Amide derivatives, processes for their preparation and their use in medicine

Abstract

The present application relates to an amide derivative and its medical use, in particular to an amide derivative as shown in general formula (I), or a stereoisomer, solvate, metabolite, deuterated product, prodrug, pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutical composition comprising the same and the use of the compound or composition of the present application in the preparation of NLRP3 inhibitors

Description

Technical Field

[0001] This invention relates to amide derivatives of general formula (I), or their stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, pharmaceutical compositions thereof, and their use in the preparation of NLRP3 inhibitors. Background Technology

[0002] NOD-like receptors (NLRs) with nucleotide-binding oligomerization domains (NOD) are a class of cytoplasmic pattern recognition receptors (PRRs) in mammalian cells, playing a crucial role in innate immune responses. NLRs are a group of cytoplasmic proteins with signal transduction functions, widely involved in the body's inflammatory responses. The NLR family includes NOD, NALP (NLRP), CIITA (NLRA), and IPAF (NLRC), with the NLRP and NLRC subfamilies being the two main types of NOD-like receptors (NLRs). NLRP can be further divided into inflammasome members such as NLRP1, NLRP3, NLRP6, NLRP7, and NLRP12. The NLRP3 inflammasome is a multi-protein complex composed of the NLRP3 protein itself, caspase-1, and apoptosis-associated speck-like protein containing CARD (ASC). It can recognize various pathogenic microorganisms and stress-related endogenous signaling molecules. Classical NLRP3 inflammasome activation is triggered by two signals: the first activates the TLR4 (Toll-like receptor 4) signaling pathway, promoting nuclear transcription factor κB translocation into the nucleus and inducing the production of precursors such as IL-1β and IL-18. The second signal promotes the formation of the NLRP3 / ASC / pro-caspase-1 complex. Upon activation, the NLRP3 complex polymerizes with apoptosis-associated specklike protein (ASC) containing caspase activation and recruitment domains. ASC then interacts with cysteine ​​protease caspase-1 to form a complex called the inflammasome. The pro-caspase-1 self-cleaves into its activated form (Wen, H., Miao, EA & Ting, JPMechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432–441 (2013)). Activated caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, converting them into their active forms and releasing them extracellularly. This recruits inflammatory cells to aggregate and amplifies the inflammatory response.ASC speckle-like proteins can also recruit and activate caspase-8, cleaving the precursor forms of IL-1β and IL-18 to convert them into mature forms and induce pyroptosis. Non-canonical NLRP3 inflammasome activation is independent of TLR4 signaling pathway activation; it is initiated by caspase-11 directly recognizing intracellular LPS, promoting the activation and release of Gasdermin D, thereby mediating cell death (Lamkanfi, M. & Dixit, VM Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014)).

[0003] Abnormal activation of the NLRP3 inflammasome is closely related to the development of various inflammatory diseases, including hereditary CAPS diseases such as Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome, neonatal multisystem inflammatory diseases, Alzheimer's disease, Parkinson's disease, non-alcoholic fatty liver disease, atherosclerosis, asthma, nephropathy, enteritis, tumors, gout, neurodegenerative diseases, diabetes, and obesity.

[0004] Current treatments for NLRP3-related diseases include the recombinant IL-1 receptor antagonist anakinra, the IL-1β neutralizing antibody canakinumab, and the soluble IL-1 receptor decoyote rilonacept, all of which are biologics. In recent years, some small-molecule NLRP3 inhibitors have been reported, such as glibenclamide, parthenolide, and 3,4-methylenedioxy-β-nitrostyrene. However, these drugs or small molecules still suffer from low specificity or poor activity. Therefore, it is necessary to develop a new generation of small-molecule NLRP3 inhibitors with high specificity and activity for the treatment of autoimmune diseases caused by NLRP3 mutations. Summary of the Invention

[0005] This invention provides novel amide derivatives, or all their stereoisomers, solvates, metabolites, deuterated derivatives, pharmaceutically acceptable salts, cocrystals, or prodrugs, pharmaceutical compositions thereof, and their use in the preparation of NLRP3 inhibitors.

[0006] One or more embodiments of the present invention relate to compounds of general formula (I), or all of their stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals:

[0007]

[0008] in:

[0009] Q is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl; the heteroaryl contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0010] R q0 Whether they are the same or different, each is independently selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, halogen, OH, cyano, nitro, -NH2, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl group, -C(=O)OC 3-8 cycloalkyl, -OC(=O)C 3-8 cycloalkyl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 5-10 heteroaryl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)(C 1-6 Alkyl)2、-NHC(=O) C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 2-6 Alkyne group, -NHC(=O)C 2-6 alkenyl, -NH (C=NR) q1 )NR q2 R q3 - C(=O)NR q4 R q5-SH, -SC 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl or -S(=O)2NR q2 R q3 The heterocyclic alkyl or heteroaryl group each contains 1 to 3 heteroatoms selected from N, O, or S, and the alkyl, alkoxy, NH2, alkenyl, alkynyl, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl group is optionally further composed of one or more atoms selected from deuterium, OH, halogen, cyano, =O, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC (=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C6-10 Aryl, C 5-10 heteroaryl, -NHC (=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further divided by one to three elements selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or it is replaced by a =O substituent;

[0011] Or at least one pair of R q0 The carbon ring and its associated atoms form a 4- to 10-membered carbon ring or a 5- to 10-membered heterocycle, wherein the heterocycle contains 1 to 2 heteroatoms selected from N, O, or S, and the carbon ring or heterocycle is optionally further surrounded by one or more atoms selected from OH, halogens, C, and N. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl or -C(=O)NR q4 R q5 The substituents are replaced by the C, and the C is said to be... 1-6 Alkyl or C 1-6 The alkoxy group may be further selected from OH, halogen, =O, -NR. q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl or -C(=O)NR q4 R q5 The substituents are replaced by the substituents.

[0012] R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl;

[0013] R q2 R q3 Selected from H or C 1-6 alkyl;

[0014] Rq4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned 1-6 Alkyl groups may optionally be further selected from OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 and N atoms form 3 to 8-membered heterocycles; said heterocycles contain 1 to 3 heteroatoms selected from N, O or S;

[0015] R q6 C 1-6 alkyl;

[0016] W is selected from O or NHR a ;

[0017] W1 is 0;

[0018] R a Selected from H, cyano, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy;

[0019] X is NH;

[0020] Y is CR b R c ;

[0021] R b R c Each is independently selected from H and C 1-6 Alkyl or 3 to 10-membered carbocyclic group, wherein the C 1-6 Alkyl groups are optionally further surrounded by 1 to 4 elements selected from F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 The substituted group is replaced by an alkoxy group, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O, or S;

[0022] Or R bWith R c Formation of double bonds;

[0023] R and R1 are each independently selected from deuterium, H, F, Cl, Br, I, CN, NH2, OH, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -O(C=O)-3 to 10-membered carbon cycloyl, -O(C=O)-3 to 10-membered heterocyclic, -(C=O)O-3 to 10-membered carbon cycloyl, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 4- to 10-membered heterocyclic, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2 or (C=O)NR a1 R a2 The heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S, wherein the alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, Cl, Br, I, CN, NR. a1 R a2 =O,C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -(C=O)O-3 to 10-membered carbon cycloyl, -O(C=O)-3 to 10-membered carbon cycloyl, -O(C=O)-3 to 10-membered heterocyclic, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, -NHCOC 1-6 Alkyl groups, -NH(C=O)-3 to 10-membered carbocyclic groups, -NH(C=O)-3 to 10-membered heterocyclic groups, or -(C=O)NR a1 R a2 The substituents are replaced;

[0024] Alternatively, R and R1, together with their attached atoms, form a 4- to 8-membered ring, the 4- to 8-membered ring containing 0 to 4 heteroatoms selected from N, O, or S, the 4- to 8-membered ring optionally further surrounded by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, -NR. a1 R a2=O,C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, -(C=O)OC 1-6 Substituents of alkyl, 3- to 10-membered carbocyclic or 5- to 10-membered heterocyclic groups;

[0025] C is a 3- to 10-membered cycloalkyl group;

[0026] R2 is selected from H, F, Cl, Br, I, OH, -NR a1 R a2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy;

[0027] G1, G2, and G3 are each independently selected from N or CH;

[0028] q and r are selected from 0, 1, or 2;

[0029] n can be selected from 0, 1, 2, or 3.

[0030] One or more embodiments of the present invention provide compounds of general formula (II) or their stereoisomers, hydrates, metabolites, deuterated derivatives, solvates, pharmaceutically acceptable salts, or cocrystals:

[0031]

[0032] in:

[0033] The definitions of Q, R, R1, R2, C, G1, G2, G3, r, q, and n are the same as those in general formula (I).

[0034] One or more embodiments of the present invention provide compounds of general formula (II-1) or their stereoisomers, hydrates, metabolites, deuterated derivatives, solvates, pharmaceutically acceptable salts, or eutectics:

[0035]

[0036] in:

[0037] The definitions of Q, R, R1, R2, C, G1, G2, G3, r, q, and n are the same as those in general formula (I).

[0038] One or more embodiments of the present invention provide compounds of general formula (II-2), or their stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals:

[0039]

[0040] Q, W, R, R1, R b R c The definitions of r and q are the same as those in general formula (I);

[0041] m can be selected from 1, 2, or 3.

[0042] One or more embodiments of the present invention provide compounds of general formula (III) or their stereoisomers, hydrates, metabolites, deuterated derivatives, solvates, pharmaceutically acceptable salts, or cocrystals:

[0043]

[0044] The definitions of Q, R, R1, G1, G2, G3, r, and q are the same as those in general formula (I).

[0045] One or more embodiments of the present invention provide compounds of general formula (III-1) or their stereoisomers, hydrates, metabolites, deuterated derivatives, solvates, pharmaceutically acceptable salts, or eutectics:

[0046]

[0047] The definitions of Q, R, R1, G1, G2, G3, r, and q are the same as those in general formula (I).

[0048] One or more embodiments of the present invention provide a compound of formula (III) or (III-1) or a stereoisomer thereof, a hydrate, a metabolite, a deuterated product, a solvate, a pharmaceutically acceptable salt, or a cocrystal, wherein:

[0049] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0050] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl group, heterocyclic alkyl group, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NRq4 R q5 The substituents are replaced;

[0051] R q4 R q5 Selected from H or C 1-4 alkyl;

[0052] W is selected from O or NH;

[0053] R and R1 are each independently selected from deuterium, H, F, CN, OH, and C. 1-6 Alkyl or 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl or heterocycle is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, CN or C. 1-6 Substituents of alkoxy groups;

[0054] Alternatively, R and R1 together with the atoms they are attached to form a 4-membered ring or a 5-membered ring;

[0055] G1, G2, and G3 are each independently selected from CH;

[0056] q and r are selected from 0, 1, or 2.

[0057] One or more embodiments of the present invention provide a compound of general formula (IV), or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals:

[0058]

[0059] The definitions of Q, W, R, R1, r, and q are the same as those in general formula (I);

[0060] m can be selected from 1, 2, or 3.

[0061] One or more embodiments of the present invention provide a compound of general formula (IV), or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein:

[0062] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0063] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl group, heterocyclic alkyl group, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced by the substituents.

[0064] R q4 R q5 Selected from H or C 1-4 alkyl;

[0065] W is selected from O or NH;

[0066] R and R1 are each independently selected from deuterium, H, F, CN, OH, and C. 1-6 Alkyl or 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl or heterocycle is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, CN or C. 1-6 Substituents of alkoxy groups;

[0067] Alternatively, R and R1 together with the atoms attached to them form a 4-membered ring or a 5-membered ring, wherein the 3- to 5-membered carbon cyclogroup is preferably a 3-, 4-, or 5-membered cycloalkyl group;

[0068] q and r are selected from 0, 1, or 2;

[0069] m can be selected from 1, 2, or 3.

[0070] One or more embodiments of the present invention provide a compound of general formula (V), or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals:

[0071]

[0072] Q, W, R b R c The definition is the same as that described in general formula (I);

[0073] m can be selected from 1, 2, or 3.

[0074] One or more embodiments of the present invention provide a compound of general formula (V), or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein:

[0075] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms.q0 replace;

[0076] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl group, heterocyclic alkyl group, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced;

[0077] R q4 R q5 Selected from H or C 1-4 alkyl;

[0078] W is selected from O or NH;

[0079] R b R c Each is independently selected from H and C 1-4 Alkyl or 3- to 5-membered carbocyclic group, wherein the 3- to 5-membered carbocyclic group is preferably a 3-, 4-, or 5-membered cycloalkyl group;

[0080] q and r are selected from 0, 1, or 2;

[0081] m can be selected from 1, 2, or 3.

