz,1H),8.00-7.98(d,J＝0.8Hz,1H),7.79-7.77(m,3H),7.51-7.48(d,J＝1.2Hz,2H),4.94-4.92(d,J＝0.8Hz,1H),4.75-4.72(d,J＝1.2Hz,1H),4.55-4.25(m,6H),3.91-3.81(m,1H),3.79-3.77(t,J＝0.8Hz,1H),3.56-3.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.82-8.81(m,1H),8.17-8.14(t,J＝1.2Hz,1H),8.00-7.98(d,J＝0.8Hz,1H),7.79-7.77(m,3H),7.51 -7.48(d,J＝1.2Hz,2H),4.94-4. 92(d,J＝0.8Hz,1H),4.75-4.72(d,J＝1.2Hz,1H),4.55-4.25(m,6H),3.91-3.81(m,1H),3.79-3.77(t, J＝0.8Hz,1H),3.56-3.38(m,2H).
实施例86：2-(3-氯-5-氟苯基)-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物86)的制备：
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):
步骤1：2-(3-氯-5-氟苯基)乙酸甲酯(化合物86B)的制备
Step 1: Preparation of methyl 2-(3-chloro-5-fluorophenyl)acetate (Compound 86B)
将2-(3-氯-5-氟苯基)乙酸(1g,5.30mmol)溶于甲醇(10mL)中,随后0℃下加入氯化亚砜(1.25g,10.59mmol),加料完成后将反应体系置于氮气氛围60℃搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物86B。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 completed, the reaction system was placed in a nitrogen atmosphere at 60°C and stirred for 3 hours. After the reaction was completed, the compound 86B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 201.2(M-H)- MS (ESI) m/z 201.2 (MH) -
步骤2：2-(3-氯-5-氟苯基)-3-羟基丙酸甲酯(化合物86C)的制备
Step 2: Preparation of methyl 2-(3-chloro-5-fluorophenyl)-3-hydroxypropanoate (Compound 86C)
将2-(3-氯-5-氟苯基)乙酸甲酯(1.01g,4.98mmol)溶于二甲基亚砜(10mL)中,随后室温下加入甲醇钠(90mg,500.00μmol)和多聚甲醛(220mg,2.44mmol),加料完成后将反应体系置于氮气氛围室温搅拌1小时，反应液用加水稀释，水相用乙酸乙酯(10.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。反应完全后，通过硅胶柱分离纯化得化合物86C。2-(3-chloro-5-fluorophenyl)acetic acid methyl ester (1.01 g, 4.98 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then sodium methoxide (90 mg, 500.00 μmol) and paraformaldehyde (220 mg, 2.44 mmol) were added at room temperature. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and stirred at room temperature for 1 hour. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate (10.0 mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the reaction was complete, the compound 86C was separated and purified by silica gel column.
MS(ESI)m/z 233.1(M+H)+ MS (ESI) m/z 233.1 (M+H) +
步骤3：2-(3-氯-5-氟苯基)-3-羟基丙酸(化合物86D)的制备
Step 3: Preparation of 2-(3-chloro-5-fluorophenyl)-3-hydroxypropanoic acid (Compound 86D)
将2-(3-氯-5-氟苯基)-3-羟基丙酸甲酯(200mg,859.71μmol)溶于四氢呋喃(3mL)和水(3mL)中，在室温下加入氢氧化锂(72mg,1.71mmol),加料完成后将反应体系置于氮气氛围室温搅拌2小时,反应结束后，反应液浓缩并用1N盐酸溶液调节pH值至3-4，水相用乙酸乙酯(10.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。反应完全后，通过硅胶柱分离纯化得化合物86D。2-(3-chloro-5-fluorophenyl)-3-hydroxypropionic acid methyl ester (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 completed, the reaction system was placed in a nitrogen atmosphere and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and the pH value was adjusted to 3-4 with 1N hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate (10.0 mL*3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the reaction was complete, the compound 86D was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 217.1(M-H)- MS (ESI) m/z 217.1 (MH) -
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(3-氯-5-氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法分离得到实施例86的化合物86。In step 8 of Example 1, pyridine-2-sulfonyl chloride is used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and in step 10, 2-(3-chloro-5-fluorophenyl)-3-hydroxypropionic acid is used instead of (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropionic acid, and the compound 86 of Example 86 is isolated using the same preparation method as in Example 1.
MS(ESI)m/z 452.1(M+H)+ MS (ESI) m/z 452.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.82-8.81(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＝5.2Hz,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). 1 H-NMR (400MHz, DMSO-d 6 )δ8.82-8.81(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),4.9 4(t,J＝5.2Hz,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).
实施例87：(S)-2-(2,4-二氟苯基)-3-羟基-1-(1'-((5-甲氧基吡啶-2-基)磺酰基)-1',4'-二氢-2H，2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物87)的制备：
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):
步骤1：2-(2,4-二氟苯基)-3-羟基丙酸甲酯(化合物87B)的制备
Step 1: Preparation of methyl 2-(2,4-difluorophenyl)-3-hydroxypropanoate (Compound 87B)
将2-(2,4-二氟苯基)乙酸甲酯(820mg,4.40mmol)溶于二甲基亚砜(8mL)中，随后室温下加入甲醇钠(80mg,444.44μmol,30％纯度)和多聚甲醛(200mg,2.22mmol),加料完成后将反应体系置于氮气氛围室温搅拌3小时，反应完全后反应液加水稀释，水相用乙酸乙酯(30.0mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。通过硅胶柱分离纯化得化合物87B。2-(2,4-difluorophenyl)acetic acid methyl ester (820mg, 4.40mmol) was dissolved in dimethyl sulfoxide (8mL), and then sodium methoxide (80mg, 444.44μmol, 30% purity) and paraformaldehyde (200mg, 2.22mmol) were added at room temperature. After the addition was completed, the reaction system was placed in a nitrogen atmosphere and stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate (30.0mL*3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 87B was obtained by separation and purification on a silica gel column.
MS(ESI)m/z 217.1(M+H)+ MS (ESI) m/z 217.1 (M+H) +
步骤2：2-(2,4-二氟苯基)-3-羟基丙酸(化合物87C)的制备
Step 2: Preparation of 2-(2,4-difluorophenyl)-3-hydroxypropanoic acid (Compound 87C)
将2-(2,4-二氟苯基)-3-羟基-丙酸甲酯(260mg,1.20mmol)溶于水(3mL)和四氢呋喃(3mL)中，在室温下加入氢氧化锂(100mg,2.38mmol),加料完成后将反应体系置于氮气氛围25℃搅拌2小时,反应完全后，通过硅胶柱分离纯化得化合物87C。2-(2,4-Difluorophenyl)-3-hydroxy-propionic acid methyl ester (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 completed, the reaction system was placed in a nitrogen atmosphere and stirred at 25°C for 2 hours. After the reaction was complete, compound 87C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 201.0(M-H)-MS (ESI) m/z 201.0 (M-H)-
在实施例1的步骤8中用5-甲氧基吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(2,4-二氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法分离得到实施例87的化合物87。In step 8 of Example 1, 5-methoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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. The compound 87 of Example 87 was isolated using the same preparation method as in Example 1.
MS(ESI)m/z 466.1(M+H)+ MS (ESI) m/z 466.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.49-8.48(d,J＝2.7Hz,1H),7.96-7.34(d,J＝8.8Hz,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＝12.9Hz,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). 1 H-NMR (400MHz, DMSO-d 6 )δ8.49-8.48(d,J＝2.7Hz,1H),7.96-7.34(d,J＝8.8Hz,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＝12.9Hz,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).
实施例88：(R)-2-(2,4-二氟苯基)-3-羟基-1-(1'-((5-甲氧基吡啶-2-基)磺酰基)-1',4'-二氢-2H，2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物88)的制备：
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):
在实施例1的步骤8中用5-甲氧基吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用2-(2,4-二氟苯基)-3-羟基丙酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法分离后通过手性分离得到实施例88的化合物88。In step 8 of Example 1, 5-methoxypyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[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. The same preparation method as in Example 1 was used for separation and chiral separation to give compound 88 of Example 88.
MS(ESI)m/z 466.1(M+H)+ MS (ESI) m/z 466.1 (M+H) +
1H-NMR(400MHz,DMSO-d6)δ8.49-8.48(d,J＝2.7Hz,1H),7.96-7.34(d,J＝8.8Hz,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＝12.9Hz,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). 1 H-NMR (400MHz, DMSO-d 6 )δ8.49-8.48(d,J＝2.7Hz,1H),7.96-7.34(d,J＝8.8Hz,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＝12.9Hz,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).
