Amide derivative and preparation method therefore and use thereof in medicine

Abstract

The present invention relates to an amide derivative and use thereof in the inhibition of NLRP3 and in the treatment of diseases related to NLRP3, and specifically to an amide derivative shown as general formula (II-2) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof, a pharmaceutical composition containing the same, and use of the compound or the composition disclosed herein in preparing an NLRP3 inhibitor and the treatment of diseases related to NLRP3 [Image disponible dans le document PDF, Image available in the PDF document]

Description

AMIDE DERIVATIVE AND PREPARATION METHOD THEREFORE AND USE THEREOF IN MEDICINE TECHNICAL FIELD The present invention relates to an amide derivative shown as general formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuteride, pharmaceutically acceptable salt or cocrystal thereof, a pharmaceutical composition thereof, and use thereof in preparing an NLRP3 inhibitor. BACKGROUND NOD-like receptors (NLRs) of the nucleotide-binding oligomerization domain (NOD) are a type of pattern recognition receptors (PRRs) in cytoplasm of mammalian cells, and they play an important role in innate immune response. NLRs are a group of cytoplasmic proteins with signal transduction function and are widely involved in inflammatory response of organisms. The NLR family is composed of NOD, NALP (NLRP), CIITA (NLRA), and IPAF (NLRC), where NLRP and NLRC subfamilies are the two major types of NLRs, and NLRP can be classified as inflammasomes such as NLRP1, NLRP3, NLRP6, NLRP7 and NLRP12. The NLRP3 inflammasome is a multi-protein complex composed of NLRP3 protein itself, caspase- 1 and apoptosis-associated speck-like protein containing CARD (ASC), and it is capable of recognizing various pathogenic microorganisms and stress-related endogenous signal molecules. Activation of classical NLRP3 inflammasome is initiated by a combined stimulation of two signals. The first signal activates the TLR4 (toll-like receptor4) signaling pathway, promotes the translocation into nucleus of nuclear transcription factor <com:Math><semantics>κB<annotation encoding="application / x-tex">\kappa B< / annotation>< / semantics>< / com:Math>, and induces production of precursors such as IL-1<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> and IL-18. The second signal promotes NLRP3 / ASC / pro-caspase-1 complex formation; namely, NLRP3 aggregates with apoptosis- associated speck-like protein containing a CARD (ASC) when activated, ASC then interacts with cysteine protease caspase-1 to form a complex called inflammasome, the precursor form of caspase (pro-caspase-1) self-cleaves into an activated form (Wen, H., Miao, E.A. & Ting, J.P, Mechanisms of NOD-like receptor-associated inflammasome activation, Immunity, 39, 432–441 (2013)), and activated caspase-1 cleaves the precursor forms of pro-inflammatory cytokines IL-1<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> and IL-18 to allow them to be converted into the active forms of IL-1<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> and IL- 18 and released to the outside of the cells, thus recruiting inflammatory cells for aggregation and amplifying the inflammatory response. The ASC speck-like protein can also recruit and activate caspase-8, then cleave the precursor forms of IL-I<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> and IL-18 to convert them into mature forms and thus trigger pyroptosis. Activation of non-classical NLRP3 inflammasomes is independent of activation of TLR4 signaling pathway, and it is initiated through direct recognition of intracellular LPS by caspase-11, thereby facilitating activation and release of Gasdermin D to mediate cell death (Lamkanfi, M. & Dixit, V.M. Mechanisms and functions of inflammasomes, Cell, 157, 1013–1022 (2014)). Abnormal activation of NLRP3 inflammasomes is closely related to the occurrence process of various inflammatory diseases, including hereditary CAPS diseases (Muckle-Wells syndrome) (MWS), familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease), Alzheimer's disease, Parkinson disease, nonalcoholic fatty liver, atherosclerosis, asthma, nephropathy, enteritis, tumor, gout, neurodegenerative disease, diabetes, obesity, etc. Currently available medicines for treating NLRP3-related diseases include: anakinra, a recombinant IL-1 receptor antagonist; canakinumab, an IL-1β-neutralizing antibody; and rilonacept, a soluble IL-1 receptor trapping agent, which are all biological products. Some NLRP3 small molecule inhibitors have been reported in recent years, such as glibenclamide, parthenolide, 3,4-methylenedioxy-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-nitrostyrene. However, the above drugs or small molecules still have such problems as low specificity or poor activity. Therefore, there is a need to develop a new generation of small molecule NLRP3 inhibitor with high specificity and activity for treating autoimmune diseases caused by NLRP3 mutation. CA SUMMARY The present invention relates to a new amide derivative or all stereoisomers, solvates, metabolites, deuterides, pharmaceutically acceptable salts, cocrystals or prodrugs thereof, a pharmaceutical composition thereof, and use thereof in preparing an NLRP3 inhibitor. One or more embodiments of the present invention relate to a compound shown as general formula (I) or all stereoisomers, solvates, prodrugs, metabolites, deuterides, pharmaceutically acceptable salts or cocrystals thereof: [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein, Q is selected from 6-10 membered aryl and 5-10 membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the aryl or heteroaryl is optionally substituted with 0 to 4 R<com:Sup>q0< / com:Sup>; <com:Math><semantics>Rq0<annotation encoding="application / x-tex">R^{q0}< / annotation>< / semantics>< / com:Math> are the same or different and are each independently selected from <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halogen, OH, cyano, nitro, -NH<com:Sub>2< / com:Sub>, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C5−10<annotation encoding="application / x-tex">C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−C(=O)C1−6<annotation encoding="application / x-tex">-C(=O)C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−C(=O)OC1−6<annotation encoding="application / x-tex">-C(=O)OC_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−OC(=O)C1−6<annotation encoding="application / x-tex">-OC(=O)C_{1-6}< / annotation>< / semantics>< / com:Math> <com:Sub>6< / com:Sub> alkyl, <com:Math><semantics>−C(=O)OC3−8<annotation encoding="application / x-tex">-C(=O)OC_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−OC(=O)C3−8<annotation encoding="application / x-tex">-OC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−OC(=O)C3−8<annotation encoding="application / x-tex">-OC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C(=O)OC3−8<annotation encoding="application / x-tex">C(=O)OC_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−C(=O)C6−10<annotation encoding="application / x-tex">-C(=O)C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−C(=O)OC6−10<annotation encoding="application / x-tex">-C(=O)OC_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−OC(=O)C6−10<annotation encoding="application / x-tex">-OC(=O)C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C(=O)C5−10<annotation encoding="application / x-tex">C(=O)C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−C(=O)OC5−10<annotation encoding="application / x-tex">-C(=O)OC_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−OC(=O)C5−10<annotation encoding="application / x-tex">-OC(=O)C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−NHC1−6<annotation encoding="application / x-tex">-NHC_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>N(C1−6 alkyl)2<annotation encoding="application / x-tex">N(C_{1-6} \text{ alkyl})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)C1−6 alkyl<annotation encoding="application / x-tex">-NHC(=O)C_{1-6} \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)(C1−6 alkyl)2<annotation encoding="application / x-tex">-NHC(=O)(C_{1-6} \text{ alkyl})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)C6−10 aryl<annotation encoding="application / x-tex">-NHC(=O)C_{6-10} \text{ aryl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> NHC(=O)C<com:Sub>5-10< / com:Sub> heteroaryl, -NHC(=O)C<com:Sub>3-8< / com:Sub> heterocycloalkyl, -NHC(=O)C<com:Sub>3-8< / com:Sub> cycloalkyl, - NHC(=O)C<com:Sub>1-6< / com:Sub> alkyl, -NHC(=O)C<com:Sub>2-6< / com:Sub> alkynyl, -NHC(=O)C<com:Sub>2-6< / com:Sub> alkenyl, -NH(C=NR<com:Sup>q1< / com:Sup>)NR<com:Sup>q2< / com:Sup>R<com:Sup>q3< / com:Sup>, - <com:Math><semantics>C(=O)NRq4Rq5<annotation encoding="application / x-tex">C(=O)NR^{q4}R^{q5}< / annotation>< / semantics>< / com:Math>, -SH, -SC<com:Sub>1-6< / com:Sub> alkyl, -S(=O)C<com:Sub>1-6< / com:Sub> alkyl, -S(=O)<com:Sub>2< / com:Sub>C<com:Sub>1-6< / com:Sub> alkyl and -S(=O)<com:Sub>2< / com:Sub>NR<com:Sup>q2< / com:Sup>R<com:Sup>q3< / com:Sup>, wherein the heterocycloalkyl or heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the alkyl, alkoxy, NH<com:Sub>2< / com:Sub>, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl or heteroaryl is optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, =O, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup>, =NR<com:Sup>q6< / com:Sup>, - <com:Math><semantics>C(=O)OC1−6<annotation encoding="application / x-tex">C(=O)OC_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−OC(=O)C1−6<annotation encoding="application / x-tex">-OC(=O)C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−C(=O)NRq4Rq5<annotation encoding="application / x-tex">-C(=O)NR^{q4}R^{q5}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C5−10<annotation encoding="application / x-tex">C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−C(=O)OC6−10<annotation encoding="application / x-tex">-C(=O)OC_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−OC(=O)C6−10<annotation encoding="application / x-tex">-OC(=O)C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−OC(=O)C5−10<annotation encoding="application / x-tex">-OC(=O)C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C(=O)OC5−10<annotation encoding="application / x-tex">C(=O)OC_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−OC(=O)C3−8<annotation encoding="application / x-tex">-OC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−C(=O)OC3−8<annotation encoding="application / x-tex">-C(=O)OC_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>OC(=O)C3−8<annotation encoding="application / x-tex">OC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−C(=O)OC3−8<annotation encoding="application / x-tex">-C(=O)OC_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−NHC(=O)C3−8<annotation encoding="application / x-tex">-NHC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> NHC(=O)C<com:Sub>6-10< / com:Sub> aryl, -NHC(=O)C<com:Sub>5-10< / com:Sub> heteroaryl, -NHC(=O)C<com:Sub>3-8< / com:Sub> cycloalkyl, -NHC(=O)C<com:Sub>3-8< / com:Sub> heterocycloalkyl, -NHC(=0)C<com:Sub>2-6< / com:Sub> alkenyl and -NHC(=0)C<com:Sub>2-6< / com:Sub> alkynyl, wherein the substituent <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C5−10<annotation encoding="application / x-tex">C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−NHC(=O)C6−10<annotation encoding="application / x-tex">-NHC(=O)C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−NHC(=O)C5−10<annotation encoding="application / x-tex">-NHC(=O)C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−NHC(=O)C3−8<annotation encoding="application / x-tex">-NHC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl or <com:Math><semantics>−NHC(=O)C3−8<annotation encoding="application / x-tex">-NHC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl is optionally further substituted with 1 to 3 substituents selected from OH, halogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup> and =O; or at least one pair of R<com:Sup>q0< / com:Sup> and an atom to which they are attached form a 4-10 membered carbocycle or a 5-10 membered heterocycle, wherein the heterocycle contains 1 to 2 heteroatoms selected from N, O and S, the carbocycle or heterocycle is optionally further substituted with 1 or more substituents selected from OH, halogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, - <com:Math><semantics>NRq4Rq5<annotation encoding="application / x-tex">NR^{q4}R^{q5}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>=NRq6<annotation encoding="application / x-tex">=NR^{q6}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OC1−6<annotation encoding="application / x-tex">-C(=O)OC_{1-6}< / annotation>< / semantics>< / com:Math> alkyl and <com:Math><semantics>−C(=O)NRq4Rq5<annotation encoding="application / x-tex">-C(=O)NR^{q4}R^{q5}< / annotation>< / semantics>< / com:Math>, and the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy is optionally further substituted with a substituent selected from OH, halogen, =O, -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup>, C =NR<com:Sup>q6< / com:Sup>, -C(=O)OC<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>3-8< / com:Sub> cycloalkyl, C<com:Sub>3-8< / com:Sub> heterocycloalkyl, C<com:Sub>6-10< / com:Sub> aryl, C<com:Sub>5-10< / com:Sub> heteroaryl and <com:Math><semantics>−C(=O)NRq4Rq5<annotation encoding="application / x-tex">-C(=O)NR^{q4}R^{q5}< / annotation>< / semantics>< / com:Math>: <com:Math><semantics>Rq1<annotation encoding="application / x-tex">R^{q1}< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy and <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl; <com:Math><semantics>Rq2<annotation encoding="application / x-tex">R^{q2}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq3<annotation encoding="application / x-tex">R^{q3}< / annotation>< / semantics>< / com:Math> are selected from H and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>Rq4<annotation encoding="application / x-tex">R^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq5<annotation encoding="application / x-tex">R^{q5}< / annotation>< / semantics>< / com:Math> are selected from H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−NH(C=NRq1)NRq2Rq3<annotation encoding="application / x-tex">-NH(C=NR^{q1})NR^{q2}R^{q3}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NRq2Rq3<annotation encoding="application / x-tex">-S(=O)_2NR^{q2}R^{q3}< / annotation>< / semantics>< / com:Math>, - <com:Math><semantics>C(=O)Rq1<annotation encoding="application / x-tex">C(=O)R^{q1}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−C(=O)NRq2Rq3<annotation encoding="application / x-tex">-C(=O)NR^{q2}R^{q3}< / annotation>< / semantics>< / com:Math>, wherein the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is optionally further substituted with 1 or more substituents selected from OH, halogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C5−10<annotation encoding="application / x-tex">C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl and <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl; or <com:Math><semantics>Rq4<annotation encoding="application / x-tex">R^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq5<annotation encoding="application / x-tex">R^{q5}< / annotation>< / semantics>< / com:Math> form a 3-8 membered heterocycle with an N atom, the heterocycle containing 1 to 3 heteroatoms selected from N, O and S; <com:Math><semantics>Rq6<annotation encoding="application / x-tex">R^{q6}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; W is selected from O and NHR<com:Sub>a< / com:Sub>; <com:Math><semantics>W1<annotation encoding="application / x-tex">W_1< / annotation>< / semantics>< / com:Math> is O; <com:Math><semantics>Ra<annotation encoding="application / x-tex">R_a< / annotation>< / semantics>< / com:Math> is selected from H, cyano, hydroxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy; X is NH: Y is CR<com:Sub>b< / com:Sub>R<com:Sub>c< / com:Sub>: <com:Math><semantics>Rb<annotation encoding="application / x-tex">R_b< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rc<annotation encoding="application / x-tex">R_c< / annotation>< / semantics>< / com:Math> are each independently selected from H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl and 3-10 membered carbocyclyl, wherein the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is optionally further substituted with 1 to 4 substituents selected from F, Cl, Br, I, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, 3-10 membered carbocyclyl and 3-10 membered heterocyclyl, the heterocyclyl optionally containing 1 to 3 heteroatoms selected from N, O and S; or R<com:Sub>b< / com:Sub> and R<com:Sub>c< / com:Sub> form a double bond; R and R<com:Sub>1< / com:Sub> are each independently selected from deuterium, H, F, Cl, Br, I, CN, NH<com:Sub>2< / com:Sub>, OH, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, <com:Math><semantics>−(C=O)−C1−6<annotation encoding="application / x-tex">-(C=O)-C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−(C=O)O−C1−6<annotation encoding="application / x-tex">-(C=O)O-C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−O(C=O)−C1−6<annotation encoding="application / x-tex">-O(C=O)-C_{1-6}< / annotation>< / semantics>< / com:Math> C<com:Sub>1-6< / com:Sub> alkyl, -O(C=O)-3-10 membered carbocyclyl, -O(C=O)-3-10 membered heterocyclyl, - <com:Math><semantics>(C=O)O−3−10<annotation encoding="application / x-tex">(C=O)O-3-10< / annotation>< / semantics>< / com:Math> membered carbocyclyl, <com:Math><semantics>−O(C=O)O−C1−6<annotation encoding="application / x-tex">-O(C=O)O-C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, 3-10 membered carbocyclyl, 4-10 membered heterocyclyl, -NHC<com:Sub>1-6< / com:Sub> alkyl, -N(C<com:Sub>1-6< / com:Sub> alkyl)<com:Sub>2< / com:Sub> and (C=O)NR<com:Sub>a1< / com:Sub>R<com:Sub>a2< / com:Sub>, wherein the heterocyclyl contains 1 to 3 heteroatoms selected from N, O and S, and the alkyl, alkenyl, alkoxy, carbocycle or heterocycle is optionally further substituted with 1 to 4 substituents selected from OH, F, Cl, Br, I, CN, NR<com:Sub>a1< / com:Sub>R<com:Sub>a2< / com:Sub>, =O, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> haloalkyl, C<com:Sub>1-6< / com:Sub> haloalkoxy, <com:Math><semantics>−(C=O)−C1−6<annotation encoding="application / x-tex">-(C=O)-C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−(C=O)O−C1−6<annotation encoding="application / x-tex">-(C=O)O-C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−O(C=O)−C1−6<annotation encoding="application / x-tex">-O(C=O)-C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−(C=O)O−3−10<annotation encoding="application / x-tex">-(C=O)O-3-10< / annotation>< / semantics>< / com:Math> membered carbocyclyl, <com:Math><semantics>−O(C=O)−3−10<annotation encoding="application / x-tex">-O(C=O)-3-10< / annotation>< / semantics>< / com:Math> membered carbocyclyl, <com:Math><semantics>−O(C=O)−3−10<annotation encoding="application / x-tex">-O(C=O)-3-10< / annotation>< / semantics>< / com:Math> membered heterocyclyl, <com:Math><semantics>−O(C=O)O−C1−6<annotation encoding="application / x-tex">-O(C=O)O-C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, 3-10 membered carbocyclyl, 5-10-membered heterocyclyl, -NHCOC<com:Sub>1-6< / com:Sub> alkyl, -NH(C=O)-3-10 membered carbocyclyl, -NH(C=O)-3-10 membered heterocyclyl and <com:Math><semantics>−(C=O)NRa1Ra2<annotation encoding="application / x-tex">-(C=O)NR_{a1}R_{a2}< / annotation>< / semantics>< / com:Math>; or R and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, together with an atom to which they are attached, form a 4-8 membered ring, wherein the 4-8 membered ring contains 0 to 4 heteroatoms selected from N, O and S, and is optionally further substituted with 0 to 4 substituents selected from H, F, CI, Br, I, OH, -NR<com:Sub>a1< / com:Sub>R<com:Sub>a2< / com:Sub>, =O, C<com:Sub>1-< / com:Sub> 6 alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, -(C=O)OC<com:Sub>1-6< / com:Sub> alkyl, 3-10 membered carbocyclyl and 5-10 membered heterocyclyl; C is 3-10 membered cycloalkyl; R<com:Sub>2< / com:Sub> is selected from H, F, Cl, Br, I, OH, -NR<com:Sub>a1< / com:Sub>R<com:Sub>a2< / com:Sub>, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl and C<com:Sub>1-6< / com:Sub> alkoxy; G1, G2 and G3 are each independently selected from N and CH; q and r are selected from 0, 1 and 2; n is selected from 0, 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as general formula (II) or a stereoisomer, hydrate, metabolite, deuteride, solvate, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein, Q, R, R<com:Sub>1< / com:Sub>, R<com:Sub>2< / com:Sub>, C, G1, G2, G3, r, q and n are defined in the same way as in general formula (I). One or more embodiments of the present invention provide a compound shown as general formula (II-1) or a stereoisomer, hydrate, metabolite, deuteride, solvate, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(II−1)<annotation encoding="application / x-tex">(II-1)< / annotation>< / semantics>< / com:Math> wherein, Q, R, <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math>, C, G1, G2, G3, r, q and n are defined in the same way as in general formula (I). One or more embodiments of the present invention provide a compound shown as general formula (II-2) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(11−2)<annotation encoding="application / x-tex">(11-2)< / annotation>< / semantics>< / com:Math> wherein, Q, W, R, R<com:Sub>1< / com:Sub>, R<com:Sub>b< / com:Sub>, R<com:Sub>c< / com:Sub>, r and q are defined in the same way as in general formula (I); m is selected from 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as general formula (III) or a stereoisomer, hydrate, metabolite, deuteride, solvate, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] (III) wherein, Q, R, R<com:Sub>1< / com:Sub>, G1, G2, G3, r and q are defined in the same way as in general formula (I). One or more embodiments of the present invention provide a compound shown as general CA formula (III-1) or a stereoisomer, hydrate, metabolite, deuteride, solvate, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(III−1)<annotation encoding="application / x-tex">(III-1)< / annotation>< / semantics>< / com:Math> wherein, Q, R, <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, G1, G2, G3, r and q are defined in the same way as in general formula (1). One or more embodiments of the present invention provide a compound shown as general formula (III) or (III-1) or a stereoisomer, hydrate, metabolite, deuteride, solvate, pharmaceutically acceptable salt or cocrystal thereof, wherein: Q is selected from 5 membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the aryl or heteroaryl is optionally substituted with 0 to 4 R<com:Sup>q0< / com:Sup>; <com:Math><semantics>Rq0<annotation encoding="application / x-tex">R^{q0}< / annotation>< / semantics>< / com:Math> are the same or different and are each independently selected from <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, halogen, OH, cyano, -NH<com:Sub>2< / com:Sub>, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>3-6< / com:Sub> heterocycloalkyl, -NHC<com:Sub>1-4< / com:Sub> alkyl and -N(C<com:Sub>1-4< / com:Sub> alkyl)2, wherein the heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and the alkyl, heterocycloalkyl and cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C<com:Sub>1-4< / com:Sub> alkyl and -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup>; <com:Math><semantics>Rq4<annotation encoding="application / x-tex">R^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq5<annotation encoding="application / x-tex">R^{q5}< / annotation>< / semantics>< / com:Math> are selected from H and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl; W is selected from O and NH; R and R<com:Sub>1< / com:Sub> are each independently selected from deuterium, H, F, CN, OH, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl and 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 to 3 heteroatoms selected from N and O, and the alkyl or heterocycle is optionally further substituted with 1 to 4 substituents selected from OH, F, CN and C<com:Sub>1-6< / com:Sub> alkoxy; or R and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, together with an atom to which they are attached, form a 4-5 membered ring; G1, G2 and G3 are each independently selected from CH; q and r are selected from 0, 1 and 2. One or more embodiments of the present invention provide a compound shown as general formula (IV) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] (IV) wherein, Q, W, R, <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, r and q are defined in the same way as in general formula (1); m is selected from 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as general formula (IV) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof, wherein: Q is selected from 5 membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the aryl or heteroaryl is optionally substituted with 0 to 4 R<com:Sup>q0< / com:Sup>; <com:Math><semantics>Rq0<annotation encoding="application / x-tex">R^{q0}< / annotation>< / semantics>< / com:Math> are the same or different and are each independently selected from <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, halogen, OH, cyano, -NH<com:Sub>2< / com:Sub>, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>3-6< / com:Sub> heterocycloalkyl, -NHC<com:Sub>1-4< / com:Sub> alkyl and -N(C<com:Sub>1-4< / com:Sub> alkyl)2, wherein the heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and CA the alkyl, heterocycloalkyl and cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl and -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup>; <com:Math><semantics>Rq4<annotation encoding="application / x-tex">R^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq5<annotation encoding="application / x-tex">R^{q5}< / annotation>< / semantics>< / com:Math> are selected from H and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl; W is selected from O and NH; R and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> are each independently selected from deuterium, H, F, CN, OH, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl and 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 to 3 heteroatoms selected from N and O, and the alkyl or heterocycle is optionally further substituted with 1 to 4 substituents selected from OH, F, CN and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy; or R and R<com:Sub>1< / com:Sub>, together with an atom to which they are attached, form a 4 membered ring or 5 membered ring; q and r are selected from 0, 1 and 2; m is selected from 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as general formula (V) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] wherein, Q, W, <com:Math><semantics>Rb<annotation encoding="application / x-tex">R_b< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rc<annotation encoding="application / x-tex">R_c< / annotation>< / semantics>< / com:Math> are defined in the same way as in general formula (I); m is selected from 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as general formula (V) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof, wherein: Q is selected from 5 membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the aryl or heteroaryl is optionally substituted with 0 to 4 R<com:Sup>q0< / com:Sup>; <com:Math><semantics>Rq0<annotation encoding="application / x-tex">R^{q0}< / annotation>< / semantics>< / com:Math> are the same or different and are each independently selected from <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, halogen, OH, cyano, -NH<com:Sub>2< / com:Sub>, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>3-6< / com:Sub> heterocycloalkyl, -NHC<com:Sub>1-4< / com:Sub> alkyl and -N(C<com:Sub>1-4< / com:Sub> alkyl)2, wherein the heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and the alkyl, heterocycloalkyl and cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C<com:Sub>1-4< / com:Sub> alkyl and -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup>; <com:Math><semantics>Rq4<annotation encoding="application / x-tex">R^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq5<annotation encoding="application / x-tex">R^{q5}< / annotation>< / semantics>< / com:Math> are selected from H and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl; W is selected from O and NH; <com:Math><semantics>Rb<annotation encoding="application / x-tex">R_b< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rc<annotation