[0082] One or more embodiments of the present invention provide a compound of general formula (VI), or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals:

[0083]

[0084] Q, W, R b R c The definition is the same as that described in general formula (I);

[0085] m can be selected from 1, 2, or 3.

[0086] One or more embodiments of the present invention provide the compound shown in (VI), or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein:

[0087] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0088] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl group, heterocyclic alkyl group, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced;

[0089] R q4 R q5 Selected from H or C 1-4 alkyl;

[0090] W is selected from O or NH;

[0091] R b R c Each is independently selected from H and C 1-4 Alkyl or 3- to 5-membered carbocyclic group, wherein the 3- to 5-membered carbocyclic group is preferably a 3-, 4-, or 5-membered cycloalkyl group;

[0092] q and r are selected from 0, 1, or 2;

[0093] m can be selected from 1, 2, or 3.

[0094] One or more embodiments of the present invention provide compounds, stereoisomers thereof, hydrates, metabolites, deuterated products, solvates, pharmaceutically acceptable salts, or cocrystals of general formulas (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V), or (VI), wherein:

[0095] Q is selected from

[0096] Selected from

[0097] The compounds provided in one or more embodiments of the present invention are selected from, but not limited to, the following structures:

[0098]

[0099]

[0100]

[0101]

[0102]

[0103] The present invention also provides an intermediate for preparing compounds of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V) or (VI), wherein the intermediate is selected from, but not limited to, the following structures:

[0104]

[0105]

[0106] One or more embodiments of this application provide pharmaceutical compositions comprising compounds of general formulas (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V), or (VI) or specific structures thereof or their stereoisomers, solvates, metabolites, deuterated derivatives, pharmaceutically acceptable salts, cocrystals, or prodrugs, and one or more pharmaceutically acceptable carriers and / or excipients.

[0107] One or more embodiments of this application provide the use of the pharmaceutical composition of this application, a compound of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V) or (VI) or the specific structure thereon or its stereoisomers, solvates, metabolites, deuterated products, pharmaceutically acceptable salts, cocrystals or prodrugs in the preparation of NLRP3 inhibitors.

[0108] In one or more embodiments of this application, the diseases treated by the NLRP3 inhibitor are selected from: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

[0109] In one or more embodiments of this application, the diseases treated by the NLRP3 inhibitor are selected from: cryptothermal protein-associated cycle syndrome (CAPS), Muker-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, and chronic kidney disease.

[0110] One or more embodiments of this application provide a method for inhibiting NLRP3, comprising contacting a compound of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V), or (VI) of this application, or a specific structure thereof or a stereoisomer thereof, a solvate, a metabolite, a deuterated product, a pharmaceutically acceptable salt, a eutectic, or a prodrug or a composition thereof, with a target in which this is desired.

[0111] One or more embodiments of this application provide a method for treating diseases associated with NLRP3, comprising applying a compound of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V), or (VI) of this application, or a specific structure thereof or a stereoisomer thereof, a solvate, a metabolite, a deuterated product, a pharmaceutically acceptable salt, a eutectic, or a prodrug or a composition thereof, to a subject in need.

[0112] One or more embodiments of this application provide compounds of general formula (I), (II), (II-1), (II-2), (III), (III-1), (IV), (V), or (VI) or the specific structures described above or their stereoisomers, solvates, metabolites, deuterated derivatives, pharmaceutically acceptable salts, cocrystals, or prodrugs for the treatment of NLRP3-related diseases or as NLRP3 inhibitors.

[0113] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0114] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14C, Isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), while isotopes of oxygen include... 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0115] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 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 isomers thereof; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0116] "Alkoxy" refers to a group formed by replacing at least one carbon atom in 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 definition of alkyl is the same as that of "alkyl" as described above.

[0117] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, composed of 2 to 20 carbon atoms, preferably alkenyl groups with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably alkenyl groups with 2 to 8 carbon atoms, and even more preferably alkenyl groups with 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-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 group may optionally be further replaced by one or more substituents.

[0118] "Alynyl" refers to a straight-chain 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, composed of 2 to 20 carbon atoms, preferably an alkynyl group with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group with 2 to 8 carbon atoms, and even more preferably an alkynyl group with 2 to 6 carbon atoms. Non-limiting embodiments include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyne-1-yl, pentyne-2-yl, hexyn-1-yl, 1-heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyne-3-yl, decanyne-4-yl, undecanyne-3-yl, and dodecanyne-4-yl. The ethynyl group may optionally be further substituted with one or more substituents.

[0119] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl and naphthyl groups. The aryl group may optionally be further substituted by one or more substituents.

[0120] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heteroaryl group can be attached to a heteroatom or a carbon atom. The heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furanyl, thiophene, pyranyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted with one or more substituents.

[0121] "Carbocyclic group" or "carbocyclic" refers to a saturated or unsaturated aromatic ring or non-aromatic ring. When it is an aromatic ring, its definition is the same as that of "aryl" above; when it is a non-aromatic ring, it can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a tricyclic system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members). It can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The “carbocyclic group” or “carbocyclic” may optionally be further replaced by one or more substituents.

[0122] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclic group" or "heterocycle" include epoxyethyl, epoxypropyl, azirropropyl, oxacyclobutyl, azirrobutyl, thioherrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, azirroheptyl, oxacycloheptyl, thioherroheptyl, oxacyclohexacycloyl, diazacyclohexacycloyl, thioazacyclohexacycloyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylalkyl, 1,3- Dithiaalkyl, dihydrofuranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydropyrroliyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiapentanyl, dihydrothiaphenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. The “heterocyclic group” or “heterocycle” may optionally be further substituted with one or more substituents.

[0123] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, whose ring can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic system, preferably with 3 to 10 carbon atoms, more preferably with 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, and cyclohepttrienyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0124] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The 1, 2, or 3 N or S atoms selectively substituted in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocyclic alkyl” include epoxide ethyl, aziridine propyl, oxacyclobutyl, aziridine butyl, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine heptyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, aziridine[5.2.0]nonyl, oxacyclo[5.3.1.1]dodecyl, aziradamantyl, and oxaspiro[3.3]heptyl.

[0125] When the terms "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclic", "carbocyclic", "heterocyclic", "cycloalkyl", "heterocyclic", or "heterocyclic" mentioned above are substituted, they may be further replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6alkynyl, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further surrounded by one to three elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or replaced by the =O substituent; R q1 Selected from C 1-6 Alkyl, C1-6 Alkoxy or C 6-10 Aryl; R q2 R q3 Selected from H or C1-6 alkyl; wherein, R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 The alkyl group may optionally be further surrounded by one or more elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 The N atom forms a 3- to 8-membered heterocycle, which may contain one or more heteroatoms selected from N, O or S.

[0126] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0127] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0128] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0129] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0130] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0131] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids in their pure states at room temperature, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0132] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0133] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0134] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0135] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0136] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0137] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0138] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4mm-0.5mm.

[0139] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0140] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0141] Nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0142] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0143] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0144] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere;

[0145] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0146] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the optimal reaction temperature is 20℃-30℃.

[0147] DCM: Dichloromethane;

[0148] EA: Ethyl acetate;

[0149] HCl: hydrochloric acid;

[0150] THF: Tetrahydrofuran;

[0151] DMF: N,N-dimethylformamide;

[0152] PE: Petroleum ether;

[0153] TLC: Thin-layer chromatography;

[0154] SFC: Supercritical Fluid Chromatography;

[0155] NCS: N-chlorosuccinimide

[0156] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride.

[0157] Example

[0158] Intermediate 1

[0159] 5-(1-Cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 1)

[0160] 5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0161]

[0162] first step:

[0163] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methyl ketone (1b)

[0164] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone

[0165] Under nitrogen protection, compound 1a (20.0 g, 150.16 mmol) was dissolved in 200 mL of 1,2-dichloroethane in a 500 mL three-necked flask. The mixture was cooled to 0 °C in an ice-salt bath, and a dichloromethane solution of boron trichloride (150 mL, 1 M, 150.16 mmol) was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature for 10 min. Then, aluminum trichloride (22.0 g, 165.20 mmol) and cyclopropyl nitrile (15.1 g, 225.24 mmol) were added. The reaction mixture was heated to 80 °C and reacted for 4 h. After cooling to room temperature, 160 mL of 2 M HCl was added in an ice bath. After the addition was complete, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (200 mL × 3). The organic phase was washed with 160 mL of 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, 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 1b as a white solid (17.1 g, yield 57.2%).

[0166] 1 H NMR (400MHz, DMSO-d6) δ = 7.87 (d, 1H), 6.90 (br, 2H), 6.54 (d, 1H), 2.84 (t, 2H), 2.80-2.74(m,1H),2.67(t,2H),2.06-1.98(m,2H),0.96-0.87(m,4H); LCMS m / z(ESI)= 202.1[M+1].

[0167] Step Two:

[0168] 5-(1-Cyclopropylvinyl)-2,3-Dihydro-1H-inden-4-amine (1c)

[0169] 5-(1-cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine

[0170] Under nitrogen protection, in a 500 mL three-necked flask, compound methyltriphenylphosphine bromide (24.8 g, 69.6 mmol) was dissolved in THF (300 mL). The mixture was cooled to 0 °C in an ice-salt bath, and potassium tert-butoxide (7.8 g, 69.6 mmol) was slowly added. The reaction was maintained at this temperature for 30 min, and then compound 1b (7.0 g, 34.8 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with EA (100 mL × 3), dried over anhydrous sodium sulfate, 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, a pale yellow oil (6.4 g, yield 92.3%).

[0171] 1 H NMR (400MHz, DMSO-d6)δ=6.64(d,1H),6.45(d,1H),5.15(d,1H),4.78(d,1H),4.37(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),0.40-0.36(m,2H); LC-MS m / z(ESI)=200.1[M+1].

[0172] Step 3:

[0173] 5-(1-Cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 1)

[0174] 5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0175] Under nitrogen protection, in a 50 mL round-bottom flask, compound 1c (700 mg, 3.51 mmol) and triethylsilane (1.23 g, 10.54 mmol) were dissolved in DCM (10 mL). Trifluoroacetic acid (2.0 g, 17.56 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature for 5 h. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction and the pH was adjusted to weakly alkaline. The mixture was extracted with DCM (20 mL × 3), dried over anhydrous sodium sulfate, 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 intermediate 1, a pale yellow oil (261 mg, yield 37.2%).

[0176] 1 H NMR (400MHz, DMSO-d6) δ = 6.93 (d, 1H), 6.47 (d, 1H), 4.60 (br, 2H), 2.75 (t, 2H), 2.63(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),0.33-0.30(m,1H),0.15-0.12(m,1H),0.05-0.01(m,1H); LC-MS m / z(ESI)=202.2[M+1].

[0177] Intermediate 2

[0178] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide amide (intermediate 2)

[0179] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0180]

[0181]

[0182] first step:

[0183] Ethyl furan-3-carboxylate (2b)

[0184] ethyl furan-3-carboxylate

[0185] Compound 2a (50 g, 0.446 mol) was dissolved in 300 mL of anhydrous ethanol under ice bath conditions. Thionyl chloride (65 mL, 0.892 mol) was slowly added dropwise. After the addition was complete, the mixture was heated to reflux for 2 hours. The reaction was monitored by TLC until complete. The solvent and excess thionyl chloride were removed by concentration under reduced pressure. Water (200 mL) and ethyl acetate were added for extraction (150 mL × 3). The organic phases were combined. The organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:10) to give compound 2b, a light brown oil (38.1 g, yield 61%).

[0186] Step Two:

[0187] 4-Ethyl carbamate-2-sulfonyl chloride furan (2c)

[0188] Ethyl furan-2-sulfonyl chloride-4-formate

[0189] Compound 2b (22.00 g, 0.157 mol) was dissolved in 250 mL of DCM at room temperature. The mixture was cooled to -15 °C in an ice-salt bath, and sulfonyl chloride (23.31 g, 0.173 mol) was slowly added dropwise while maintaining the temperature below -10 °C. After the addition was complete, the mixture was allowed to react at room temperature for 12 h. Then, pyridine (13.66 g, 0.173 mol) was slowly added dropwise after the mixture was cooled to below -15 °C in an ice-salt bath, followed by phosphorus pentachloride (36.00 g, 0.137 mol) in portions while maintaining the temperature below -10 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. The reaction was monitored for completeness using TLC. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding compound 2c, a brown oily substance (33.00 g, 90% yield), which was directly added to the next step without purification.