实施例89：(3-苯基氧杂环丁烷-3-基)(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)甲酮(化合物89)的制备：
Example 89: Preparation of (3-phenyloxetane-3-yl)(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)methanone (Compound 89):
步骤1：2-(3-苯基氧杂环丁烷-3-基)乙酸乙酯(化合物89B)的制备
Step 1: Preparation of ethyl 2-(3-phenyloxetane-3-yl)acetate (Compound 89B)
将2-(氧杂环丁烷-3-亚基)乙酸乙酯(5g，35.17mmol)溶于1,4-二氧六环中，随后依次加入氢氧化钾(2.57g，1.5N，45.72mmol)的水溶液，苯硼酸(6.43g，52.76mmol)和(1,5-环辛二烯)氯铑(I)二聚体(1.73g，3.52mmol)。加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物89B。2-(Oxetane-3-ylidene) ethyl acetate (5 g, 35.17 mmol) was dissolved in 1,4-dioxane, followed by the addition of potassium hydroxide (2.57 g, 1.5 N, 45.72 mmol) aqueous solution, phenylboronic acid (6.43 g, 52.76 mmol) and (1,5-cyclooctadiene) rhodium chloride (I) dimer (1.73 g, 3.52 mmol). After the addition was complete, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 89B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 221.1(M+H)+ MS (ESI) m/z 221.1 (M+H) +
步骤2：2-(3-苯基氧杂环丁烷-3-基)乙-1-醇(化合物89C)的制备
Step 2: Preparation of 2-(3-phenyloxetane-3-yl)ethan-1-ol (Compound 89C)
将2-(3-苯基氧杂环丁烷-3-基)乙酸乙酯(3g，13.62mmol)溶于四氢呋喃溶液中，将反应体系降温至0℃，随后缓慢加入四氢铝锂(0.52g，13.62mmol)。加料完毕后反应自然升温至室温下搅拌2小时。反应完全后，通过硅胶柱分离纯化得化合物89C。 Ethyl 2-(3-phenyloxetane-3-yl)acetate (3 g, 13.62 mmol) was dissolved in tetrahydrofuran solution, the reaction system was cooled to 0°C, and then lithium aluminum tetrahydride (0.52 g, 13.62 mmol) was slowly added. After the addition was completed, the reaction was naturally heated to room temperature and stirred for 2 hours. After the reaction was complete, the compound 89C was separated and purified by silica gel column.
MS(ESI)m/z 179.1(M+H)+ MS (ESI) m/z 179.1 (M+H) +
步骤3：2-(3-苯基氧杂环丁烷-3-基)乙基甲磺酸酯(化合物89D)的制备
Step 3: Preparation of 2-(3-phenyloxetane-3-yl)ethyl methanesulfonate (Compound 89D)
将2-(3-苯基氧杂环丁烷-3-基)乙-1-醇(2.43g,13.63mmol)溶于二氯甲烷中。将反应体系降温至0℃后加入三乙胺(2.48g,24.54mmol)，随后缓慢滴加甲基磺酰氯(2.81g,24.54mmol)，加料完毕后反应自然升至室温下搅拌2小时。反应完全后，通过硅胶柱分离纯化得化合物89D。2-(3-phenyloxetane-3-yl)ethan-1-ol (2.43 g, 13.63 mmol) was dissolved in dichloromethane. After the reaction system was cooled to 0°C, triethylamine (2.48 g, 24.54 mmol) was added, followed by slow dropwise addition of methylsulfonyl chloride (2.81 g, 24.54 mmol). After the addition was completed, the reaction was naturally heated to room temperature and stirred for 2 hours. After the reaction was complete, the compound was separated and purified by silica gel column to obtain compound 89D.
步骤4：3-苯基-3-乙烯基氧杂环丁烷(化合物89E)的制备
Step 4: Preparation of 3-phenyl-3-vinyloxetane (Compound 89E)
将2-(3-苯基氧杂环丁烷-3-基)乙基甲磺酸酯(3.4g,13.26mmol)溶于二甲亚砜中。随后分批加入叔丁醇钾(1.64g,14.59mmol)。加料完毕后将反应体系在室温下搅拌16小时。反应完全后，向反应体系中加入饱和的碳酸氢钠水溶液并用乙酸乙酯(200mL*3)萃取，合并有机相后通过硅胶柱分离纯化得化合物89E。2-(3-phenyloxetane-3-yl)ethyl methanesulfonate (3.4 g, 13.26 mmol) was dissolved in dimethyl sulfoxide. Potassium tert-butoxide (1.64 g, 14.59 mmol) was then added in batches. After the addition was completed, the reaction system was stirred at room temperature for 16 hours. After the reaction was complete, a saturated aqueous sodium bicarbonate solution was added to the reaction system and extracted with ethyl acetate (200 mL*3). The organic phases were combined and separated and purified by silica gel column to obtain compound 89E.
MS(ESI)m/z 161.1(M+H)+ MS (ESI) m/z 161.1 (M+H) +
步骤5：3-苯基氧杂环丁烷-3-羧酸(化合物89F)的制备
Step 5: Preparation of 3-phenyloxetane-3-carboxylic acid (Compound 89F)
将3-苯基-3-乙烯基氧杂环丁烷(1.4g,8.74mmol)溶于乙酸乙酯，乙腈和水的混合溶液中。将反应体系降温至0℃下加入三氯化钌(91mg,0.43mmol)，加料完毕后反应在0℃下搅拌10分钟后缓慢分批加入高碘酸钠(7.17g,33.21mmol)。加料完毕后反应保持0℃下搅拌30分钟。反应完全后将反应体系通过硅藻土过滤，水相用乙酸乙酯(200mL*3)萃取，合并有机相浓缩后加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取一次。水相缓慢滴加1N盐酸水溶液调节pH至1并旋干后得化合物89F。3-Phenyl-3-vinyloxetane (1.4 g, 8.74 mmol) was dissolved in a mixed solution of ethyl acetate, acetonitrile and water. The reaction system was cooled to 0°C and ruthenium trichloride (91 mg, 0.43 mmol) was added. After the addition was completed, the reaction was stirred at 0°C for 10 minutes and sodium periodate (7.17 g, 33.21 mmol) was slowly added in batches. After the addition was completed, the reaction was stirred at 0°C for 30 minutes. After the reaction was complete, the reaction system was filtered through diatomaceous earth, the aqueous phase was extracted with ethyl acetate (200 mL*3), the organic phases were combined and concentrated, and saturated sodium bicarbonate aqueous solution was added, and extracted once with ethyl acetate. 1N hydrochloric acid aqueous solution was slowly added to the aqueous phase to adjust the pH to 1 and spin-dried to obtain compound 89F.
在实施例1的步骤8中用吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，步骤10中用3-苯基氧杂环丁烷-3-羧酸替代(S)-3-((叔丁基二苯基硅基)氧基)-2-苯丙酸，采用与实施例1相同的制备方法分离后通过手性分离得到实施例89的化合物89。In step 8 of Example 1, 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride was replaced with pyridine-2-sulfonyl chloride, and in step 10, (S)-3-((tert-butyldiphenylsilyl)oxy)-2-phenylpropanoic acid was replaced with 3-phenyloxetane-3-carboxylic acid. The same preparation method as in Example 1 was used for separation and chiral separation to give Compound 89 of Example 89.
MS(ESI)m/z 412.1(M+H)+ MS (ESI) m/z 412.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.79(m,1H),8.14(m,1H),7.96(dd,J＝7.9,1.2Hz,1H),7.75(m,1H),7.43(dd,J＝8.2,6.8Hz,2H),7.35(m,3H),5.09(d,J＝6.2Hz,2H),4.69(d,J＝6.2Hz,2H),4.48(m,4H),4.41–4.33(m,2H),4.12–4.03(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.79(m,1H),8.14(m,1H),7.96(dd,J＝7.9,1.2Hz,1H),7.75(m,1H),7.43(dd,J＝8.2,6.8Hz,2H ),7.35 (m,3H),5.09(d,J＝6.2Hz,2H),4.69(d,J＝6.2Hz,2H),4.48(m,4H),4.41–4.33(m,2H),4.12–4.03( m,2H).