encoding="application / x-tex">R_c< / annotation>< / semantics>< / com:Math> are each independently selected from H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl and 3-5 membered carbocyclyl, wherein the 3-5 membered carbocyclyl is preferably a 3 membered, 4 membered or 5 membered cycloalkyl; q and r are selected from 0, 1 and 2; m is selected from 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as general formula (VI) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof: [Image disponible dans le document PDF, Image available in the PDF document] (VI) wherein, Q, W, <com:Math><semantics>Rb<annotation encoding="application / x-tex">R_b< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rc<annotation encoding="application / x-tex">R_c< / annotation>< / semantics>< / com:Math> are defined in the same way as in general formula (I); m is selected from 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as (VI) or a stereoisomer, solvate, metabolite, deuteride, prodrug, pharmaceutically acceptable salt or cocrystal thereof, wherein: Q is selected from 5 membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the aryl or heteroaryl is optionally substituted with 0 to 4 R<com:Sup>q0< / com:Sup>; <com:Math><semantics>Rq0<annotation encoding="application / x-tex">R^{q0}< / annotation>< / semantics>< / com:Math> are the same or different and are each independently selected from <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, halogen, OH, cyano, -NH<com:Sub>2< / com:Sub>, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>3-6< / com:Sub> heterocycloalkyl, -NHC<com:Sub>1-4< / com:Sub> alkyl and -N(C<com:Sub>1-4< / com:Sub> alkyl)2, wherein the heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and the alkyl, heterocycloalkyl and cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C<com:Sub>1-4< / com:Sub> alkyl and -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup>; <com:Math><semantics>Rq4<annotation encoding="application / x-tex">R^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq5<annotation encoding="application / x-tex">R^{q5}< / annotation>< / semantics>< / com:Math> are selected from H and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl; W is selected from O and NH; <com:Math><semantics>Rb<annotation encoding="application / x-tex">R_b< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rc<annotation encoding="application / x-tex">R_c< / annotation>< / semantics>< / com:Math> are each independently selected from H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl and 3-5 membered carbocyclyl, wherein the 3-5 membered carbocyclyl is preferably a 3 membered, 4 membered or 5 membered cycloalkyl; q and r are selected from 0, 1 and 2; m is selected from 1, 2 and 3. One or more embodiments of the present invention provide a compound shown as general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V) or (VI) or a stereoisomer, hydrate, metabolite, deuteride, solvate, pharmaceutically acceptable salt or cocrystal thereof, wherein: [Image disponible dans le document PDF, Image available in the PDF document] The compound provided in one or more embodiments of the present invention is selected from, but is not limited to, the following structures: [Image disponible dans le document PDF, Image available in the PDF document] CA [Image disponible dans le document PDF, Image available in the PDF document] 9 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ř The present invention also provides an intermediate for preparing a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V) or (VI), wherein the intermediate is selected from, but is not limited to, the following structures: [Image disponible dans le document PDF, Image available in the PDF document] mill _ [Image disponible dans le document PDF, Image available in the PDF document] One or more embodiments of the present application provide a pharmaceutical composition comprising the compound of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V) or (VI) or the specific structure described above or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. One or more embodiments of the present application provide use of the pharmaceutical composition, the compound of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (<com:Math><semantics>V<annotation encoding="application / x-tex">V< / annotation>< / semantics>< / com:Math>) or <com:Math><semantics>(mVI)<annotation encoding="application / x-tex">({m VI})< / annotation>< / semantics>< / com:Math> or the specific structure described above, or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof disclosed herein, in preparing an NLRP3 inhibitor. In one or more embodiments of the present application, a disease treated by the NLRP3 inhibitor is selected from inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancers, renal system diseases, gastrointestinal diseases, respiratory system diseases, endocrine system diseases and central nervous system diseases. In one or more embodiments of the present application, a disease treated by the NLRP3 inhibitor is selected from cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I diabetes, type II diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout and chronic kidney disease. One or more embodiments of the present application provide a method for inhibiting NLRP3, which comprises contacting the compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (<com:Math><semantics>mV<annotation encoding="application / x-tex">m V< / annotation>< / semantics>< / com:Math>) or (<com:Math><semantics>mVI<annotation encoding="application / x-tex">m VI< / annotation>< / semantics>< / com:Math>) or the specific structure described above or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof disclosed herein, or the composition disclosed herein, with a subject in need thereof. One or more embodiments of the present application provide a method for treating a disease associated with NLRP3, which comprises administering to a subject in need thereof the compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (<com:Math><semantics>V<annotation encoding="application / x-tex">V< / annotation>< / semantics>< / com:Math>) or (<com:Math><semantics>V<annotation encoding="application / x-tex">V< / annotation>< / semantics>< / com:Math>I) or the specific structure described above or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof disclosed herein, or the composition disclosed herein. One or more embodiments of the present application provide a compound of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V) or (VI) or the specific structure described above or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof, for use in treating a disease associated with NLRP3 or as an NLRP3 inhibitor. Unless stated to the contrary, the terms used in the specification and claims have the following meanings. Carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br and I involved in the groups and compounds described herein are each inclusive of isotopes thereof, and carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described herein is optionally further replaced by one or more isotopes thereof corresponding thereto, wherein isotopes of carbon include <com:Sup>12< / com:Sup>C, <com:Sup>13< / com:Sup>C and <com:Sup>14< / com:Sup>C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen) and tritium (T, also called superheavy hydrogen), isotopes of oxygen include <com:Sup>16< / com:Sup>O, <com:Sup>17< / com:Sup>O and <com:Sup>18< / com:Sup>O, isotopes of sulfur include <com:Sup>32< / com:Sup>S, <com:Sup>33< / com:Sup>S, <com:Sup>34< / com:Sup>S and <com:Sup>36< / com:Sup>S, isotopes of nitrogen include <com:Sup>14< / com:Sup>N and <com:Sup>15< / com:Sup>N, isotopes of fluorine include <com:Sup>17< / com:Sup>F and <com:Sup>19< / com:Sup>F, isotopes of chlorine include <com:Sup>35< / com:Sup>Cl and <com:Sup>37< / com:Sup>Cl, and isotopes of bromine include <com:Sup>79< / com:Sup>Br and <com:Sup>81< / com:Sup>Br. "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group consisting of 1 to 20 carbon atoms, preferably an alkyl group consisting of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8) carbon atoms, more preferably an alkyl group consisting of 1 to 6 carbon atoms, and further preferably an alkyl group consisting of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof; when the alkyl is substituted, it may be optionally further substituted with 1 or more substituents. "Alkoxy" refers to a group formed by substitution of at least 1 carbon atom of an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy. The alkyl is defined in the same way as for the "alkyl" described above. "Alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon-carbon double bonds and consisting of 2 to 20 carbon atoms, preferably an alkenyl group consisting of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably an alkenyl group consisting of 2 to 8 carbon atoms, and further preferably an alkenyl group consisting of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen- 3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3- yl. The alkenyl may be optionally further substituted with 1 or more substituents. "Alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon-carbon triple bonds and consisting of 2 to 20 carbon atoms, preferably an alkynyl group consisting of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably an alkynyl group consisting of 2 to 8 carbon atoms, and further preferably an alkynyl group consisting of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3- dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn- 4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undec-3-yl, and dodecyn-4-yl. The alkynyl may be optionally further substituted with one or more substituents. "Aryl" refers to a substituted or unsubstituted aromatic ring. It may be a 5-8 membered (e.g., 5, 6, 7 or 8 membered) monocyclic ring system, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11 or 12 membered) bicyclic ring system or a 10-15 membered (e.g., 10, 11, 12, 13, 14 or 15 membered) tricyclic ring system, and may be a bridged ring or a spiro ring. Non-limiting examples include phenyl and naphthyl. The aryl may be optionally further substituted with 1 or more substituents. "Heteroary!" refers to a substituted or unsubstituted aromatic ring. It may be a 3-8 membered (e.g., 3, 4, 5, 6, 7 or 8 membered) monocyclic ring system, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11 or 12 membered) bicyclic ring system or a 10-15 membered (e.g., 10, 11, 12, 13, 14 or 15 membered) tricyclic ring system, and it contains 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6) heteroatoms selected from N, O and S, and is preferably 5-8 membered heteroaryl. 1 to 4 (e.g., 1, 2, 3 or 4) N and S optionally substituted in the ring of the heteroaryl can be oxidized to various oxidation states. Heteroaryl may be attached to a heteroatom or carbon atom and it may be a bridged ring or a spiro ring. Non-limiting examples include cyclic pyridinyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, benzimidazolyl, benzopyridinyl and pyrrolopyridinyl. Heteroaryl is optionally further substituted with 1 or more substituents. "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated, aromatic or non-aromatic ring. When being an aromatic ring, it is defined in the same way as for the "aryl" described above; when being an non-aromatic ring, it may be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 membered) monocyclic ring system, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11 or 12- membered) bicyclic ring system or a 10-15 membered (e.g., 10, 11, 12, 13, 14 or 15 membered) tricyclic ring system, and it may be a bridged ring or a spiro ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1- cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] cyclododecyl, and . The "carbocyclyl" or "carbocycle" is optionally further substituted with 1 or more substituents. "Heterocycly!" or "heterocycle" refers to a saturated or unsaturated, aromatic or non-aromatic heterocycle. When being an aromatic heterocycle, it is defined in the same way as for the "heteroaryl" described above; when being a non-aromatic heterocycle, it may be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 membered) monocyclic ring system, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered) bicyclic ring system or a 10-15 membered (e.g., 10, 11, 12, 13, 14 or 15 membered) tricyclic ring system, and it contains 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms selected from N, O and S, and is preferably 3-8 membered heterocyclyl. 1 to 4 (e.g., 1, 2, 3 or 4) N and S optionally substituted in the ring of the "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" may be attached to a heteroatom or a carbon atom, and may be a bridged ring or a spiro ring. Non- limiting examples of "heterocyclyl" or "heterocycle" include epoxyethyl, epoxypropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxoazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, 1,3-dithianyl, dihydrofuranyl, dithiacyclopentyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxacyclohexyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3- azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H- indolylquinolizinyl, <com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-pyridylurea, <com:Math><semantics>1,1<annotation encoding="application / x-tex">1,1< / annotation>< / semantics>< / com:Math>-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, aza-adamantyl and oxaspiro[3.3]heptyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted with 1 or more substituents. "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 membered) monocyclic ring system, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered) bicyclic ring system or a 10-20 membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) polycyclic ring system. The ring carbon atoms are preferably 3 to 10 carbon atoms, further preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5- cyclooctadienyl, 1,4-cyclohexadienyl, cycloheptatrienyl, and the like. When the cycloalkyl is substituted, it may be optionally further substituted with 1 or more substituents. "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group. It may be a 3-8 membered (e.g., 3, 4, 5, 6, 7 or 8 membered) monocyclic ring system, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered) bicyclic ring system or a 10-15 membered (e.g., 10, 11, 12, 13, 14 or 15 membered) tricyclic ring system, and it contains 1, 2 or 3 heteroatoms selected from N, O and S, and is preferably 3-8 membered heterocyclyl. 1, 2 or 3 N and S optionally substituted in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or a carbon atom and may be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, aza-adamantyl and oxaspiro[3.3]heptyl. When the "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" described above is substituted, it may be optionally further substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituents selected from F, CI, Br, I, hydroxy, mercapto, nitro, cyano, amino, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, =0, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, -NR<com:Sup>q4< / com:Sup>R<com:Sup>q5< / com:Sup>, =NR<com:Sup>q6< / com:Sup>, - <com:Math><semantics>C(=O)OC1−6<annotation encoding="application / x-tex">C(=O)OC_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−OC(=O)C1−6<annotation encoding="application / x-tex">-OC(=O)C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−C(=O)NRq4Rq5<annotation encoding="application / x-tex">-C(=O)NR^{q4}R^{q5}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C5−10<annotation encoding="application / x-tex">C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−C(=O)OC6−10<annotation encoding="application / x-tex">-C(=O)OC_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−OC(=O)C6−10<annotation encoding="application / x-tex">-OC(=O)C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−OC(=O)C5−10<annotation encoding="application / x-tex">-OC(=O)C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C(=O)OC5−10<annotation encoding="application / x-tex">C(=O)OC_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−OC(=O)C3−8<annotation encoding="application / x-tex">-OC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−C(=O)OC3−8<annotation encoding="application / x-tex">-C(=O)OC_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>OC(=O)C3−8<annotation encoding="application / x-tex">OC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−C(=O)OC3−8<annotation encoding="application / x-tex">-C(=O)OC_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−NHC(=O)C3−8<annotation encoding="application / x-tex">-NHC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> NHC(=O)C<com:Sub>6-10< / com:Sub> aryl, -NHC(=O)C<com:Sub>5-10< / com:Sub> heteroaryl, -NHC(=O)C<com:Sub>3-8< / com:Sub> cycloalkyl, -NHC(=O)C<com:Sub>3-8< / com:Sub> heterocycloalkyl, -NHC(=0)C<com:Sub>2-6< / com:Sub> alkenyl and -NHC(=0)C<com:Sub>2-6< / com:Sub> alkynyl, wherein the substituent <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C5−10<annotation encoding="application / x-tex">C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−NHC(=O)C6−10<annotation encoding="application / x-tex">-NHC(=O)C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−NHC(=O)C5−10<annotation encoding="application / x-tex">-NHC(=O)C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−NHC(=O)C3−8<annotation encoding="application / x-tex">-NHC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl or <com:Math><semantics>−NHC(=O)C3−8<annotation encoding="application / x-tex">-NHC(=O)C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl is optionally further substituted with 1 to 3 substituents selected from OH, F, Cl, Br, I, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>−NRq4Rq5<annotation encoding="application / x-tex">-NR^{q4}R^{q5}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>=O<annotation encoding="application / x-tex">=O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Rq1<annotation encoding="application / x-tex">R^{q1}< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy and <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, and <com:Math><semantics>Rq2<annotation encoding="application / x-tex">R^{q2}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq3<annotation encoding="application / x-tex">R^{q3}< / annotation>< / semantics>< / com:Math> are selected from H and <com:Math><semantics>C1−1<annotation encoding="application / x-tex">C_{1-1}< / annotation>< / semantics>< / com:Math> 6 alkyl, wherein <com:Math><semantics>Rq4<annotation encoding="application / x-tex">R^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rq5<annotation encoding="application / x-tex">R^{q5}< / annotation>< / semantics>< / com:Math> are selected from H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, -NH(C=N<com:Math><semantics>Rq1<annotation encoding="application / x-tex">R^{q1}< / annotation>< / semantics>< / com:Math>)N<com:Math><semantics>Rq2Rq3<annotation encoding="application / x-tex">R^{q2}R^{q3}< / annotation>< / semantics>< / com:Math>, - <com:Math><semantics>S(=O)2NRq2Rq3<annotation encoding="application / x-tex">S(=O)_2NR^{q^2}R^{q^3}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)Rq1<annotation encoding="application / x-tex">-C(=O)R^{q^1}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−C(=O)NRq2Rq3<annotation encoding="application / x-tex">-C(=O)NR^{q^2}R^{q^3}< / annotation>< / semantics>< / com:Math>, wherein the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is optionally further substituted with 1 or more substituents selected from OH, F, CI, Br, I, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C5−10<annotation encoding="application / x-tex">C_{5-10}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl and <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocycloalkyl; or <com:Math><semantics>ℝq4<annotation encoding="application / x-tex">\mathbb{R}^{q4}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝq5<annotation encoding="application / x-tex">\mathbb{R}^{q5}< / annotation>< / semantics>< / com:Math>, together with an N atom, form a 3-8 membered heterocycle, which may contain 1 or more heteroatoms selected from N. O and S. "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt obtained by reaction of a compound disclosed herein in a free acid form with a nontoxic inorganic or organic base or by reaction of a compound disclosed herein in a free base form with a nontoxic inorganic or organic acid, and in this salt, the bioavailability and characteristics of the compound disclosed herein in the free acid or free base form is retained. "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein the "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents. "Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and characteristics of the administered compound. "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrants. "Prodrug" refers to a compound disclosed herein that can be metabolized in vivo to become biologically active. A prodrug disclosed herein is prepared by modifying amino or carboxyl in a compound disclosed herein, and the modification can be removed by conventional operation or be removed in vivo to obtain the parent compound. When a prodrug disclosed herein is administered to a mammalian subject, the prodrug is cleaved to form free amino or carboxyl. "Cocrystal" refers to a crystal formed by binding of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) via a hydrogen bond or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature, and the components are present in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, including both a binary cocrystal formed by two neutral solids and a multiple cocrystal formed by a neutral solid and a salt or solvate. "Stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformers. "Optional", "optionally", "selective" or "selectively" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl may, but does not necessarily, be present, and the description includes the case where the heterocyclyl is substituted with alkyl and the case where the heterocyclyl is not substituted with alkyl. DETAILED DESCRIPTION The following examples illustrate the technical schemes of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto. The structure of a compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (<com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>) are expressed in <com:Math><semantics>10−6<annotation encoding="application / x-tex">10^{-6}< / annotation>< / semantics>< / com:Math> (ppm). NMR determination is performed using NMR spectrometers (Bruker<com:Sup>TM< / com:Sup> Avance III 400 and Bruker Avance 300), with deuterated dimethyl sulfoxide (DMSO-d<com:Sub>6< / com:Sub>), deuterated chloroform (CDCl<com:Sub>3< / com:Sub>) and deuterated methanol (CD<com:Sub>3< / com:Sub>OD) as solvents and tetramethylsilane (TMS) as an internal standard; MS determination is performed using Agilent 6120B (ESI) and Agilent 6120B (APCI); HPLC determination is performed using Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 <com:Math><semantics>100×4.6 mm<annotation encoding="application / x-tex">100 \times 4.6 \text{ mm}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.5μM<annotation encoding="application / x-tex">3.5 \mu\text{M}< / annotation>< / semantics>< / com:Math>); Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is used as a thin layer chromatography (TLC) silica gel plate. The specification of the silica gel plate for TLC is 0.15– 0.20 mm, and that for product separation and purification of TLC is 0.4–0.5 mm; Yantai Yellow Sea silica gel of 200–300 mesh is generally used as a carrier in column chromatography; known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from companies such as Shanghai Titan Scientific, Energy Chemical, Shanghai DEMO Medical, Chengdu Kelong Chemical, Accela ChemBio, and J&K Scientific; nitrogen atmosphere means that a reaction flask is connected with a nitrogen balloon with a volume of about 1 L; hydrogen atmosphere means that a reaction flask is connected with a nitrogen balloon with a volume of about 1 L; in hydrogenation reaction, the operation of vacuumizing and introducing hydrogen is usually performed, and repeated 3 times; reactions are performed under nitrogen atmosphere if not otherwise specified in examples; a solution is an aqueous solution if not otherwise specified in examples; reaction temperature is room temperature and the optimum reaction temperature of room temperature is 20–30 °C if not otherwise specified in examples; DCM: dichloromethane: EA: ethyl acetate; HCI: hydrochloric acid; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; PE: petroleum ether; TLC: thin layer chromatography; SFC: supercritical fluid chromatography; NCS: N-chlorosuccinimide; Pd(dppf)Cl<com:Sub>2< / com:Sub>: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. Example Intermediate 1 5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 1) [Image disponible dans le document PDF, Image available in the PDF document] orch T. (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone (1b) Compound 1a (20.0 g, 150.16 mmol) was dissolved in 1,2-dichloroethane (200 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. A solution of boron trichloride (150 mL, 1 M, 150.16 mmol) in dichloromethane was then added dropwise slowly, and the temperature was maintained and the resulting solution was reacted for 10 min after the dropwise addition was completed. Aluminum trichloride (22.0) g, 165.20 mmol) and cyclopropyl cyanide (15.1 g, 225.24 mmol) were then added, and the reaction system was warmed to 80 °C, reacted for 4 h and then cooled to room temperature. 2 M HCI (160 mL) was added in an ice bath, and the resulting reaction system was warmed to reflux and reacted for 1 h. After the reaction was completed, the reaction system was cooled to room temperature and extracted with DCM (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3). The organic phase was washed with 2 M sodium hydroxide solution (160 mL), dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = <com:Math><semantics>20:1<annotation encoding="application / x-tex">20:1< / annotation>< / semantics>< / com:Math>) to give compound 1b in the form of a white solid (17.1 g, 57.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> =7.87 (d, 1H), 6.90 (br, 2H), 6.54 (d, 1H), 2.84 (t, 2H), 2.80- <com:Math><semantics>2.74 (m, 1H),2.67 (t, 2H),2.06−1.98 (m, 2H),0.96−0.87 (m, 4H);LCMSm / z(ESI)=<annotation encoding="application / x-tex">2.74 \text{ (m, 1H)}, 2.67 \text{ (t, 2H)}, 2.06-1.98 \text{ (m, 2H)}, 0.96-0.87 \text{ (m, 4H)}; LCMS m / z(ESI) =< / annotation>< / semantics>< / com:Math> 202.1[M+1]. Step 2: 5-(1-cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine (1c) Compound methyl triphenyl phosphonium bromide (24.8 g, 69.6 mmol) was dissolved in THF (300 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. Potassium tert-butoxide (7.8 g, 69.6 mmol) was added slowly, and the temperature was maintained and the reaction system was reacted for 30 min. Compound CA 1b (7.0 g, 34.8 mmol) was added, and the resulting reaction system was reacted at room temperature for 4 h. After the reaction was completed, water was added to guench the reaction, and EA (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to give compound 1c in the form of a pale yellow oil (6.4 g, 92.3% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=6.64<annotation encoding="application / x-tex">\delta = 6.64< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>6.45<annotation encoding="application / x-tex">6.45< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>5.15<annotation encoding="application / x-tex">5.15< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>4.78<annotation encoding="application / x-tex">4.78< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>4.37<annotation encoding="application / x-tex">4.37< / annotation>< / semantics>< / com:Math> (br, 2H), 2.77 (t, 2H), 2.64 (t, 2H), 2.02-1.96 (m, 2H), 1.62-1.57 (m, 1H), 0.69-0.64 (m, 2H), <com:Math><semantics>0.40−0.36 (m, 2H); LC-MS m / z(ESI)=200.1[M+1].<annotation encoding="application / x-tex">0.40-0.36 \text{ (m, 2H); LC-MS m / z(ESI)} = 200.1[M+1].