[0190] Step 3:

[0191] Ethyl furan-2-sulfonamide-4-carboxylate (2d)

[0192] Furan-2-sulfonamide-4-ethyl formate

[0193] Compound 2c (33.00 g, 0.138 mol) was dissolved in 350 mL of acetone at room temperature. A saturated aqueous solution of ammonium bicarbonate (49.74 g, 0.553 mol) was added dropwise at room temperature, and the reaction was carried out for 3 h at room temperature. The reaction was monitored by TLC until complete. The mixture was extracted with EA (200 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding compound 2d as a brown solid powder (23 g, 77% yield).

[0194] 1 H NMR (400MHz, DMSO-d6) δ = 8.64 (s, 1H), 7.97 (s, 2H), 7.13 (s, 1H), 4.27 (q, 2H), 1.28 (t, 3H); LCMS m / z = 218.2 [Ml].

[0195] Step 4:

[0196] 4-(2-hydroxypropyl)furan-2-sulfonamide (2e)

[0197] 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0198] Compound 2d (23 g, 0.105 mol) was dissolved in 500 mL of dry THF at room temperature. The solution was cooled to -15 °C in an ice-salt bath, and methylmagnesium bromide (140 mL, 0.418 mol) was slowly added dropwise while maintaining the temperature below 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4 to 1:1) to give compound 2e, a white solid powder (16 g, yield 76%).

[0199] LCMS m / z = 204.2 [Ml].

[0200] Step 5:

[0201] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl)furan-2-sulfonamide (2f)

[0202] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0203] Compound 2e (5.0 g, 24.39 mmol) was dissolved in 50 mL of dry THF at room temperature. The solution was cooled to -10 °C in an ice-salt bath, and sodium hydride (0.9 g, 36.58 mmol) was slowly added to maintain the temperature below -10 °C. Then, a solution of tert-butyldimethylchlorosilane (4.8 g, 31.70 mmol) in THF (50 mL) was added. The reaction was carried out at room temperature for 12 h, and the reaction was monitored by TLC to ensure complete reaction. The reaction solution was quenched in 20 mL of ice water and extracted with EA (50 mL × 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. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2 to 2:1) to give compound 2f as a white solid (5.1 g, yield 66%).

[0204] 1 H NMR (400MHz, CDCl3) δ = 7.85 (s, 1H), 7.68 (s, 1H), 6.93 (s, 1H), 5.07 (s, 1 H), 1.38 (s, 6H), 0.88 (s, 9H), 0.16 (s, 6H); LCMS m / z = 320.2 [M+l].

[0205] Step 6:

[0206] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide amide (intermediate 2)

[0207] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0208] In a 250 mL three-necked flask under nitrogen protection, DCM (100 mL) and triphenyl diphosphine chloride (11.3 g, 33.86 mmol) were added. The mixture was cooled to 0 °C in an ice bath, and diisopropylethylamine (5.8 g, 45.16 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 10 min. The reaction system was then cooled to 0 °C, and 2f (3.6 g, 11.29 mmol) of dichloromethane (10 mL) solution was added dropwise. After the addition was complete, the mixture was kept at 0 °C and reacted for another 30 min. Ammonia gas was then introduced into the reaction system for 15 min. The reaction was allowed to return to room temperature for 2 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to give intermediate 2, a white solid (816 mg, yield 23%).

[0209] 1LCMS m / z=319.2[M+l].

[0210] Intermediate 3-Intermediate 4

[0211] The synthesis of intermediates 3 and 4 was carried out in accordance with the preparation of intermediate 2.

[0212]

[0213] Intermediate 5

[0214] 5-(3-hydroxyoxetane-3-yl)thiophene-2-sulfonamide (intermediate 5)

[0215] 5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonamide

[0216]

[0217] first step:

[0218] 5-Bromo-N-(tert-butyldimethylsilyl)thiophene-2-sulfonamide (5b)

[0219] 5-bromo-N-(tert-butyldimethylsilyl)thiophene-2-sulfonamide

[0220] Under nitrogen protection, 5a (10.0 g, 41.31 mmol) was dissolved in anhydrous THF (200 mL) in 500 mL. Sodium hydride (2.5 g, 61.96 mmol) was added under ice bath conditions. After the addition was complete, the reaction was maintained at this temperature for 20 min. After 20 min, a solution of tert-butyldimethylchlorosilane (7.2 g, 49.67 mmol) in THF (50 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to return to room temperature for 2 h. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, 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 as a yellow solid (10.3 g, yield 70.0%).

[0221] LCMS m / z(ESI) = 356.0[M+1].

[0222] Step Two:

[0223] N-(tert-butyldimethylsilyl)-5-(3-hydroxyoxetane-3-yl)thiophene-2-sulfonamide (5c)

[0224] N-(tert-butyldimethylsilyl)-5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonamide

[0225] Under nitrogen protection, compound 5b (10.0 g, 29.4 mmol) was dissolved in tetrahydrofuran (100 mL) in a 1 L three-necked flask. The mixture was cooled to -70 °C in a dry ice-ethanol bath, and n-butyllithium (3.0 M in THF, 24.5 mL, 73.5 mmol) was slowly added dropwise. The reaction was maintained at -70 °C for 30 min, and then 3-oxetane (3.1 g, 44.0 mmol) was added. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 1 h. After the reaction was completed, the mixture was poured into 200 mL of ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 5c, a yellow solid (6 g, yield 61.2%).

[0226] 1 LCMS m / z(ESI)=350.3[M+1].

[0227] Step 3:

[0228] 5-(3-hydroxyoxetane-3-yl)thiophene-2-sulfonamide (intermediate 5)

[0229] 5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonamide

[0230] Under nitrogen protection, 5c (6.0 g, 17.17 mmol) and THF (100 mL) were added sequentially to a 100 mL round-bottom flask. The mixture was cooled to 0 °C in an ice bath, and tetrabutylammonium fluoride (35 mL, 1 M in THF, 34.34 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 h. After the reaction was completed, the mixture was quenched with water and extracted with EA (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, 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, a pale yellow solid (3.3 g, yield 82.5%).

[0231] LCMS m / z(ESI) = 236.0[M+l].

[0232] Intermediate 6-Intermediate 7

[0233] Intermediates 6 and 7 were prepared in accordance with intermediate 5.

[0234]

[0235] Intermediate 8

[0236] (R)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-inden-4-amine (Intermediate 8)

[0237] (R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0238]

[0239] first step:

[0240] Intermediate 8 was prepared according to patent CN108017559. In a 500 mL autoclave, 1c (8.3 g, 41.7 mmol) and dichloromethane (90 mL) were added, followed by the catalyst [(R)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (1.8 g, 2.09 mmol). After the addition was complete, the autoclave was tightly sealed, purged three times with hydrogen, and then purged with hydrogen. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give intermediate 8, a pale yellow oil (8.2 g, yield 97.8%, ee%: 97.74%, 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; diode array detector start and stop wavelength: 200–400 nm): RT = 3.295 min).

[0241] 1 H NMR (400MHz, DMSO-d6) δ = 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,1 H),0.50–0.44(m,1H),0.34–0.28(m,1H),0.17–0.11(m,1H),0.06–0.00(m,1H); LCMS m / z(ESI)=202.1[M+1].

[0242] Intermediate 9

[0243] (S)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-inden-4-amine (Intermediate 9)

[0244] (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0245]

[0246] first step:

[0247] Intermediate 9 was prepared according to patent CN108017559. In a 500 mL autoclave, 1c (7.3 g, 36.7 mmol) and dichloromethane (80 mL) were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (1.54 g, 1.83 mmol). After the addition was complete, the autoclave was tightly sealed, purged three times with hydrogen, and then filled with hydrogen. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give intermediate 9, a pale yellow oil (7.1 g, yield 96.3%, ee%: 98.18%, chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35; mobile phase (%): 15; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector starting wavelength: 200–400 nm): RT = 2.802 min).

[0248] 1 H NMR(400MHz, DMSO-d6)δ=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 LCMS m / z(ESI)=202.1[M+l].

[0249] Example 1

[0250] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 1)

[0251] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0252]

[0253] first step:

[0254] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 1)

[0255] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0256] Under nitrogen protection, intermediate 1 (360 mg, 1.79 mmol), triethylamine (218 mg, 2.15 mmol), and 20 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (213 mg, 0.72 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (367 mg, 1.79 mmol) and sodium methoxide (194 mg, 3.58 mmol) were added to the filtrate. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete, quenched with water (100 mL), and extracted with DCM (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed. The crude product was purified by medium-pressure preparation to give compound 1 as a yellow solid (190 mg, yield 24.5%).

[0257] 1 H NMR (400MHz, DMSO-d6) δ = 7.69 (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),0.01–-0.01(m,1H); LCMS m / z=433.1[M+l].

[0258] Example 2

[0259] N-((5-(1-cyclopropenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 2)

[0260] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0261]

[0262] first step:

[0263] N-(tert-butyldimethylsilyl)-N'-((5-(1-cyclopropenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (2A)

[0264] N-(tert-butyldimethylsilyl)-N'-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carba moyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0265] Under nitrogen protection, intermediate 1 (400 mg, 1.99 mmol), triethylamine (242 mg, 2.397 mmol), and 20 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (237 mg, 0.796 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2 (632 mg, 1.99 mmol) and sodium methoxide (215 mg, 3.98 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by thin-layer chromatography to give 2A, a pale yellow oily solid (639 mg, yield 59%).

[0266] LCMS m / z = 546.3 [M+l].

[0267] Step Two:

[0268] N-((5-(1-cyclopropenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 2)

[0269] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0270] Under nitrogen protection, 2A (639 mg, 1.17 mmol) and THF (10 mL) were added sequentially to a 100 mL round-bottom flask. The mixture was cooled to 0 °C in an ice bath, and tetrabutylammonium fluoride (2.4 mL, 1 M in THF, 2.34 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 h. After the reaction was completed, the mixture was quenched with water, extracted with EA (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the residue was removed under reduced pressure. Compound 2 was purified under medium pressure to obtain a white solid (221 mg, yield 43.8%).

[0271] 1 H NMR (400MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.68 (s, 1H), 7.64 (br, 1H), 7.1 3(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),0.15–0.08(m,1H),0.004–0.01(m,1H); LCMS m / z = 43 2.2[M+l].

[0272] Example 3

[0273] N-((5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 3)

[0274] N-((5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0275]

[0276] first step:

[0277] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanol (3A)

[0278] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanol

[0279] In a 50 mL round-bottom flask under nitrogen protection, methanol (20 mL) and compound 1b (1.8 g, 8.96 mmol) were added. The mixture was cooled to 0 °C in an ice bath, and sodium borohydride (678 mg, 17.91 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. After the reaction was complete, the system was cooled to 0 °C, and the reaction was quenched dropwise with 20 mL of water. The mixture was extracted with DCM (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 3A, a colorless oil (1.2 g, yield 66%).

[0280] LCMS m / z = 186.1 [M-17].

[0281] Step Two:

[0282] 5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-amine (3B)

[0283] 5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-amine

[0284] Under nitrogen protection, compound 3A (1.2 g, 5.91 mmol) and triethylsilane (2.1 g, 17.73 mmol) were dissolved in DCM (20 mL), cooled to 0 °C in an ice bath, and trifluoroacetic acid (3.4 g, 29.63 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate water, extracted with DCM (50 mL × 3), dried over anhydrous sodium sulfate, 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, a colorless oil (832 mg, yield 75.6%).

[0285] 1H NMR (400MHz, DMSO-d6) δ = 6.83 (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 m / z(ESI)=188.1[M+1].

[0286] Step 3:

[0287] N-((5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 3)

[0288] N-((5-(cyclopropylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0289] In a 100 mL round-bottom flask under nitrogen protection, 3B (116 mg, 0.62 mmol), triethylamine (75 mg, 0.74 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (74 mg, 0.25 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (127 mg, 0.62 mmol) and sodium methoxide (67 mg, 1.24 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by medium-pressure preparation to give compound 3 as a yellow solid (73 mg, yield 28.2%).

[0290] 1 H NMR (400MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.78 (s, 1H), 7.20 (s, 1H), 7.11-7. 00(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(m,1H),0.39–0.37(m,2H),0.11–0.07(m,2H); LCMS m / z=419.2 [M+l].