实施例90：2-环己基-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物90)的制备：
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):
步骤1：2-环己基丙二酸二甲酯(化合物90B)的制备
Step 1: Preparation of dimethyl 2-cyclohexylmalonate (Compound 90B)
将钠(1.6g,71.41mmol)在冰浴下分批缓慢加入到无水甲醇(100.0mL)中，待钠丝溶解完全后加入丙二酸二甲酯(6.3g,47.61mmol)和碘代环己烷(10.0g,47.61mmol)。反应液在70℃下反应18小时。反应完全后，通过硅胶柱分离纯化得化合物90B。Sodium (1.6 g, 71.41 mmol) was slowly added to anhydrous methanol (100.0 mL) in batches under an ice bath. After the sodium filaments were 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 compound 90B was separated and purified by silica gel column.
MS(ESI)m/z 215.3(M+H)+ MS (ESI) m/z 215.3 (M+H) +
步骤2：2-环己基-3-甲氧基-3-氧代丙酸(化合物90C)的制备
Step 2: Preparation of 2-cyclohexyl-3-methoxy-3-oxopropanoic acid (Compound 90C)
将2-环己基丙二酸二甲酯(100.0mg,0.47mmol)溶于甲醇(3.0mL)和水(1.0mL)中，随后加入氢氧化钾(26.2mg,0.47mmol)的水溶液(1.0mL)，反应液在室温搅拌3小时。LCMS显示反应基本完全，反应液用1N盐酸调pH至5，用乙酸乙酯(50mL*3)萃取，合并有机相饱和食盐水洗涤后用无水硫酸钠干燥。浓缩得黄色油状化合物直接用于下一步反应。Dissolve dimethyl 2-cyclohexylmalonate (100.0 mg, 0.47 mmol) in methanol (3.0 mL) and water (1.0 mL), then add potassium hydroxide (26.2 mg, 0.47 mmol) in water (1.0 mL), and stir the reaction solution at room temperature for 3 hours. LCMS shows that the reaction is basically complete, adjust the pH of the reaction solution to 5 with 1N hydrochloric acid, extract with ethyl acetate (50 mL*3), wash the combined organic phases with saturated brine, and dry with anhydrous sodium sulfate. Concentrate to obtain a yellow oily compound that is directly used in the next step.
步骤3：2-环己基-3-氧代-3-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙酸甲酯(化合物90D)的制备
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)propanoate (Compound 90D)
将2-环己基-3-甲氧基-3-氧代丙酸(93.4mg,0.46mmol)，1-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-3,3'-二联氮杂环丁烷亚基(94.78mg,0.26mmol)，HATU(197.3mg,0.52mmol)和N,N-二异丙基乙胺(134.1mg,1.04mmol)溶于N,N-二甲基甲酰胺(5.0mL)中，反应液在室温搅拌3小时。反应完全后，通过硅胶柱分离纯化得化合物90D。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'-diazetidine (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), and the reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the compound 90D was separated and purified by silica gel column.
MS(ESI)m/z 434.2(M+H)+ MS (ESI) m/z 434.2 (M+H) +
步骤4：2-环己基-3-羟基-1-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙-1-酮(化合物90)的制备
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)
将2-环己基-3-氧代-3-(1'-(吡啶-2-基磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)丙酸甲酯(60.0mg,0.14mmol)溶于甲醇(6.0mL)和四氢呋喃(6.0mL)中，随后加入硼氢化钠(52.4mg,1.38mmol)，反应液在80℃搅拌72小时。反应完全后，通过反相高压液相制备分离纯化得化合物90。Methyl 2-cyclohexyl-3-oxo-3-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)propanoate (60.0 mg, 0.14 mmol) was dissolved in methanol (6.0 mL) and tetrahydrofuran (6.0 mL), and then sodium borohydride (52.4 mg, 1.38 mmol) was added, and the reaction solution was stirred at 80° C. for 72 hours. After the reaction was complete, compound 90 was obtained by reverse phase high pressure liquid preparative separation and purification.
MS(ESI)m/z 406.2(M+H)+ MS (ESI) m/z 406.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.83-8.82(d,J＝4.4Hz,1H),8.19-8.17(m,1H),8.00-7.98(d,J＝8.0Hz,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) 1 H NMR (400MHz, DMSO-d 6 )δ8.83-8.82(d,J＝4.4Hz,1H),8.19-8.17(m,1H),8.00-7.98(d,J＝8.0Hz,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)
实施例91：(S)-3-羟基-1-(1'-((5-(甲氧基-d3)吡啶-2-基)磺酰基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)-2-苯基丙烷-1-酮(化合物91)的制备：
Example 91: Preparation of (S)-3-hydroxy-1-(1'-((5-(methoxy-d 3 )pyridin-2-yl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)-2-phenylpropan-1-one (Compound 91):
步骤1：2-溴-5-(甲氧基-d3)吡啶(化合物91B)的制备
Step 1: Preparation of 2-bromo-5-(methoxy-d 3 )pyridine (Compound 91B)
将2-溴-5-羟基吡啶(3g，17.24mmol)溶于1,4-二氧六环溶液中，随后依次加入氘代甲醇(3.11g，86.20mmol)，三苯基膦(4.97g，18.96mmol)和DIAD(3.83g，18.96mmol)。加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物91B。2-Bromo-5-hydroxypyridine (3 g, 17.24 mmol) was dissolved in 1,4-dioxane solution, 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 was stirred at room temperature for 16 hours. After the reaction was complete, the compound 91B was obtained by separation and purification by silica gel column.
MS(ESI)m/z 191.0(M+H)+ MS (ESI) m/z 191.0 (M+H) +
步骤2：2-(苄硫基)-5-(甲氧基-d3)吡啶(化合物91C)的制备
Step 2: Preparation of 2-(benzylthio)-5-(methoxy-d 3 )pyridine (Compound 91C)
将2-溴-5-(甲氧基-d3)吡啶(2.53g，13.24mmol)溶于1,4-二氧六环溶液中，随后依次加入苄硫醇(1.64g，13.24mmol)，DIPEA(3.42g，26.49mmol)，Pd2(dba)3CHCl3(1.35g，1.32mmol)和xantphos(1.53g，2.65mmol)。加料完毕后反应在氮气环境下置换3次后升温至80℃下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物91C。2-Bromo-5-(methoxy-d 3 )pyridine (2.53 g, 13.24 mmol) was dissolved in 1,4-dioxane solution, followed by the addition of benzyl mercaptan (1.64 g, 13.24 mmol), DIPEA (3.42 g, 26.49 mmol), Pd 2 (dba) 3 CHCl 3 (1.35 g, 1.32 mmol) and xantphos (1.53 g, 2.65 mmol). After the addition was completed, the reaction was replaced three times under nitrogen atmosphere and then heated to 80° C. and stirred for 16 hours. After the reaction was complete, the compound 91C was obtained by separation and purification by silica gel column.
MS(ESI)m/z 235.1(M+H)+ MS (ESI) m/z 235.1 (M+H) +
步骤3：5-(甲氧基-d3)吡啶-2-磺酰氯(化合物91D)的制备
Step 3: Preparation of 5-(methoxy-d 3 )pyridine-2-sulfonyl chloride (Compound 91D)
将2-(苄硫基)-5-(甲氧基-d3)吡啶(1.1g,4.69mmol)溶于乙腈中。随后依次加入乙酸(1.41g,23.47mmol)，水(846mg,46.94mmol)和1,3-二氯-5,5-二甲基海因(1.85g,9.39mmol)，加料完毕后反应在室温下搅拌16小时。反应完全后，通过硅胶柱分离纯化得化合物91D。2-(Benzylthio)-5-(methoxy-d3)pyridine (1.1 g, 4.69 mmol) was dissolved in acetonitrile. 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 then added in sequence. After the addition was completed, the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the compound 91D was obtained by separation and purification by silica gel column.
MS(ESI)m/z 211.0(M+H)+ MS (ESI) m/z 211.0 (M+H) +
在实施例1的步骤8中用5-(甲氧基-d3)吡啶-2-磺酰氯替代2,3-二氢-[1,4]二噁并[2,3-b]吡啶-7-磺酰氯，采用与实施例1相同的制备方法分离得到实施例91的化合物91。In step 8 of Example 1, 5-(methoxy-d 3 )pyridine-2-sulfonyl chloride was used instead of 2,3-dihydro-[1,4]dioxo[2,3-b]pyridine-7-sulfonyl chloride, and the compound 91 of Example 91 was isolated using the same preparation method as Example 1.