< / annotation>< / semantics>< / com:Math> Step 3: 5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 1) Compound 1c (700 mg, 3.51 mmol) and triethylsilane (1.23 g, 10.54 mmol) were dissolved in DCM (10 mL) in a 50 mL round-bottomed flask under nitrogen atmosphere, and trifluoroacetic acid (2.0 g, 17.56 mmol) was added dropwise in an ice bath. After the dropwise addition was completed, the reaction system was warmed to room temperature and reacted for 5 h. After the reaction was completed, water was added to guench the reaction, saturated sodium bicarbonate was added to adjust pH to weak alkalinity, and DCM (20 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = <com:Math><semantics>10:1<annotation encoding="application / x-tex">10:1< / annotation>< / semantics>< / com:Math>) to give intermediate 1 in the form of a pale yellow oil (261 mg, 37.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=6.93<annotation encoding="application / x-tex">\delta = 6.93< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>6.47<annotation encoding="application / x-tex">6.47< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>4.60<annotation encoding="application / x-tex">4.60< / annotation>< / semantics>< / com:Math> (br, 2H), <com:Math><semantics>2.75<annotation encoding="application / x-tex">2.75< / annotation>< / semantics>< / com:Math> (t, 2H), <com:Math><semantics>2.63<annotation encoding="application / x-tex">2.63< / annotation>< / semantics>< / com:Math> (t, 2H), 2.28-2.18 (m, 1H), 2.00-1.94 (m, 2H), 1.14 (d, 3H), 1.02-0.97 (m, 1H), 0.49-0.44 (m, 1H), <com:Math><semantics>0.33−0.30<annotation encoding="application / x-tex">0.33-0.30< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.15−0.12<annotation encoding="application / x-tex">0.15-0.12< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.05−0.01<annotation encoding="application / x-tex">0.05-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LC-MS m / z(ESI) = 202.2[M+1]. Intermediate 2 N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (Intermediate 2) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Ethyl furan-3-carboxylate (2b) Compound 2a (50 g, 0.446 mol) was dissolved in absolute ethanol (300 mL) in an ice bath, and thionyl chloride (65 mL, 0.892 mol) was added dropwise slowly. After the dropwise addition CA was completed, the reaction system was warmed to reflux and reacted for 2 h. After the reaction was completed as detected by TLC, the reaction system was concentrated under reduced pressure to remove the solvent and excess thionyl chloride. Water (200 mL) was added, and ethyl acetate (150 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phases were combined, washed with saturated brine (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = <com:Math><semantics>1:50−1:10<annotation encoding="application / x-tex">1:50-1:10< / annotation>< / semantics>< / com:Math>) to give compound 2b in the form of a pale brown oil (38.1 g, 61% yield). Step 2: Ethyl furan-2-sulfonyl chloride-4-formate (2c) Compound 2b (22.00 g, 0.157 mol) was dissolved in DCM (250 mL) at room temperature, and the solution was cooled to -15 °C in an ice salt bath. Sulfonyl chloride (23.31 g, 0.173 mol) was added dropwise slowly while controlling the temperature to be not higher than -10 °C. After dropwise addition was completed, the reaction system was reacted for 12 h at room temperature and cooled to -15 °C or lower in an ice salt bath. Pyridine (13.66 g, 0.173 mol) was added dropwise slowly, and then phosphorus pentachloride (36.00 g, 0.137 mol) was added in batches while controlling the temperature to be not higher than -10 °C. After the addition was completed, the reaction system was reacted for 2 h at room temperature. After the reaction was completed as detected by TLC, the reaction system was added into ice water (200 mL) to quench the reaction, and then extracted with EA (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, so as to give compound 2c in the form of a brown oil (33.00 g, 90% yield), which was directly used in the next step without purification. Step 3: Furan-2-sulfonamide-4-ethyl formate (2d) Compound 2c (33.00 g, 0.138 mol) was dissolved in acetone (350 mL) at room temperature, and then a solution of saturated aqueous ammonium bicarbonate (49.74 g, 0.553 mol) solution was added dropwise at room temperature. The reaction system was reacted for 3 h at room temperature. After the reaction was completed as detected by TLC, the reaction system was extracted with EA (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, so as to give compound 2d in the form of a brown solid powder (23 g, 77 % yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.64<annotation encoding="application / x-tex">\delta = 8.64< / annotation>< / semantics>< / com:Math> (s, 1H), 7.97 (s, 2H), 7.13 (s, 1H), 4.27 (q, 2H), 1.28 <com:Math><semantics>(t,3H)<annotation encoding="application / x-tex">(t, 3H)< / annotation>< / semantics>< / com:Math>; LCMS m / z = 218.2[M-1]. Step 4: 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (2e) Compound 2d (23 g, 0.105 mol) was dissolved in dry THF (500 mL) at room temperature, and then the solution was cooled to -15 °C in an ice salt bath. Methylmagnesium bromide (140 mL, 0.418 mol) was added dropwise slowly while maintaining the temperature to be not higher than 0 °C. After the addition was completed, the reaction system was reacted for 4 h at room temperature. After the reaction was completed as detected by TLC, the reaction system was poured into ice water (200 mL) to quench the reaction, and then extracted with EA (200 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:4-1:1) to give compound 2e in the form of a white solid powder (16 g, 76% yield). LCMS <com:Math><semantics>m / z=204.2[M−1]<annotation encoding="application / x-tex">m / z = 204.2[M-1]< / annotation>< / semantics>< / com:Math>. Step 5: <com:Math><semantics>N−(tert−buty|dimethy|sily|)−4−(2−hydroxypropan−2−y|)furan−2−sulfonamide(2f)<annotation encoding="application / x-tex">N-(tert-buty|dimethy|sily|)-4-(2-hydroxypropan-2-y|)furan-2-sulfonamide (2f)< / annotation>< / semantics>< / com:Math> Compound 2e (5.0 g, 24.39 mmol) was dissolved in dry THF (50 mL) at room temperature, and then the solution was cooled to -10 °C in an ice salt bath. Sodium hydride (0.9 g, 36.58 mmol) was added slowly while controlling the temperature to be lower than -10 °C, and then a solution of tert-butyldimethylchlorosilane (4.8 g, 31.70 mmol) in THF (50 mL) was added. The reaction system was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, the reaction system was poured into ice water (20 mL) to quench the reaction, and then extracted with EA (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl- acetate: petroleum ether = <com:Math><semantics>1:2−2:1<annotation encoding="application / x-tex">1:2-2:1< / annotation>< / semantics>< / com:Math>) to give compound 2f in the form of a white solid (5.1 g, 66%) yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl3) <com:Math><semantics>δ=7.85<annotation encoding="application / x-tex">\delta = 7.85< / annotation>< / semantics>< / com:Math> (s, 1H), 7.68 (s, 1H), 6.93 (s, 1H), 5.07 (s, 1H), 1.38 (s, 6 H), 0.88 (s, 9H), 0.16 (s, 6H); LCMS <com:Math><semantics>m / z=320.2[M+1]<annotation encoding="application / x-tex">m / z = 320.2[M+1]< / annotation>< / semantics>< / com:Math>. Step 6: N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (Intermediate 2) DCM (100 mL) and triphenylphosphine dichloride (11.3 g, 33.86 mmol) were added into a 250 mL three-necked flask under nitrogen atmosphere, and then the reaction system was cooled to 0 °C in an ice bath, and diisopropylethylamine (5.8 g, 45.16 mmol) was added dropwise slowly. After the dropwise addition was completed, the reaction system was warmed to room temperature, reacted for 10 min, and then cooled to 0 °C. A solution of 2f (3.6 g, 11.29 mmol) in dichloromethane (10 mL) was added, and after the addition was completed, the temperature was maintained at 0 °C and the reaction system was reacted for 30 min. Ammonia gas was introduced into the reaction system for 15 min, and then the reaction system was warmed to room temperature and reacted for 2 h. After the reaction was completed as detected by TLC, the reaction system was concentrated under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give intermediate 2 in the form of a white solid (816 mg, 23% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.56<annotation encoding="application / x-tex">\delta = 7.56< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.86<annotation encoding="application / x-tex">6.86< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>6.73<annotation encoding="application / x-tex">6.73< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.01<annotation encoding="application / x-tex">5.01< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>1.37<annotation encoding="application / x-tex">1.37< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,6H),0.85(s,9H),0.03(s,3H),0.01(s,3H);LCMSm / z=319.2[M+1].<annotation encoding="application / x-tex">(s, 6H), 0.85 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); LCMS m / z = 319.2[M+1].< / annotation>< / semantics>< / com:Math> Intermediate 3-intermediate 4 For synthesis of intermediates 3 and 4, reference was made to preparation method of intermediate 2. [Image disponible dans le document PDF, Image available in the PDF document] CA Intermediate 5 5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonamide (Intermediate 5) [Image disponible dans le document PDF, Image available in the PDF document] 5-bromo-N-(tert-butyldimethylsilyl)thiophene-2-sulfonamide (5b) 5a (10.0 g, 41.31 mmol) was dissolved in anhydrous THF (200 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and then sodium hydride (2.5 g, 61.96 mmol) was added in an ice bath. After the addition was completed, the temperature was maintained and the reaction system was reacted for 20 min. A solution of tert-butyldimethylchlorosilane (7.2 g, 49.67 mmol) in THF (50 mL) was then added dropwise slowly, and after the addition was completed, the reaction system was warmed to room temperature and reacted for 2 h. After the reaction was completed, water was added to quench the reaction, and ethyl acetate (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 5b in the form of a yellow solid (10.3 g, 70.0% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 356.0[M+1]. Step 2: <com:Math><semantics>N−(tert−butyldimethylsilyl)−5−(3−hydroxyoxetan−3−yl)thiophene−2−sulfonamide(5c)<annotation encoding="application / x-tex">N-(tert-butyldimethylsilyl)-5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonamide (5c)< / annotation>< / semantics>< / com:Math> Compound 5b (10.0 g, 29.4 mmol) was dissolved in tetrahydrofuran (100 mL) in a 1 L three- necked flask under nitrogen atmosphere, and then the solution was cooled to -70 °C in a dry ice-ethanol bath. n-butyllithium (3.0 M in THF, 24.5 mL, 73.5 mmol) was added dropwise slowly, and then the reaction system was reacted for 30 min while maintaining the temperature at -70 °C. 3-oxetanone (3.1 g, 44.0 mmol) was then added, and after the addition was completed, the reaction system was slowly warmed to room temperature and reacted for 1 h. After the reaction was completed, the reaction system was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = <com:Math><semantics>1:1<annotation encoding="application / x-tex">1:1< / annotation>< / semantics>< / com:Math>) to give compound 5c in the form of a yellow solid (6 g, 61.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO) <com:Math><semantics>δ=7.89<annotation encoding="application / x-tex">\delta = 7.89< / annotation>< / semantics>< / com:Math> (s, 1H), 7.43 (d, 1H), 7.25 (d, 1H), 7.03 (s, 1H), 4.75 (d, 2H), <com:Math><semantics>4.68<annotation encoding="application / x-tex">4.68< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>0.88<annotation encoding="application / x-tex">0.88< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>9H<annotation encoding="application / x-tex">9H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>0.16<annotation encoding="application / x-tex">0.16< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>); LCMS m / z (ESI) = <com:Math><semantics>350.3<annotation encoding="application / x-tex">350.3< / annotation>< / semantics>< / com:Math>[M+1]. Step 3: 5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonamide (Intermediate 5) 5c (6.0 g, 17.17 mmol) and THF (100 mL) were added successively into a 100 mL round- bottomed flask under nitrogen atmosphere, and then the reaction system was cooled to 0 °C in an ice bath. Tetrabutylammonium fluoride (35 mL, 1 M in THF, 34.34 mmol) was then added dropwise slowly, and the reaction system was warmed to room temperature and reacted for 2 h after the dropwise addition was completed. After the reaction was completed, water was added to quench the reaction, and EA (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 5 in the form of a pale yellow solid (3.3 g, 82.5% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 236.0[M+1]. Intermediate 6-intermediate 7 For preparation of intermediates 6 and 7, reference was made to preparation method of intermediate 5. [Image disponible dans le document PDF, Image available in the PDF document] Intermediate 8 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-5-(1-cyclopropylethyl)-2,3-dihydro-1<com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>-inden-4-amine (Intermediate 8) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: For synthesis of intermediate 8, reference was made to patent CN108017559. 1c (8.3 g, 41.7 mmol) and dichloromethane (90 mL) were added into a 500 mL autoclave, and then a catalyst ruthenium <com:Math><semantics>[(R)−2,2′−bis(diphenylphosphino)−1,11−binaphthyl]diacetate(1.8g,2.09mmol)was<annotation encoding="application / x-tex">[(R)-2,2'-bis(diphenylphosphino)-1,11-binaphthyl]diacetate (1.8 g, 2.09 mmol) was< / annotation>< / semantics>< / com:Math> added. After the addition was completed, the autoclave was tightly closed and sealed, and purged with hydrogen 3 times. The hydrogen was introduced until the pressure gauge on the autoclave showed 12 atm, and then the reaction system was reacted for 30 h at room temperature. The reaction system was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give intermediate 8 in the form of a pale yellow oil (8.2 g, 97.8% yield, ee%: 97.74%, chiral HPLC (CHIRALPAK<com:Sup>TM< / com:Sup> AY-3 (4.6×100 mm); mobile phase: methanol; column temperature: 35 °C; mobile phase (%): 15; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm@4.8 nm; start / stop wavelength of diode array detector: 200–400 nm): RT = 3.295 min). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> = 6.92 (d, 1H), 6.45 (d, 1H), 4.43 (s, 2H), 2.75 (t, 2H), 2.62 (t, 2H), 2.26–2.20 (m, 1H), 2.00–1.92 (m, 2H), 1.14 (d, 3H), 1.02-0.96 (m, 1H), 0.50–0.44 (m, 1H), <com:Math><semantics>0.34−0.28<annotation encoding="application / x-tex">0.34-0.28< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.17−0.11<annotation encoding="application / x-tex">0.17-0.11< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.06−0.00<annotation encoding="application / x-tex">0.06-0.00< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = 202.1[M+1]. Intermediate 9 (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 9) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: For synthesis of intermediate 9, reference was made to patent CN108017559. 1c (7.3 g, 36.7 mmol) and dichloromethane (80 mL) were added into a 500 mL autoclave, and then a catalyst ruthenium [(S)-2,2'-bis(diphenylphosphino)-1,11-binaphthyl]diacetate (1.54 g, 1.83 mmol) was added. After the addition was completed, the autoclave was tightly closed and sealed, and purged with hydrogen 3 times. The hydrogen was introduced until the pressure gauge on the autoclave showed 12 atm, and then the reaction system was reacted for 30 h at room temperature. The reaction system was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give intermediate 9 in the form of a pale yellow oil (7.1 g, 96.3% yield, ee%: 98.18%, chiral HPLC (CHIRALPAK AY-3 (4.6×100 mm); mobile phase: methanol; column temperature: 35 °C; mobile phase (%): 15; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm@4.8 nm; start / stop wavelength of diode array detector: 200–400 nm): RT = 2.802 min). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> = 6.92 (d, 1H), 6.46 (d, 1H), 4.43 (s, 2H), 2.75 (t, 2H), 2.63 (t, 2H),2.26–2.20 (m, 1H),2.00–1.93 (m, 2H),1.15 (d, 3H),1.02–0.96 (m, 1H), 0.50–0.44 (m, 1H), <com:Math><semantics>0.36−0.28<annotation encoding="application / x-tex">0.36-0.28< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.17−0.11<annotation encoding="application / x-tex">0.17-0.11< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.06−0.01<annotation encoding="application / x-tex">0.06-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = <com:Math><semantics>202.1<annotation encoding="application / x-tex">202.1< / annotation>< / semantics>< / com:Math> [M+1]. Example 1 N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2- yl)furan-2-sulfonamide (Compound 1) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 1) Intermediate 1 (360 mg, 1.79 mmol), triethylamine (218 mg, 2.15 mmol) and tetrahydrofuran (20 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (213 mg, 0.72 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (367) mg, 1.79 mmol) and sodium methoxide (194 mg, 3.58 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 2 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The crude product was purified by preparative medium pressure liquid chromatography to give compound 1 in the form of a yellow solid (190 mg, 24.5% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.69<annotation encoding="application / x-tex">\delta = 7.69< / annotation>< / semantics>< / com:Math> (d, 1H), 7.54 (s, 1H), 7.10 (d, 1H), 7.02 (d, 1H), 6.84 (br, 1H), 5.00 (s, 1H), 2.81 (t, 2H), 2.62 (t, 2H), 2.28–2.17 (m, 1H), 1.94–1.87 (m, 2H), 1.38 (d, 6H), 1.11 (d, 3H), 0.95–0.90 (m, 1H), 0.47–0.44 (m, 1H), 0.22–0.18 (m, 1H), 0.10–0.07 (m, 1H), <com:Math><semantics>0.01<annotation encoding="application / x-tex">0.01< / annotation>< / semantics>< / com:Math>–<com:Math><semantics>0.01<annotation encoding="application / x-tex">0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z = <com:Math><semantics>433.1<annotation encoding="application / x-tex">433.1< / annotation>< / semantics>< / com:Math>[M+1]. Example 2 <com:Math><semantics>N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 2) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>N−(tert−butyldimethylsilyl)−N′−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−<annotation encoding="application / x-tex">N-(tert-butyldimethylsilyl)-N'-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-< / annotation>< / semantics>< / com:Math> yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (2A) Intermediate 1(400 mg, 1.99 mmol), triethylamine (242 mg, 2.397 mmol) and tetrahydrofuran (20 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (237 mg, 0.796 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Intermediate 2 (632 mg, 1.99 mmol) and sodium methoxide (215 mg, 3.98 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The crude product was purified by thin layer chromatography to give 2A in the form of a pale yellow oily solid (639 mg, 59%) yield). LCMS <com:Math><semantics>m / z=546.3[M+1]<annotation encoding="application / x-tex">m / z = 546.3[M+1]< / annotation>< / semantics>< / com:Math>. Step 2: <com:Math><semantics>N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 2) 2A (639 mg, 1.17 mmol) and THF (10 mL) were added successively into a 100 mL round- bottomed flask under nitrogen atmosphere, and then the reaction system was cooled to 0 °C in an ice bath. Tetrabutylammonium fluoride (2.4 mL, 1 M in THF, 2.34 mmol) was then added dropwise slowly, and the reaction system was warmed to room temperature and reacted for 2 h after the dropwise addition was completed. After the reaction was completed, water was added to guench the reaction, and EA (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography to give compound 2 in the form of a white solid (221 mg, 43.8% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.24<annotation encoding="application / x-tex">\delta = 8.24< / annotation>< / semantics>< / com:Math> (s, 1H), 7.68 (s, 1H), 7.64 (br, 1H), 7.13 (d, 1H), 7.04 (d, 1H), 6.98 (s, 1H), 4.54 (br, 1H), 2.82 (t, 2H), 2.67 (t, 2H), 2.29–2.19 (m, 1H), 1.99–1.91 (m, 2H), 1.38 (s, 6H), 1.17–1.03 (m, 3H), 0.97–0.91 (m, 1H), 0.48–0.42 (m, 1H), 0.23–0.18 (m, 1H), <com:Math><semantics>0.15−0.08<annotation encoding="application / x-tex">0.15-0.08< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.004−0.01<annotation encoding="application / x-tex">0.004-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z = <com:Math><semantics>432.2<annotation encoding="application / x-tex">432.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 3 <com:Math><semantics>N−((5−(cyclopropylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 3) [Image disponible dans le document PDF, Image available in the PDF document] with T. <com:Math><semantics>(4−amino−2,3−dihydro−1H−inden−5−yl)(cyclopropyl)methanol(3A)<annotation encoding="application / x-tex">(4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanol (3A)< / annotation>< / semantics>< / com:Math> Methanol (20 mL) and compound 1b (1.8 g, 8.96 mmol) were added into a 50 mL round- bottomed flask under nitrogen atmosphere, and then the reaction system was cooled to 0 °C in an ice bath. Sodium borohydride (678 mg, 17.91 mmol) was then added slowly, and the reaction system was warmed to room temperature and reacted for 1 h after the addition was completed. After the reaction was completed, the reaction system was cooled to 0 °C, water (20 mL) was CA added dropwise to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether: ethyl acetate = <com:Math><semantics>1:1<annotation encoding="application / x-tex">1:1< / annotation>< / semantics>< / com:Math>) to give compound 3A in the form of a colorless oil (1.2 g, 66% yield). LCMS <com:Math><semantics>m / z=186.1[M−17]<annotation encoding="application / x-tex">m / z = 186.1[M-17]< / annotation>< / semantics>< / com:Math>. Step 2: 5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-amine (3B) Compound 3A (1.2 g, 5.91 mmol) and triethylsilane (2.1 g, 17.73 mmol) were dissolved in DCM (20 mL) under nitrogen atmosphere, and then the solution was cooled to 0 °C in an ice bath. Trifluoroacetic acid (3.4 g, 29.63 mmol) was then added dropwise slowly, and the reaction system was reacted overnight at room temperature after the addition was completed. After the reaction was completed, saturated aqueous sodium bicarbonate was added to quench the reaction, and DCM (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give 3B in the form of a colorless oil (832 mg, 75.6% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=6.83<annotation encoding="application / x-tex">\delta = 6.83< / annotation>< / semantics>< / com:Math> (d, 1H), 6.41 (d, 1H), 4.50 (s, 2H), 2.75 (t, 2H), 2.63 (t, 2H), 2.34 (d, 2H), 2.00–1.92 (m, 2H), 1.01–0.93 (m, 1H), 0.45–0.39 (m, 2H), 0.13–0.10 (m, 2H); LCMS <com:Math><semantics>m / z(ESI)=188.1[M+1]<annotation encoding="application / x-tex">m / z(ESI) = 188.1[M+1]< / annotation>< / semantics>< / com:Math>. Step 3: <com:Math><semantics>N−((5−(cyclopropylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 3) 3B (116 mg, 0.62 mmol), triethylamine (75 mg, 0.74 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (74 mg, 0.25 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (127 mg, 0.62 mmol) and sodium methoxide (67 mg, 1.24 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100) mL) was added to guench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative medium pressure liquid chromatography to give compound 3 in the form of a yellow solid (73 mg, 28.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.98<annotation encoding="application / x-tex">\delta = 7.98< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.78<annotation encoding="application / x-tex">7.78< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.20<annotation encoding="application / x-tex">7.20< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.11<annotation encoding="application / x-tex">7.11< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>7.00<annotation encoding="application / x-tex">7.00< / annotation>< / semantics>< / com:Math> (m, 2H), 5.12 (s, 1H), 2.82 (t, 2H), 2.58 (t, 2H), 2.35 (d, 2H), 1.96–1.89 (m, 2H), 1.37 (s, 6H), 0.84–0.80 <com:Math><semantics>(m,1H),0.39−0.37(m,2H),0.11−0.07(m,2H);LCMSm / z=419.2[M+1].<annotation encoding="application / x-tex">(m, 1H), 0.39-0.37 (m, 2H), 0.11-0.07 (m, 2H); LCMS m / z = 419.2[M+1].< / annotation>< / semantics>< / com:Math> Example 4 N-((2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2- hydroxypropan-2-yl)furan-2-sulfonamide (Compound 4) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 2-chloro-6-(1-cyclopropylvinyl)-4-fluoroaniline (4B) 4A <com:Math><semantics>(8.66 g,38.56 mmol),2−(1−cyclopropylvinyl)−4,4,5,5−tetramethyl−1,3,2−dioxaborolane<annotation encoding="application / x-tex">(8.66 \text{ g}, 38.56 \text{ mmol}), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane< / annotation>< / semantics>< / com:Math> (9.73 g, 50.13 mmol), potassium phosphate (16.30 g, 77.12 mmol), bis(triphenylphosphine)palladium(II) chloride (4.23 g, 5.78 mmol) and 1,4-dioxane / water (120 mL / 40 mL) were added successively into a 500 mL three-necked flask under nitrogen atmosphere, and then the reaction system was warmed to 100 °C and reacted for 8 h. After the reaction was completed, the reaction system was cooled to room temperature and filtered to remove the solids. The filtrate was poured into water, and EA (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by column chromatography (ethyl- acetate:petroleum ether = <com:Math><semantics>1:200<annotation encoding="application / x-tex">1:200< / annotation>< / semantics>< / com:Math>) to give compound 4B in the form of a pale yellow oil (5.4 g, 66% yield). LCMS <com:Math><semantics>m / z=212.1[M+1]<annotation encoding="application / x-tex">m / z = 212.1[M+1]< / annotation>< / semantics>< / com:Math>. Step 2: 2-(1-cyclopropylvinyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline (4C) 4B (4.24 g, 20.09 mmol), (2-methoxypyridin-4-yl)boronic acid (4.61 g, 30.14 mmol), potassium phosphate (12.80 g, 60.27 mmol), <com:Math><semantics>pd(dppf)Cl2<annotation encoding="application / x-tex">pd(dppf)Cl_2< / annotation>< / semantics>< / com:Math> (2.20 g, 3.01 mmol) and DMF (60 mL) were added successively into a 100 mL three-necked flask under nitrogen atmosphere, and then the reaction system was warmed to 140 °C and reacted for 4 h, and then filtered to remove the solids. The filtrate was poured into water, and EA (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by column chromatography (ethyl acetate:petroleum) ether = 1:5) to give compound 4C in the form of a pale yellow oil (330 mg, <com:Math><semantics>5.7%<annotation encoding="application / x-tex">5.7\%< / annotation>< / semantics>< / com:Math> yield). LCMS <com:Math><semantics>m / z=285.1[M+1]<annotation encoding="application / x-tex">m / z = 285.1[M+1]< / annotation>< / semantics>< / com:Math>. Step 3: 2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline (4D) 4C (170 mg, 0.60 mmol), Pd / C (25.5 mg, 0.15% w / w) and methanol / tetrahydrofuran (5 mL / 10 mL) were added into a 100 mL round-bottomed flask, and then purge with hydrogen was performed 3 times. The reaction system was then reacted at 45 °C for 3 h under hydrogen atmosphere. After the reaction was completed as detected by TLC, the reaction system was filtered to remove the solids, and the organic solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography to give 4D in the form of a pale yellow oil (155 mg, 90.6% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.23<annotation encoding="application / x-tex">\delta = 8.23< / annotation>< / semantics>< / com:Math> (d, 1H), 7.04 (dd, 1H), 6.94 (dd, 1H), 6.85 (s, 1H), 6.81 (dd, 1 H), 3.89 (s, 3H), 2.65–2.61 (m, 1H), 1.23–1.16 (m, 3H), 0.94–0.85 (m, 1H), 0.42– <com:Math><semantics>0.38(m,2H),0.10−0.08(m,2H);LCMSm / z=287.2[M+1].<annotation encoding="application / x-tex">0.38 (m, 2H), 0.10-0.08 (m, 2H); LCMS m / z = 287.2[M+1].