[0291] Example 4

[0292] N-((2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 4)

[0293] N-((2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0294]

[0295] first step:

[0296] 2-Chloro-6-(1-Cyclopropylvinyl)-4-fluoroaniline (4B)

[0297] 2-chloro-6-(1-cyclopropylvinyl)-4-fluoroaniline

[0298] In a 500 mL three-necked flask, under nitrogen protection, 4A (8.66 g, 38.56 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (9.73 g, 50.13 mmol), potassium phosphate (16.30 g, 77.12 mmol), dichlorobis(triphenylphosphine)palladium (4.23 g, 5.78 mmol), and 1,4-dioxane / water (120 mL / 40 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 8 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove the solid, and the filtrate was poured into water and extracted with EA (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:200) to give compound 4B, a pale yellow oil (5.4 g, yield 66%).

[0299] LCMS m / z = 212.1[M+l].

[0300] Step Two:

[0301] 2-(1-Cyclopropylvinyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline (4C)

[0302] 2-(1-cyclopropylvinyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline

[0303] In a 100 mL three-necked flask under nitrogen protection, 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), Pd(dppf)Cl2 (2.20 g, 3.01 mmol), and DMF (60 mL) were added sequentially. The mixture was heated to 140 °C and reacted for 4 h. The solid was removed by filtration, and the filtrate was poured into water and extracted with EA (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to give compound 4C, a pale yellow oil (330 mg, yield 5.7%).

[0304] LCMS m / z = 285.1 [M+l].

[0305] Step 3:

[0306] 2-(1-Cyclopropylethyl)-4-fluoro-6-(2-Methoxypyridin-4-yl)aniline (4D)

[0307] 2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline

[0308] In a 100 mL round-bottom flask, 4C (170 mg, 0.60 mmol), palladium / carbon (25.5 mg, 0.15% w / w), and methanol / tetrahydrofuran (5 mL / 10 mL) were added. The mixture was purged with hydrogen three times, and the reaction was carried out at 45 °C for 3 h under a hydrogen atmosphere. The reaction was monitored by TLC until complete. The solid was removed by filtration, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation to give 4D, a pale yellow oil (155 mg, yield 90.6%).

[0309] 1 H NMR (400MHz, DMSO-d6) δ = 8.23 ​​(d, 1H), 7.04 (dd, 1H), 6.94 (dd, 1H), 6.8 5(s,1H),6.81(dd,1H),3.89(s,3H),2.65–2.61(m,1H),1.23–1.16(m,3H),0.94–0.85 (m,1H),0.42–0.38(m,2H),0.10–0.08(m,2H); LCMS m / z=287.2[M+l].

[0310] Step 4:

[0311] N-((2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 4)

[0312] N-((2-(1-cyclopropylethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0313] In a 100 mL round-bottom flask, under nitrogen protection, 4D (155 mg, 0.54 mmol), triethylamine (66 mg, 0.65 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (64 mg, 0.22 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (111 mg, 0.54 mmol) and sodium methoxide (59 mg, 1.08 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by medium-pressure preparation to give compound 4 as a yellow solid (70 mg, yield 25.0%).

[0314] 1 H NMR (400MHz, DMSO-d6) δ = 8.07 (d, 1H), 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 m / z=518.2[M+l].

[0315] Example 5

[0316] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 5)

[0317] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0318]

[0319] first step:

[0320] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 5)

[0321] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0322] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 8 (745 mg, 3.7 mmol), triethylamine (450 mg, 4.45 mmol), and 30 mL of tetrahydrofuran were added sequentially. Triphosgene (440 mg, 1.48 mmol) was added under ice bath conditions. The mixture was heated to reflux for 2 h, and the solid was removed by filtration. 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. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted by DC M (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by medium-pressure preparation (acetonitrile / water = 45%) to give compound 5, a white solid (320 mg, yield 20.0%, ee%: 98.46%, 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; diode array detector wavelength: 200–400 nm): RT = 14.707 min).

[0323] 1H NMR (400MHz, DMSO-d6) δ = 7.68 (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),0.04–0.01(m,1H); LCMS m / z(ESI)=433.2[M+l].

[0324] Example 6

[0325] (R S ,R C )- and (S S ,R C )-N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 6-1 and 6-2)

[0326] (R S ,R C )-and(S S ,R C )-N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)- 4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0327]

[0328] first step:

[0329] (R)-N'-(tert-butyldimethylsilyl)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (6A)

[0330] (R)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)c arbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0331] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 8 (3.1 g, 15.4 mmol), triethylamine (1.87 g, 18.5 mmol), and 100 mL of tetrahydrofuran were added sequentially. Triphosgene (1.83 g, 6.2 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2 (4.9 g, 15.4 mmol) and sodium methoxide (1.66 g, 30.8 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete, yielding compound 6A, which could be directly added to the next step without further purification.

[0332] LCMS m / z = 546.3 [M+l].

[0333] Step Two:

[0334] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (6B)

[0335] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypro pan-2-yl)furan-2-sulfonimidamide

[0336] Tetrabutylammonium fluoride (6.2 mL, 61.6 mmol, 1 M in THF) was added to the previous reaction system, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until completion. The reaction mixture was poured into water, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The mixture was washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give 6B as a transparent solid (1.2 g, yield 18.2%).

[0337] LCMS m / z(ESI) = 432.2[M+l].

[0338] Step 3:

[0339] (RS ,R C )- and (S S ,R C )-N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 6-1 and 6-2)

[0340] (R S ,R C )-and(S S ,R C )-N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)- 4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0341] 6B was resolved by SFC to yield compounds 6-1 (537 mg, yield 44.8%, RT = 14.041 min, ee%: 98.80%) and 6-2 (1.23 g, yield 47%, RT = 17.846 min, ee%: 99.38%). Chiral HPLC (OZ) was performed with the following mobile phases: 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; diode array detector wavelength: 200–400 nm.

[0342] Compound 6-1: 1 H NMR (400MHz, DMSO-d6)δ=8.23(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,2 H),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),0.23–0.20(m,1H),0.13–0.10(m,1H),0.06–0.05(m,1H); LCMS m / z (ESI) = 432.2[M+l].

[0343] Compound 6-2: 1H NMR (400MHz, DMSO-d6)δ=8.24(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,1 H),0.48–0.45(m,1H),0.23–0.20(m,1H),0.13–0.10(m,1H),0.06–0.05(m,1H); LCMS m / z(ESI) = 432.2[M+l].

[0344] Example 7

[0345] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (Compound 7)

[0346] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0347]

[0348] first step:

[0349] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (Compound 7)

[0350] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0351] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 9 (770 mg, 3.83 mmol), triethylamine (464 mg, 4.60 mmol), and 30 mL of tetrahydrofuran were added sequentially. Triphosgene (455 mg, 1.53 mmol) was added under ice bath conditions. The mixture was heated to reflux for 2 h, and the solid was removed by filtration. 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. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted by DC M (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by medium-pressure preparation (acetonitrile / water = 45%) to obtain compound 7, a transparent solid (300 mg, yield 18.1%, 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; diode array detector wavelength: 200–400 nm): RT = 15.935 min).

[0352] 1 H NMR (400MHz, DMSO-d6) δ = 7.80 (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,1 H),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),0.11–0.06(m,1H),0.03–0.05(m,1H); LCMS m / z(ESI) = 433.2[M+ l].

[0353] Example 8

[0354] (R S ,S C )- and (S S ,S C )-N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compounds 8-1 and 8-2)

[0355] (R S ,S C )-and(S S ,SC )-N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4 -(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0356]

[0357] first step:

[0358] (S)-N'-(tert-butyldimethylsilyl)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (8A)

[0359] (S)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)c arbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0360] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 9 (2.60 g, 12.9 mmol), triethylamine (1.57 g, 15.5 mmol), and 100 mL of tetrahydrofuran were added sequentially. Triphosgene (1.54 g, 5.2 mmol) was added in an ice bath, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2 (4.10 g, 12.9 mmol) and sodium methoxide (1.40 g, 25.8 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete, yielding compound 8A, which was directly added to the next step without purification.

[0361] LCMS m / z(ESI) = 546.3 [M+l].

[0362] Step Two:

[0363] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (Compound 8B)

[0364] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonimidamide

[0365] Tetrabutylammonium fluoride (5.2 mL, 51.7 mmol, 1 M / THF) was added to the previous reaction system, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was poured into water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give 8B, a transparent solid (2.6 g, yield 46.6%).

[0366] LCMS m / z = 432.2[M+l].

[0367] Step 3:

[0368] (R S ,S C )- and (S S ,S C )-N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compounds 8-1 and 8-2)

[0369] (R S ,S C )-and(S S ,S C )-N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4 -(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0370] 8B was resolved by SFC to obtain compound 8-1 (1.17 g, yield 45%, ee%: 99.70%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 14.463 min) and compound 8-2 (1.23 g, yield 47%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 19.375 min).

[0371] Compound 8-1: 1 H NMR (400MHz, DMSO-d6)δ=8.24(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),0.23–0.14(m,1H),0.11–0.08(m,1H),0.04–0.0(m,1H); LCMS m / z =432.2[M+l].

[0372] Compound 8-2: 1 H NMR (400MHz, DMSO-d6)δ=8.24(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),0.22–0.20(m,1H),0.12–0.10(m,1H),0.04–0.0(m,1H); LCMS m / z =432.2[M+l].

[0373] Example 9

[0374] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 9)

[0375] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)furan-2-sulfonamide

[0376]

[0377] first step:

[0378] 4-Bromo-7-fluoro-2,3-dihydro-1H-indan-1-ol (9B)

[0379] 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol

[0380] In a 1000 mL round-bottom flask under nitrogen protection, 9A (25.0 g, 109.15 mmol) and 300 mL of methanol were added sequentially. Sodium borohydride (8.3 g, 218.3 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 h. Once the reaction was complete, the reaction mixture was poured into ice water and filtered to obtain compound 9B as a white solid (23.8 g, 94% yield).

[0381] 1 H NMR (400MHz, DMSO-d6) δ = 7.50 (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)=214.0[M-l7].

[0382] Step Two:

[0383] 4-Bromo-7-fluoro-2,3-dihydro-1H-indene (9C)

[0384] 4-bromo-7-fluoro-2,3-dihydro-1H-indene

[0385] In a 500 mL round-bottom flask under nitrogen protection, 9B (23.0 g, 99.6 mmol), triethylsilane (69.3 g, 597.4 mmol), and 300 mL of dichloromethane were added sequentially. Trifluoroacetic acid (34.1 g, 298.7 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 12 h. Once the reaction was complete, the reaction mixture was poured into ice water, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:1-40:1) to give compound 9C as a pale yellow oil (19.4 g, yield 87.7%).

[0386] 1 H NMR (400MHz, DMSO-d6) δ = 7.38 (dd, 1H), 6.75 (t, 1H), 2.99 (t, 2H), 2.88 (t, 2H), 2.11–2.04 (m, 2H).

[0387] Step 3:

[0388] tert-butyl (7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamate (9D)

[0389] tert-butyl(7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamate

[0390] In a 500 mL round-bottom flask under nitrogen protection, 9C (19.0 g, 88.3 mmol), tert-butyl carbamate (15.5 g, 132.5 mmol), 2-dicyclohexylphosphine-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 sequentially. The mixture was heated to 100 °C and reacted for 8 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was poured into water. The mixture was extracted with ethyl acetate (150 mL × 3), dried over anhydrous sodium sulfate, 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 as a pale yellow solid (7.7 g, yield 34.8%).

[0391] LCMS m / z(ESI)=195.1[M-56].

[0392] Step 4:

[0393] 7-Fluoro-2,3-dihydro-1H-inden-4-amine (9E)

[0394] 7-fluoro-2,3-dihydro-1H-inden-4-amine

[0395] In a 250 mL round-bottom flask under nitrogen protection, 9D (7.7 g, 30.7 mmol) and 100 mL of dichloromethane were added sequentially. 25 mL of trifluoroacetic acid was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the reaction mixture was poured into water, the pH was adjusted with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (100 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was then subjected to medium pressure to prepare compound 9E, a pale yellow oil (3.9 g, yield 84.7%).

[0396] 1 H NMR (400MHz, DMSO-d6) δ = 6.63 (t, 1H), 6.37–6.34 (dd, 1H), 4.68 (s, 2H), 2.80 (t, 2H), 2.65 (t, 2H), 2.04–1.97 (m, 2H); LCMS m / z (ESI) = 152.1 [M+l].