MS(ESI)m/z 433.2(M+H)+ MS (ESI) m/z 433.2 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝2.9Hz,1H),7.94(d,J＝8.8Hz,1H),7.64(dd,J＝8.8,3.0Hz,1H),7.27(m,5H),4.80(t,J＝5.2Hz,1H),4.72(d,J＝13.4Hz,1H),4.48(s,4H),4.41–4.27(m,2H),4.21(d,J＝14.7Hz,1H),3.89(m,1H),3.62(dd,J＝8.9,5.4Hz,1H),3.46(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ8.48(d,J＝2.9Hz,1H),7.94(d,J＝8.8Hz,1H),7.64(dd,J＝8.8,3.0Hz,1H),7.27(m,5H),4.80( t,J＝5.2Hz,1H),4.72(d,J＝ 13.4Hz,1H),4.48(s,4H),4.41–4.27(m,2H),4.21(d,J＝14.7Hz,1H),3.89(m,1H),3.62(dd,J＝8.9,5.4 Hz,1H),3.46(m,1H).
实施例92：(S)-4-((1'-(2-(2,4-二氟苯基)-3-羟丙基)-1',4'-二氢-2H,2'H-[3,3'-二联氮杂环丁烷亚基]-1(4H)-基)磺酰基)苯甲腈(化合物92)的制备：
Example 92: Preparation of (S)-4-((1'-(2-(2,4-difluorophenyl)-3-hydroxypropyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile (Compound 92):
在实施例35的步骤3中用4-氰基苯磺酰氯替代2-甲基苯并[d]噻唑-6-磺酰氯，步骤5中用(S)-2-(2,4-二氟苯基)-3-羟基丙酸替代(S)-3-羟基-2-苯基丙酸，采用与实施例35相同的制备方法分离得到实施例92的化合物92。In step 3 of Example 35, 4-cyanobenzenesulfonyl chloride was used instead of 2-methylbenzo[d]thiazole-6-sulfonyl chloride, and in step 5, (S)-2-(2,4-difluorophenyl)-3-hydroxypropionic acid was used instead of (S)-3-hydroxy-2-phenylpropionic acid. The same preparation method as in Example 35 was used to isolate compound 92 of Example 92.
MS(ESI)m/z 460.1(M+H)+ MS (ESI) m/z 460.1 (M+H) +
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝8.2Hz,2H),8.01(d,J＝8.2Hz,2H),7.41(m,1H),7.20(m,1H),7.04(m,1H),4.91(t,J＝5.0Hz,1H),4.70(d,J＝12.5Hz,1H),4.40–4.27(m,6H),4.21(d,J＝13.4Hz,1H),3.85(d,J＝5.3Hz,2H),3.61–3.46(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ8.17(d,J＝8.2Hz,2H),8.01(d,J＝8.2Hz,2H),7.41(m,1H),7.20(m,1H),7.04(m,1H),4.91( t,J＝5.0Hz,1H) ,4.70(d,J＝12.5Hz,1H),4.40–4.27(m,6H),4.21(d,J＝13.4Hz,1H),3.85(d,J＝5.3Hz,2H),3.61–3.46( m,1H).
生物测试数据Biological test data
如无特别说明，以下活性实施例中所用的实验材料、试剂、操作和方法均可从市售渠道获得或基于现有技术容易地获知或制备。Unless otherwise specified, the experimental materials, reagents, operations and methods used in the following active examples can be obtained from commercial channels or can be easily known or prepared based on existing technologies.
试验例1丙酮酸激酶(PKM2)体外酶学活性实验Experimental Example 1 Pyruvate kinase (PKM2) in vitro enzymatic activity experiment
1.实验目的1. Purpose of the experiment
测试本发明化合物对重组人PKM2酶的激活作用。The compounds of the present invention were tested for their activation effects on recombinant human PKM2 enzyme.
2.实验材料及仪器2. Experimental Materials and Instruments
试剂及耗材
Reagents and consumables
仪器
instrument
3.实验步骤3. Experimental Procedure
3.1配置重组人PKM2酶溶液，浓度为10ng/孔(20μL反应体系)，于黑色透明底384孔板中每孔加入5μL。3.1 Prepare recombinant human PKM2 enzyme solution with a concentration of 10 ng/well (20 μL reaction system) and add 5 μL to each well of a black transparent bottom 384-well plate.
3.2配置不同浓度化合物溶液，终浓度为3000/1000/300nM(含有1％DMSO)，于3.1孔板中加入5μL化合物，混匀。室温孵育10min。 3.2 Prepare compound solutions of different concentrations, with a final concentration of 3000/1000/300 nM (containing 1% DMSO), add 5 μL of compound to the well plate in 3.1, mix well, and incubate at room temperature for 10 min.
3.3按照试剂盒说明书配置反应体系(如下表)，于384孔板中每孔加入10μL，与3.2中溶液混匀。
3.3 Prepare the reaction system according to the kit instructions (as shown in the table below), add 10 μL to each well of a 384-well plate, and mix well with the solution in 3.2.
3.4将384孔板置于酶标仪检测荧光值，540/590nm处检测荧光，每2分钟读值一次，连续测定1小时。3.4 Place the 384-well plate in an ELISA reader to detect the fluorescence value. Detect the fluorescence at 540/590 nm, read the value every 2 minutes, and continue measuring for 1 hour.
3.5计算测定时间内的Slope值，以1％DMSO孔为对照孔，计算化合物激活率。3.5 Calculate the Slope value within the measurement time, take the 1% DMSO well as the control well, and calculate the compound activation rate.
激活率％＝(化合物孔Slope/对照孔Slope)×100％Activation rate % = (compound well slope / control well slope) × 100%
3.6拟合量效曲线3.6 Fitting the dose-effect curve
以化合物浓度的log值作为X轴，百分比激活率为Y轴，采用分析软件GraphPad Prism 5的log(激动剂)vs.响应-可变斜率(Variable slope)拟合量效曲线，从而得出各个化合物对PKM2活性的AC50值。The log value of compound concentration was used as the X-axis and the percentage activation rate was used as the Y-axis. The log (agonist) vs. response-variable slope (Variable slope) of the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the AC 50 value of each compound on PKM2 activity.
计算公式：Y＝min+(max-min)/(1+10^((LogAC50-X)×Hillslope))。Calculation formula: Y = min + (max - min) / (1 + 10^((LogAC 50 -X) × Hillslope)).
4.实验结果：4. Experimental results:
本发明化合物对PKM2酶激活作用通过以上的试验进行测定，测得的AC50值如下(A表示0～100nM，B表示101～300nM，C表示300～1000nM)。
The PKM2 enzyme activation effect of the compounds of the present invention was determined by the above test, and the measured AC 50 values were as follows (A represents 0-100 nM, B represents 101-300 nM, and C represents 300-1000 nM).
试验例2丙酮酸激酶(PKM2)细胞活性实验Experimental Example 2 Pyruvate kinase (PKM2) cell activity experiment
1.实验目的1. Purpose of the experiment
测试本发明化合物对人脑星形胶质母细胞瘤(U118-MG)中PKM2的激活作用。The compounds of the present invention were tested for their effects on activation of PKM2 in human brain glioblastoma (U118-MG).
2.实验材料及仪器2. Experimental Materials and Instruments
试剂及耗材
Reagents and consumables
仪器
instrument
3.实验步骤3. Experimental Procedure
3.1将培养的U118-MG细胞用胰酶消化，接种于96孔板中，密度为2500个细胞/孔(100μL)，置于CO2培养箱中贴壁过夜。3.1 The cultured U118-MG cells were digested with trypsin, seeded in a 96-well plate at a density of 2500 cells/well (100 μL), and placed in a CO2 incubator to adhere overnight.
3.2将待测化合物稀释后加入3.1中的96孔板中，每孔加入100μL，化合物终浓度为3000/1000/300nM(含有1％DMSO)。细胞与化合物在37℃、5％CO2孵箱中培养4h。弃去上清液，每孔加入100μL PBS清洗残留培养基，弃去PBS，每孔加入100μL PierceTM IP裂解液，震荡20min，4000g离心10min，取上清液进行检测。3.2 Dilute the test compound and add it to the 96-well plate in 3.1, add 100 μL to each well, and the final concentration of the compound is 3000/1000/300 nM (containing 1% DMSO). The cells and the compound are cultured in a 37°C, 5% CO 2 incubator for 4 hours. Discard the supernatant, add 100 μL PBS to each well to wash the residual culture medium, discard the PBS, add 100 μL Pierce TM IP lysis buffer to each well, shake for 20 minutes, centrifuge at 4000g for 10 minutes, and take the supernatant for detection.
3.3按照试剂盒说明书配置反应体系(如下表)，于384孔板中每孔加入10μL，取10μL细胞裂解液混匀(20μL反应体系)。
3.3 Prepare the reaction system according to the kit instructions (as shown in the table below), add 10 μL to each well of the 384-well plate, and take 10 μL of cell lysate and mix well (20 μL reaction system).