< / annotation>< / semantics>< / com:Math> Step 4: <com:Math><semantics>N−((2−(1−cyclopropylethyl)−4−fluoro−6−(2−methoxypyridin−4−yl)phenyl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">N-((2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 4) 4D (155 mg, 0.54 mmol), triethylamine (66 mg, 0.65 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (64 mg, 0.22 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (111 mg, 0.54 mmol) and sodium methoxide (59 mg, 1.08 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100) mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative medium pressure liquid chromatography to give compound 4 in the form of a yellow solid (70 mg, 25.0% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> = 8.07 (d, 1 H), 7.49 (s, 1H), 7.38 (s, 1H), 7.08 (dd, 1H), 6.97–6.94 (m, 2H), 6.79 (s, 1H), 6.57 (br, 1H), 4.93 (s, 1H), 3.86 (s, 3H), 2.68–2.57 (m, 1H), 1.36 (s, 6H), 1.24 (s, 3H), 0.87–0.81 (m, 1H), 0.40–0.35 (m, 2H), 0.05–0.04 (m, 2H); LCMS <com:Math><semantics>m / z=518.2[M+1].<annotation encoding="application / x-tex">m / z = 518.2[M+1].< / annotation>< / semantics>< / com:Math> Example 5 <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)furan-2-sulfonamide (Compound 5) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)furan-2-sulfonamide (Compound 5) Intermediate 8 (745 mg, 3.7 mmol), triethylamine (450 mg, 4.45 mmol) and tetrahydrofuran (30 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (440 mg, 1.48 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (111 mg, 0.54 mmol) and sodium methoxide (59 mg, 1.08 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 45%) to give compound 5 in the form of a white solid (320 mg, 20.0% yield, ee%: 98.46%, chiral HPLC (OZ); mobile phase: <com:Math><semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics>< / com:Math>-hexane / ethanol = 90 / 10; column temperature: 35 °C; column pressure: 80 bar; flow rate: 0.8 mL / min; detector signal channel: 215 nm@4.8 nm; wavelength of diode array detector: 200-400 nm; RT = 14.707 min). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.68<annotation encoding="application / x-tex">\delta = 7.68< / annotation>< / semantics>< / com:Math> (br, 1H), 7.53 (s, 1H), 7.11 (d, 1H), 7.02 (d, 1H), 6.81 (br, 1H), 5.00 (s, 1H), 2.81 (t, 2H), 2.71–2.53 (m, 2H), 2.30–2.16 (m, 1H), 1.91 (t, 2H), 1.36 (s, 6H), 1.11 (d, 3H), 1.00–0.86 (m, 1H), 0.51–0.38 (m, 1H), 0.27–0.14 (m, 1H), 0.12–0.06 (m, 1H), <com:Math><semantics>0.04−0.01<annotation encoding="application / x-tex">0.04-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = <com:Math><semantics>433.2<annotation encoding="application / x-tex">433.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 6 <com:Math><semantics>(RS,RC)<annotation encoding="application / x-tex">(R_S, R_C)< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>(SS,RC)<annotation encoding="application / x-tex">(S_S, R_C)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((5−(−1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">((5-(-1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-4- (2-hydroxypropan-2-yl)furan-2-sulfonimidamide (Compounds 6-1 and 6-2) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(R)−N′−(tert−butyldimethylsilyl)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−<annotation encoding="application / x-tex">(R)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-< / annotation>< / semantics>< / com:Math> yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (6A) Intermediate 8 (3.1 g, 15.4 mmol), triethylamine (1.87 g, 18.5 mmol) and tetrahydrofuran (100 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (1.83 g, 6.2 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Intermediate 2 (4.9) g, 15.4 mmol) and sodium methoxide (1.66 g, 30.8 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, compound 6A was obtained and was directly used in the next step without purification. LCMS <com:Math><semantics>m / z=546.3[M+1]<annotation encoding="application / x-tex">m / z = 546.3[M+1]< / annotation>< / semantics>< / com:Math>. Step 2: <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)furan-2-sulfonimidamide (6B) Tetrabutylammonium fluoride (6.2 mL, 61.6 mmol, 1 M in THF) was added to the reaction system from the previous step, and the resulting reaction system was reacted overnight at room temperature. After the reaction was completed as detected by TLC, the reaction system was poured into water and extracted with ethyl acetate (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, washed once with 1 M diluted HCl, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 50%) to give 6B in the form of a transparent solid (1.2 g, 18.2% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 432.2[M+1]. Step 3: <com:Math><semantics>(RS,RC)<annotation encoding="application / x-tex">(R_S, R_C)< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>(SS,RC)<annotation encoding="application / x-tex">(S_S, R_C)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((5−(−1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">((5-(-1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-4- (2-hydroxypropan-2-yl)furan-2-sulfonimidamide (Compounds 6-1 and 6-2) 6B was resolved by SFC to give compound 6-1 (537 mg, 44.8% yield, RT = <com:Math><semantics>14.041<annotation encoding="application / x-tex">14.041< / annotation>< / semantics>< / com:Math> min, ee%: 98.80%) and compound 6-2 (1.23 g, 47% yield, RT = <com:Math><semantics>17.846<annotation encoding="application / x-tex">17.846< / annotation>< / semantics>< / com:Math> min, ee%: 99.38%). Chiral HPLC (OZ), mobile phase: <com:Math><semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics>< / com:Math>-hexane / ethanol = 90 / 10; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; wavelength of diode array detector: 200-400 nm. Compound 6-1: HNMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.23<annotation encoding="application / x-tex">\delta = 8.23< / annotation>< / semantics>< / com:Math> (br, 1H), 7.67 (s, 1H), 7.62 (br, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.96 (br, 1H), 5.09 (s, 1H), 2.82 (t, 2H), 2.71–2.62 (m, 2H), 2.33– 2.19 (m, 1H), 1.94–1.91 (m, 2H), 1.38 (s, 6H), 1.09 (d, 3H), 0.98–0.91 (m, 1H), 0.48–0.45 (m, 1H), <com:Math><semantics>0.23−0.20<annotation encoding="application / x-tex">0.23-0.20< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.13−0.10<annotation encoding="application / x-tex">0.13-0.10< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.06−0.05<annotation encoding="application / x-tex">0.06-0.05< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = <com:Math><semantics>432.2<annotation encoding="application / x-tex">432.2< / annotation>< / semantics>< / com:Math>[M+1]. Compound 6-2: HNMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.24<annotation encoding="application / x-tex">\delta = 8.24< / annotation>< / semantics>< / com:Math> (br, 1H), 7.67 (s, 1H), 7.62 (br, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.96 (br, 1H), 5.09 (s, 1H), 2.82 (t, 2H), 2.73–2.61 (m, 2H), 2.29– 2.18 (m, 1H), 1.94–1.91 (m, 2H), 1.38 (s, 6H), 1.09 (d, 3H), 0.96–0.94 (m, 1H), 0.48–0.45 (m, 1H), <com:Math><semantics>0.23−0.20<annotation encoding="application / x-tex">0.23-0.20< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.13−0.10<annotation encoding="application / x-tex">0.13-0.10< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.06−0.05<annotation encoding="application / x-tex">0.06-0.05< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = <com:Math><semantics>432.2<annotation encoding="application / x-tex">432.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 7 <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)furan-2-sulfonamide (Compound 7) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)furan-2-sulfonamide (Compound 7) Intermediate 9 (770 mg, 3.83 mmol), triethylamine (464 mg, 4.60 mmol) and tetrahydrofuran (30 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (455 mg, 1.53 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (785) mg, 3.83 mmol) and sodium methoxide (414 mg, 7.66 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 45%) to give compound 7 in the form of a transparent solid (300 mg, 18.1% yield, ee%: 98.9%, chiral HPLC (OZ); mobile phase: n-hexane / ethanol = 90 / 10; column temperature: 35 °C; column pressure: 80 bar; flow rate: 0.8 mL / min; detector signal channel: 215 nm@4.8 nm; wavelength of diode array detector: 200-400 nm; RT = 15.935 min). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.80<annotation encoding="application / x-tex">\delta = 7.80< / annotation>< / semantics>< / com:Math> (br, 1H), 7.63 (s, 1H), 7.12 (d, 1H), 7.02 (d, 1H), 6.95-6.91 (m, 1H), 5.05 (s, 1H), 2.81 (t, 2H), 2.60-2.56 (m, 2H), 2.25-2.14 (m, 1H), 1.99-1.89 (m, 2H), 1.37 (s, 6H), 1.11 (d, 3H), 0.96–0.89 (m, 1H), 0.48–0.42 (m, 1H), 0.24–0.17 (m, 1H), <com:Math><semantics>0.11−0.06<annotation encoding="application / x-tex">0.11-0.06< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.03−0.05<annotation encoding="application / x-tex">0.03-0.05< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = <com:Math><semantics>433.2<annotation encoding="application / x-tex">433.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 8 <com:Math><semantics>(RS,SC)<annotation encoding="application / x-tex">(R_S, S_C)< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>(SS,SC)<annotation encoding="application / x-tex">(S_S, S_C)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((5−(1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">((5-(1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)furan-2-sulfonimidamide (Compounds 8-1 and 8-2) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(S)−N′−(tert−butyldimethylsilyl)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">(S)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4- yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (8A) Intermediate 9 (2.60 g, 12.9 mmol), triethylamine (1.57 g, 15.5 mmol) and tetrahydrofuran (100 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (1.54 g, 5.2 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Intermediate 2 (4.10 g, 12.9 mmol) and sodium methoxide (1.40 g, 25.8 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, compound 8A was obtained and was directly used in the next step without purification. LCMS <com:Math><semantics>m / z(ESI)=546.3[M+1]<annotation encoding="application / x-tex">m / z(ESI) = 546.3[M+1]< / annotation>< / semantics>< / com:Math>. Step 2: <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)furan-2-sulfonimidamide (Compound 8B) Tetrabutylammonium fluoride (5.2 mL, 51.7 mmol, 1 M / THF) was added to the reaction system. from the previous step, and the resulting reaction system was reacted overnight at room temperature. After the reaction was completed as detected by TLC, the reaction system was poured into water and extracted with ethyl acetate (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, washed once with 1 M diluted HCl, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 50%) to give 8B in the form of a transparent solid (2.6 g, 46.6% yield). LCMS <com:Math><semantics>m / z=432.2[M+1]<annotation encoding="application / x-tex">m / z = 432.2[M+1]< / annotation>< / semantics>< / com:Math>. Step 3: <com:Math><semantics>(RSr,SC)<annotation encoding="application / x-tex">(R_{S_r}, S_C)< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>(SSr,SC)<annotation encoding="application / x-tex">(S_{S_r}, S_C)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((5−(1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">((5-(1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)furan-2-sulfonimidamide (Compounds 8-1 and 8-2) 8B was resolved by SFC to give compound 8-1 (1.17 g, 45% yield, ee%: 99.70%, chiral HPLC (OZ); mobile phase: <com:Math><semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics>< / com:Math>-hexane / ethanol = 90 / 10; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 nm; <com:Math><semantics>RT=14.463<annotation encoding="application / x-tex">RT = 14.463< / annotation>< / semantics>< / com:Math> min) and compound 8-2 (1.23g, 47% yield, ee%: 99.66%, chiral HPLC (OZ); mobile phase: n-hexane / ethanol = 90 / 10; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: <com:Math><semantics>400 nm<annotation encoding="application / x-tex">400 \text{ nm}< / annotation>< / semantics>< / com:Math>; RT = <com:Math><semantics>19.375 min<annotation encoding="application / x-tex">19.375 \text{ min}< / annotation>< / semantics>< / com:Math>). Compound 8-1: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.24<annotation encoding="application / x-tex">\delta = 8.24< / annotation>< / semantics>< / com:Math> (br, 1H), 7.67 (s, 1H), 7.62 (br, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.97 (br, 1H), 5.09 (s, 1H), 2.82 (t, 2H), 2.74–2.66 (m, 2H), 2.28– 2.19 (m, 1H), 1.94–1.91 (m, 2H), 1.38 (s, 6H), 1.11 (d, 3H), 0.98–0.85 (m, 1H), 0.48–0.43 (m, 1H), <com:Math><semantics>0.23−0.14<annotation encoding="application / x-tex">0.23-0.14< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.11−0.08<annotation encoding="application / x-tex">0.11-0.08< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.04−0.0<annotation encoding="application / x-tex">0.04-0.0< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z = <com:Math><semantics>432.2<annotation encoding="application / x-tex">432.2< / annotation>< / semantics>< / com:Math>[M+1]. Compound 8-2: HNMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.24<annotation encoding="application / x-tex">\delta = 8.24< / annotation>< / semantics>< / com:Math> (br, 1H), 7.67 (s, 1H), 7.64 (br, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.97 (br, 1H), 5.09 (s, 1H), 2.82 (t, 2H), 2.71–2.62 (m, 2H), 2.28– 2.19 (m, 1H), 1.99–1.91 (m, 2H), 1.38 (s, 6H), 1.09 (d, 3H), 0.96–0.94 (m, 1H), 0.47–0.45 (m, 1H), <com:Math><semantics>0.22−0.20<annotation encoding="application / x-tex">0.22-0.20< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.12−0.10<annotation encoding="application / x-tex">0.12-0.10< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.04−0.0<annotation encoding="application / x-tex">0.04-0.0< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z = <com:Math><semantics>432.2<annotation encoding="application / x-tex">432.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 9 <com:Math><semantics>N−((5−(1−cyclopropylethyl)−7−fluoro−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 9) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (9B) 9A (25.0 g, 109.15 mmol) and methanol (300 mL) were added successively into a 1000 mL round-bottomed flask under nitrogen atmosphere, and then sodium borohydride (8.3 g, 218.3 mmol) was added slowly in an ice bath. The reaction system was warmed to room temperature and reacted for 2 h after the addition was completed. After the reaction was completed, the reaction system was poured into ice water and filtered to give compound 9B in the form of a white solid (23.8 g, 94% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.50<annotation encoding="application / x-tex">\delta = 7.50< / annotation>< / semantics>< / com:Math> (dd, 1H), 7.00 (t, 1H), 5.42 (br, 1H), 5.32 (br, 1H), 3.04–2.98 (m, 1H), 2.77–2.70 (m, 1H), 2.34–2.27 (m, 1H), 1.94–1.87 (m, 1H); LCMS m / z (ESI) <com:Math><semantics>=214.0[M−17].<annotation encoding="application / x-tex">= 214.0[M-17].< / annotation>< / semantics>< / com:Math> Step 2: 4-bromo-7-fluoro-2,3-dihydro-1H-indene (9C) 9B (23.0 g, 99.6 mmol), triethylsilane (69.3 g, 597.4 mmol) and dichloromethane (300 mL) are added successively into a 500 mL round-bottomed flask under nitrogen atmosphere, and then trifluoroacetic acid (34.1 g, 298.7 mmol) was added dropwise slowly in an ice bath. The reaction system was warmed to room temperature and reacted for 12 h after the addition was completed. After the reaction was completed, the reaction system was poured into ice water, saturated sodium bicarbonate was added to adjust the pH to alkalinity, and dichloromethane (150 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = <com:Math><semantics>100:1−40:1<annotation encoding="application / x-tex">100:1-40:1< / annotation>< / semantics>< / com:Math>) to give compound 9C in the form of a pale yellow oil (19.4 g, 87.7% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.38<annotation encoding="application / x-tex">\delta = 7.38< / annotation>< / semantics>< / com:Math> (dd, 1H), 6.75 (t, 1H), 2.99 (t, 2H), 2.88 (t, 2H), 2.11– 2.04 (m, 2H). Step 3: Tert-butyl (7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamate (9D) 9C (19.0 g, 88.3 mmol), tert-butyl carbamate (15.5 g, 132.5 mmol), 2-dicyclohexylphosphino- 2,4,6-triisopropylbiphenyl (4.2 g, 8.83 mmol), palladium acetate (992 mg, 4.42 mmol), cesium carbonate (57.6 g, 176.7 mmol) and 1,4-dioxane (200 mL) were added successively into a 500 mL round-bottomed flask under nitrogen atmosphere, and the reaction system was warmed to 100 °C and reacted for 8 h. After the reaction was completed, the reaction system was cooled to room temperature, poured into water and extracted with ethyl acetate (150 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 9D in the form of a pale yellow solid (7.7 g, 34.8% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 195.1[M-56]. Step 4: 7-fluoro-2,3-dihydro-1H-inden-4-amine (9E) 9D (7.7 g, 30.7 mmol) and dichloromethane (100 mL) were added successively into a 250 mL round-bottomed flask under nitrogen atmosphere, and trifluoroacetic acid (25 mL) was added dropwise in an ice bath. The reaction system was reacted at room temperature for 3 h after the dropwise addition was completed. After the reaction was completed, the reaction system was poured into water, saturated sodium bicarbonate was added to adjust the pH, and dichloromethane (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by preparative medium pressure liquid chromatography to give compound 9E in the form of a pale yellow oil (3.9 g, 84.7% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=6.63<annotation encoding="application / x-tex">\delta = 6.63< / annotation>< / semantics>< / com:Math> (t, 1H), <com:Math><semantics>6.37<annotation encoding="application / x-tex">6.37< / annotation>< / semantics>< / com:Math>–<com:Math><semantics>6.34<annotation encoding="application / x-tex">6.34< / annotation>< / semantics>< / com:Math> (dd, 1H), <com:Math><semantics>4.68<annotation encoding="application / x-tex">4.68< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>2.80<annotation encoding="application / x-tex">2.80< / annotation>< / semantics>< / com:Math> (t, 2H), 2.65 (t, 2H), <com:Math><semantics>2.04−1.97<annotation encoding="application / x-tex">2.04-1.97< / annotation>< / semantics>< / com:Math> (m, 2H); LCMS m / z (ESI) = <com:Math><semantics>152.1<annotation encoding="application / x-tex">152.1< / annotation>< / semantics>< / com:Math>[M+1]. Step 5: (4-amino-7-fluoro-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone (9F) Compound 9E (3.9 g, 25.8 mmol) was dissolved in 1,2-dichloroethane (50 mL) in a 250 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. A solution of boron trichloride (28 mL, 1 M, 28.4 mmol) in dichloromethane was then added dropwise slowly, and the temperature was maintained and the resulting solution was reacted for 10 min after the dropwise addition was completed. Aluminum trichloride (7.5 g, 30.9 mmol) and cyclopropyl cyanide (2.6 g, 38.7 mmol) were then added, and the reaction system was warmed to 80 °C, reacted for 4 h and then cooled to room temperature. 2 M HCI (28 mL) was added in an ice bath, and the resulting reaction system was warmed to reflux and reacted for 1 h. After the reaction was completed, the reaction system was cooled to room temperature and extracted with DCM (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3). The organic phase was washed with 2 M sodium hydroxide solution (28 mL), dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 9F in the form of a white solid (4.8 g, 86.3% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.68<annotation encoding="application / x-tex">\delta = 7.68< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>6.78<annotation encoding="application / x-tex">6.78< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>2.90<annotation encoding="application / x-tex">2.90< / annotation>< / semantics>< / com:Math> (t, 2H), <com:Math><semantics>2.80<annotation encoding="application / x-tex">2.80< / annotation>< / semantics>< / com:Math>–<com:Math><semantics>2.77<annotation encoding="application / x-tex">2.77< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.72(t,2H),2.12−2.05(m,2H),0.95−0.89(m,4H);LCMSm / z(ESI)=220.1[M+1].<annotation encoding="application / x-tex">2.72 (t, 2H), 2.12-2.05 (m, 2H), 0.95-0.89 (m, 4H); LCMS m / z(ESI) = 220.1[M+1].< / annotation>< / semantics>< / com:Math> Step 6: 5-(1-cyclopropylvinyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine (9G) CA Compound methyl triphenyl phosphonium bromide (15.7 g, 43.8 mmol) was dissolved in THF (100 mL) in a 250 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. Potassium tert-butoxide (4.9 g, 43.8 mmol) was added slowly, and the temperature was maintained and the reaction system was reacted for 30 min. Compound 9F (7.0 g, 21.9 mmol) was added, and the resulting reaction system was reacted at room temperature for 4 h. After the reaction was completed, water was added to quench the reaction, and EA (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 9G in the form of a pale yellow oil (4.6 g, 95% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.49 (d, 1H), 5.17 (s, 1H), 4.83 (s, 1H), 4.28 (s, 2H), 2.81 (t, 2H), 2.69 (t, 2H), 2.07–1.98 (m, 2H), 1.61–1.57 (m, 1H), 0.71–0.66 (m, 2H), 0.42–0.39 (m, 2H); LCMS <com:Math><semantics>m / z(ESI)=218.1[M+1]<annotation encoding="application / x-tex">m / z(ESI) = 218.1[M+1]< / annotation>< / semantics>< / com:Math>. Step 7: 5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine (9H) Compound 9G (1.0 g, 4.59 mmol) and Pd / C (20 mg, <com:Math><semantics>w / w=5%<annotation encoding="application / x-tex">w / w = 5\%< / annotation>< / semantics>< / com:Math>, Pd content 10%) were dissolved in a mixed solvent of tetrahydrofuran / methanol (10 / 5 mL) in a 250 mL three-necked flask, and the solution was reacted at room temperature for 15 min under hydrogen atmosphere. After the reaction was completed, Pd / C was removed by filtration, and the organic solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography to give compound 9H in the form of a pale yellow oil (343 mg, 34.3%) yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.74 (d, 1H), 4.34 (s, 2H), 2.79 (t, 2H), 2.68–2.65 (m, 2H), 2.25–2.20 (m, 1H), 2.05–1.97 (m, 2H), 1.13 (d, 3H), 1.02–0.94 (m, 1H), 0.51–0.45 (m, 1H), <com:Math><semantics>0.37−0.30 (m, 1H),0.19−0.13 (m, 1H),0.06−0.01 (m, 1H);LCMSm / z(ESI)=220.1[M+1].<annotation encoding="application / x-tex">0.37-0.30 \text{ (m, 1H)}, 0.19-0.13 \text{ (m, 1H)}, 0.06-0.01 \text{ (m, 1H)}; LCMS m / z(ESI) = 220.1[M+1].< / annotation>< / semantics>< / com:Math> Step 8: <com:Math><semantics>N−((5−(1−cyclopropylethyl)−7−fluoro−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 9) Compound 9H (120 mg, 0.55 mmol), triethylamine (65 mg, 0.66 mmol) and tetrahydrofuran (20 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (65 mg, 0.22 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (113) mg, 0.55 mmol) and sodium methoxide (59 mg, 1.1 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (20 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The crude product was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 45%) to give compound 9 in the form of a white solid (28 mg, 11.3% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> = 7.68 (s, 1H), 7.15 (br, 2H), 6.88 (d, 1H), 6.56 (s, 1H), 4.94 (s, 1H), 2.83 (t, 2H), 2.74–2.64 (m, 2H), 2.32–2.25 (m, 1H), 1.97–1.90 (m, 2H), 1.35 (s, 6H), 1.10 (d, 3H), 0.97–0.88 (m, 1H), 0.448–0.40 (m, 1H), 0.26–0.19 (m, 1H), 0.13–0.01 (m, 2H); LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 451.2[M+1]. Example 10 <com:Math><semantics>N−((5−(1−cyclopropylethyl)−7−fluoro−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonimidamide (Compound 10) CA [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>N′−(tert<annotation encoding="application / x-tex">N'-(tert< / annotation>< / semantics>< / com:Math>-butyldimethylsilyl)-<com:Math><semantics>N−((5−(1−cyclopropylethyl)−7−fluoro−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4- yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (10A) 9H (190 mg, 0.87 mmol), triethylamine (105 mg, 1.04 mmol) and tetrahydrofuran (30 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (103 mg, 0.35 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Intermediate 2 (277) mg, 0.87 mmol) and sodium methoxide (94 mg, 1.74 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, compound 10A was obtained and was directly used in the next step without purification. <com:Math><semantics>LCMSm / z=564.3[M+1].<annotation encoding="application / x-tex">LCMS m / z = 564.3[M+1].< / annotation>< / semantics>< / com:Math> Step 2: <com:Math><semantics>N−((5−(1−cyclopropylethyl)−7−fluoro−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonimidamide (Compound 10) Tetrabutylammonium fluoride (3.5 mL, 3.48 mmol, 1 M / THF) was added to the reaction system. from the previous step, and the resulting reaction system was reacted overnight at room temperature. After the reaction was completed as detected by TLC, the reaction system was poured into water and extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, washed once with 1 M diluted HCl, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 50%) to give compound 10 in the form of a transparent solid (95 mg, 23.4% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.18<annotation encoding="application / x-tex">\delta = 8.18< / annotation>< / semantics>< / com:Math> (br, 1H), 7.64 (s, 1H), 7.45 (br, 1H), 6.94 (s, 1H), 6.91 (s, 1H), 5.08 (s, 1H), 2.84 (t, 2H), 2.71-2.66 (m, 2H), 2.28-2.17 (m, 1 H), 2.01–1.92 (m, 2H), 1.37 (s, 6H), 1.09 (t, 3H), 0.96–0.91 (m, 1H), 0.48–0.40 (m, 1H), <com:Math><semantics>0.25−0.20<annotation encoding="application / x-tex">0.25-0.20< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.16−0.08<annotation encoding="application / x-tex">0.16-0.08< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.04−0.02<annotation encoding="application / x-tex">0.04-0.02< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z(ESI) = 45 <com:Math><semantics>0.2[M+1]<annotation encoding="application / x-tex">0.2[M+1]< / annotation>< / semantics>< / com:Math>. Example 11 <com:Math><semantics>N−((7−cyano−5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 11) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 7-bromo-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (11A) Intermediate 1 (600 mg, 2.98 mmol) and dichloromethane (20 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then pyridinium tribromide (1.0 g, 3.28 mmol) was added dropwise slowly in an ice bath. The reaction system was warmed to room temperature and reacted for 1 h after the addition was completed. After the reaction was completed, the reaction system was added into aqueous sodium sulfite solution to quench the reaction, and dichloromethane (20 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = <com:Math><semantics>10:1−5:1<annotation encoding="application / x-tex">10:1-5:1< / annotation>< / semantics>< / com:Math>) to give compound 11A in the form of a pale yellow oil (446 mg, 53% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.05<annotation encoding="application / x-tex">\delta = 7.05< / annotation>< / semantics>< / com:Math> (s, 1H), 4.67 (s, 2H), 2.77–2.72 (dd, 4H), 2.24–2.20 (m, 1H), 2.03–1.95 (m, 2H), 1.13 (d, 3H), 1.01–0.96 (m, 1H), 0.50–0.47 (m, 1H), 0.36–0.32 (m, 1H), <com:Math><semantics>0.17−0.13<annotation encoding="application / x-tex">0.17-0.13< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.05−0.01<annotation encoding="application / x-tex">0.05-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS(ESI) m / z = <com:Math><semantics>280.0[M+1]<annotation encoding="application / x-tex">280.0[M+1]< / annotation>< / semantics>< / com:Math>. Step 2: 7-amino-6-(1-cyclopropylethyl)-2,3-dihydro-1H-indene-4-carbonitrile (11B) Compound 11A (440 mg, 1.57 mmol), potassium ferrocyanide (266 mg, 0.63 mmol), tetrakis(triphenylphosphine)palladium (182 mg, 0.16 mmol), 1,8-diazabicycloundec-7-ene (24 mg, 0.16 mmol) and a mixed solvent of tert-butanol / water (1:1, 20 mL) were added successively into a 100 mL three-necked flask under nitrogen atmosphere, and the reaction system was warmed to 85 °C, reacted for 6 h, and then cooled to room temperature after the reaction was completed. The reaction system was then poured into water and extracted with ethyl acetate (20 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 11B in the form of a pale yellow oil (304 mg, 85.6% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.30<annotation encoding="application / x-tex">\delta = 7.30< / annotation>< / semantics>< / com:Math> (s, 1H), 5.56 (s, 2H), 2.88 (t, 2H), 2.67 (t, 2H), 2.26– 2.22 (m, 1H), 2.07–1.99 (m, 2H), 1.13 (d, 3H), 1.07–1.02 (m, 1H), 0.52–0.48 (m, 1H), 0.38– <com:Math><semantics>0.34 (m, 1H),0.17−0.14 (m, 1H),0.02−0.01 (m, 1H);LCMSm / z(ESI)=227.2[M+1].