[0397] Step 5:

[0398] (4-Amino-7-Fluoro-2,3-Dihydro-1H-Indene-5-yl)(Cyclopropyl)methyl ketone (9F)

[0399] (4-amino-7-fluoro-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone

[0400] Under nitrogen protection, compound 9E (3.9 g, 25.8 mmol) was dissolved in 1,2-dichloroethane (50 mL) in a 250 mL three-necked flask. The mixture was cooled to 0 °C in an ice-salt bath, and a dichloromethane solution of boron trichloride (28 mL, 1 M, 28.4 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 10 min. Then, aluminum trichloride (7.5 g, 30.9 mmol) and cyclopropyl nitrile (2.6 g, 38.7 mmol) were added. The reaction system was heated to 80 °C and reacted for 4 h. After cooling to room temperature, 28 mL (2 M HCl) was added in an ice bath. After the addition was complete, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (100 mL × 3). The organic phase was washed with 28 mL of 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, 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 as a white solid (4.8 g, yield 86.3%).

[0401] 1LCMS m / z(ESI)=220.1[M+1].

[0402] Step 6:

[0403] 5-(1-Cyclopropylvinyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine (9G)

[0404] 5-(1-cyclopropylvinyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine

[0405] Under nitrogen protection, in a 250 mL three-necked flask, compound methyltriphenylphosphine bromide (15.7 g, 43.8 mmol) was dissolved in THF (100 mL). The mixture was cooled to 0 °C in an ice-salt bath, and potassium tert-butoxide (4.9 g, 43.8 mmol) was slowly added. The reaction was maintained at this temperature for 30 min, and then compound 9F (7.0 g, 21.9 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with EA (100 mL × 3), dried over anhydrous sodium sulfate, 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, a pale yellow oil (4.6 g, yield 95%).

[0406] 1 H NMR(400MHz,DMSO-d6)δ6.49(d,1H),5.17(s,1H),4.83(s,1H),4.28(s,2H),2.8 1(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 m / z(ESI)=218.1[M+1].

[0407] Step 7:

[0408] 5-(1-Cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine (9H)

[0409] 5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine

[0410] In a 250 mL three-necked flask, compound 9G (1.0 g, 4.59 mmol) and Pd / C (20 mg, w / w = 5%, Pd content 10%) were dissolved in a mixed solvent of tetrahydrofuran / methanol (10 / 5 mL). The reaction was carried out at room temperature for 15 min under a hydrogen atmosphere. After the reaction was completed, palladium on carbon was removed by filtration, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation to give compound 9H, a pale yellow oil (343 mg, yield 34.3%).

[0411] 1 H NMR(400MHz,DMSO-d6)δ6.74(d,1H),4.34(s,2H),2.79(t,2H),2.68–2.65(m,2H),2.2 5–2.20(m,1H),2.05–1.97(m,2H),1.13(d,3H),1.02–0.94(m,1H),0.51–0.45(m,1H), 0.37–0.30(m,1H),0.19–0.13(m,1H),0.06–0.01(m,1H); LCMS m / z(ESI)=220.1[M+1].

[0412] Step 8:

[0413] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 9)

[0414] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)furan-2-sulfonamide

[0415] In a 100 mL round-bottom flask, under nitrogen protection, compound 9H (120 mg, 0.55 mmol), triethylamine (65 mg, 0.66 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (65 mg, 0.22 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 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. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation (acetonitrile / water = 45%) to give compound 9 as a white solid (28 mg, yield 11.3%).

[0416] 1 H NMR (400MHz, DMSO-d6) δ = 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 m / z(ESI)=451.2[M+l].

[0417] Example 10

[0418] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (Compound 10)

[0419] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)furan-2-sulfonimidamide

[0420]

[0421] first step:

[0422] N'-(tert-butyldimethyl)-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (10A)

[0423] N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4 -yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0424] In a 100 mL round-bottom flask, under nitrogen protection, 9H (190 mg, 0.87 mmol), triethylamine (105 mg, 1.04 mmol), and 30 mL of tetrahydrofuran were added sequentially. Triphosgene (103 mg, 0.35 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2 (277 mg, 0.87 mmol) and sodium methoxide (94 mg, 1.74 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete, yielding compound 10A, which was directly added to the next step without purification.

[0425] LCMS m / z = 564.3 [M+l].

[0426] Step Two:

[0427] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (Compound 10)

[0428] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)furan-2-sulfonimidamide

[0429] Tetrabutylammonium fluoride (3.5 mL, 3.48 mmol, 1 M / THF) was added to the previous reaction system, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was poured into water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give compound 10 as a transparent solid (95 mg, yield 23.4%).

[0430] 1H NMR (400MHz, DMSO-d6)δ=8.18(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,1H), 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),0.25– 0.20(m,1H),0.16–0.08(m,1H),0.04–-0.02(m,1H); LCMS m / z(ESI) = 450.2[M+l].

[0431] Example 11

[0432] N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 11)

[0433] N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxy propan-2-yl)furan-2-sulfonamide

[0434]

[0435] first step:

[0436] 7-Bromo-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-Indene-4-amine (11A)

[0437] 7-bromo-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0438] In a 100 mL round-bottom flask under nitrogen protection, intermediate 1 (600 mg, 2.98 mmol) and dichloromethane (20 mL) were added sequentially. Pyridinium tribromide (1.0 g, 3.28 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. Once the reaction was complete, an aqueous sodium sulfite solution was added to quench the reaction. The mixture was then extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1-5:1) to give compound 11A as a pale yellow oil (446 mg, yield 53%).

[0439] 1 H NMR (400MHz, DMSO-d6) δ = 7.05 (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),0.17–0.13(m,1H),0.05–0.01(m,1H); LCMS(ESI)m / z=280.0[M+l].

[0440] Step Two:

[0441] 7-Amino-6-(1-Cyclopropylethyl)-2,3-Dihydro-1H-Indene-4-Carbaonitrile (11B)

[0442] 7-amino-6-(1-cyclopropylethyl)-2,3-dihydro-1H-indene-4-carbonitrile

[0443] In a 100 mL three-necked flask under nitrogen protection, compound 11A (440 mg, 1.57 mmol), prussiate of Taurine (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 tert-butanol / water mixed solvent (1:1, 20 mL) were added sequentially. The mixture was heated to 85 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate, 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, a pale yellow oil (304 mg, yield 85.6%).

[0444] 1H NMR(400MHz, DMSO-d6)δ=7.30(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),0.38–0.34(m,1H),0.17–0.14(m,1H),0.02-0.01(m,1H); LCMS m / z(ESI)=227.2[M+l].

[0445] Step 3:

[0446] N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 11)

[0447] N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxy propan-2-yl)furan-2-sulfonamide

[0448] In a 100 mL round-bottom flask, under nitrogen protection, compound 11B (116 mg, 0.51 mmol), triethylamine (62 mg, 0.62 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (61 mg, 0.20 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 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. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted by DC-M (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by medium-pressure preparation (acetonitrile / water = 45%) to give compound 11, a pale yellow solid (60 mg, yield 27.5%).

[0449] 1H NMR (400MHz, DMSO-d6) δ = 7.83 (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),2.0 3–1.96(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),0.14–0.10(m,1H),0.07–0.01(m,1H); LCMS m / z(ESI) = 458.2[M+l].

[0450] Example 12

[0451] N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (Compound 12)

[0452] N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxy propan-2-yl)furan-2-sulfonimidamide

[0453]

[0454] first step:

[0455] N'-(tert-butyldimethylsilyl)-N-(((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (12A)

[0456] N'-(tert-butyldimethylsilyl)-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4 -yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0457] In a 100 mL round-bottom flask, under nitrogen protection, 11B (200 mg, 0.88 mmol), triethylamine (107 mg, 1.06 mmol), and tetrahydrofuran (30 mL) were added sequentially. Triphosgene (104 mg, 0.35 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2 (280 mg, 0.88 mmol) and sodium methoxide (9.5 mg, 1.76 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete, yielding compound 12A, which was directly added to the next step without purification.

[0458] LCMS m / z = 571.3 [M+l].

[0459] Step Two:

[0460] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (Compound 12)

[0461] N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)furan-2-sulfonimidamide

[0462] Tetrabutylammonium fluoride (3.5 mL, 3.52 mmol, 1 M / THF) was added to the previous reaction system, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until completion. The reaction solution was poured into water, extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give compound 12 as a transparent solid (160 mg, yield 39.6%).

[0463] 1H NMR (400MHz, DMSO-d6) δ = 8.62 (s, 1H), 7.70 (br, 1H), 7.69 (s, 1H), 7.5 9(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,1 H),0.26–0.22(m,1H),0.15–0.11(m,1H),0.05–0.01(m,1H); LCMS m / z(ESI) = 457.2[M+l].

[0464] Example 13

[0465] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)thiazole-2-sulfonamide (compound 13)

[0466] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypro pan-2-yl)thiazole-2-sulfonamide

[0467]

[0468] first step:

[0469] 2-(benzylthio)thiazole-4-carboxylic acid methyl ester (13B)

[0470] methyl 2-(benzylthio)thiazole-4-carboxylate

[0471] Under nitrogen protection, 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 sequentially to a 500 mL three-necked flask and stirred overnight at room temperature. The reaction endpoint was determined by TLC. Water was added to the reaction mixture under ice bath conditions, and the mixture was extracted three times with EA. The organic phases were combined, washed three times with saturated brine, dried, concentrated, and separated by column chromatography to obtain compound 13B, a pale yellow waxy substance (6.5 g, yield: 22%).

[0472] 1 H NMR (400MHz, DMSO-d6) δ = 8.44 (s, 1H), 7.45 (d, 1H), 7.43 (t, 1H), 7.37–7.24 (m, 3H), 4.52 (s, 2H), 3.83 (s, 3H); LCMS m / z (ESI) = 266.0 [M+1].

[0473] Step Two:

[0474] 2-Aminosulfonylthiazol-4-carboxylic acid methyl ester (13C)

[0475] methyl 2-sulfamoylthiazole-4-carboxylate

[0476] Compound 13B (2.5 g, 9.42 mmol) was added to a 100 mL three-necked flask, followed by the addition of glacial acetic acid (20 mL) and stirring until dissolved. Water (10 mL) was then added, followed by N-chlorosuccinimide (6.3 g, 47.11 mmol). The mixture was stirred at room temperature for 3 h. After TLC, the mixture was extracted three times with water and ethyl acetate. The organic phases were combined and dried to dryness to obtain the crude product. The crude product was dissolved in acetone, stirred in an ice bath for 10 min, and then ammonium bicarbonate (6.5 g, 24.54 mmol) was added. The mixture was stirred and kept at this temperature for 2 h. The reaction endpoint was determined by TLC. The reaction solution was then extracted three times with DCM, and the combined solutions were dried to dryness. Column chromatography was used to separate compound 13C, a pale yellow solid (210 mg, 10% yield).

[0477] 1 H NMR (400MHz, DMSO-d6) δ = 8.79 (s, 1H), 8.30 (s, 2H), 3.87 (s, 3H); LCMS m / z (ESI) = 222.9 [M+1].

[0478] Step 3:

[0479] 4-(2-Hydroxypropyl-2-yl)thiazol-2-sulfonamide (13D)

[0480] 4-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide

[0481] Under nitrogen protection, compound 13C (210 mg, 0.94 mmol) and THF (10 mL) were added to a 50 mL three-necked flask. The mixture was cooled to -10 °C in an ice-salt bath, and a tetrahydrofuran solution of methyl magnesium bromide (34 mL, 34 mmol, 1 M) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound 13D as a light brown oil (194 mg, yield 92%).

[0482] 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.70 (s, 2H), 5.38 (s, 1H), 1.46 (s, 6H); LCMS m / z (ESI) = 223.1 [M+1].

[0483] Step 4:

[0484] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)thiazole-2-sulfonamide (compound 13)

[0485] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypro pan-2-yl)thiazole-2-sulfonamide

[0486] Under nitrogen protection, 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. The mixture was cooled to 0 °C in an ice-salt bath, and triphosgene (70 mg, 0.239 mmol) was slowly added. The reaction was maintained at this temperature for 5 min, then the reaction mixture was heated to 80 °C and reacted for 1 h. After cooling to room temperature, the reaction solution was filtered, and the filtrate was collected. In a 100 mL single-necked flask, compound 13D (121 mg, 0.597 mmol) and sodium methoxide (64 mg, 1.194 mmol) were dissolved in methanol (10 mL) and stirred at room temperature for 1 h. The methanol was then evaporated, and the residue was dissolved in the previously collected filtrate. Nitrogen gas was purged three times, and the mixture was heated to 80 °C and reacted for 1 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparation (acetonitrile / water = 45%) to give compound 13, a pale yellow solid (35.0 mg, yield 13.3%).