3.4将黑色透明底384孔板置于酶标仪检测荧光值，540/590nm处检测荧光，每2分钟读值一次，连续测定1小时。3.4 Place a black transparent bottom 384-well plate on an ELISA reader to detect the fluorescence value. Detect the fluorescence at 540/590 nm, read the value every 2 minutes, and continue measuring for 1 hour.
3.5计算测定时间内的Slope值，以0.1％DMSO孔为对照孔，计算化合物激活率。3.5 Calculate the Slope value within the measurement time, take the 0.1% DMSO well as the control well, and calculate the compound activation rate.
激活率％＝(化合物孔Slope/对照孔Slope)×100％Activation rate % = (compound well slope / control well slope) × 100%
3.6拟合量效曲线3.6 Fitting the dose-effect curve
以化合物浓度的log值作为X轴，百分比激活率为Y轴，采用分析软件GraphPad Prism 5的log(激动剂)vs.响应-可变斜率(Variable slope)拟合量效曲线，从而得出各个化合物对PKM2活性的AC50值。The log value of compound concentration was used as the X-axis and the percentage activation rate was used as the Y-axis. The log (agonist) vs. response-variable slope (Variable slope) of the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the AC 50 value of each compound on PKM2 activity.
计算公式：Y＝min+(max-min)/(1+10^((LogAC50-X)×Hillslope))。Calculation formula: Y = min + (max - min) / (1 + 10^((LogAC 50 -X) × Hillslope)).
4.实验结果4. Experimental Results
本发明化合物对人脑星形胶质母细胞瘤(U118-MG)PKM2酶激活作用通过以上的试验进行测定，测得的AC50值如下(A表示0～100nM，B表示101～300nM，C表示300～1000nM)。
The activation effect of the compounds of the present invention on PKM2 enzyme in human brain glioblastoma (U118-MG) was determined by the above test, and the measured AC 50 values were as follows (A represents 0-100 nM, B represents 101-300 nM, and C represents 300-1000 nM).
试验例3小鼠触须毛囊(vibrissa follicles)体外生长实验Experimental Example 3: In vitro growth experiment of mouse vibrissa follicles
1.实验目的 1. Purpose of the experiment
测试代表性本发明化合物(化合物83)在体外对小鼠毛囊生长的促进作用。所述化合物具有如下结构：
The representative compound of the present invention (Compound 83) was tested for its promoting effect on mouse hair follicle growth in vitro. The compound has the following structure:
2.实验材料及仪器2. Experimental Materials and Instruments
主要试剂：DMEM培养基，庆大霉素，双抗(青霉素/链霉素)，二甲亚砜(DMSO)Main reagents: DMEM culture medium, gentamicin, double antibody (penicillin/streptomycin), dimethyl sulfoxide (DMSO)
主要仪器：细胞培养箱，显微镜Main instruments: cell culture box, microscope
3.实验步骤3. Experimental Procedure
3.1显微镜下从6周龄C57BL/6N小鼠身上提取小鼠触须毛囊，于24孔板中培养(DMEM培养基，含12.5ug/mL庆大霉素，1％双抗)3.1 Mouse vibrissa follicles were extracted from 6-week-old C57BL/6N mice under a microscope and cultured in 24-well plates (DMEM medium containing 12.5ug/mL gentamicin and 1% double antibody)
3.2将待测化合物用DMSO稀释为不同浓度，加入到24孔板中，DMSO终浓度为0.1％(化合物终浓度见下表)。3.2 The test compound was diluted with DMSO to different concentrations and added to a 24-well plate. The final DMSO concentration was 0.1% (the final concentration of the compound is shown in the table below).
3.3每2天更换一次培养基，于第10天测定毛囊的毛干长度。
3.3 The culture medium was replaced every 2 days and the hair shaft length of the hair follicles was measured on the 10th day.
4.实验结果4. Experimental Results
如图1中的结果所示，本发明的化合物83在不同浓度下均能显著增加毛干长度，对毛发生长有促进作用(图1a)和图1b))。As shown in the results in FIG. 1 , compound 83 of the present invention can significantly increase hair shaft length at different concentrations and has a promoting effect on hair growth ( FIG. 1 a ) and FIG. 1 b )).
试验例4小鼠毛发生长实验Test Example 4 Mouse hair growth experiment
1.实验目的1. Purpose of the experiment
测试代表性本发明化合物(化合物83)对小鼠毛发生长的促进作用。The representative compound of the present invention (Compound 83) was tested for its effect on promoting hair growth in mice.
2.实验材料2. Experimental Materials
主要试剂：丙二醇，乙醇Main reagents: propylene glycol, ethanol
3.实验步骤 3. Experimental Procedure
3.1 6周龄C57BL/6N小鼠适应新环境1周后，将毛囊进入休止期的7周龄小鼠注射麻醉，剃除小鼠背部毛发，将不同浓度的每种药物各150μL均匀涂抹至小鼠背部皮肤，每天一次，持续4周。3.1 After 6-week-old C57BL/6N mice adapted to the new environment for 1 week, 7-week-old mice whose hair follicles entered the resting phase were injected with anesthesia, the hair on the back of the mice was shaved, and 150 μL of each drug of different concentrations was evenly applied to the back skin of the mice once a day for 4 weeks.
3.2化合物溶媒配方如下：
3.2 The compound solvent formula is as follows:
3.3试验结束后，对动物背部进行拍照并收集重新生长的头发，使用精密天平测量毛发重量。3.3 After the experiment, the animals' backs were photographed and the regrown hair was collected and the hair weight was measured using a precision balance.
4.实验结果4. Experimental Results
如图2中的结果所示，本发明化合物对小鼠毛发生长具有明显促进作用，1mM浓度下的本发明化合物(化合物83)组动物新生毛发重量显著优于对照组(图2a)和图2b))。As shown in the results in FIG. 2 , the compound of the present invention has a significant promoting effect on hair growth in mice. The weight of new hair in the group of animals treated with the compound of the present invention (Compound 83) at a concentration of 1 mM was significantly better than that in the control group ( FIG. 2 a ) and FIG. 2 b ).
本发明不局限于上述可选的实施方式，任何人在本发明的启示下都可得出其他各种形式的产品。上述具体实施方式不应理解成对本发明的保护范围的限制，本发明的保护范围应当以权利要求书中界定的为准，并且说明书可以用于解释权利要求书。 The present invention is not limited to the above optional implementations, and anyone can derive other various forms of products under the enlightenment of the present invention. The above specific implementations should not be understood as limiting the scope of protection of the present invention. The scope of protection of the present invention should be based on the definition in the claims, and the description can be used to interpret the claims.