<annotation encoding="application / x-tex">0.34 \text{ (m, 1H)}, 0.17-0.14 \text{ (m, 1H)}, 0.02-0.01 \text{ (m, 1H)}; LCMS m / z (ESI) = 227.2[M+1].< / annotation>< / semantics>< / com:Math> Step 3: <com:Math><semantics>N−((7−cyano−5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl)−4−(2<annotation encoding="application / x-tex">N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl)-4-(2< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 11) Compound 11B (116 mg, 0.51 mmol), triethylamine (62 mg, 0.62 mmol) and tetrahydrofuran (20 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (61 mg, 0.20 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (105 mg, 0.55 mmol) and sodium methoxide (55 mg, 1.02 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (20 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 45%) to give compound 11 in the form of a pale yellow solid (60 mg, 27.5% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.83<annotation encoding="application / x-tex">\delta = 7.83< / annotation>< / semantics>< / com:Math> (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.09 (br, 1H), 6.57 (s, 1H), 4.93 (s, 1H), 2.95 (t, 2H), 2.80–2.74 (m, 2H), 2.39–2.32 (m, 1H), 2.03–1.96 (m, 2H), 1.35 (s, 6H), 1.22 (d, 3H), 1.03-0.94 (m, 1H), 0.52-0.44 (m, 1H), 0.29-0.23 (m, 1H), 0.14- <com:Math><semantics>0.10(m,1H),0.07−0.01(m,1H);LCMSm / z(ESI)=458.2[M+1].<annotation encoding="application / x-tex">0.10 (m, 1H), 0.07-0.01 (m, 1H); LCMS m / z(ESI) = 458.2[M+1].< / annotation>< / semantics>< / com:Math> Example 12 <com:Math><semantics>N−((7−cyano−5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonimidamide (Compound 12) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>N′<annotation encoding="application / x-tex">N'< / annotation>< / semantics>< / com:Math>-(tert-butyldimethylsilyl)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1<com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>-inden-4- yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (12A) 11B (200 mg, 0.88 mmol), triethylamine (107 mg, 1.06 mmol) and tetrahydrofuran (30 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (104 mg, 0.35 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Intermediate 2 (280) mg, 0.88 mmol) and sodium methoxide (95 mg, 1.76 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, compound 12A was obtained and was directly used in the next step without purification. LCMS <com:Math><semantics>m / z=571.3[M+1]<annotation encoding="application / x-tex">m / z = 571.3[M+1]< / annotation>< / semantics>< / com:Math>. Step 2: <com:Math><semantics>N−((5−(1−cyclopropylethyl)−7−fluoro−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−1)carbamoyl)−4−(2−1)carbamoyl<annotation encoding="application / x-tex">N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-1)carbamoyl)-4-(2-1)carbamoyl< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonimidamide (Compound 12) Tetrabutylammonium fluoride (3.5 mL, 3.52 mmol, 1 M / THF) was added to the reaction system. from the previous step, and the resulting reaction system was reacted overnight at room temperature. After the reaction was completed as detected by TLC, the reaction system was poured into water and extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, washed once with 1 M diluted HCl, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 50%) to give compound 12 in the form of a transparent solid (160 mg, 39.6% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.62<annotation encoding="application / x-tex">\delta = 8.62< / annotation>< / semantics>< / com:Math> (s, 1H), 7.70 (br, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 6.99 (s, 1H), 5.09 (s, 1H), 2.98 (t, 2H), 2.78–2.67 (m, 2H), 2.32–2.23 (m, 1H), 2.05–2.00 (m, 2H), 1.38 (s, 6H), 1.14–1.09 (dd, 3H), 1.07–0.96 (m, 1H), 0.53–0.44 (m, 1H), 0.26–0.22 (m, 1H), <com:Math><semantics>0.15−0.11<annotation encoding="application / x-tex">0.15-0.11< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.05−0.01<annotation encoding="application / x-tex">0.05-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z(ESI) = <com:Math><semantics>457.2<annotation encoding="application / x-tex">457.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 13 <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)thiazole-2-sulfonamide (Compound 13) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Methyl 2-(benzylthio)thiazole-4-carboxylate (13B) Compound 13A (25.0 g, 112.58 mmol), DMF (150 mL), potassium carbonate (46.7 g, 150.16 mmol) and benzyl mercaptan (14.3 g, 114.84 mmol) were added successively into a 500 mL three-necked flask under nitrogen atmosphere, and the reaction system was stirred overnight at room temperature. After the reaction was completed as determined by TLC, water was added to the reaction system in an ice bath, and EA was added for extraction 3 times. The organic phases were combined, washed with saturated brine 3 times, dried and concentrated, and the residue was separated by column chromatography to give compound 13B in the form of a pale yellow wax (6.5 g, 22% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=8.44<annotation encoding="application / x-tex">\delta = 8.44< / annotation>< / semantics>< / com:Math> (s, 1H), 7.45 (d, 1H), 7.43 (t, 1H), 7.37–7.24 (m, 3H), <com:Math><semantics>4.52(s,2H),3.83(s,3H);LCMSm / z(ESI)=266.0[M+1].<annotation encoding="application / x-tex">4.52 (s, 2H), 3.83 (s, 3H); LCMS m / z (ESI) = 266.0[M+1].< / annotation>< / semantics>< / com:Math> Step 2: Methyl 2-sulfamoylthiazole-4-carboxylate (13C) Compound 13B (2.5 g, 9.42 mmol) was added into a 100 mL three-necked flask, and then glacial acetic acid (20 mL) was added. The reaction system was stirred until it was clarified, and then water (10 mL) was added, followed by addition of N-chlorosuccinimide (6.3 g, 47.11 mmol). The reaction system was stirred for 3 h at room temperature. After the reaction was completed as detected by TLC, the reaction system was extracted with water and ethyl acetate for 3 times. The organic phases were combined, dried and concentrated by rotary evaporation to give the crude product. The crude product was dissolved in acetone until the solution was clarified, and the solution was then stirred for 10 min in an ice bath. Ammonium bicarbonate (6.5 g, 24.54 mmol) was added, the temperature was maintained and the reaction system was stirred for 2 h. After the reaction was completed as determined by TLC, water was added into the reaction system, and DCM was added for extraction 3 times. The organic phases were combined, dried and concentrated by rotary evaporation, and the residue was separated by column chromatography to give compound 13C in the form of a pale yellow solid (210 mg, 10%) yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=8.79<annotation encoding="application / x-tex">\delta = 8.79< / annotation>< / semantics>< / com:Math> (s, 1H), 8.30 (s, 2H), 3.87 (s, 3H); LCMS m / z (ESI) <com:Math><semantics>=222.9[M+1].<annotation encoding="application / x-tex">= 222.9[M+1].< / annotation>< / semantics>< / com:Math> Step 3: 4-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (13D) Compound 13C (210 mg, 0.94 mmol) and THF (10 mL) were added into a 50 mL three-necked flask under nitrogen atmosphere, and the reaction system was cooled to -10 °C in an ice salt bath. A solution of methylmagnesium bromide in tetrahydrofuran (34 mL, 34 mmol, 1 M) was added dropwise, and the reaction system was stirred at room temperature for 2 h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (20 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = <com:Math><semantics>20:1<annotation encoding="application / x-tex">20:1< / annotation>< / semantics>< / com:Math>) to give compound 13D in the form of a pale brown oil (194 mg, 92% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.05 (s, 1H), 7.70 (s, 2H), 5.38 (s, 1H), 1.46 (s, 6H); LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 223.1 [M+1]. Step 4: <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)thiazole-2-sulfonamide (Compound 13) Intermediate 8 (120 mg, 0.597 mmol) and triethylamine (114 mg, 0.716 mmol) were dissolved in tetrahydrofuran (10 mL) in a 100 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. Triphosgene (70 mg, 0.239 mmol) was added slowly, the temperature was maintained, and the reaction system was reacted for 5 min. The reaction system was then warmed to 80 °C, reacted for 1 h, and then cooled to room temperature. The reaction system was filtered and the filtrate was collected. Compound 13D (121 mg, 0.597) mmol) and sodium methoxide (64 mg, 1.194 mmol) were dissolved in methanol (10 mL) in a 100 mL single-necked flask, and the solution was stirred at room temperature for 1 h and then concentrated by rotary evaporation to remove methanol. The residue was dissolved in the previously collected filtrate, purge with nitrogen was performed three times, and the resulting mixture was warmed to 80 °C and reacted for 1 h. After the reaction was completed, water (50) mL) was added, and ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative chromatography (acetonitrile / water) = 45%) to give compound 13 in the form of a pale yellow solid (35.0 mg, 13.3% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.35 (br, 1H), 7.06 (d, 1H), 6.95 (d, 1H), 5.37 (s, 1H), 2.78 (t, 2H), 2.68–2.62 (m, 2H), 2.337–2.25 (m, 1H), 1.87 (t, 2H), 1.42 (s, 6H), 1.09 (d, 3H), 0.99–0.88 (m, 1H), 0.51–0.39 (m, 1H)), 0.23–0.16 (m, 1H)), 0.11–0.07 (m, 2H); LCMS <com:Math><semantics>m / z(ESI)=450.1[M+1].<annotation encoding="application / x-tex">m / z(ESI) = 450.1[M+1].< / annotation>< / semantics>< / com:Math> Example 14 <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)thiazole-2-sulfonamide (Compound 14) CA [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)thiazole-2-sulfonamide (Compound 14) Intermediate 9 (120 mg, 0.597 mmol) and triethylamine (114 mg, 0.716 mmol) were dissolved in tetrahydrofuran (10 mL) in a 100 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. Triphosgene (70 mg, 0.239 mmol) was added slowly, the temperature was maintained, and the reaction system was reacted for 5 min. The reaction system was then warmed to 80 °C, reacted for 1 h, and then cooled to room temperature. The reaction system was filtered and the filtrate was collected. 13D (121 mg, 0.597 mmol) and sodium methoxide (64 mg, 1.194 mmol) were dissolved in methanol (10 mL) in a 100 mL single-necked flask, and the solution was stirred at room temperature for 1 h and then concentrated by rotary evaporation to remove methanol. The residue was dissolved in the previously collected filtrate, purge with nitrogen was performed three times, and the resulting mixture was warmed to 80 °C and reacted for 1 h. After the reaction was completed, water (50 mL) was added, and ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative chromatography (acetonitrile / water) = 45%) to give compound 14 in the form of a pale yellow solid (30.0 mg, 11.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.19 (br, 1H), 7.06 (d, 1H), 6.96 (d, 1H), 5.16 (s, 1H), 2.79 (t, 2H), 2.68–2.60 (m, 2H), 2.37–2.28 (m, 1H), 1.95–1.82 (m, 2H), 1.42 (s, 6H), 1.09 (d, 3H), 1.01–0.87 (m, 1H), 0.51–0.38 (m, 1H)), 0.29–0.12 (m, 1H)), 0.07–0.02 (m, 2H); LCMS <com:Math><semantics>m / z(ESI)=450.1[M+1]<annotation encoding="application / x-tex">m / z(ESI) = 450.1[M+1]< / annotation>< / semantics>< / com:Math>. Example 15 <com:Math><semantics>N−((5−(1−cyclobutylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 15) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanone (15A) Compound 1a (5.0 g, 37.54 mmol) was dissolved in 1,2-dichloroethane (50 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. A solution of boron trichloride (37.5 mL, 1 M, 37.54 mmol) in dichloromethane was then added dropwise slowly, and the temperature was maintained and the resulting solution was reacted for 10 min after the dropwise addition was completed. Aluminum trichloride (5.5 g, 41.3 mmol) and cyclobutyl cyanide (4.5 g, 56.3 mmol) were then added, and the reaction system was warmed to 80 °C, reacted for 4 h and then cooled to room temperature. 2 M HCl (40 mL) was added in an ice bath, and the resulting reaction system was warmed to reflux and reacted for 1 h. After the reaction was completed, the reaction system was cooled to room temperature and extracted with DCM (75 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3). The organic phase was washed with 2 M NaOH solution (40 mL), dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 15A in the form of a white solid (2.6 g, 32.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ=7.45<annotation encoding="application / x-tex">\delta = 7.45< / annotation>< / semantics>< / com:Math> (d, 1H), 6.56 (d, 1H), 4.00–3.96 (m, 1H), 2.91 (t, 2H), 2.70 (t, 2H), 2.44–2.3 (m, 2H), 2.25 (m, 2H), 2.14–2.08 (m, 2H), 2.07–2.00 (m, 1H), 1.90–1.81 <com:Math><semantics>(m,1H);LCMSm / z(ESI)=216.1[M+1].<annotation encoding="application / x-tex">(m, 1H); LCMS m / z(ESI) = 216.1[M+1].< / annotation>< / semantics>< / com:Math> Step 2: 5-(1-cyclobutylvinyl)-2,3-dihydro-1H-inden-4-amine (15B) Compound methyl triphenyl phosphonium bromide (4.0 g, 11.2 mmol) was dissolved in THF (30 mL) in a 100 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice salt bath. Potassium tert-butoxide (1.3 g, 11.2 mmol) was added slowly, and the temperature was maintained and the reaction system was reacted for 30 min. Compound 15A (1.6 g, 7.43 mmol) was added, and the resulting reaction system was reacted at room temperature for 4 h. After the reaction was completed, water was added to quench the reaction, and EA (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to give compound 15B in the form of a pale yellow oil (1.3 g, 82.0% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ=6.80<annotation encoding="application / x-tex">\delta = 6.80< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>6.66<annotation encoding="application / x-tex">6.66< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>5.27<annotation encoding="application / x-tex">5.27< / annotation>< / semantics>< / com:Math> (t, 1H), <com:Math><semantics>5.07<annotation encoding="application / x-tex">5.07< / annotation>< / semantics>< / com:Math> (t, 1H), <com:Math><semantics>3.29−1.24<annotation encoding="application / x-tex">3.29-1.24< / annotation>< / semantics>< / com:Math> (m, 1H), 2.92 (t, 2H), 2.74 (t, 2H), 2.16–2.06 (m, 3H), 2.04–1.96 (m, 2H), 1.94–1.88 (m, 1H), <com:Math><semantics>1.87−1.80 (m, 1H),1.75−1.68 (m, 1H);LCMSm / z(ESI)=214.1[M+1].<annotation encoding="application / x-tex">1.87-1.80 \text{ (m, 1H)}, 1.75-1.68 \text{ (m, 1H)}; LCMS m / z(ESI) = 214.1[M+1].< / annotation>< / semantics>< / com:Math> Step 3: <com:Math><semantics>5−(1−cyclobutylethyl)−2,3−dihydro−1H−inden−4−amine(15C)<annotation encoding="application / x-tex">5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-amine (15C)< / annotation>< / semantics>< / com:Math> Compound 15B (1.3 g, 6.10 mmol) was dissolved in methanol (20 mL) in a 50 mL round- bottomed flask, and then the catalyst Pd / C (70 mg) was added. The reaction system was stirred at room temperature for three hours under hydrogen atmosphere. After the reaction was completed, the reaction system was filtered with celite, and the filtrate was concentrated under reduced pressure to remove the organic solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 15C in the form of a pale yellow oil (1.0 g, 76.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ=6.86<annotation encoding="application / x-tex">\delta = 6.86< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>6.68<annotation encoding="application / x-tex">6.68< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>2.90<annotation encoding="application / x-tex">2.90< / annotation>< / semantics>< / com:Math> (t, 2H), <com:Math><semantics>2.74<annotation encoding="application / x-tex">2.74< / annotation>< / semantics>< / com:Math> (t, 2H), <com:Math><semantics>2.69−2.59<annotation encoding="application / x-tex">2.69-2.59< / annotation>< / semantics>< / com:Math> (m, 2H), 2.18–2.08 (m, 3H), 1.98–1.90 (m, 1H), 1.85–1.72 (m, 3H), 1.61–1.55 (m, 1H), 1.11 <com:Math><semantics>(d,3H)<annotation encoding="application / x-tex">(d, 3H)< / annotation>< / semantics>< / com:Math>; LCMS <com:Math><semantics>m / z(ESI)=216.2[M+1]<annotation encoding="application / x-tex">m / z(ESI) = 216.2[M+1]< / annotation>< / semantics>< / com:Math>. CA Step 4: <com:Math><semantics>N−((5−(1−cyclobutylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 15) Compound 15C (200 mg, 0.93 mmol), triethylamine (112 mg, 1.12 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphospene (110 mg, 0.37 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (190 mg, 0.93 mmol) and sodium methoxide (100 mg, 1.86 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 2 h. After the reaction was completed as detected by TLC, water (20 mL) was added to guench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The crude product was purified by preparative medium pressure liquid chromatography to give compound 15 in the form of a yellow solid (100 mg, 24.1% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.54<annotation encoding="application / x-tex">\delta = 7.54< / annotation>< / semantics>< / com:Math> (s, 1H),7.36 (d, 1H), 6.91 (d, 1H), 6.83 (d, 1H), 6.60 (s, 1 H), 4.91 (s, 1H), 2.98–2.94 (m, 1H), 2.79–2.75 (t, 2H), 2.68–2.63 (m, 2H), 2.45–2.41 (m, 1H), 2.05–2.02 (m, 1H), 1.90–1.86 (m, 2H), 1.78–1.59 (m, 4H), 1.49–1.46 (m, 1H), 1.34 (s, 6H), <com:Math><semantics>0.96<annotation encoding="application / x-tex">0.96< / annotation>< / semantics>< / com:Math> (d, 3H); LCMS m / z(ESI) = <com:Math><semantics>447.2<annotation encoding="application / x-tex">447.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 16 <com:Math><semantics>N−((5−(1−cyclobutylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonimidamide (Compound 16) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>N−(tert−buty|dimethy|sily|)−N′−((5−(1−cyclobuty|ethy|)−2,3−dihydro−1H−inden−4−y|)carbamoy|)−1<annotation encoding="application / x-tex">N-(tert-buty|dimethy|sily|)-N'-((5-(1-cyclobuty|ethy|)-2,3-dihydro-1H-inden-4-y|)carbamoy|)-1< / annotation>< / semantics>< / com:Math> 4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (16A) Compound 15C (200 mg, 0.93 mmol), triethylamine (112 mg, 1.12 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (110 mg, 0.37 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Intermediate 2 (296 mg, 0.93 mmol) and sodium methoxide (100 mg, 1.86 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (50 mL) was added to guench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The crude product was purified by thin layer chromatography to give Compound 16A in the form of a pale yellow oily solid (320 mg, 61.5%) yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 560.3[M+1]. Step 2: <com:Math><semantics>N−((5−(1−cyclobutylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonimidamide (Compound 16) Compound 16A (320 mg, 0.57 mmol) and THF (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then the reaction system was cooled to 0 °C in an ice bath. Tetrabutylammonium fluoride (1.14 mL, 1 M in THF, 1.14 mmol) was then added dropwise slowly, and the reaction system was warmed to room temperature and reacted for 2 h after the dropwise addition was completed. After the reaction was completed, water was added to guench the reaction, and EA (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography to give compound 16 in the form of a white solid (100 mg, 43.8% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.33<annotation encoding="application / x-tex">\delta = 8.33< / annotation>< / semantics>< / com:Math> (s, 1H), 7.66 (s, 1H), 7.65 (br, 2H), 6.98 (d, 2H), 6.88 (d, 1H), 5.09 (br, 1H), 2.92–2.88 (m, 1H), 2.82–2.78 (t, 2H), 2.66–2.63 (m, 2H), 2.45–2.40 (m, 1H), 2.07–2.05 (m, 1H), 1.93-1.90 (m, 2H), 1.69–1.59 (m, 4H), 1.47–1.42 (m, 1H), 1.34 (s, 6H), <com:Math><semantics>0.96(d,3H);LCMSm / z(ESI)=446.2[M+1].<annotation encoding="application / x-tex">0.96 (d, 3H); LCMS m / z (ESI) = 446.2[M+1].< / annotation>< / semantics>< / com:Math> Example 17 <com:Math><semantics>N−((5−(cyclobutylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 17) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol (17A) Ethanol (20 mL) and compound 15A (2.0 g, 9.30 mmol) were added into a 50 mL round- bottomed flask under nitrogen atmosphere, and then the reaction system was cooled to 0 °C in an ice bath. Sodium borohydride (703 mg, 18.60 mmol) was then added slowly, and the reaction system was warmed to room temperature and reacted for 1 h after the addition was completed. After the reaction was completed, the reaction system was cooled to 0 °C, water (20 mL) was added dropwise to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 17A in the form of a colorless oil (1.8 g, 89% yield). LCMS <com:Math><semantics>m / z(ESI)=200.1[M−17]<annotation encoding="application / x-tex">m / z(ESI) = 200.1[M-17]< / annotation>< / semantics>< / com:Math>. Step 2: 5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine (17B) Compound 17A (1.3 g, 5.98 mmol) and triethylsilane (2.1 g, 17.94 mmol) were dissolved in DCM (20 mL) under nitrogen atmosphere, and then the solution was cooled to 0 °C in an ice bath. Trifluoroacetic acid (3.5 g, 29.90 mmol) was then added dropwise slowly, and the reaction system was reacted overnight at room temperature after the addition was completed. After the reaction was completed, saturated aqueous sodium bicarbonate was added to quench the reaction, and DCM (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 17B in the form of a colorless oil (1.0 g, 83.1% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ=6.83<annotation encoding="application / x-tex">\delta = 6.83< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>6.66<annotation encoding="application / x-tex">6.66< / annotation>< / semantics>< / com:Math> (d, 1H), <com:Math><semantics>2.89<annotation encoding="application / x-tex">2.89< / annotation>< / semantics>< / com:Math> (t, 2H), <com:Math><semantics>2.74<annotation encoding="application / x-tex">2.74< / annotation>< / semantics>< / com:Math> (t, 2H), <com:Math><semantics>2.66−2.62<annotation encoding="application / x-tex">2.66-2.62< / annotation>< / semantics>< / com:Math> (m, 1H), 2.59 (d, 2H), 2.13-2.07 (m, 4H), 1.88-1.83 (m, 2H), 1.77-1.70 (m, 2H); LCMS <com:Math><semantics>m / z(ESI)=201.1[M+1].<annotation encoding="application / x-tex">m / z(ESI) = 201.1[M+1].< / annotation>< / semantics>< / com:Math> Step 3: <com:Math><semantics>N−((5−(cyclobutylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 17) Compound 17B (201 mg, 1.00 mmol), triethylamine (121 mg, 1.20 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (103 mg, 0.40 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (205) mg, 1.00 mmol) and sodium methoxide (108 mg, 2.00 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to guench the reaction, and dichloromethane (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative medium pressure liquid chromatography to give compound 17 in the form of a yellow solid (70 mg, 16.2% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.47<annotation encoding="application / x-tex">\delta = 7.47< / annotation>< / semantics>< / com:Math> (s, 1H), 7.36 (s, 1H), 6.86 (d, 1H), 6.80 (d, 1H), 6.56 (d, 1H), 4.91 (s, 1H), 2.77 (t, 2H), 2.66 (t, 2H), 2.58 (d, 2H), 2.48–2.44 (m, 1H), 1.92–1.89 (m, 2H), 1.88–1.85 (m, 2H), 1.78–1.74 (m, 2H), 1.65–1.58 (m, 2H), 1.34 (s, 6H); LCMS m / z (ESI) <com:Math><semantics>=433.2[M+1].<annotation encoding="application / x-tex">= 433.2[M+1].< / annotation>< / semantics>< / com:Math> Example 18 Rs- and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)furan-2-sulfonimidamide (Compounds 18-1 and 18-2) [Image disponible dans le document PDF, Image available in the PDF document] Compounds 18-1 and 18-2 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>N−(tert−buty|dimethy|sily|)−N′−((5−(cyclobuty|methy|)−2,3−dihydro−1H−inden−4−y|)carbamoy|)−<annotation encoding="application / x-tex">N-(tert-buty|dimethy|sily|)-N'-((5-(cyclobuty|methy|)-2,3-dihydro-1H-inden-4-y|)carbamoy|)-< / annotation>< / semantics>< / com:Math> 4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide (18A) 17B (1.5 g, 7.46 mmol), triethylamine (11.02 g, 8.95 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (882 mg, 2.98 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Intermediate 2 (2.4 g, 7.46) mmol) and sodium methoxide (806 mg, 14.9 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (50 mL) was added to guench the reaction, and DCM (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed to give 18A, which was directly used in the next step without purification. LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 546.3[M+1]. Step 2: <com:Math><semantics>N−((5−(cyclobutylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−1)carbamoyl)−4−(2−hydroxypropan−2−1)carbamoyl<annotation encoding="application / x-tex">N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-1)carbamoyl)-4-(2-hydroxypropan-2-1)carbamoyl< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonimidamide (Compound 18B) Tetrabutylammonium fluoride (15 mL, 1 M in THF, 15 mmol) was added dropwise into the reaction system from the previous step under nitrogen atmosphere, and the resulting reaction system was warmed to room temperature and reacted for 2 h after the dropwise addition was completed. After the reaction was completed, water was added to guench the reaction, and ethyl- acetate (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography to give compound 18B in the form of a white solid (1.43 g, 44.0% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 432.2[M+1]. Step 3: Rs- and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)furan-2-sulfonimidamide (Compounds 18-1 and 18-2) 18B was resolved by SFC to give compound 18-1 (670 mg, ee%: 99.68%, chiral HPLC (OX- 3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 nm; RT = 15.062 min) and compound 18-2 (680 mg, ee%: 99.45%, chiral HPLC (OX-3); mobile phase: methanol; column CA temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: <com:Math><semantics>400 nm<annotation encoding="application / x-tex">400 \text{ nm}< / annotation>< / semantics>< / com:Math>; RT = <com:Math><semantics>10.896 min<annotation encoding="application / x-tex">10.896 \text{ min}< / annotation>< / semantics>< / com:Math>). Compound 18-1: <com:Sup>1< / com:Sup>H NMR(400 MHz, DMSO-d6) <com:Math><semantics>δ=8.30<annotation encoding="application / x-tex">\delta = 8.30< / annotation>< / semantics>< / com:Math> (s, 1H), 7.69 (d, 1H), 7.68 (s, 2H), 6.98 (s, 1H), 6.95 (d, 1H), 6.86 (d, 1H), 5.09 (s, 1H), 2.80 (t, 2H), 2.66 (d, 2H), 2.58 (d, 2H), <com:Math><semantics>2.00−1.84<annotation encoding="application / x-tex">2.00-1.84< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>1.83−1.70<annotation encoding="application / x-tex">1.83-1.70< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.63<annotation encoding="application / x-tex">1.63< / annotation>< / semantics>< / com:Math> (dd, 2H), <com:Math><semantics>1.38<annotation encoding="application / x-tex">1.38< / annotation>< / semantics>< / com:Math> (s, 6H); LCMS m / z (ESI) = 432.2[M+1]. Compound 18-2: <com:Sup>1< / com:Sup>H NMR(400 MHz, DMSO-d6) <com:Math><semantics>δ=8.30<annotation encoding="application / x-tex">\delta = 8.30< / annotation>< / semantics>< / com:Math> (s, 1H), 7.69 (d, 1H), 7.67 (s, 2H), 6.99 (s, 1H), 6.95 (d, 1H), 6.86 (d, 1H), 5.10 (s, 1H), 2.80 (t, 2H), 2.66 (d, 2H), 2.58 (d, 2H), <com:Math><semantics>2.00−1.84<annotation encoding="application / x-tex">2.00-1.84< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>1.83−1.70<annotation encoding="application / x-tex">1.83-1.70< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.63<annotation encoding="application / x-tex">1.63< / annotation>< / semantics>< / com:Math> (dd, 2H), <com:Math><semantics>1.38<annotation encoding="application / x-tex">1.38< / annotation>< / semantics>< / com:Math> (s, 6H); LCMS m / z (ESI) = 432.2[M+1]. Example 19 Rs- and <com:Math><semantics>SS−N−((5−(cyclobutylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−2−(2−<annotation encoding="application / x-tex">S_{S}-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Compounds 19-1 and 19-2) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] # 2FF % Step 1: <com:Math><semantics>N−((1R,2S)−2−hydroxy−2,3−dihydro−1H−inden−1−yl)−2,4,6−trimethylbenzenesulfonamide(19B)<annotation encoding="application / x-tex">N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2,4,6-trimethylbenzenesulfonamide (19B)< / annotation>< / semantics>< / com:Math> Sodium bicarbonate (28.2 g, 33.5 mmol) was dissolved in a mixed solvent of H₂O / THF / EA (1:2:5, 100:200:250 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice bath. Compound 19A (25.0 g, 16.76 mmol) was added with stirring, and the temperature was maintained and the reaction system was reacted for 10 min. 2,4,6-trimethylbenzenesulfonyl chloride (36.7 g, 16.76 mmol) was added, and the reaction system was slowly warmed to room temperature and reacted for 6 h. After the reaction was completed as detected by TLC, the reaction system was poured into water, 1 M HCl was added to adjust the pH to weak acidity, and ethyl acetate (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by slurring with petroleum ether to give compound 19B in the form of a white solid (26.4 g, 59% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 314.1[M+1]. Step 2: <com:Math><semantics>(3aS,8aS)−3−(mesity|sulfony|)−3,3a,8,8a−tetrahydroindeno[1,2−d][1,2,3]oxathiazole<annotation encoding="application / x-tex">(3aS,8aS)-3-(mesity|sulfony|)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole< / annotation>< / semantics>< / com:Math> 2-oxide (19C) 19B (16.3 g, 4.92 mmol) and THF (300 mL) were added into a 500 mL three-necked flask, and the reaction system was cooled to -45 °C. Thionyl chloride (7.3 g, 8.80 mmol) was added dropwise slowly, and the temperature was maintained and the reaction system was reacted for 30 min after the addition was completed. 