[0487] 1 H NMR(400MHz,DMSO-d6)δ7.46(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,2 H); LCMS m / z(ESI)=450.1[M+1].

[0488] Example 14

[0489] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)thiazole-2-sulfonamide (compound 14)

[0490] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)thiazole-2-sulfonamide

[0491]

[0492] first step:

[0493] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)thiazole-2-sulfonamide (compound 14)

[0494] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)thiazole-2-sulfonamide

[0495] Under nitrogen protection, intermediate 9 (120 mg, 0.597 mmol) and triethylamine (11.4 mg, 0.716 mmol) were dissolved in tetrahydrofuran (10 mL) in a 100 mL three-necked flask. The mixture was cooled to 0 °C in an ice-salt bath, and triphosgene (70 mg, 0.239 mmol) was slowly added. The reaction was maintained at this temperature for 5 min, then the reaction mixture was heated to 80 °C and reacted for 1 h. After cooling to room temperature, the reaction solution was filtered, and the filtrate was collected. In a 100 mL single-necked flask, 13D (121 mg, 0.597 mmol) and sodium methoxide (6.4 mg, 1.194 mmol) were dissolved in methanol (10 mL) and stirred at room temperature for 1 h. The methanol was then evaporated, and the residue was dissolved in the previously collected filtrate. Nitrogen gas was purged three times, and the mixture was heated to 80 °C and reacted for 1 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by preparation (acetonitrile / water = 45%) to give compound 14, a pale yellow solid (30.0 mg, yield 11.2%).

[0496] 1 H NMR(400MHz, DMSO-d6)δ7.36(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,2 H); LCMS m / z (ESI) = 450.1 [M+1].

[0497] Example 15

[0498] N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 15)

[0499] N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2 -yl)furan-2-sulfonamide

[0500]

[0501] first step:

[0502] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl) ketone (15A)

[0503] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanone

[0504] Under nitrogen protection, compound 1a (5.0 g, 37.54 mmol) was dissolved in 1,2-dichloroethane (50 mL) in a 500 mL three-necked flask. The mixture was cooled to 0 °C in an ice-salt bath, and a dichloromethane solution of boron trichloride (37.5 mL, 1 M, 37.54 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 10 min. Then, aluminum trichloride (5.5 g, 41.3 mmol) and cyclobutyronitrile (4.5 g, 56.3 mmol) were added. The reaction system was heated to 80 °C and reacted for 4 h. After cooling to room temperature, 40 mL of 2 M HCl was added in an ice bath. After the addition was complete, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (75 mL × 3). The organic phase was washed with 40 mL of 2 M NaOH solution, dried over anhydrous sodium sulfate, 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 as a white solid (2.6 g, yield 32.2%).

[0505] 1 H NMR(400MHz, CDCl3)δ=7.45(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(m,1H); LCMS m / z(ESI)=216.1[M+1].

[0506] Step Two:

[0507] 5-(1-Cyclobutylvinyl)-2,3-dihydro-1H-inden-4-amine (15B)

[0508] 5-(1-cyclobutylvinyl)-2,3-dihydro-1H-inden-4-amine

[0509] Under nitrogen protection, methyltriphenylphosphine bromide (4.0 g, 11.2 mmol) was dissolved in THF (30 mL) in a 100 mL three-necked flask. The mixture was cooled to 0 °C in an ice-salt bath, and potassium tert-butoxide (1.3 g, 11.2 mmol) was slowly added. The reaction was maintained at this temperature for 30 min, and then compound 15A (1.6 g, 7.43 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with EA (50 mL × 3), dried over anhydrous sodium sulfate, 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, a pale yellow oil (1.3 g, yield 82.0%).

[0510] 1 H NMR(400MHz, CDCl3)δ=6.80(d,1H),6.66(d,1H),5.27(t,1H),5.07(t,1H),3.2 9–1.24(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),1.87–1.80(m,1H),1.75–1.68(m,1H); LCMS m / z(ESI)=214.1[M+1].

[0511] Step 3:

[0512] 5-(1-Cyclobutylethyl)-2,3-dihydro-1H-inden-4-amine (15C)

[0513] 5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-amine

[0514] In a 50 mL round-bottom flask, compound 15B (1.3 g, 6.10 mmol) was dissolved in methanol (20 mL), and palladium on carbon catalyst (70 mg) was added. The mixture was stirred at room temperature for three hours under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The organic solvent was removed from the filtrate under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 15C, a pale yellow oil (1.0 g, yield 76.2%).

[0515] 1 H NMR(400MHz, CDCl3)δ=6.86(d,1H),6.68(d,1H),2.90(t,2H),2.74(t,2H),2.69–2.59(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(d,3H); LCMS m / z(ESI)=216.2[M+1].

[0516] Step 4:

[0517] N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 15)

[0518] N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2 -yl)furan-2-sulfonamide

[0519] Under nitrogen protection, compound 15C (200 mg, 0.93 mmol), triethylamine (112 mg, 1.12 mmol), and 10 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (110 mg, 0.37 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (190 mg, 0.93 mmol) and sodium methoxide (100 mg, 1.86 mmol) were added to the filtrate. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to give compound 15 as a yellow solid (100 mg, yield 24.1%).

[0520] 1H NMR (400MHz, DMSO-d6) δ = 7.54 (s, 1H), 7.36 (d, 1H), 6.91 (d, 1H), 6.83 (d, 1H), 6 .60(s,1H),4.91(s,1H),2.98–2.94(m,1H),2.79–2.75(t,2H),2.68–2.63(m,2 LCMS m / z(ESI)=447.2[M+l].

[0521] Example 16

[0522] N-((5-(1-cyclobutenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (Compound 16)

[0523] N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carba moyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0524]

[0525] first step:

[0526] N-(tert-butyldimethylsilyl)-N'-((5-(1-cyclobutenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (16A)

[0527] N-(tert-butyldimethylsilyl)-N'-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carba moyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0528] Under nitrogen protection, compound 15C (200 mg, 0.93 mmol), triethylamine (112 mg, 1.12 mmol), and 10 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (110 mg, 0.37 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2 (296 mg, 0.93 mmol) and sodium methoxide (100 mg, 1.86 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (50 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by thin-layer chromatography to give compound 16A as a pale yellow oily solid (320 mg, yield 61.5%).

[0529] LCMS m / z(ESI) = 560.3[M+l].

[0530] Step Two:

[0531] N-((5-(1-cyclobutenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (Compound 16)

[0532] N-((5-(1-cyclobutylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2 -yl)furan-2-sulfonimidamide

[0533] Under nitrogen protection, compound 16A (320 mg, 0.57 mmol) and THF (10 mL) were added sequentially to a 100 mL round-bottom flask. The mixture was cooled to 0 °C in an ice bath, and tetrabutylammonium fluoride (1.14 mL, 1 M in THF, 1.14 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 h. After the reaction was completed, the mixture was quenched with water, extracted with EA (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the residue was removed under reduced pressure. Compound 16 was then purified under medium pressure to obtain a white solid (100 mg, yield 43.8%).

[0534] 1H NMR (400MHz, DMSO-d6) δ = 8.33 (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),0.96(d,3H); LCMS m / z(ESI)=446.2[M+l].

[0535] Example 17

[0536] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 17)

[0537] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0538]

[0539] first step:

[0540] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol (17A)

[0541] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol

[0542] In a 50 mL round-bottom flask under nitrogen protection, ethanol (20 mL) and compound 15A (2.0 g, 9.30 mmol) were added. The mixture was cooled to 0 °C in an ice bath, and sodium borohydride (703 mg, 18.60 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. After the reaction was completed, the system was cooled to 0 °C, and the reaction was quenched dropwise with 20 mL of water. The mixture was extracted with DCM (30 mL × 3), dried over anhydrous sodium sulfate, 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 as a colorless oil (1.8 g, yield 89%).

[0543] LCMS m / z(ESI)=200.1[M-17].

[0544] Step Two:

[0545] 5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine (17B)

[0546] 5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine

[0547] Under nitrogen protection, compound 17A (1.3 g, 5.98 mmol) and triethylsilane (2.1 g, 17.94 mmol) were dissolved in DCM (20 mL), cooled to 0 °C in an ice bath, and trifluoroacetic acid (3.5 g, 29.90 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate water, extracted with DCM (50 mL × 3), dried over anhydrous sodium sulfate, 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, a colorless oil (1.0 g, yield 83.1%).

[0548] 1 H NMR(400MHz, CDCl3)δ=6.83(d,1H),6.66(d,1H),2.89(t,2H),2.74(t,2H),2.66–2.6 2(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 m / z(ESI)=201.1[M+1].

[0549] Step 3:

[0550] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (compound 17)

[0551] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0552] In a 100 mL round-bottom flask under nitrogen protection, compound 17B (201 mg, 1.00 mmol), triethylamine (121 mg, 1.20 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (103 mg, 0.40 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (205 mg, 1.00 mmol) and sodium methoxide (108 mg, 2.00 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with dichloromethane (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by medium-pressure preparation to give compound 17, a yellow solid (70 mg, yield 16.2%).

[0553] 1 H NMR (400MHz, DMSO-d6) δ = 7.47 (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) = 433.2 [M+l].

[0554] Example 18

[0555] Rs- and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 18-1 and 18-2)

[0556] Rs-and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)furan-2-sulfonimidamide

[0557]

[0558] first step:

[0559] N-(tert-butyldimethylsilyl)-N'-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (18A)

[0560] N-(tert-butyldimethylsilyl)-N'-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carba moyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0561] Under nitrogen protection, 17B (1.5 g, 7.46 mmol), triethylamine (11.02 g, 8.95 mmol), and 10 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (882 mg, 2.98 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2 (2.4 g, 7.46 mmol) and sodium methoxide (806 mg, 14.9 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. After the reaction was complete, it was used directly for the next step without purification. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (50 mL), extracted with DCM (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed to obtain 18A, which was used directly for the next reaction without purification.

[0562] LCMS m / z(ESI) = 546.3 [M+l].

[0563] Step Two:

[0564] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compound 18B)

[0565] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0566] Under nitrogen protection, tetrabutylammonium fluoride (15 mL, 1 M in THF, 15 mmol) was slowly added dropwise to the reaction system from the previous step. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the residue was removed under reduced pressure. Compound 18B was then purified under medium pressure to obtain a white solid (1.43 g, yield 44.0%).

[0567] LCMS m / z(ESI) = 432.2[M+l].

[0568] Step 3:

[0569] Rs- and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 18-1 and 18-2)

[0570] Rs-and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)furan-2-sulfonimidamide

[0571] 18B was resolved by SFC to obtain 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 15.062 min) and compound 18-2 (680 mg, ee%: 99.45%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 10.896 min).

[0572] Compound 18-1: 1H NMR (400MHz, DMSO-d6) δ = 8.30 (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),2.00–1.84(m,4H),1.83–1.70(m,2H),1.63(dd,2H),1.38(s,6 H); LCMS m / z (ESI) = 432.2 [M+l].

[0573] Compound 18-2: 1 H NMR (400MHz, DMSO-d6) δ = 8.30 (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),2.00–1.84(m,4H),1.83–1.70(m,2H),1.63(dd,2H),1.38(s,6 H); LCMS m / z (ESI) = 432.2 [M+l].

[0574] Example 19

[0575] R S -and S S -N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimide (compounds 19-1 and 19-2)

[0576] R S -and S S -N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydrox ypropan-2-yl)thiazole-5-sulfonimidamide

[0577]

[0578]

[0579] first step:

[0580] N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indan-1-yl)-2,4,6-trimethylbenzenesulfonamide (19B)

[0581] N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2,4,6-trimethylbenzenesulfonamide

[0582] In a 500 mL three-necked flask under nitrogen protection, 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). The mixture was cooled to 0 °C in an ice bath, and compound 19A (25.0 g, 16.76 mmol) was added with stirring, maintaining this temperature for the reaction. After 10 min, 2,4,6-trimethylbenzenesulfonyl chloride (36.7 g, 16.76 mmol) was added, and the mixture was slowly heated to room temperature for 6 h. The reaction was monitored by TLC until it ended. The reaction mixture was poured into water, adjusted to weak acidity with 1 M HCl, extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by slurrying with petroleum ether to obtain compound 19B, a white solid (26.4 g, yield 59%).