Claims (38)

  1. 下式Ⅰ或Ⅱ的化合物或其异构体、药学上可接受盐或溶剂化物作为PKM2激动剂的用途：
    Use of the compound of the following formula I or II or its isomer, pharmaceutically acceptable salt or solvate as a PKM2 agonist:
    其中：in:
    R1、R2和R3独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb、-SRb、-NRcRd、-S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf或-C(O)ORg，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-SRb、-NO2、-NRcRd、-S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf和-C(O)ORg；R 1 , R 2 and R 3 are 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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 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 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents 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 ;
    或者，R1和R2、R1和R3或者R2和R3连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、-(C5-C8)螺环基、含有1-4个独立地选自O、N和S的杂原子的5至8元螺杂环基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基或含有1-4个独立地选自O、N和S的杂原子的5-14元的杂芳基；Alternatively, R1 and R2 , R1 and R3 , or R2 and R3, together with the atoms to which they are attached, may optionally combine to form -( C3 - C8 )cycloalkyl, 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, -( C5 - C8 )spirocyclyl, 5- to 8-membered spiroheterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, or 5-14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S;
    R4为-NH2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb、-SRb、-NRcRd、-S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf、-C(O)ORg或-NRc(CRhRi)t-Ra，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-SRb、-NO2、-NRcRd、-S(O)2Re、-S(O)2NRcRd、-S(O)Re、-S(O)NRcRd、-NRcS(O)2Re、-NRcS(O)Re、-C(O)Rf和-C(O)ORg； R4 is -NH2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S , -ORb , -SRb , -NRcRd , -S(O ) 2Re , -S(O) 2NRcRd , -S(O )Re , -S ( O ) NRcRd , -NRcS (O) 2Re -NRcS (O) Re , -C(O) Rf , -C(O) ORg , or -NRc ( CRhRi ) t - Ra , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from: =O, halogen, -CN, -R a , -ORb , -SRb , -NO2 , -NRcRd , -S( O ) 2Re , -S(O) 2NRcRd , -S (O) Re , -S (O)NRcRd, -NRcS(O)2Re, -NRcS(O)Re , -C ( O ) Rf , and -C(O) ORg ;
    t为0、1、2或3；t is 0, 1, 2, or 3;
    Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh和Ri在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-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、-NHS(O)OH、-C(O)H或-C(O)OH，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-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、-(C1-C6)烷基、-(C3-C8)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基； Ra , Rb , Rc , Rd , Re , Rf , Rg , Rh and Ri are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -SH, -S(O) 2H , -S(O) 2NH 2 , -S(O)H, -S(O) NH2 , -NHS(O) 2H , -NHS(O)H, -S(O) 2OH , -S(O)OH, -NHS(O) 2OH , -NHS(O)OH, -C(O)H, or -C(O)OH, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents 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, -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, and 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
    或者，在相邻原子上的任意两个选自Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh和Ri的基团连同它们所附接的原子任选的可结合形成任选地被一个或多个Ra取代的C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基；Alternatively, any two groups selected from Ra , Rb , Rc , Rd , Re , Rf , Rg , Rh and Ri on adjacent atoms together with the atoms to which they are attached may optionally combine to form a C6 - C14 aryl group, a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, a ( C3 - C8 ) cycloalkyl group, a 3-14 membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S, which is optionally substituted with one or more Ra;
    式Ⅱ中：In Formula II:
    各个Rj独立的为-H、卤素、-OH、-NH2、-CN、＝O、-NO2、-(C1-C6)烷基、-(C1-C6)烷氧基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-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、-NHS(O)OH、-C(O)H或-C(O)OH，其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-H、＝O、卤素、-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、-NHS(O)OH、-C(O)H、-C(O)OH、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基或含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基；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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic 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 alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: -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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, or a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S;
    m独立的为选自0、1、2、3、4、5或6；m is independently selected from 0, 1, 2, 3, 4, 5 or 6;
    v为0或1；v is 0 or 1;
    环B为(C3-C8)环烷基、(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基。Ring B is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, a 3-14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a 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 cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
  2. 根据权利要求1所述的用途，所述化合物或其异构体、药学上可接受的盐或溶剂化物用于制备治疗PKM2相关疾病的药物。According to the use according to claim 1, the compound or its isomer, pharmaceutically acceptable salt or solvate is used to prepare a drug for treating PKM2-related diseases.
  3. 根据权利要求2所述的用途，所述疾病包括肿瘤、免疫性疾病、毛发缺失、代谢性疾病、增殖依赖性疾病、冠状动脉疾病、布鲁姆综合征和肺动脉高压。The use according to claim 2, wherein the disease includes tumors, immune diseases, hair loss, metabolic diseases, proliferation-dependent diseases, coronary artery disease, Bloom's syndrome and pulmonary hypertension.
  4. 根据权利要求2所述的用途，所述疾病包括肝癌、肺癌、结直肠癌、胶质母细胞瘤、乳腺癌、淋巴瘤、胰腺癌、肾癌。According to the use of claim 2, the disease includes liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, lymphoma, pancreatic cancer, and kidney cancer.
  5. 根据权利要求3所述的用途，所述免疫性疾病包括炎症和自身免疫性疾病。The use according to claim 3, wherein the immune disease includes inflammation and autoimmune diseases.
  6. 根据权利要求2所述的用途，所述疾病包括实验性自身免疫性脑脊髓炎、炎症性肠病、溃疡性结肠炎。The use according to claim 2, wherein the disease comprises experimental autoimmune encephalomyelitis, inflammatory bowel disease, and ulcerative colitis.
  7. 根据权利要求2所述的用途，所述疾病包括脱发、无毛症和少毛症。 The use according to claim 2, wherein the diseases include alopecia, alopecia and hypotrichosis.
  8. 根据权利要求2所述的用途，所述化合物通过促进PKM2四聚体的生成，减少PKM2二聚体的产生发挥相应疾病的治疗作用。According to the use according to claim 2, the compound exerts a therapeutic effect on the corresponding disease by promoting the generation of PKM2 tetramers and reducing the generation of PKM2 dimers.
  9. 根据权利要求2所述的用途，所述化合物通过阻止PKM2进入细胞核发挥相应疾病的治疗作用。According to the use according to claim 2, the compound exerts a therapeutic effect on the corresponding disease by preventing PKM2 from entering the cell nucleus.
  10. 根据权利要求1所述的用途，所述式Ⅰ化合物具有式Ⅰ-1或Ⅰ-2所示结构：
    The use according to claim 1, wherein the compound of formula I has a structure shown in formula I-1 or I-2:
  11. 根据权利要求1或10所述的用途，其中：The use according to claim 1 or 10, wherein:
    R1和R2独立的为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb或-NRcRd，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd； R1 and R2 are independently -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -ORb or -NRcRd , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: =0, halogen, -CN, -Ra , -ORb , -NO2 , -NRcRd ;
    或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
    Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C8)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 -C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C6 -C6-alkyl, -( C2 - C6- alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, The invention also includes but is not limited to alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl is optionally substituted by one or more substituents selected from the group consisting of: =O, halogen, -CN, -OH, -NO2 , -NH2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl and a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S.
  12. 根据权利要求11所述的用途，其中：The use according to claim 11, wherein:
    R1和R2独立的为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-ORb或-NRcRd，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd；R 1 and R 2 are 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, 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, -OR b or -NR c R d , wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the following: =O, halogen, -CN, -R a , -OR b , -NO 2 , -NR c R d ;
    或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
    Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8 芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C6)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基。 Ra , Rb , Rc and Rd are independently -H, halogen, -OH, -NH2 , -CN, -NO2 , -( 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 fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: =O, halogen, -CN, -OH, -NO2 , -NH2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl and 3-6 membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S.
  13. 根据权利要求12所述的用途，其中：The use according to claim 12, wherein:
    R1和R2独立的为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)直链烷基、-(C1-C6)支链烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元二环或三环稠合环基、-ORb或-NRcRd，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra、-ORb、-NRcRd； R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain 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 cyclic group containing 0-4 heteroatoms independently selected from O, N and S , -ORb or -NRcRd , wherein each alkyl, cycloalkyl, heterocyclyl, aryl , heteroaryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra, -ORb , -NRcRd ;
    或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
    Ra、Rb、Rc和Rd在每次出现时独立地为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基或含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-OH、-NO2、-NH2和-(C1-C6)烷基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C8 aryl, or a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
  14. 根据权利要求13所述的用途，其中：The use according to claim 13, wherein:
    R1和R2独立的为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)直链烷基、-(C1-C6)支链烷基、-(C3-C6)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra、-ORb、-NRcRd； R1 and R2 are independently -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) straight chain alkyl, -( C1 - C6 ) branched chain alkyl, -( C3 - C6 ) cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the following: -F, -Cl, -Br, -CN, -Ra, -ORb , -NRcRd ;
    或者，R1和R2连同它们所附接的原子任选的可结合以形成-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基；Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally be combined to form -(C 3 -C 8 )cycloalkyl or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S;
    Ra、Rb、Rc和Rd在每次出现时独立地为-H、-F、-Cl、-Br、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C6)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-OH、-NO2、-NH2和-(C1-C6)烷基。 Ra , Rb , Rc and Rd are independently at each occurrence -H, -F, -Cl, -Br, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C6 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
  15. 根据权利要求14所述的用途，其中：The use according to claim 14, wherein:
    R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
    R1为-H、-F、-Cl、-Br、-OH、-NH2、-(CH2)qCH3、-(CH2)qOH、-CH(OH)(CH2)qCH3、-C(OH)((CH2)qCH3)2、-(CH2)qNH2、-(CH2)qNH(CH2)qCH3、-(CH2)qN((CH2)qCH3)2、含有1个N原子的3-6元杂环烷基、被含有1个N原子的3-6元杂环烷基所取代的-(C1-C6)烷基；R 1 is -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 , -(CH 2 ) q NH 2 , -(CH 2 ) q NH(CH 2 ) q CH 3 , -(CH 2 ) q N((CH 2 ) q CH 3 ) 2 , 3- 6-membered heterocycloalkyl, -(C 1 -C 6 )alkyl substituted by a 3-6-membered heterocycloalkyl containing 1 N atom;
    q在每次出现时独立的为0、1、2、3或4；q is 0, 1, 2, 3, or 4 independently at each occurrence;
    或者，R1和R2连同它们所附接的原子任选的可结合以形成环丙烷环、环丁烷环、环戊烷环、环己烷环、四氢呋喃、四氢吡喃、吗啉、二噁烷、2,3-二氢苯并呋喃环或四氢-2H-吡喃。 Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, tetrahydrofuran, tetrahydropyran, morpholine, dioxane, a 2,3-dihydrobenzofuran ring or tetrahydro-2H-pyran.