2,4,6-trimethylpyridine (6.0 g, 9.84 mmol) was then added dropwise slowly. After the dropwise addition was completed, the reaction system was warmed to room temperature slowly and reacted overnight. After the reaction was completed as detected by TLC, the reaction system was poured into ice saturated sodium bicarbonate solution to guench the reaction, and extracted with ethyl acetate (300 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3). The solvent was removed by concentration under reduced pressure, and the residue was slurried with petroleum ether to give the crude product, which was slurried with ice acetonitrile to give compound 19C in the form of a white solid (16.7 g, 90.2% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 378.1[M+1]. Step 3: 2-(thiazol-2-yl)propan-2-ol (19E) 19D (30.0 g, 23.60 mmol) was dissolved in tetrahydrofuran (300 mL) in a 500 mL three-necked flask, and the solution was cooled to -78 °C. A solution of methylmagnesium bromide (9.5 mL, 28.32 mmol, 3 M) in tetrahydrofuran was added dropwise slowly, and the temperature was maintained and the reaction system was reacted for 2 h after the dropwise addition was completed. After the reaction was completed as detected by TLC, saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (300 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = <com:Math><semantics>20:1−5:1<annotation encoding="application / x-tex">20:1-5:1< / annotation>< / semantics>< / com:Math>) to give 19E in the form of a pale yellow oil (20g, 58.8% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 144.0 [M+1]. Step 4: (1R, <com:Math><semantics>2S<annotation encoding="application / x-tex">2S< / annotation>< / semantics>< / com:Math>)-1-((2,4,6-trimethylphenyl)sulfonamido)-2,3-dihydro-1<com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>-inden-2-yl <com:Math><semantics>(S)−2−(2−<annotation encoding="application / x-tex">(S)-2-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)thiazole-5-sulfinate (19F) 19E (15.0 g, 10.42 mmol) was dissolved in tetrahydrofuran (300 mL) in a 500 mL three-necked flask, and the solution was cooled to -78 °C. Lithium diisopropylamide (11 mL, 20.83 mmol, 2 M) was added dropwise slowly, and the temperature was maintained and the reaction system was reacted for 1 h after the dropwise addition was completed. 1 h later, a solution of 19C (39.3 g, 10.42 mmol) in THF was added dropwise slowly, and the temperature was maintained and the reaction system was reacted for 3 h after the dropwise addition was completed. After the reaction was completed as detected by TLC, saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = <com:Math><semantics>20:1−3:1<annotation encoding="application / x-tex">20:1-3:1< / annotation>< / semantics>< / com:Math>) to give 19F in the form of a pale yellow solid (25.0 g, 46.1% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ=7.23−7.15<annotation encoding="application / x-tex">\delta = 7.23-7.15< / annotation>< / semantics>< / com:Math> (m, 3H), 7.11 (d, 1H), 7.00 (s, 2H), 5.40 (d, 1H), 4.63-4.59 (dd, 1H), 4.41-4.38 (m, 1H), 3.09-3.04 (dd, 1H), 2.90 (d, 1H), 2.71 (s, 6H), 2.23 (s, 3H); LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = <com:Math><semantics>521.1[M+1]<annotation encoding="application / x-tex">521.1[M+1]< / annotation>< / semantics>< / com:Math>. Step 5: (S)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfinamide (19G) 19F (25 g, 4.81 mmol) was dissolved in THF (300 mL) in a 500 mL three-necked flask, and the solution was cooled to -78 °C. A solution of lithium bis(trimethylsilyl)amide (5 mL, 14.42 mmol, 3 M) in THF was added dropwise slowly, and the temperature was maintained and the reaction system was reacted for 1 h after the dropwise addition was completed. After the reaction was completed as detected by TLC, saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1–15:1) to give 19G in the form of a pale yellow solid (8.5 g, 86.7% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.76<annotation encoding="application / x-tex">\delta = 7.76< / annotation>< / semantics>< / com:Math> (s, 1H), 6.72 (br, 2H), 6.16 (s, 1H), 1.50 (s, 6H); LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 207.1[M+1]. Step 6: Tert-butyl (S)-<com:Math><semantics>((2−(2−hydroxypropan−2−yl)thiazol−5−yl)sulfinyl)carbamate(19H)<annotation encoding="application / x-tex">((2-(2-hydroxypropan-2-yl)thiazol-5-yl)sulfinyl)carbamate (19H)< / annotation>< / semantics>< / com:Math> 19G (8.0 g, 3.88 mmol) was dissolved in THF (100 mL) in a 250 mL three-necked flask, and the solution was cooled to 0 °C. Potassium <com:Math><semantics>tert<annotation encoding="application / x-tex">tert< / annotation>< / semantics>< / com:Math>-butoxide (5.2 g, 4.67 mmol) was added slowly, and the temperature was maintained and the reaction system was reacted for 30 min after the addition was completed. A solution of di-tert-butyl dicarbonate (8.9 g, 4.07 mmol) in THF was then added dropwise slowly, and the reaction system was warmed to room temperature and reacted for 1 h after the dropwise addition was completed. After the reaction was completed as detected by TLC, water was added to guench the reaction, 1 M HCl was added to adjust the pH to neutrality, and ethyl acetate (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = <com:Math><semantics>2:1<annotation encoding="application / x-tex">2:1< / annotation>< / semantics>< / com:Math>) to give 19H in the form of a pale yellow solid (8.8 g, 74%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> = 10.98 (s, 1H), 8.00 (s, 1H), 6.27 (s, 1H), 1.51 (d, 6H), 1.45 <com:Math><semantics>(s,9H)<annotation encoding="application / x-tex">(s, 9H)< / annotation>< / semantics>< / com:Math>; LCMS m / z (ESI) = 307.1[M+1]. Step 7: Tert-butyl <com:Math><semantics>(amino(2−(2−hydroxypropan−2−yl)thiazol−5−yl)(oxo)−λ6−sulfanylidene)carbamate<annotation encoding="application / x-tex">(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-\lambda^6-sulfanylidene)carbamate< / annotation>< / semantics>< / com:Math> (19I) CA 19H (8.8 g, 2.64 mmol) was dissolved in tetrahydrofuran (100 mL) in a 250 mL three-necked flask, and the solution was cooled to 0 °C. Trichloroisocyanuric acid (215 mg, 0.924 mmol) was added dropwise slowly, and the temperature was maintained and the reaction system was reacted for 10 min after the addition was completed. A solution of ammonia solution (10 mL, 7 M) was then added dropwise slowly, and the temperature was maintained and the reaction system was reacted for 3 h after the dropwise addition was completed. After the reaction was completed as detected by TLC, water was added to quench the reaction, 1 M HCl was added to adjust the pH to neutrality, and ethyl acetate (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = <com:Math><semantics>2:1<annotation encoding="application / x-tex">2:1< / annotation>< / semantics>< / com:Math> to dichloromethane:methanol = <com:Math><semantics>15:1<annotation encoding="application / x-tex">15:1< / annotation>< / semantics>< / com:Math>) to give 191 in the form of a pale yellow solid (1.8 g, 19.6%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.04<annotation encoding="application / x-tex">\delta = 8.04< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>8.03<annotation encoding="application / x-tex">8.03< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.33<annotation encoding="application / x-tex">6.33< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.76<annotation encoding="application / x-tex">5.76< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>1.51<annotation encoding="application / x-tex">1.51< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(d,6H),1.28(s,9H);LCMSm / z(ESI)=322.1[M+1].<annotation encoding="application / x-tex">(d, 6H), 1.28 (s, 9H); LCMS m / z (ESI) = 322.1[M+1].< / annotation>< / semantics>< / com:Math> Step 8: Tert-butyl <com:Math><semantics>((3−(5−(cyclobutylmethyl)−2,3−dihydro−1H−inden−4−yl)ureido)(2−(2−hydroxypropan−<annotation encoding="application / x-tex">((3-(5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)ureido)(2-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)thiazol-5-yl)(oxo)-<com:Math><semantics>λ6<annotation encoding="application / x-tex">\lambda^6< / annotation>< / semantics>< / com:Math>-sulfanylidene)carbamate (Compound 19J) Compound 17B (607 mg, 3.02 mmol), triethylamine (366 mg, 3.62 mmol) and tetrahydrofuran (20 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (61.7 mg, 0.21 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Compound 191 (970 mg, 3.02 mmol) and sodium methoxide (327 mg, 6.04 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 2 h. After the reaction was completed as detected by TLC, water (20 mL) was added to quench the reaction, and DCM (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed to give the crude product compound 19], which was directly used in the next step without purification. Step 9: <com:Math><semantics>N−((5−(cyclobuty|methyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−2−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(cyclobuty|methyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)thiazole-5-sulfonimidamide (Compound 19K) The crude product from the previous step was dissolved in DCM (30 mL) in a 250 mL round- bottomed flask, and then trifluoroacetic acid (3 mL) was added dropwise in an ice bath. After the dropwise addition was completed, the reaction system was reacted at room temperature for 1.5 h. After the reaction was completed as detected by TLC, the reaction system was poured into ice aqueous sodium bicarbonate solution, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by thin layer chromatography (dichloromethane:methanol = <com:Math><semantics>15:1<annotation encoding="application / x-tex">15:1< / annotation>< / semantics>< / com:Math>) to give 19K in the form of a white solid (201 mg, 14.1% yield). LCMS <com:Math><semantics>m / z=449.2[M+1]<annotation encoding="application / x-tex">m / z = 449.2[M+1]< / annotation>< / semantics>< / com:Math>. Step 10: Rs- and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Compounds 19-1 and 19-2) 19K was resolved by SFC to give compound 19-1 (98 mg, ee%: 99.90%, chiral HPLC (OX- 3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 C mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 nm; RT = <com:Math><semantics>9.566<annotation encoding="application / x-tex">9.566< / annotation>< / semantics>< / com:Math> min) and compound 19- 2 (85 mg, ee%: 99.38%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 <com:Math><semantics>nm<annotation encoding="application / x-tex">nm< / annotation>< / semantics>< / com:Math>; RT = 11.442 min). Compound 19-1: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.30<annotation encoding="application / x-tex">\delta = 8.30< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>8.04<annotation encoding="application / x-tex">8.04< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.80<annotation encoding="application / x-tex">7.80< / annotation>< / semantics>< / com:Math> (s, 2H), 6.92 (d, 2H), 6.26 (s, 1H), 2.89–2.82 (m, 2H), 2.77–2.63 (m, 2H), 2.38–2.24 (m, 1H), 2.05– 1.91 (m, 4H), 1.81–1.70 (m, 2H), 1.70–1.67 (m, 2H), 1.60–1.58 (m, 2H), 1.51 (s, 6H); LCMS <com:Math><semantics>m / z=449.2[M+1]<annotation encoding="application / x-tex">m / z = 449.2[M+1]< / annotation>< / semantics>< / com:Math>. Compound 19-2: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.25<annotation encoding="application / x-tex">\delta = 8.25< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>8.02<annotation encoding="application / x-tex">8.02< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.72<annotation encoding="application / x-tex">7.72< / annotation>< / semantics>< / com:Math> (br, 2H), 6.95 (d, 1H), 6.86 (d, 1H), 6.24 (s, H), 2.81 (t, 2H), 2.72–2.64 (m, 2H), 2.61–2.55 (m, 2H), 2.38–2.28 (m, 1H), 1.91–1.89 (m, 4H), 1.80–1.69 (m, 2H), 1.61–1.58 (m, 2H), 1.50 (s, 6H); LCMS <com:Math><semantics>m / z=449.2[M+1]<annotation encoding="application / x-tex">m / z = 449.2[M+1]< / annotation>< / semantics>< / com:Math>. Example 20 <com:Math><semantics>(RS,SC)<annotation encoding="application / x-tex">(R_S, S_C)< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>(SS,SC)<annotation encoding="application / x-tex">(S_S, S_C)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((5−(1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">((5-(1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Compounds 20-1 and 20-2) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Tert-butyl <com:Math><semantics>(N−((5−((S)−1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−2−(2−<annotation encoding="application / x-tex">(N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate (Compound 20A) Intermediate 9 (289 mg, 1.44 mmol), triethylamine (175 mg, 1.73 mmol) and tetrahydrofuran (20 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (171 mg, 0.58 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Compound 191 (462 mg, 1.44 mmol) and sodium methoxide (156 mg, 2.88 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 2 h. After the reaction was completed as detected by TLC, water (20 mL) was added to quench the reaction, and DCM (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed to give the crude product compound 20A, which was directly used in the next step without purification. <com:Math><semantics>N−((5−((S)−1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−2−(2−hydroxypropan−<annotation encoding="application / x-tex">N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)thiazole-5-sulfonimidamide (Compound 20B) The crude product from the previous step was dissolved in DCM (30 mL) in a 250 mL round- bottomed flask, and then TFA (3 mL) was added dropwise in an ice bath. After the dropwise addition was completed, the reaction system was reacted at room temperature for 1.5 h. After the reaction was completed as detected by TLC, the reaction system was poured into ice aqueous sodium bicarbonate solution, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by thin layer chromatography (dichloromethane:methanol = 15:1) to give 20B in the form of a white solid (272 mg, 42.1% yield). Step 3: <com:Math><semantics>(RS,SC)<annotation encoding="application / x-tex">(R_S, S_C)< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>(SS,SC)<annotation encoding="application / x-tex">(S_S, S_C)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((5−(1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">((5-(1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Compounds 20-1 and 20-2) 20B was resolved by SFC to give compound 20-1 (161 mg, ee%: 99.90%, chiral HPLC (OX- 3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 nm; RT = <com:Math><semantics>5.420<annotation encoding="application / x-tex">5.420< / annotation>< / semantics>< / com:Math> min) and compound 20- 2 (89 mg, ee%: 97.76%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 <com:Math><semantics>nm;RT=8.16min).<annotation encoding="application / x-tex">nm; RT = 8.16 min).< / annotation>< / semantics>< / com:Math> Compound 20-1: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.30<annotation encoding="application / x-tex">\delta = 8.30< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>8.04<annotation encoding="application / x-tex">8.04< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.80<annotation encoding="application / x-tex">7.80< / annotation>< / semantics>< / com:Math> (s, 2H), 6.92 (d, 2H), 6.26 (s, 1H), 2.89–2.82 (m, 2H), 2.77–2.63 (m, 2H), 2.38–2.24 (m, 1H), 2.05– 1.91 (m, 4H), 1.81–1.70 (m, 2H), 1.70–1.67 (m, 2H), 1.60–1.58 (m, 2H), 1.51 (s, 6H); LCMS <com:Math><semantics>m / z=449.2[M+1].<annotation encoding="application / x-tex">m / z = 449.2[M+1].< / annotation>< / semantics>< / com:Math> Compound 20-2: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.25<annotation encoding="application / x-tex">\delta = 8.25< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>8.02<annotation encoding="application / x-tex">8.02< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.72<annotation encoding="application / x-tex">7.72< / annotation>< / semantics>< / com:Math> (br, 2H), 6.95 (d, 1H), 6.86 (d, 1H), 6.24 (s, H), 2.81 (t, 2H), 2.72-2.64 (m, 2H), 2.61-2.55 (m, 2H), 2.38–2.28 (m, 1H), 1.91–1.89 (m, 4H), 1.80–1.69 (m, 2H), 1.61–1.58 (m, 2H), 1.50 (s, 6H); LCMS <com:Math><semantics>m / z=449.2[M+1]<annotation encoding="application / x-tex">m / z = 449.2[M+1]< / annotation>< / semantics>< / com:Math>. Example 21 Rs- and <com:Math><semantics>SS−N−((5−(cyclobutylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">S_S-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (Compounds 21-1 and 21-2) [Image disponible dans le document PDF, Image available in the PDF document] Compounds 21-1 and 21-2 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Methyl 2-methyl-5-sulfamoylfuran-3-carboxylate (21B) Compound 21A (40 g, 285.43 mmol) was dissolved in DCM (300 mL) in a 500 mL three- necked flask, and the solution was cooled to -10 °C under nitrogen atmosphere. Chlorosulfonic acid (21 mL, 313.98 mmol) was added dropwise slowly, and the reaction system was stirred at room temperature until the starting material 21A was completely consumed. The reaction system was then cooled to -15 °C, and pyridine (26 mL, 313.98 mmol) was added dropwise slowly. The temperature was maintained at -15 °C, and phosphorus pentachloride (47.6 g, 228.35 mmol) was added in batches. After no starting material was left as detected by TLC, the reaction system was poured into ice water (500 mL) to quench the reaction, and extracted with ethyl acetate (500 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to give the crude product, which was directly used in the next step without purification. The crude product was dissolved in acetone (400 mL), and saturated aqueous ammonium bicarbonate solution (80 g, 1.01 mol) was added slowly. After the addition was completed, the reaction system was reacted at room temperature. After the reaction was completed as detected by TLC, ice water (300 mL) was added to quench the reaction, and EA (300 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to give compound 21B in the form of a white solid <com:Math><semantics>(31.2 g,49.86%)<annotation encoding="application / x-tex">(31.2 \text{ g}, 49.86\%)< / annotation>< / semantics>< / com:Math> yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=7.88<annotation encoding="application / x-tex">\delta = 7.88< / annotation>< / semantics>< / com:Math> (s, 2H), 7.02 (s, 1H), 3.79 (s, 3H), 2.61 (s, 3H). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 220.0[M+1]. Step 2: 4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide (21C) 21B (31.2 g, 142.33 mmol) was dissolved in THF (300 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to -15 °C. Methylmagnesium bromide (150 mL, 455.45 mmol, 3.0 mol / L) was added dropwise slowly, and the reaction system was stirred overnight at room temperature after the dropwise addition was completed. After 21B disappeared as detected by TLC, ammonium chloride (200 mL) was added to guench the reaction, and EA (300 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (ethyl acetate:petroleum ether = <com:Math><semantics>1:10−1:3<annotation encoding="application / x-tex">1:10-1:3< / annotation>< / semantics>< / com:Math>) to give compound 21C in the form of a pale yellow oil (27 g, 86.52% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=7.56<annotation encoding="application / x-tex">\delta = 7.56< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>6.80<annotation encoding="application / x-tex">6.80< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.00<annotation encoding="application / x-tex">5.00< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.40<annotation encoding="application / x-tex">2.40< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.38<annotation encoding="application / x-tex">1.38< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,6H)<annotation encoding="application / x-tex">(s, 6H)< / annotation>< / semantics>< / com:Math>; LCMS m / z (ESI) = 202.1[M-17]. Step 3: <com:Math><semantics>N−(tert−butyldimethylsilyl)−4−(2−hydroxypropan−2−yl)−5−methylfuran−2−sulfonamide(21D)<annotation encoding="application / x-tex">N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide (21D)< / annotation>< / semantics>< / com:Math> 21C (20.0 g, 91.32 mmol) was dissolved in tetrahydrofuran (300 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and the solution was cooled to -10 °C in an ice salt bath. Sodium hydride (7.3 g, 182.44 mmol) was added in batches, and the reaction system was stirred at room temperature for 30 min after the addition was completed. A solution of tert- butyldimethylchlorosilane (20.6 g, 136.83 mmol) in tetrahydrofuran (30 mL) was then added dropwise slowly at this temperature, and the reaction system was reacted at -10 °C for 3 h. After the reaction was completed, water was added to quench the reaction, 2 M HCl was added to adjust the pH to weak acidity, and ethyl acetate (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl- acetate:petroleum ether = 1:3) to give <com:Math><semantics>21D<annotation encoding="application / x-tex">21D< / annotation>< / semantics>< / com:Math> in the form of a white solid (15.0 g, 49.31% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=7.74<annotation encoding="application / x-tex">\delta = 7.74< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.76<annotation encoding="application / x-tex">6.76< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.00<annotation encoding="application / x-tex">5.00< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.39<annotation encoding="application / x-tex">2.39< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.38<annotation encoding="application / x-tex">1.38< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,6H),0.88(s,9H),0.15(s,6H);LCMSm / z(ESI)=334.1[M+1].<annotation encoding="application / x-tex">(s, 6H), 0.88 (s, 9H), 0.15 (s, 6H); LCMS m / z (ESI) = 334.1[M+1].< / annotation>< / semantics>< / com:Math> Step 4: <com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (21E) Triphenylphosphine (8.65 g, 32.98 mmol) and hexachloroethane (8.52 g, 35.98 mmol) were dissolved in chloroform (120 mL) in a 500 mL three-necked flask under nitrogen atmosphere, and the solution was warmed to reflux, reacted for 1 h, and cooled to -10 °C. Diisopropylethylamine (6 g, 46.47 mmol) was added dropwise slowly, and the reaction system was reacted at this temperature for 10 min after the dropwise addition was completed. A solution of 21D (10 g, 29.98 mmol) in chloroform was then added dropwise slowly, and the reaction system was reacted for 30 min after the dropwise addition was completed. Ammonia gas was introduced for 1 h at this temperature. After the reaction was completed as detected by TLC, water was added to guench the reaction, and DCM (120 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl- acetate: petroleum ether <com:Math><semantics>(v / v)=1:5<annotation encoding="application / x-tex">(v / v) = 1:5< / annotation>< / semantics>< / com:Math>) to give the product compound 21E in the form of a white solid (3 g, 30% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.81 (s, 2H), 6.61 (s, 1H), 4.99 (s, 1H), 2.41 (s, 3H), 1.41 (s, 6H), <com:Math><semantics>0.89<annotation encoding="application / x-tex">0.89< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>9H<annotation encoding="application / x-tex">9H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>0.01<annotation encoding="application / x-tex">0.01< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>); LCMS m / z (ESI) = <com:Math><semantics>333.1<annotation encoding="application / x-tex">333.1< / annotation>< / semantics>< / com:Math>[M+1]. Step 5: <com:Math><semantics>N′−(tert−buty|dimethy|sily|)−N−((5−(cyclobuty|methy|)−2,3−dihydro−1H−inden−4−y|)carbamoy|)−1<annotation encoding="application / x-tex">N'-(tert-buty|dimethy|sily|)-N-((5-(cyclobuty|methy|)-2,3-dihydro-1H-inden-4-y|)carbamoy|)-1< / annotation>< / semantics>< / com:Math> 4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (21F) Compound 17B (800 mg, 3.97 mmol), triethylamine (482.56 mg, 4.77 mmol) and tetrahydrofuran (100 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (471.67 mg, 1.59 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Compound 21E (1.32 g, 3.97 mmol) and sodium methoxide (257.64 mg, 4.77 mmol) CA were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, compound 21F was obtained and was directly used in the next step without purification. LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 560.3 [M+1]. Step 6: R- and S-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (21G) Tetrabutylammonium fluoride (5.2 mL, 51.7 mmol, 1 M / THF) was added to the reaction system. from the previous step, and the resulting reaction system was reacted overnight at room temperature. After the reaction was completed as detected by TLC, the reaction system was poured into water and extracted with ethyl acetate (100 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined, washed once with 1 M diluted HCl, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 50%) to give 21G in the form of a transparent solid (180 mg, 10% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 446.2[M+1]. Step 7: Rs- and <com:Math><semantics>Ss−N−((5−(cyclobutylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−<annotation encoding="application / x-tex">Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (Compounds 21-1 and 21-2) 21G was resolved by SFC to give compound 21-1(75 mg, ee%: 99.99%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 nm; RT = 13.716 min) and compound 21-2 (70 mg, ee%: 99.99 %, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 <com:Math><semantics>nm;RT=16.660min).<annotation encoding="application / x-tex">nm; RT = 16.660 min).< / annotation>< / semantics>< / com:Math> Compound 21-1: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.28<annotation encoding="application / x-tex">\delta = 8.28< / annotation>< / semantics>< / com:Math> (s, 1H), 7.58 (s, 2H), 6. 95 (d, 1H), 6.90–6.81 (m, 2H), 5.03 (s, 1H), 2.81 (dd, 2H), 2.71–2.62 (m, 3H), 2.59 (d, 2H), 2.41 (s, 3H), 1.96–1.87 (m, 4H), 1.82–1.73 (m, 2H), 1.67–1.57 (m, 2H), 1.38 (s, 6H); LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 446.2[M+1]. Compound 21-2: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.28<annotation encoding="application / x-tex">\delta = 8.28< / annotation>< / semantics>< / com:Math> (s, 1H), 7.58 (s, 2H), 6. 