[0583] LCMS m / z(ESI) = 314.1[M+1].

[0584] Step Two:

[0585] (3aS,8aS)-3-(tris(toluenesulfonyl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole-2-oxide (19 C)

[0586] (3aS,8aS)-3-(mesitylsulfonyl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2-oxide

[0587] In a 500 mL three-necked flask, 19B (16.3 g, 4.92 mmol) and THF (300 mL) were added, and the temperature was lowered to -45 °C. Thionyl chloride (7.3 g, 8.80 mmol) was slowly added dropwise, and the reaction was maintained at this temperature for 30 min. After 30 min, 2,4,6-trimethylpyridine (6.0 g, 9.84 mmol) was slowly added dropwise, and the temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight. The reaction was monitored by TLC until it was complete. The reaction solution was quenched in ice-cold saturated sodium bicarbonate solution, extracted with ethyl acetate (300 mL × 3), and the solvent was removed by concentration under reduced pressure. The residue was slurried with petroleum ether to obtain a crude product. The crude product was slurried with ice-cold acetonitrile to obtain compound 19C, a white solid (16.7 g, yield 90.2%).

[0588] LCMS m / z(ESI) = 378.1 [M+l].

[0589] Step 3:

[0590] 2-(thiazolyl-2-yl)prop-2-ol (19E)

[0591] 2-(thiazol-2-yl)propan-2-ol

[0592] In a 500 mL three-necked flask, 19D (30.0 g, 23.60 mmol) was dissolved in tetrahydrofuran (300 mL). The temperature was lowered to -78 °C, and a tetrahydrofuran solution of methyl magnesium bromide (9.5 mL, 28.32 mmol, 3 M) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 h. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (300 mL × 3), and the solvent was removed by concentration under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to give 19E, a pale yellow oil (20 g, yield 58.8%).

[0593] LCMS m / z(ESI) = 144.0[M+l].

[0594] Step 4:

[0595] (1R, 2S)-1-(((2,4,6-trimethylphenyl)sulfonamido)-2,3-dihydro-1H-indan-2-yl(S)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfinate (19F)

[0596] (1R,2S)-1-((2,4,6-trimethylphenyl)sulfonamido)-2,3-dihydro-1H-inden-2-yl(S)-2-(2-h ydroxypropan-2-yl)thiazole-5-sulfinate

[0597] In a 500 mL three-necked flask, 19E (15.0 g, 10.42 mmol) was dissolved in tetrahydrofuran (300 mL), and the temperature was lowered to -78 °C. Diisopropylaminolithium (11 mL, 20.83 mmol, 2 M) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 h. After 1 h, a THF solution of 19C (39.3 g, 10.42 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 h. The reaction was monitored by TLC until it ended. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (200 mL × 3), concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 20:1-3:1) to give 19F, a pale yellow solid (25.0 g, yield 46.1%).

[0598] 1 H NMR (400MHz, CDCl3) δ = 7.23–7.15 (m, 3H), 7.11 (d, 1H), 7.00 (s, 2H), 5.4 0(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 m / z(ESI)=521.1[M+l].

[0599] Step 5:

[0600] (S)-2-(2-hydroxypropyl-2-yl)thiazolyl-5-sulfinamide (19G)

[0601] (S)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfinamide

[0602] In a 500 mL three-necked flask, 19F (25 g, 4.81 mmol) was dissolved in THF (300 mL). The temperature was lowered to -78 °C, and a THF solution of bis(trimethylsilyl)aminolithium (5 mL, 14.42 mmol, 3 M) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 h. The reaction was monitored by TLC until it ended. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (200 mL × 3), concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (dichloromethane:methanol = 20:1-15:1) to give 19G, a pale yellow solid (8.5 g, yield 86.7%).

[0603] 1 H NMR (400MHz, DMSO-d6) δ = 7.76 (s, 1H), 6.72 (br, 2H), 6.16 (s, 1H), 1.50 (s, 6H); LCMS m / z (ESI) = 207.1 [M+l].

[0604] Step 6:

[0605] (S)-(((2-(2-hydroxypropyl-2-yl)thiazolyl-5-yl)sulfinyl)tert-butyl carbamate (19H)

[0606] tert-butyl(S)-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)sulfinyl)carbamate

[0607] In a 250 mL three-necked flask, 19H (8.0 g, 3.88 mmol) was dissolved in 100 mL of THF. The temperature was lowered to 0 °C, and potassium tert-butoxide (5.2 g, 4.67 mmol) was slowly added. After the addition was complete, the reaction was maintained at this temperature for 30 min. After 30 min, a THF solution of di-tert-butyl dicarbonate (8.9 g, 4.07 mmol) was slowly added dropwise. After the addition was complete, the reaction was brought back to room temperature and reacted for 1 h. The reaction was monitored by TLC until it ended. The solution was quenched with water, and the pH was adjusted to neutral with 1 M HCl. The mixture was extracted with ethyl acetate (100 mL × 3), and the solvent was removed by concentration under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 19H, a pale yellow solid (8.8 g, 74%).

[0608] 1 H NMR (400MHz, DMSO-d6) δ = 10.98 (s, 1H), 8.00 (s, 1H), 6.27 (s, 1H), 1.51 (d, 6H), 1.45 (s, 9H); LCMS m / z (ESI) = 307.1 [M+l].

[0609] Step 7:

[0610] Amino(2-(2-(2-hydroxypropyl-2-yl)thiazolyl-5-yl)(oxo)-16-sulfinylimino)tert-butylcarbamate (19 I)

[0611] tert-butyl(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-l6-sulfanylidene)carbamate

[0612] In a 250 mL three-necked flask, 19H (8.8 g, 2.64 mmol) was dissolved in tetrahydrofuran (100 mL). The temperature was lowered to 0 °C, and trichloroisocyanuric acid (215 mg, 0.924 mmol) was slowly added. After the addition was complete, the reaction was maintained at this temperature for 10 min. After 10 min, ammonia (10 mL, 7 M) solution was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 h. The reaction was monitored by TLC until it ended. The reaction was quenched with water, and the pH was adjusted to neutral with 1 M HCl. The mixture was extracted with ethyl acetate (100 mL × 3), and the solvent was removed by concentration under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 2:1 to dichloromethane: methanol = 15:1) to give 19I, a pale yellow solid (1.8 g, 19.6%).

[0613] 1 H NMR (400MHz, DMSO-d6) δ = 8.04 (s, 1H), 8.03 (s, 1H), 6.33 (s, 1H), 5.76 (s, 1H), 1.51 (d, 6H), 1.28 (s, 9H); LCMS m / z (ESI) = 322.1 [M+l].

[0614] Step 8:

[0615] tert-Butyl((3-(5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)ureoyl)(2-(2-hydroxypropane-2-yl)thiazolyl-5-yl)(oxo)-16-sulfinamide carbamate (compound 19J)

[0616] tert-butyl((3-(5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)ureido)(2-(2-hydroxypr opan-2-yl)thiazol-5-yl)(oxo)-l6-sulfanylidene)carbamate

[0617] Under nitrogen protection, compound 17B (607 mg, 3.02 mmol), triethylamine (366 mg, 3.62 mmol), and 20 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (61.7 mg, 0.21 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and compound 19I (970 mg, 3.02 mmol) and sodium methoxide (327 mg, 6.04 mmol) were added to the filtrate. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with DCM (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent, yielding the crude product compound 19J, which could be used directly in the next step without further purification.

[0618] Step 9:

[0619] N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimide (compound 19K)

[0620] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0621] In a 250 mL round-bottom flask, the crude product from the previous step was added to 30 mL of DCM. 3 mL of trifluoroacetic acid was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.5 h. The reaction was monitored by TLC. Once the reaction was complete, the reaction mixture was poured into an ice-cold sodium bicarbonate aqueous solution and extracted with DCM (30 mL × 3). The extract was dried over anhydrous sodium sulfate, 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 19K (201 mg, white solid, yield 14.1%). LCMS m / z = 449.2 [M+l].

[0622] Step 10:

[0623] Rs- and Ss-N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimide (compounds 19-1 and 19-2)

[0624] Rs-and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydrox ypropan-2-yl)thiazole-5-sulfonimidamide

[0625] 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 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 9.5 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 11.442 min) were obtained by SFC resolution.

[0626] Compound 19-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.30 (s, 1H), 8.04 (s, 1H), 7.80 (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, 1 H), 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 m / z=449.2[M+l].

[0627] Compound 19-2: 1 H NMR (400MHz, DMSO-d6)δ=8.25(s,1H),8.02(s,1H),7.72 (br,2H),6.95(d,1H),6.86(d,1H),6.24(s,H),2.81(t,2H),2.72–2.64(m,2H),2.61–2.5 5(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 m / z=449.2[M+l].

[0628] Example 20

[0629] (R S ,S C )- and (S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydroxypropyl-2-yl)thiazole-5-sulfonylimide (compounds 20-1 and 20-2)

[0630] (R S ,S C )-and(S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0631]

[0632] first step:

[0633] tert-Butyl(N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimideamide)formate (compound 20A)

[0634] tert-butyl(N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hy droxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate

[0635] Under nitrogen protection, intermediate 9 (289 mg, 1.44 mmol), triethylamine (175 mg, 1.73 mmol), and 20 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (171 mg, 0.58 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. Compound 19I (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. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with DCM (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent, yielding the crude product compound 20A, which could be used directly in the next step without further purification.

[0636] Step Two:

[0637] N-(((5-((S)-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimide (compound 20B)

[0638] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydroxyprop an-2-yl)thiazole-5-sulfonimidamide

[0639] In a 250 mL round-bottom flask, the crude product from the previous step was added to DCM (30 mL), and 3 mL of T FA was added dropwise under ice bath conditions. After the addition was complete, the reaction was carried out at room temperature for 1.5 h. The reaction was monitored by TLC. When the reaction was complete, the reaction system was poured into an ice-cold sodium bicarbonate aqueous solution and extracted with DCM (30 mL × 3). The product was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain 20B (272 mg, white solid, yield 42.1%).

[0640] Step 3:

[0641] (R S ,S C )- and (S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-(2-hydroxypropyl-2-yl)thiazole-5-sulfonylimide (compounds 20-1 and 20-2)

[0642] (R S ,S C )-and(SS ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl) -2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0643] 20B was resolved by SFC to obtain 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: diode array detector, initial wavelength: 200 nm; diode array detector, termination wavelength: 400 nm): RT = 5.420 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; diode array detector, initial wavelength: 200 nm; diode array detector, termination wavelength: 400 nm): RT = 8.16 min).

[0644] Compound 20-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.30 (s, 1H), 8.04 (s, 1H), 7.80 (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, 1 H), 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 m / z=449.2[M+l].

[0645] Compound 20-2: 1H NMR (400MHz, DMSO-d6)δ=8.25(s,1H),8.02(s,1H),7.72 (br,2H),6.95(d,1H),6.86(d,1H),6.24(s,H),2.81(t,2H),2.72–2.64(m,2H),2.61–2.5 5(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 m / z=449.2[M+l].

[0646] Example 21

[0647] R S -and S S -N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonylimide (compounds 21-1 and 21-2)

[0648] R S -and S S -N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)-5-methylfuran-2-sulfonimidamide

[0649]

[0650]

[0651] first step:

[0652] 2-Methyl-5-aminosulfonylfuran-3-carboxylic acid methyl ester (21B)

[0653] methyl 2-methyl-5-sulfamoylfuran-3-carboxylate

[0654] In a 500 mL three-necked flask, compound 21A (40 g, 285.43 mmol) was dissolved in 300 mL of DCM. Under nitrogen protection, the mixture was cooled to -10 °C, and chlorosulfonic acid (21 mL, 313.98 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature until the reactant 21A had completely reacted. Then, the mixture was cooled to -15 °C, and pyridine (26 mL, 313.98 mmol) was slowly added dropwise. After the addition was complete, phosphorus pentachloride (47.6 g, 228.35 mmol) was added in portions while maintaining the temperature at -15 °C. The reaction mixture was monitored by TLC. Once no reactant remained, the reaction mixture was discharged. The reaction was quenched by slowly pouring in ice water (500 mL), extracted with ethyl acetate (500 mL × 3), and the organic phases were combined. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a crude product that could be used directly in the next step without further purification. The crude product was dissolved in acetone (400 mL), and saturated ammonium bicarbonate solution (80 g, 1.01 mol) was slowly added. After the addition was complete, the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC until completion, then quenched by pouring in ice water (300 mL), extracted with ethyl acetate (300 mL × 3), and the organic phases were combined. The mixture was 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 as a white solid (31.2 g, yield 49.86%).