  16. 根据权利要求13所述的用途，其中：The use according to claim 13, wherein:
    R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
    R1为-H、-F、-Cl、-Br、-OH、-NH2、-CH3、-CH(OH)CH3、-(CH2)qCH3、-(CH2)qOH、-CH(OH)(CH2)qCH3、-C(OH)((CH2)qCH3)2、-C(OH)(CH2)qCH3)(CH3)、-C(OH)(CH3)2、 -CH2F、-CHF2、-(CH2)qCH2F、-(CH2)qCHF2、-CH2Cl、-CHCl2、-(CH2)qCH2Cl、-(CH2)qCHCl2、-(CH2)qNH2、-NHCH3、-NH(CH2)qCH3、-(CH2)qNHCH3、-(CH2)qNH(CH2)qCH3、-N(CH3)2、-N((CH2)qCH3)2、-(CH2)qN(CH3)((CH2)qCH3)、-(CH2)q N(CH3)2、-(CH2)qN((CH2)qCH3)2、含有1个N原子的3-6元杂环烷基、被含有1个N原子的3-6元杂环烷基所取代的-(C1-C6)烷基；R 1 is -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 , -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 , 3-6 membered heterocycloalkyl containing 1 N atom, -( C 1 -C 6 )alkyl;
    q在每次出现时独立的为1、2、3或4；q is 1, 2, 3, or 4 independently at each occurrence;
    或者，R1和R2连同它们所附接的原子任选的可结合以形成环丙烷环、环丁烷环、环戊烷环、环己烷环、氧杂环丁烷、四氢呋喃、四氢吡喃、吗啉、二噁烷、2,3-二氢苯并呋喃环或四氢-2H-吡喃。Alternatively, R 1 and R 2 together with the atoms to which they are attached may optionally combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an oxetane, a tetrahydrofuran, a tetrahydropyran, a morpholine, a dioxane, a 2,3-dihydrobenzofuran ring or a tetrahydro-2H-pyran.
  17. 根据权利要求11所述的用途，其中：The use according to claim 11, wherein:
    R2为-H、-F、-Cl或-Br； R2 is -H, -F, -Cl or -Br;
    R1为-H、-F、-Cl、-Br、-OH、-NH2、 R 1 is -H, -F, -Cl, -Br, -OH, -NH 2 ,
    或者，R1和R2连同它们所附接的原子任选的可结合以形成 Alternatively, R1 and R2 together with the atoms to which they are attached may optionally be combined to form
  18. 根据权利要求1～17任一所述的用途，其中：The use according to any one of claims 1 to 17, wherein:
    R3为-H、卤素、-(C1-C6)烷基、-(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd； R3 is -H, halogen, -( C1 - C6 ) alkyl, -( C3 - C8 ) cycloalkyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the following: =O, halogen, -CN, -R a , -OR b , -NO 2 , -NR c R d ;
    Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C8)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C2 -C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, C6 - C6 -C6-alkyl, -( C2 - C6- alkynyl, -(C3-C8)cycloalkyl, -( C4 - C8 )cycloalkenyl, The invention also includes but is not limited to alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or fused cyclyl is optionally substituted by one or more substituents selected from the group consisting of: =O, halogen, -CN, -OH, -NO2 , -NH2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl and a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S.
  19. 根据权利要求18所述的用途，其中：The use according to claim 18, wherein:
    R3为-H、卤素、-(C1-C6)烷基、-(C3-C6)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元二环或三环稠合环基，其中各烷基、 环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-Ra、-ORb、-NO2、-NRcRd； R3 is -H, halogen, -( C1 - C6 ) alkyl, -( C3 - C6 ) cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a 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 or tricyclic fused ring containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, The cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from: =0, halogen, -CN , -Ra, -ORb , -NO2 , -NRcRd ;
    Ra、Rb、Rc和Rd在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基、C6-C8芳基、含有1-4个独立地选自O、N和S的杂原子的5-8元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基，其中各烷基、环烷基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-CN、-OH、-NO2、-NH2、-(C1-C6)烷基、-(C3-C6)环烷基和含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基。 Ra , Rb , Rc and Rd are independently, at each occurrence, -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C8 aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: =O, halogen, -CN, -OH, -NO2, -NH2, -(C1-C6)alkyl, -( C3 - C8) cycloalkyl, a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6- C8 aryl, a 5-8 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S , or a 7-14 membered fused cyclic group containing 0-4 heteroatoms independently selected from O , N and S )cycloalkyl and 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S.
  20. 根据权利要求19所述的用途，其中，The use according to claim 19, wherein
    R3为-H、-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、C6-C8芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元二环稠合环基，其中各烷基、环烷基、芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-Ra和-ORb； R3 is -H, -F, -Cl, -Br, -( C1 - C6 ) alkyl, -( C3 - C6 ) cycloalkyl, C6 - C8 aryl, or a 7-14 membered bicyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl, aryl or fused cyclic group is optionally substituted by one or more substituents selected from the following: -F, -Cl, -Br, -CN, -R a and -OR b ;
    Ra和Rb在每次出现时独立地为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C3-C8)环烷基或含有1-4个独立地选自O、N和S的杂原子的3-6元杂环基，其中各烷基、环烷基或杂环基任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-OH、-NO2、-NH2和-(C1-C6)烷基。 Ra and Rb, at each occurrence, are independently -H, halogen, -OH, -NH2 , -CN, -NO2 , -( C1 - C6 )alkyl, -( C3 - C8 )cycloalkyl, or a 3-6 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from: -F, -Cl, -Br, -CN, -OH, -NO2 , -NH2 and -( C1 - C6 )alkyl.
  21. 根据权利要求18所述的用途，其中，The use according to claim 18, wherein
    R3为-H、-F、-Cl、-Br、-(C1-C6)烷基、-(C3-C6)环烷基、吡啶基、苯基、萘基、苯并噻唑基、苯并吗啉基、苯并吡咯烷基或其中吡啶基、苯基、苯并噻唑基、苯并吗啉基、苯并吡咯烷基、任选地被一个或多个选自以下的取代基取代：-F、-Cl、-Br、-CN、-(C1-C6)烷基、-(C3-C6)环烷基、-O-(C1-C6)烷基、-O-(C3-C6)环烷基、-(C1-C6)卤代烷基、-(C3-C6)卤代环烷基、-O-(C1-C6)卤代烷基、-O-(C3-C6)卤代环烷基、吡唑基、被任意数量卤素或-(C1-C6)烷基取代的吡唑基、哌嗪基、被任意数量卤素或-(C1-C6)烷基取代的哌嗪基；R 3 is -H, -F, -Cl, -Br, -(C 1 -C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, pyridyl, phenyl, naphthyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl or Among them, pyridyl, phenyl, benzothiazolyl, benzomorpholinyl, benzopyrrolidinyl, Optionally substituted with one or more substituents selected from the group consisting of -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, pyrazolyl substituted with any number of halogen or -(C 1 -C 6 )alkyl, piperazinyl, piperazinyl substituted with any number of halogen or -(C 1 -C 6 )alkyl;
    环为通过N原子连接的3-6元饱和或不饱和含N杂环基，所述杂环基除N原子外还任选地包含1-2个独立地选自O、N和S的杂原子。ring It is a 3-6 membered saturated or unsaturated N-containing heterocyclic group linked via a N atom, and the heterocyclic group optionally contains 1-2 heteroatoms independently selected from O, N and S in addition to the N atom.
  22. 根据权利要求18所述的用途，其中，The use according to claim 18, wherein
    R3为-H、-F、-Cl、-Br、-CH3、-CH2CH3、 R 3 is -H, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 ,
  23. 根据权利要求1～22任一所述的用途，其中：The use according to any one of claims 1 to 22, wherein:
    R4为 R4 is
    X为化学键、-(CRhRi)t-、-NRc(CRhRi)t-或-O-；X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t - or -O-;
    代表单键或双键； represents a single bond or a double bond;
    Y1为N、C或CH； Y1 is N, C or CH;
    Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
    各个Rj独立的为-H、卤素、-OH、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C1-C6)烷氧基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-O-(C3-C6)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-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、-NHS(O)OH、-C(O)H或-C(O)OH，其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：-H、＝O、卤素、-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、-NHS(O)OH、-C(O)H、-C(O)OH、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基或含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基；each Rj is independently -H, halogen, -OH, -NH2 , -CN, -NO2, -( C1 - C6 ) alkyl, -( C1 - C6 )alkoxy, -( C2 - C6 )alkenyl, -( C2 - C6 )alkynyl, -( C3 - C8 )cycloalkyl, -O-( C3 - C6 )cycloalkyl, -( C4 - C8 )cycloalkenyl, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C6 - C14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic group containing 0-4 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 , -NHS(O)OH, -C(O)H, or -C(O)OH, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: -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) 2 OH, -NHS(O)OH, -C(O)H, -C(O)OH, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, or a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S;
    m为选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6;
    n为0、1或2，n is 0, 1, or 2,
    Rc、Rh、Ri和t如权利要求1-22任一项中所定义。R c , R h , Ri and t are as defined in any one of claims 1-22.