95 (d, 1H), 6.90–6.80 (m, 2H), 5.03 (s, 1H), 2.81 (dd, 2H), 2.71–2.62 (m, 3H), 2.59 (d, 2H), 2.41 (s, 3H), 1.96–1.86 (m, 4H), 1.82–1.73 (m, 2H), 1.67–1.57 (m, 2H), 1.38 (s, 6H); LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 446.2[M+1]. Example 22 <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)-5-methylfuran-2-sulfonamide (Compound 22) [Image disponible dans le document PDF, Image available in the PDF document] Compound 22 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)-5-methylfuran-2-sulfonamide (Compound 22) Intermediate 8 (201 mg, 1.0 mmol), triethylamine (121 mg, 1.2 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (118.4 mg, 0.4 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Compound 22F (218 mg, 1.0 mmol) and sodium methoxide (108 mg, 2.0 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative high pressure liquid chromatography to give compound 22 in the form of a white solid (120 mg, 26.9% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.80<annotation encoding="application / x-tex">\delta = 7.80< / annotation>< / semantics>< / com:Math> (s, 1H), 7.55 (s, 1H), 7.14 (d, 1H), 7.07 (d, 1H) 4.99 (d, 1H), 2.82 (t, 2H), 2.59 (t, 2H), 2.40 (s, 3H), 2.18–2.13 (m, 1H), 1.96–1.90 (m, 2H), 1.37 (s, 6H), 1.11 (d, 3H), 0.96–0.90 (m, 1H), 0.50–0.41 (m, 1H), 0.23–0.18 (m, 1H), 0.10–0.06 (m, 1H), <com:Math><semantics>0.06−0.01<annotation encoding="application / x-tex">0.06-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z = 447.2[M+1]. Example 23 <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)-5-methylfuran-2-sulfonamide (Compound 23) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)-5-methylfuran-2-sulfonamide (Compound 23) Intermediate 9 (201 mg, 1.0 mmol), triethylamine (121 mg, 1.2 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (118.4 mg, 0.4 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. Compound 22F (218 mg, 1.0 mmol) and sodium methoxide (108 mg, 2.0 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The residue was purified by preparative high pressure liquid chromatography to give compound 23 in the form of a white solid (100 mg, 22.4% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.84<annotation encoding="application / x-tex">\delta = 7.84< / annotation>< / semantics>< / com:Math> (s, 1 H), 7.56 (s, 1H), 7.15 (d, 1H), 7.08 (d, 1H) 5.00 (d, 1H), 2.82 (t, 2H), 2.59 (t, 2H), 2.40 (s, 3H), 2.18–2.13 (m, 1H), 1.96–1.90 (m, 2H), 1.37 (s, 6H), 1.11 (d, 3H), 0.96–0.90 (m, 1H), 0.50–0.41 (m, 1H), 0.23–0.18 (m, 1H), 0.10–0.06 (m, 1H), <com:Math><semantics>0.06−0.01<annotation encoding="application / x-tex">0.06-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z = <com:Math><semantics>447.2<annotation encoding="application / x-tex">447.2< / annotation>< / semantics>< / com:Math>[M+1]. Example 24 Rs- and <com:Math><semantics>SS<annotation encoding="application / x-tex">S_{S}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-((5-(1-cyclopropylethyl)-2,3-dihydro-1<com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (Compounds 24-1 and 24-2) [Image disponible dans le document PDF, Image available in the PDF document] For preparation of compound 24-1 and compound 24-2, reference was made to preparation method of compounds 21-1 and 21-2. Compound 24-1 (310 mg, ee%: 99.5%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 nm; RT = 6.453 min) and compound 24-2 (311 mg, ee%: 97.1%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: <com:Math><semantics>400 nm<annotation encoding="application / x-tex">400 \text{ nm}< / annotation>< / semantics>< / com:Math>; RT = <com:Math><semantics>8.147 min<annotation encoding="application / x-tex">8.147 \text{ min}< / annotation>< / semantics>< / com:Math>). Compound 24-1: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.55 (s, 2H), 7.12 (d, 1H), 7.04 (d, 1H), 6.83 (s, 1H), 5.00 (s, 1H), 2.82 (dd, 2H), 2.75–2.56 (m, 2H), 2.41 (s, 3H), 2.31– 2.19 (m, 1H), 2.01–1.85 (m, 2H), 1.38 (s, 6H), 1.13–1.11 (m, 3H), 0.98–0.88 (m, 1H), 0.50– <com:Math><semantics>0.40 (m, 1H),0.24−0.15 (m, 1H),0.13−0.06 (m, 1H),0.04−0.00 (m, 1H);LCMSm / z(ESI)=<annotation encoding="application / x-tex">0.40 \text{ (m, 1H)}, 0.24-0.15 \text{ (m, 1H)}, 0.13-0.06 \text{ (m, 1H)}, 0.04-0.00 \text{ (m, 1H)}; LCMS m / z (ESI)=< / annotation>< / semantics>< / com:Math> 446.20[M+1]. Compound 24-2: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.21 (s, 1H), 7.56 (s, 2H), 7.13 (d, 1H), 7.04 (d, 1H), 6.82 (s, 1H), 5.00 (s, 1H), 2.82 (t, 2H), 2.75–2.56 (m, 2H), 2.40 (s, 3H), 2.31–2.19 (m, 1H), 1.97–1.89 (m, 2H), 1.38 (s, 6H), 1.11–1.06 (m, 3H), 0.98–0.92 (m, 1H), 0.50–0.40 (m, 1H), <com:Math><semantics>0.24−0.15<annotation encoding="application / x-tex">0.24-0.15< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.13−0.06<annotation encoding="application / x-tex">0.13-0.06< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.04−0.00<annotation encoding="application / x-tex">0.04-0.00< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = 446.20[M+1]. Example 25 <com:Math><semantics>(RSrSCr)<annotation encoding="application / x-tex">(R_{S_r}S_{C_r})< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>(SSrSCr)<annotation encoding="application / x-tex">(S_{S_r}S_{C_r})< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((5−(1−cyclopropylethyl)−2,3−dihydro−1<math>H<annotation encoding="application / x-tex">((5-(1-cyclopropylethyl)-2,3-dihydro-1H< / annotation>< / semantics>< / com:Math>-inden-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (Compounds 25-1 and 25-2) [Image disponible dans le document PDF, Image available in the PDF document] Compounds 25-1 and 25-2 For preparation of compound 25-1 and compound 25-2, reference was made to preparation method of compounds 21-1 and 21-2. Compound 25-1 (290 mg, ee%: 100%, chiral HPLC) (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: <com:Math><semantics>400 nm<annotation encoding="application / x-tex">400 \text{ nm}< / annotation>< / semantics>< / com:Math>; RT = <com:Math><semantics>10.626 min<annotation encoding="application / x-tex">10.626 \text{ min}< / annotation>< / semantics>< / com:Math>) and compound 25-2 (302 mg, ee%: 97.56%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: <com:Math><semantics>400 nm<annotation encoding="application / x-tex">400 \text{ nm}< / annotation>< / semantics>< / com:Math>; RT = <com:Math><semantics>14.722 min<annotation encoding="application / x-tex">14.722 \text{ min}< / annotation>< / semantics>< / com:Math>). Compound 25-1: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.23<annotation encoding="application / x-tex">\delta = 8.23< / annotation>< / semantics>< / com:Math> (s, 1H), 7.56 (s, 2H), 7.12 (d, 1H), 7.03 (d, 1H), 6.82 (s, 1H), 5.01 (s, 1H), 2.82 (t, 2H), 2.75–2.59 (m, 2H), 2.39 (s, 3H), 2.30–2.18 (m, 1H), 1.93 (dd, 2H), 1.38 (s, 6H), 1.13–1.04 (m, 3H), 1.0–0.90 (m, 1H), 0.49–0.42 (m, 1H), <com:Math><semantics>0.25−0.17<annotation encoding="application / x-tex">0.25-0.17< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.13−0.07<annotation encoding="application / x-tex">0.13-0.07< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.06−0.01<annotation encoding="application / x-tex">0.06-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z(ESI) = <com:Math><semantics>446.20<annotation encoding="application / x-tex">446.20< / annotation>< / semantics>< / com:Math>[M+1]. Compound 25-2: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=8.23<annotation encoding="application / x-tex">\delta = 8.23< / annotation>< / semantics>< / com:Math> (s, 1H), 7.57 (s, 2H), 7.13 (d, 1H), 7.04 (d, 1H), 6.83 (s, 1H), 5.02 (s, 1H), 2.82 (dd, 2H), 2.75–2.58 (m, 2H), 2.41 (s, 3H), 2.30– 2.18 (m, 1H), 1.93 (dd, 2H), 1.38 (s, 6H), 1.13–1.07 (m, 3H), 1.0–0.90 (m, 1H), 0.47–0.43 (m, 1H), <com:Math><semantics>0.25−0.17<annotation encoding="application / x-tex">0.25-0.17< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.14−0.08<annotation encoding="application / x-tex">0.14-0.08< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.07−0.01<annotation encoding="application / x-tex">0.07-0.01< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z(ESI) = 446.20[M+1]. Example 26 <com:Math><semantics>(R)−N−((5−(1−cyclopentylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-< / annotation>< / semantics>< / com:Math> 2-yl)furan-2-sulfonamide (Compound 26) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopentyl)methanone (26A) 1a (23.0 g, 172.68 mmol) was dissolved in dichloroethane (300 mL) in a 500 mL thr ee-necked flask, and the solution was cooled to -10 °C under nitrogen atmosphere. A solution of boron trichloride (210 mL, 210 mmol, 1 mol / L) in dichloromethane was a dded dropwise slowly, and the reaction system was reacted at -10 °C for 10 min after the dropwise addition was completed. Anhydrous aluminum chloride (27.6 g, 207.22 mmol) and cyclopentyl cyanide (24.7 g, 259.02 mmol) were added under nitrogen atm osphere, and the reaction system warmed to reflux, and reacted for 4–6 h after the ad dition was completed. The reaction system was cooled to room temperature, and then cooled to -10 °C in an ice salt bath. 1 M diluted HCl (210 mL) was added dropwise, and then the reaction system was warmed to reflux and reacted for 30 min after the dropwise addition was completed. After the reaction was completed as detected by TL C, the reaction system was cooled to room temperature, water (400 mL) was added to quench the reaction, and DCM (300 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under re- duced pressure to remove the organic solvent. The residue was purified by column chr omatography (petroleum ether:ethyl acetate = 10:1) to give 26A in the form of a pale yellow oil (31 g, 78.3% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.66 (d, 1H), 6.96 (s, 2H), 6.50 (d, 1H), 3.78–3.70 (m, 1H), 2.82 (dd, 2H), 2.66 (dd, 2H), 2.05–1.94 (m, 2H), 1.88–1.77 (m, 2H), 1.76 <com:Math><semantics>−1.65<annotation encoding="application / x-tex">-1.65< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.63−1.53<annotation encoding="application / x-tex">1.63-1.53< / annotation>< / semantics>< / com:Math> (m, 4H); LCMS m / z (ESI) = <com:Math><semantics>230.2<annotation encoding="application / x-tex">230.2< / annotation>< / semantics>< / com:Math>[M+1]. Step 2: 5-(1-cyclopentylvinyl)-2,3-dihydro-1H-inden-4-amine (26B) Methyl triphenyl phosphonium bromide (11.7 g, 32.70 mmol) was dissolved in THF (80 mL) in a 1 L three-necked flask under nitrogen atmosphere, and the solution was cooled to 0 °C in an ice bath. Potassium tert-butoxide (3.7 g, 32.70 mmol) was adde d, the temperature was maintained, and the reaction system was reacted for 1 h. 1 h l ater, a solution of 26A (5.0 g, 21.80 mmol) in THF was added dropwise at 0 °C, an d the reaction system was reacted for 3 h at room temperature. After the reaction was completed as detected by TLC, water was added to quench the reaction, and EA (10) <com:Math><semantics>0 mL×3<annotation encoding="application / x-tex">0 \text{ mL} \times 3< / annotation>< / semantics>< / com:Math>) was added for extraction. The organic phase was dried over anhydrous so dium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:20) to give 26B in the for m of a pale yellow oil (4.2 g, 84.73% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=6.64<annotation encoding="application / x-tex">\delta = 6.64< / annotation>< / semantics>< / com:Math> (d, 1H), 6.45 (d, 1H), 5.21 (s, 1H), 4.85 (d, 1H), 4.31 (s, 2H), 2.77 (dd, 2H), 2.65 (dd, 2H), 2.02–1.94 (m, 3H), 1.74–1.66 (m,2) H), <com:Math><semantics>1.65−1.54<annotation encoding="application / x-tex">1.65-1.54< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.55−1.47<annotation encoding="application / x-tex">1.55-1.47< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.42−1.34<annotation encoding="application / x-tex">1.42-1.34< / annotation>< / semantics>< / com:Math> (m, 2H); LCMS m / z (ESI) = 22 8.1 [M+1]. Step 3: <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-amine (26C) 26B (2.1 g, 9.24 mmol) and dichloromethane (30 mL) were added into a 500 mL aut oclave, and then a catalyst ruthenium <com:Math><semantics>[(R)−(−)−2,2′−bis(diphenylphosphino)−1,11−binaphthy<annotation encoding="application / x-tex">[(R)-(-)-2,2'-bis(diphenylphosphino)-1,11-binaphthy< / annotation>< / semantics>< / com:Math> l]diacetate (1.5 g, 1.83 mmol) was added. After the addition was completed, the autoc lave was tightly closed and sealed, purged with nitrogen 3 times, and then purged wit h hydrogen 3 times. The hydrogen was introduced until the pressure gauge on the aut oclave showed 12 atm, and then the reaction system was reacted for 30 h at room te mperature. The reaction system was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give 26C in the form of a pale yellow oil (1.0 g, 47.1) 7% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=6.78<annotation encoding="application / x-tex">\delta = 6.78< / annotation>< / semantics>< / com:Math> (d, 1H), 6.43 (d, 1H), 4.45 (s, 2H), 2.74 (t, 2H), 2.67–2.58 (m, 3H), 2.06–1.92 (m, 3H), 1.85–1.78 (m, 1H), 1.68–1.58 (m, 1H), 1.53–1.38 (m, 4H), 1.29–1.17 (m, 1H), 1.07 (d, 3H), 1.02–0.91 (m, 1H); LCMS m / z <com:Math><semantics>(ESI)=230.2[M+1].<annotation encoding="application / x-tex">(ESI) = 230.2[M+1].< / annotation>< / semantics>< / com:Math> Step 4: <com:Math><semantics>(R)−N−((5−(1−cyclopentylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−1)carbamoyl)−4−(2−hydroxypropan−2−1)carbamoyl)−4−(2−hydroxypropan−2−1)carbamoyl)−4−(2−hydroxypropan−2−1)carbamoyl)−4−(2−hydroxyprop<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-1)carbamoyl)-4-(2-hydroxypropan-2-1)carbamoyl)-4-(2-hydroxypropan-2-1)carbamoyl)-4-(2-hydroxypropan-2-1)carbamoyl)-4-(2-hydroxyprop< / annotation>< / semantics>< / com:Math> -yl)furan-2-sulfonamide (Compound 26) Compound 26C (200 mg, 0.872 mmol), triethylamine (106.0 mg, 1.05 mmol) and tetr ahydrofuran (30 mL) were added successively into a 100 mL round-bottomed flask un der nitrogen atmosphere, and then triphosgene (104.0 mg, 0.349 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filt ered to remove the solids. 2e (179.0 mg, 0.872 mmol) and sodium methoxide (57.0 m g, 1.05 mmol) were added to the filtrate, and the mixture was reacted at room temper ature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the org anic solvent was removed. The crude product was purified by preparative medium pre- ssure liquid chromatography (acetonitrile / water = <com:Math><semantics>45%<annotation encoding="application / x-tex">45\%< / annotation>< / semantics>< / com:Math>) to give compound 26 in the f orm of a white powdered solid (150 mg, 37.35% yield, ee%: 79%, chiral HPLC (OX- 3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flo w rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diod e array detector: 200 nm; stop wavelength of diode array detector: 400 nm; RT = 3.8 54 min). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.95 (s, 1H), 7.78 (s, 1H), 7.22 (s, 1H), 7.08 (d, 1H), 7.02 (d, 1H), 5.11 (s, 1H), 2.82 (dd, 2H), 2.64–2.52 (m, 3H), 1.98–1.88 (m, 3H), 1.84–1.77 (m, 1H), 1.62–1.55 (m,1H), 1.52–1.41 (m, 2H), 1.38 (s, 6H), 1.30–1.10 (m, 3H), 1.04 (d, 3H), <com:Math><semantics>0.85−0.76<annotation encoding="application / x-tex">0.85-0.76< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z (ESI) = <com:Math><semantics>443.20<annotation encoding="application / x-tex">443.20< / annotation>< / semantics>< / com:Math>[M+1]. Example 27 <com:Math><semantics>(S)−N−((5−(1−cyclopentylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 27) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>-5-<com:Math><semantics>(1<annotation encoding="application / x-tex">(1< / annotation>< / semantics>< / com:Math>-cyclopentylethyl)-2,3-dihydro-<com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>-inden-4-amine (27A) 26B (2.1 g, 9.24 mmol) and dichloromethane (30 mL) were added into a 500 mL aut oclave, and then a catalyst ruthenium <com:Math><semantics>[(S)−(−)−2,2′−bis(diphenylphosphino)−1,11−binaphthy<annotation encoding="application / x-tex">[(S)-(-)-2,2'-bis(diphenylphosphino)-1,11-binaphthy< / annotation>< / semantics>< / com:Math> l]diacetate (1.5 g, 1.83 mmol) was added. After the addition was completed, the autoc lave was tightly closed and sealed, purged with nitrogen 3 times, and then purged wit h hydrogen 3 times. The hydrogen was introduced until the pressure gauge on the aut oclave showed 12 atm, and then the reaction system was reacted for 30 h at room te mperature. The reaction system was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give compound 27A in the form of a pale yellow oil (1 g, 47.17% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.78 (d, 1H), 6.43 (d, 1H), 4.45 (s, 2H), 2.74 (t, 2) H), 2.67–2.58 (m, 3H), 2.06–1.92 (m, 3H), 1.85–1.78 (m, 1H), 1.68–1.58 (m, 1H), 1.5 3–1.38 (m, 4H), 1.29–1.17 (m, 1H), 1.07 (d, 3H), 1.02–0.91 (m, 1H); LCMS m / z (ES I) = <com:Math><semantics>230.2[M+1]<annotation encoding="application / x-tex">230.2[M+1]< / annotation>< / semantics>< / com:Math>. Step 2: <com:Math><semantics>(R)−N−((5−(1−cyclopentylethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2)<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2)< / annotation>< / semantics>< / com:Math> -yl)furan-2-sulfonamide (Compound 27) Compound 27A (200 mg, 0.872 mmol), triethylamine (106.0 mg, 1.05 mmol) and tetr ahydrofuran (30 mL) were added successively into a 100 mL round-bottomed flask un der nitrogen atmosphere, and then triphosgene (104.0 mg, 0.349 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filt ered to remove the solids. 2e (179.0 mg, 0.872 mmol) and sodium methoxide (57.0 m g, 1.05 mmol) were added to the filtrate, and the mixture was reacted at room temper ature for 12 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and DCM (30 mL × 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the org anic solvent was removed. The crude product was purified by preparative medium pre- ssure liquid chromatography (acetonitrile / water = <com:Math><semantics>45%<annotation encoding="application / x-tex">45\%< / annotation>< / semantics>< / com:Math>) to give compound 27 in the f orm of a white powdered solid (145 mg, 36.1% yield, ee%: 77.8%, chiral HPLC (OX -3); mobile phase: methanol; column temperature: 35 °C; column pressure: 80 bar; flo w rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diod e array detector: 200 nm; stop wavelength of diode array detector: 400 nm; RT = 5.0 05 min). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.96<annotation encoding="application / x-tex">\delta = 7.96< / annotation>< / semantics>< / com:Math> (s, 1H), 7.79 (d, 1H), 7.23 (d, 1H), 7.08 (d, 1H), 7.02 (d, 1H), 5.12 (s, 1H), 2.82 (t, 2H), 2.64–2.52 (m, 3H), 1.97–1.87 (m, 3 H), 1.65–1.54 (m, 1H), 1.60 (dtd, 1H), 1.53–1.43 (m, 2H), 1.38 (s, 6H), 1.29–1.10 (m, 3H), 1.05 (d, 3H), <com:Math><semantics>0.86−0.74<annotation encoding="application / x-tex">0.86-0.74< / annotation>< / semantics>< / com:Math> (m, 1H). LCMS m / z (ESI) = <com:Math><semantics>443.20<annotation encoding="application / x-tex">443.20< / annotation>< / semantics>< / com:Math>[M+1]. Example 28 <com:Math><semantics>N−((5−(cyclopentylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(cyclopentylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 28) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(4−amino−2,3−dihydro−1H−inden−5−yl)(cyclopentyl)methanol(28A)<annotation encoding="application / x-tex">(4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopentyl)methanol (28A)< / annotation>< / semantics>< / com:Math> Compound 26A (5.0 g, 21.80 mmol) was dissolved in ethanol (80 mL) in a 250 mL three- necked flask, and sodium borohydride (3.5 g, 92.51 mmol) was added in an ice bath. The reaction system was reacted at room temperature for 4 h. After the reaction was completed as detected by TLC, water was added to quench the reaction, and the reaction system was filtered to give the crude product, which was slurried with ethyl acetate / petroleum ether (1:100) to give 28A (5 g, 99.13% yield). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 214.1 [M-17]. Step 2: 5-(cyclopentylmethyl)-2,3-dihydro-1H-inden-4-amine (28B) Compound 28A (5.0 g, 21.61 mmol) was dissolved in DCM (60 mL) in a 250 mL three-necked flask, and triethylsilane (12.6 g, 108.36 mmol) and trifluoroacetic acid (4.9 g, 49.99 mmol) were added in an ice bath. After the addition was completed, the reaction system was stirred overnight at room temperature. After the reaction was completed, the reaction system was poured into water, saturated sodium bicarbonate was added to adjust pH to neutrality, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether = <com:Math><semantics>1:5<annotation encoding="application / x-tex">1:5< / annotation>< / semantics>< / com:Math>) to give compound 28B (3.0 g, 64.46%). LCMS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> (ESI) = 216.1[M+1]. Step 3: <com:Math><semantics>N−((5−(cyclopentylmethyl)−2,3−dihydro−1H−inden−4−yl)carbamoyl)−4−(2−hydroxypropan−2−<annotation encoding="application / x-tex">N-((5-(cyclopentylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-< / annotation>< / semantics>< / com:Math> yl)furan-2-sulfonamide (Compound 28) 28B (500 mg, 2.32 mmol), triethylamine (282.0 mg, 2.79 mmol) and tetrahydrofuran (30 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (276.0 mg, 0.929mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (1.48 g, 2.32 mmol) and sodium methoxide (151.0 mg, 2.79 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. After the reaction was completed as detected by TLC, water (20 mL) was added to quench the reaction, and DCM (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The crude product was purified by preparative medium pressure liquid chromatography (acetonitrile / water = 45%) to give compound 28 in the form of a white powdered solid (350 mg, 33.76% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ=7.81<annotation encoding="application / x-tex">\delta = 7.81< / annotation>< / semantics>< / com:Math> (s, 1H), 7.63 (s, 1H), 6.98 (d, 2H), 6.92 (d, 1H), 5.04 (s, 1H), 2.81 (dd, 2H), 2.60 (dd, 2H), 2.45 (d, 2H), 1.98–1.84 (m, 3H), 1.62–1.50 (m, 4H), 1.47– 1.39 (m, 2H), 1.37 (s, 6H), <com:Math><semantics>1.15−1.04<annotation encoding="application / x-tex">1.15-1.04< / annotation>< / semantics>< / com:Math> (m, 2H); LCMS m / z (ESI) = <com:Math><semantics>429.1<annotation encoding="application / x-tex">429.1< / annotation>< / semantics>< / com:Math>[M+1]. Example 29 <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl−7−d)carbamoyl)−4−(2−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 29) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: (R)-7-bromo-5-(1-cyclopropylethyl)-2,3-dihydro-1<com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>-inden-4-amine (29A) Intermediate 8 (2.0 g, 9.95 mmol) and dichloromethane (50 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and pyridinium tribromide (3.5 g, 10.9 mmol) was added slowly in an ice bath. After the addition was completed, the reaction system was warmed to room temperature and reacted for 1 h. After the reaction was completed, aqueous sodium sulfite solution was added into the reaction system to quench the reaction, and dichloromethane (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50:1–20:1) to give compound 29A in the form of a pale yellow oil (2.7 g, 97% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=7.05<annotation encoding="application / x-tex">\delta = 7.05< / annotation>< / semantics>< / com:Math> (s, 1H), 4.64 (s, 2H), 2.77–2.72 (m, 4H), 2.24–2.20 (m, 1H), 2.00–1.96 (m, 2H), 1.12 (d, 3H), 0.99–0.97 (m, 1H), 0.50–0.48 (m, 1H), 0.34–0.33 (m, 1H), <com:Math><semantics>0.17−0.16<annotation encoding="application / x-tex">0.17-0.16< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.09−0.05<annotation encoding="application / x-tex">0.09-0.05< / annotation>< / semantics>< / com:Math> (m, 1H); LCMS m / z = <com:Math><semantics>281.2<annotation encoding="application / x-tex">281.2< / annotation>< / semantics>< / com:Math>[M+1]. Step 2: <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-5-(1-cyclopropylethyl)-2,3-dihydro-1<com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>-inden-7-<com:Math><semantics>d<annotation encoding="application / x-tex">d< / annotation>< / semantics>< / com:Math>-4-amine (29B) 29A (1.5 g, 5.4 mmol), deuterated sodium formate (0.75 g, 10.8 mmol), tris(dibenzylideneacetone)dipalladium (247 mg, 0.27 mmol), tri-tert-butylphosphine (109 mg, 0.54 mmol) and dimethyl sulfoxide (30 mL) were added successively into a 100 mL round- bottomed flask under nitrogen atmosphere, and the reaction system was warmed to 80 °C and reacted for 8 h. After the reaction was completed, the reaction system was cooled to room temperature, poured into water, and extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum) ether:ethyl acetate = 20:1) to give compound 29B in the form of a pale yellow solid (1 g, 85%) yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ=6.92<annotation encoding="application / x-tex">\delta = 6.92< / annotation>< / semantics>< / com:Math> (s, 1H), 4.43 (s, 1H), 2.74 (t, 2H), 2.60 (t, 2H), 2.25– 2.21 (m, 1H), 1.99–1.92 (m, 2H), 1.13 (d, 3H), 1.10–0.96 (m, 1H), 0.49–0.44 (m, 1H), 0.33– <com:Math><semantics>0.28 (m, 1H),0.15−0.10 (m, 1H),0.04−0.01 (m, 1H);LCMS m / z=203.2[M+1].<annotation encoding="application / x-tex">0.28 \text{ (m, 1H)}, 0.15-0.10 \text{ (m, 1H)}, 0.04-0.01 \text{ (m, 1H)}; LCMS \text{ m / z} = 203.2[M+1].< / annotation>< / semantics>< / com:Math> Step 3: <com:Math><semantics>(R)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl−7−d)carbamoyl)−4−(2−<annotation encoding="application / x-tex">(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 29) Compound 29B (201 mg, 1.0 mmol), triethylamine (121 mg, 1.2 mmol) and tetrahydrofuran (10 mL) were added successively into a 100 mL round-bottomed flask under nitrogen atmosphere, and then triphosgene (118.4 mg, 0.4 mmol) was added in an ice bath. The reaction system was warmed to reflux, reacted for 2 h, and then filtered to remove the solids. 2e (205) mg, 1.0 mmol) and sodium methoxide (108 mg, 2.0 mmol) were added to the filtrate, and the mixture was reacted at 60 °C for 2 h. After the reaction was completed as detected by TLC, water (100 mL) was added to quench the reaction, and ethyl acetate (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math>3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was removed. The crude product was purified by preparative high pressure liquid chromatography to give compound 29 in the form of a white solid (100 mg, 23.1% yield, ee%: 98.64%, chiral HPLC (OZ); mobile phase: <com:Math><semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics>< / com:Math>-hexane / ethanol = 90 / 10; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm@4.8 nm; start wavelength of diode array detector: 200 nm; stop wavelength of diode array detector: 400 <com:Math><semantics>nm;RT=12.342min).<annotation encoding="application / x-tex">nm; RT = 12.342 min).< / annotation>< / semantics>< / com:Math> <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ=7.63<annotation encoding="application / x-tex">\delta = 7.63< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.15<annotation encoding="application / x-tex">7.15< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>5.10<annotation encoding="application / x-tex">5.10< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.81<annotation encoding="application / x-tex">2.81< / annotation>< / semantics>< / com:Math> (t, 2H), <com:Math><semantics>2.77<annotation encoding="application / x-tex">2.77< / annotation>< / semantics>< / com:Math> (t, 2H), 2.17–2.14 (m, 1H), 1.97–1.85 (m, 2H), 1.35 (s, 6H), 1.10 (d, 3H), 0.93 (m,1H), 0.52– CA <com:Math><semantics>0.43 (m, 1H),0.27−0.19 (m, 1H),0.14−0.07 (m, 1H),0.04−0.01 (m,1H);LCMSm / z(ESI)=<annotation encoding="application / x-tex">0.43 \text{ (m, 1H)}, 0.27-0.19 \text{ (m, 1H)}, 0.14-0.07 \text{ (m, 1H)}, 0.04-0.01 \text{ (m,1H)}; LCMS m / z(ESI) =< / annotation>< / semantics>< / com:Math> 434.2 [M+1]. Example 30 <com:Math><semantics>(S)−N−((5−(1−cyclopropylethyl)−2,3−dihydro−1H−inden−4−yl−7−d)carbamoyl)−4−(2−<annotation encoding="application / x-tex">(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-< / annotation>< / semantics>< / com:Math> hydroxypropan-2-yl)furan-2-sulfonamide (Compound 30) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>-7-bromo-5-<com:Math><semantics>(1<annotation encoding="application / x-tex">(1< / annotation>< / semantics>< / com:Math>-cyclopropylethyl)-2,3-dihydro-1<com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>-inden-4-amine (30<com:Math><semantics>A<annotation encoding="application / x-tex">A< / annotation>< / seman...

Claims

1. A compound shown as general formula (II-2) or a stereoisomer, deuteride, or pharmaceutically acceptable salt thereof: [Image disponible dans le document PDF, Image available in the PDF document] ( I I − 2 ) (II-2) wherein, Q is selected from 5 membered heteroaryl, wherein the 5-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the 5-membered heteroaryl is optionally substituted with 0 to 4 R q 0 R^{q0} ; R q 0 R^{q0} are the same or different and are each independently selected from C 1 − 6 C_{1-6} alkyl, C 2 − 6 C_{2-6} alkenyl, halogen, cyano, C 3 − 8 C_{3-8} cycloalkyl, and C 3 − 8 C_{3-8} heterocycloalkyl, wherein the C 3 − 8 C_{3-8} heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S, and the C 1 − 6 C_{1-6} alkyl, C 2 − 6 C_{2-6} alkenyl, C 3 − 8 C_{3-8} heterocycloalkyl, or C 3-8 cycloalkyl is optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, and -NR q4 R q5 , wherein the substituent C 1 − 6 C_{1-6} alkyl, or C 1 − 6 C_{1-6} alkoxy is optionally further substituted with 1 to 3 substituents selected from OH, and C 1 − 6 C_{1-6} alkyl; R q 4 R^{q4} and R q 5 R^{q5} are selected from H, and C 1 − 6 C_{1-6} alkyl; W is selected from O and NH; R b and R c are each independently selected from H, C 1-6 alkyl and 3-10 membered carbocyclyl, wherein the C 1 − 6 C_{1-6} alkyl is optionally further substituted with 1 to 4 substituents selected from F, Cl, Br, I, and C 1 − 6 C_{1-6} alkyl; or R b and R c form a double bond; R and R 1 are each independently selected from deuterium, H, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 alkoxy, and 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl contains 1 to 3 N atoms, and the C 1 − 6 C_{1-6} alkyl or 4-10 membered heterocyclyl is optionally further substituted with 1 to 4 substituents selected from F, Cl, Br, I, CN, C 1-6 alkyl, and C 1-6 alkoxy; or R and R 1 , together with an atom to which they are attached, form a 4-8 membered ring, wherein the 4-8 membered ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, and OH; q and r are selected from 0, 1 and 2; m is selected from 1, 2 and 3.

2. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from compounds shown as formulas (III) and (III-1): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (III) or ( I I I − 1 ) (III-1) wherein, Q, R, R 1 , r and q are defined in the same way as in general formula (II-2); and wherein G1, G2, and G3 are each C.

3. The compound or the stereoisomer, deuteride, pharmaceutically acceptable salt thereof according to claim 2, wherein: Q is selected from 5 membered heteroaryl, wherein the 5-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the 5-membered heteroaryl is optionally substituted with 0 to 4 R q 0 R^{q0} ; R q0 are the same or different and are each independently selected from C 1-4 alkyl, halogen, cyano, C 2-4 alkenyl, C 3-6 cycloalkyl, and C 3-6 heterocycloalkyl, wherein the C 3-6 heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and the C 1-4 alkyl, C 3-6 heterocycloalkyl and C 3-6 cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C 1-4 alkyl and -NR q4 R q5 ; R q 4 R^{q4} and R q 5 R^{q5} are selected from H and C 1 − 4 C_{1-4} alkyl; R and R 1 are each independently selected from deuterium, H, F, CN, OH, C 1-6 alkyl and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl contains 1 to 3 heteroatoms selected from N and O, and the C 1 − 6 C_{1-6} alkyl or 4-6-membered heterocycle is optionally further substituted with 1 to 4 substituents selected from OH, F, CN and C 1-6 alkoxy; or R and R 1 , together with an atom to which they are attached, form a 4-5 membered ring; q and r are selected from 0, 1 and 2.

4. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from a compound shown as formula (IV): [Image disponible dans le document PDF, Image available in the PDF document] (IV) wherein, Q, W, R, R 1 , r and q are defined in the same way as in general formula (II-2); m is selected from 1, 2 and 3.

5. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 4, wherein: Q is selected from 5 membered heteroaryl, wherein the 5 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the 5 membered heteroaryl is optionally substituted with 0 to 4 R q 0 R^{q0} ; R q 0 R^{q0} are the same or different and are each independently selected from C 1 − 4 C_{1-4} alkyl, halogen, cyano, C 2-4 alkenyl, C 3-6 cycloalkyl, and C 3-6 heterocycloalkyl, wherein the C 3-6 heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and the C 1-4 alkyl, C 3-6 heterocycloalkyl and C 3-6 cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C 1-4 alkyl, -NR q4 R q5 , C 3-6 cycloalkyl and C 3-6 heterocycloalkyl; R q 4 R^{q4} and R q 5 R^{q5} are selected from H and C 1 − 4 C_{1-4} alkyl; W is selected from O and NH; R and R 1 are each independently selected from deuterium, H, F, CN, OH, C 1-6 alkyl and 4-6 membered heterocyclyl, wherein the 4-6-membered heterocyclyl contains 1 to 3 heteroatoms selected from N and O, and the C 1 − 6 C_{1-6} alkyl or 4-6-membered heterocycle is optionally further substituted with 1 to 4 substituents selected from OH, F, CN and C 1-6 alkoxy; or R and R 1 , together with an atom to which they are attached, form a 4-5 membered ring; q and r are selected from 0, 1 and 2; m is selected from 1, 2 and 3.

6. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from a compound shown as formula (V): [Image disponible dans le document PDF, Image available in the PDF document] wherein, Q, W, R b and R c are defined in the same way as in general formula (II-2); m is selected from 1, 2 and 3.

7. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 6, wherein: Q is selected from 5 membered heteroaryl, wherein the 5-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the 5-membered heteroaryl is optionally substituted with 0 to 4 R q 0 R^{q0} ; R q 0 R^{q0} are the same or different and are each independently selected from C 1 − 4 C_{1-4} alkyl, halogen, cyano, C 2 − 4 C_{2-4} alkenyl, C 3 − 6 C_{3-6} cycloalkyl, and C 3 − 6 C_{3-6} heterocycloalkyl, wherein the C 3 − 6 C_{3-6} heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and the C 1-4 alkyl, C 3-6 heterocycloalkyl and C 3-6 cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C 1-4 alkyl and -NR q4 R q5 ; R q 4 R^{q4} and R q 5 R^{q5} are selected from H and C 1 − 4 C_{1-4} alkyl; W is selected from O and NH; R b R_b and R c R_c are each independently selected from H, C 1 − 4 C_{1-4} alkyl and 3-5 membered carbocyclyl, or R b and R c form a double bond; m is selected from 1, 2 and 3.

8. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 3, wherein the compound is selected from a compound shown as formula (VI): [Image disponible dans le document PDF, Image available in the PDF document] (VI) wherein, Q, W, R b and R c are defined in the same way as in general formula (II-2); m is selected from 1, 2 and 3.

9. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 8, wherein: Q is selected from 5 membered heteroaryl, wherein the 5-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S, and the 5-membered heteroaryl is optionally substituted with 0 to 4 R q 0 R^{q0} ; R q 0 R^{q0} are the same or different and are each independently selected from C 1 − 4 C_{1-4} alkyl, halogen, cyano, C 2-4 alkenyl, C 3-6 cycloalkyl, and C 3-6 heterocycloalkyl, wherein the C 3-6 heterocycloalkyl contains 1 to 3 heteroatoms selected from N and O, and the C 1-6 alkyl, C 3-6 heterocycloalkyl and C 3-6 cycloalkyl are optionally further substituted with 1 or more substituents selected from deuterium, OH, halogen, cyano, C 1-4 alkyl and -NR q4 R q5 ; R q4 and R q5 are selected from H and C 1-4 alkyl; W is selected from O and NH; R b and R c are each independently selected from H, C 1-4 alkyl and 3-5 membered carbocyclyl; m is selected from 1, 2 and 3.

10. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 9, wherein: [Image disponible dans le document PDF, Image available in the PDF document]11. The compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]12. An intermediate for preparing the compound according to any one of claims 1 to 11, wherein the intermediate is selected from one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]13. A pharmaceutical composition, comprising the compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and one or more pharmaceutically acceptable carriers and / or excipients.

14. Use of the pharmaceutical composition according to claim 13 or the compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 in preparing an NLRP3 inhibitor or in preparing a medicament for treating a disease associated with NLRP3.

15. Use of the pharmaceutical composition according to claim 13 or the compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for treating a disease associated with NLRP3.

16. The use according to claim 14 or 15, wherein a disease treated by the NLRP3 inhibitor or the disease associated with NLRP3 is selected from inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancers, renal system diseases, gastrointestinal diseases, respiratory system diseases, endocrine system diseases and central nervous system diseases.

17. The use according to claim 16, wherein the disease is cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I diabetes, type II diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout or chronic kidney disease.

18. The pharmaceutical composition according to claim 13 or the compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for use in treating a disease associated with NLRP3.

19. The pharmaceutical composition for use of claim 18 or the compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof for use of claim 18, wherein the disease associated with NLRP3 is selected from inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancers, renal system diseases, gastrointestinal diseases, respiratory system diseases, endocrine system diseases and central nervous system diseases.

20. The pharmaceutical composition for use of claim 19 or the compound or the stereoisomer, deuteride, or pharmaceutically acceptable salt thereof for use of claim 19, wherein the disease is cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I diabetes, type II diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout or chronic kidney disease.