  24. 根据权利要求23所述的用途，其中，The use according to claim 23, wherein
    X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
    代表单键或双键； represents a single bond or a double bond;
    Y1为N、C或CH； Y1 is N, C or CH;
    Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
    各个Rj各自独立的为-H、卤素、-OH、-NH2、-CN、-(C1-C6)烷基、-(C3-C6)环烷基、-(C1-C6)烷氧基、-O-(C3-C6)环烷基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷氧基、任意数量卤素取代的-(C3-C6)环烷基、任意数量卤素取代的-O-(C3-C6)环烷基、噁唑基、噻唑基和三唑基；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 halogen, -(C 1 -C 6 )alkoxy substituted with any number of halogen, -(C 3 -C 6 )cycloalkyl substituted with any number of halogen, -O-(C 3 -C 6 )cycloalkyl substituted with any number of halogen, oxazolyl, thiazolyl and triazolyl;
    m为选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6;
    n为0、1或2。n is 0, 1 or 2.
  25. 根据权利要求1～22任一所述的用途，其中：The use according to any one of claims 1 to 22, wherein:
    R4为 R4 is
    X为化学键、-(CRhRi)t-、-NRc(CRhRi)t-或-O-；X is a chemical bond, -(CR h R i ) t -, -NR c (CR h R i ) t - or -O-;
    代表单键或双键； represents a single bond or a double bond;
    Y1为N、C或CH； Y1 is N, C or CH;
    Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
    各个Rj独立的为-H、卤素、-OH、＝O、-NH2、-CN、-NO2、-(C1-C6)烷基、-(C1-C6)烷氧基、-(C2-C6)烯基、-(C2-C6)炔基、-(C3-C8)环烷基、-(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基、含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基、-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、-NHS(O)OH、-C(O)H或-C(O)OH，其中各烷基、烷氧基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基或稠合环基任选地被一个或多个选自以下的取代基取代：＝O、卤素、-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、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基或含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基；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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl, a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, a 7-14 membered fused cyclic 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 wherein each alkyl , alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , heterocyclyl , aryl, heteroaryl, or fused cyclic group is optionally substituted with one or more substituents selected from the group consisting of: =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, a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N, and S, a C6 -C 14 aryl or a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S;
    m、p独立的为选自0、1、2、3、4、5或6；m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
    n为0、1或2；n is 0, 1 or 2;
    环A为(C3-C8)环烷基、(C4-C8)环烯基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元稠合环基；Ring A is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, a 3-14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, a 5-14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14-membered fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S;
    Rc、Rh、Ri和t如权利要求1-22任一项中所定义。R c , R h , Ri and t are as defined in any one of claims 1-22.
  26. 根据权利要求25所述的用途，其中，The use according to claim 25, wherein
    X为化学键、-CH2-、-CH2CH2-、-NHCH2-、-NHCH2CH2-或-O-；X is a chemical bond, -CH 2 -, -CH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -O-;
    代表单键或双键； represents a single bond or a double bond;
    Y1为N、C或CH； Y1 is N, C or CH;
    Y2和Y3各自独立的为N、CH2或CH，Y2和Y3不同时为N；Y 2 and Y 3 are each independently N, CH 2 or CH, and Y 2 and Y 3 are not N at the same time;
    各个Rj各自独立的为-H、卤素、-OH、-NH2、-CN、＝O、-(C1-C6)烷基、-(C1-C6)烷氧基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷氧基、噁唑基、噻唑基或三唑基；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、p独立的为选自0、1、2、3、4、5或6；m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;
    n为0、1或2；n is 0, 1 or 2;
    环A为呋喃、噻吩、噁唑、噻唑、三唑、哌啶、吡啶、吡喃、噻喃、吗啉、1,4-二氧环己烷、哌嗪、吡嗪、三嗪、4,5-二氢-1H-咪唑或1,3-二氧戊环。Ring A is furan, thiophene, oxazole, thiazole, triazole, piperidine, pyridine, pyran, thiopyran, morpholine, 1,4-dioxacyclohexane, piperazine, pyrazine, triazine, 4,5-dihydro-1H-imidazole or 1,3-dioxolane.
  27. 根据权利要求1所述的用途，其中，The use according to claim 1, wherein
    R4为 R4 is
  28. 根据权利要求1所述的用途，式Ⅱ中：The use according to claim 1, wherein in formula II:
    各个Rj独立的为-H、卤素、-OH、-NH2、-CN、＝O、-(C1-C6)烷基、-(C1-C6)烷氧基、任意数量卤素取代的-(C1-C6)烷基、任意数量卤素取代的-(C1-C6)烷氧基、噁唑基、噻唑基或三唑基；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;
    环B为(C3-C8)环烷基、含有1-4个独立地选自O、N和S的杂原子的3-14元杂环基、C6-C14芳基、含有1-4个独立地选自O、N和S的杂原子的5-14元杂芳基或含有0-4个独立地选自O、N和S的杂原子的7-14元二环或三环稠合环基。Ring B is (C 3 -C 8 )cycloalkyl, a 3-14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, a C 6 -C 14 aryl group, a 5-14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, or a 7-14-membered bicyclic or tricyclic fused cyclic group containing 0-4 heteroatoms independently selected from O, N and S.
  29. 根据权利要求28所述的用途，式Ⅱ中：The use according to claim 28, wherein in formula II:
    环B为3-7元氧杂环烷基或8-10元氮杂二环稠合杂芳基。Ring B is a 3- to 7-membered oxacycloalkyl group or an 8- to 10-membered azabicyclic condensed heteroaryl group.
  30. 根据权利要求29所述的用途，式Ⅱ中：The use according to claim 29, wherein in formula II:
    环B为氧杂环庚烷、氧杂环己烷、四氢呋喃、氧杂环丁烷、氧杂环丙烷、1H-吲哚或异吲哚啉。Ring B is oxepane, oxhexane, tetrahydrofuran, oxetane, oxirane, 1H-indole or isoindoline.
  31. 根据权利要求30所述的用途，式Ⅱ中： The use according to claim 30, wherein in formula II:
    环B为 Ring B is
  32. 根据权利要求1～31任一所述的用途，其中：The use according to any one of claims 1 to 31, wherein:
    式Ⅰ或Ⅱ的化合物中的任意1个或以上的H被D所取代。Any one or more H in the compound of formula I or II is replaced by D.
  33. 根据权利要求32所述的用途，其中：The use according to claim 32, wherein:
    式Ⅰ或Ⅱ的化合物中的结构中的任意1个或以上的H被D所取代，或者R4中的任意1个或以上的H被D所取代。The structure of the compound of formula I or II Any one or more H in R 4 are replaced by D.
  34. 根据权利要求33所述的用途，其中：The use according to claim 33, wherein:
    式Ⅰ或Ⅱ的化合物中的结构中的所有H均被D所取代。The structure of the compound of formula I or II All H in are replaced by D.
  35. 根据权利要求32所述的用途，其中：The use according to claim 32, wherein:
    R1、R2或R3选择为H时，其独立的任选被D所取代。When R 1 , R 2 or R 3 is H, it is independently optionally substituted with D.
  36. 根据权利要求1所述的用途，其中，所述化合物选自：








    The use according to claim 1, wherein the compound is selected from:








  37. 治疗PKM2介导的相关疾病的方法，所述方法包括向有需要的个体施用治疗有效量的权利要求1和10至36任一项中所定义的化合物。A method for treating PKM2-mediated related diseases, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 and 10 to 36.
  38. 权利要求37所述的方法，其中所述的疾病如权利要求3～7中任一项所定义。 The method of claim 37, wherein the disease is as defined in any one of claims 3 to 7.
PCT/CN2024/090827 2023-05-05 2024-04-30 New use of compound containing diazepine sulfonyl structure as pkm2 agonist WO2024230586A1 (en)

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