[0655] 1 H NMR (400MHz, DMSO-d6) δ = 7.88 (s, 2H), 7.02 (s, 1H), 3.79 (s, 3H), 2.61 (s, 3H). LCMS m / z(ESI)=220.0[M+l].

[0656] Step Two:

[0657] 4-(2-Hydroxypropyl-2-yl)-5-methylfuran-2-sulfonamide (21C)

[0658] 4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

[0659] In a 500 mL three-necked flask under a nitrogen atmosphere, 21B (31.2 g, 142.33 mmol) was dissolved in THF (300 mL), cooled to -15 °C, and methyl magnesium bromide (150 mL, 455.45 mmol, 3.0 mol / L) was slowly added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After 21B disappeared as monitored by TLC, ammonium chloride (200 mL) was added to quench the reaction, and the mixture was extracted with EA (300 mL × 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. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:10-1:3) to give compound 21C, a pale yellow oil (27 g, yield 86.52%).

[0660] 1 H NMR (400MHz, DMSO-d6) δ = 7.56 (s, 2H), 6.80 (s, 1H), 5.00 (s, 1H), 2.40 (s, 3H), 1.38 (s, 6H); LCMS m / z (ESI) = 202.1 [M-l7].

[0661] Step 3:

[0662] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)-5-methylfuran-2-sulfonamide (21D)

[0663] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

[0664] In a 500 mL three-necked flask under a nitrogen atmosphere, 21C (20.0 g, 91.32 mmol) was dissolved in tetrahydrofuran (300 mL). The mixture was cooled to -10 °C in an ice-salt bath, and sodium hydride (7.3 g, 182.44 mmol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 30 min. After 30 min, a tetrahydrofuran (30 mL) solution of tert-butyldimethylchlorosilane (20.6 g, 136.83 mmol) was slowly added dropwise at this temperature. The reaction was carried out at -10 °C for 3 h. After the reaction was completed, the mixture was quenched with water, the pH was adjusted to weakly acidic with 2 M HCl, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:3) to give 21D, a white solid (15.0 g, yield 49.31%).

[0665] 1H NMR (400MHz, DMSO-d6) δ = 7.74 (s, 1H), 6.76 (s, 1H), 5.00 (s, 1H), 2.39 (s, 3H), 1.38 (s, 6H), 0.88 (s, 9H), 0.15 (s, 6H); LCMS m / z (ESI) = 334.1 [M+l].

[0666] Step 4:

[0667] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)-5-methylfuran-2-sulfonylimide (21E)

[0668] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

[0669] In a 500 mL three-necked flask under a nitrogen atmosphere, triphenylphosphine (8.65 g, 32.98 mmol) and hexachloroethane (8.52 g, 35.98 mmol) were dissolved in chloroform (120 mL). The mixture was refluxed for 1 h, then cooled to -10 °C. Diisopropylethylamine (6 g, 46.47 mmol) was slowly added dropwise, and the reaction was allowed to proceed at this temperature for 10 min after the addition was complete. After 10 min, a chloroform solution of 21D (10 g, 29.98 mmol) was slowly added dropwise, and the reaction was allowed to proceed for 30 min after the addition was complete. Ammonia was then passed through the flask at this temperature for 1 h. The reaction was monitored by TLC until it was complete. The mixture was quenched with water, extracted with DCM (120 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate: petroleum ether (v / v) = 1:5) to give compound 21E as a white solid (3 g, yield 30%).

[0670] 1 H NMR (400MHz, DMSO-d6) δ6.81(s,2H),6.61(s,1H),4.99(s,1H),2.41(s,3H),1.41(s,6H),0.89(s,9H),0.01(d,6H); LCMS m / z(ESI)=333.1[M+l].

[0671] Step 5:

[0672] N'-(tert-butyldimethylsilyl)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonylimide (21F)

[0673] N'-(tert-butyldimethylsilyl)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carba moyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

[0674] In a 100 mL round-bottom flask, under nitrogen protection, compound 17B (800 mg, 3.97 mmol), triethylamine (482.56 mg, 4.77 mmol), and 100 mL of tetrahydrofuran were added sequentially. Triphosgene (471.67 mg, 1.59 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and compound 21E (1.32 g, 3.97 mmol) and sodium methoxide (257.64 mg, 4.77 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete, yielding compound 21F, which was directly added to the next step without purification.

[0675] LCMS m / z(ESI) = 560.3[M+l].

[0676] Step 6:

[0677] R- and SN-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonylimide (21G)

[0678] R-and SN-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxy propan-2-yl)-5-methylfuran-2-sulfonimidamide

[0679] Tetrabutylammonium fluoride (5.2 mL, 51.7 mmol, 1 M / THF) was added to the previous reaction system, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was poured into water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give 21 g of white solid (180 mg, yield 10%).

[0680] LCMS m / z(ESI)=446.2[M+l].

[0681] Step 7:

[0682] Rs- and Ss-N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonylimide amides (compounds 21-1 and 21-2)

[0683] Rs-and Ss-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl)-5-methylfuran-2-sulfonimidamide

[0684] 21G was resolved by SFC to obtain 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 16.660 min).

[0685] Compound 21-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.28 (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); LC MS m / z(ESI)=446.2[M+l].

[0686] Compound 21-2: 1H NMR (400MHz, DMSO-d6) δ = 8.28 (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); LC MS m / z(ESI)=446.2[M+l].

[0687] Example 22

[0688] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonamide (Compound 22)

[0689] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypro pan-2-yl)-5-methylfuran-2-sulfonamide

[0690]

[0691] first step:

[0692] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonamide (Compound 22)

[0693] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypro pan-2-yl)-5-methylfuran-2-sulfonamide

[0694] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 8 (201 mg, 1.0 mmol), triethylamine (121 mg, 1.2 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (118.4 mg, 0.4 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 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. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by high-pressure preparation to give compound 22 as a white solid (120 mg, yield 26.9%).

[0695] 1 H NMR (400MHz, DMSO-d6) δ = 7.80 (s, 1H), 7.55 (s, 1H), 7.14 (d, 1H), 7.0 7(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),0.06–0.01(m,1H); LCMS m / z=447.2[M+l].

[0696] Example 23

[0697] (S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonamide (Compound 23)

[0698] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)-5-methylfuran-2-sulfonamide

[0699]

[0700] first step:

[0701] (S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonamide (Compound 23)

[0702] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)-5-methylfuran-2-sulfonamide

[0703] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 9 (201 mg, 1.0 mmol), triethylamine (121 mg, 1.2 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (118.4 mg, 0.4 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 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. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The residue was purified by high-pressure preparation to give compound 23 as a white solid (100 mg, yield 22.4%).

[0704] 1 H NMR (400MHz, DMSO-d6) δ = 7.84 (s, 1H), 7.56 (s, 1H), 7.15 (d, 1H), 7.0 8(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),0.06–0.01(m,1H); LCMS m / z=447.2[M+l].

[0705] Example 24

[0706] R S -and S S -N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonylimide (24-1 and 24-2)

[0707] R S -and S S -N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hy droxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

[0708]

[0709] Compounds 24-1 and 24-2 were prepared according to compounds 21-1 and 21-2. (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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 8.147 min.

[0710] Compound 24-1: 1 H NMR(400MHz,DMSO-d6)δ8.21(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,3 H),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),0.50–0.40(m,1H),0.24–0.15(m,1H),0.13–0.06(m,1H),0.04–0.00(m,1H); LCMS m / z(ESI) = 446.20[M+l].

[0711] Compound 24-2: 1H NMR(400MHz,DMSO-d6)δ8.21(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,3 H),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),0.24–0.15(m,1H),0.13–0.06(m,1H),0.04–0.00(m,1H); LCM S m / z(ESI)=446.20[M+l].

[0712] Example 25

[0713] (R S ,S C ,)- and (S S ,S C ,)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)-5-methylfuran-2-sulfonylimide (25-1 and 25-2)

[0714] (R S ,S C ,)-and(S S ,S C ,)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl) -4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

[0715]

[0716] Compounds 25-1 and 25-2 were prepared according to the same procedures as compounds 21-1 and 22-2. 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 10.626 min) 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 14.722 min)

[0717] Compound 25-1: 1 H NMR (400MHz, DMSO-d6)δ=8.23(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,3 H),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),0.25–0.17(m,1H),0.13–0.07(m,1H),0.06–0.01(m,1H); L CMS m / z(ESI) = 446.20[M+l].

[0718] Compound 25-2: 1 H NMR (400MHz, DMSO-d6) δ = 8.23 ​​(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),0.25–0.17(m,1H),0.14–0.08(m,1H),0.07–0.01(m,1H); LCMS m / z (ESI) = 446.20[M+l].

[0719] Example 26

[0720] (R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (26)

[0721] (R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0722]

[0723] first step:

[0724] (4-Amino-2,3-dihydro-1H-indenyl-5-yl)(cyclopentyl)methyl ketone (26A)

[0725] amino-2,3-dihydro-1H-inden-5-yl)(cyclopentyl)methanone

[0726] In a 500 mL three-necked flask, 1a (23.0 g, 172.68 mmol) was dissolved in 300 mL of dichloroethane. Under nitrogen protection, the mixture was cooled to -10 °C, and a dichloromethane solution of boron trichloride (210 mL, 210 mmol, 1 mol / L) was slowly added dropwise. After the addition was complete, the mixture was reacted at -10 °C for 10 min. Under nitrogen protection, anhydrous aluminum chloride (27.6 g, 207.22 mmol) and cyclopentyl nitrile (24.7 g, 259.02 mmol) were added, and the mixture was refluxed for 4–6 hours. The mixture was cooled to room temperature, then cooled to -10 °C in an ice-salt bath. 1 M dilute HCl (210 mL) was added dropwise, and the mixture was refluxed for 30 min. The reaction was confirmed to be complete by TLC, cooled to room temperature, quenched with 400 mL of water, and extracted with DCM (300 mL × 3). The organic phases were combined. The product was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 26A, a pale yellow oil (31 g, yield 78.3%).

[0727] 1H NMR(400MHz,DMSO-d6)δ7.66(d,1H),6.96(s,2H),6.50(d,1H),3.78–3.7 0(m,1H),2.82(dd,2H),2.66(dd,2H),2.05–1.94(m,2H),1.88–1.77(m,2H),1.76–1.65 (m,2H),1.63–1.53(m,4H); LCMS m / z(ESI)=230.2[M+l].

[0728] Step Two:

[0729] 5-(1-Cyclopentylvinyl)-2,3-dihydro-1H-indan-4-amine (26B)

[0730] 5-(1-cyclopentylvinyl)-2,3-dihydro-1H-inden-4-amine

[0731] In a 1L three-necked flask under a nitrogen atmosphere, methyltriphenylphosphine bromide (11.7 g, 32.70 mmol) was dissolved in THF (80 mL), cooled to 0°C in an ice bath, and potassium tert-butoxide (3.7 g, 32.70 mmol) was added. The reaction was maintained at this temperature for 1 h. After 1 h, a THF solution of 26A (5.0 g, 21.80 mmol) was added dropwise at 0°C, and the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until it ended. The solution was quenched with water, extracted with EA (100 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:20) to obtain 26B, a pale yellow oil (4.2 g, yield 84.73%).

[0732] 1 H NMR (400MHz, DMSO-d6)δ=6.64(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,2H),1. 65–1.54(m,2H),1.55–1.47(m,2H),1.42–1.34(m,2H); LCMS m / z(ESI)=228.1[M+ l].

[0733] Step 3:

[0734] (R)-5-(1-cyclopentylethyl)-2,3-dihydro-1H-indan-4-amine (26C)

[0735] (R)-5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-amine

[0736] In a 500 mL autoclave, 26B (2.1 g, 9.24 mmol) and dichloromethane (30 mL) were added, followed by the catalyst [(R)-(-)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (1.5 g, 1.83 mmol). After the addition was complete, the autoclave was tightly sealed. The air inside the autoclave was purged three times with nitrogen, and then three times with hydrogen. Hydrogen was then introduced. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give 26C, a pale yellow oil (1.0 g, yield 47.17%).

[0737] 1 H NMR (400MHz, DMSO-d6) δ = 6.78 (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(ESI)=2 30.2[M+l].

[0738] Step 4:

[0739] (R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (26)

[0740] (R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0741] In a 100 mL round-bottom flask, under nitrogen protection, compound 26C (200 mg, 0.872 mmol), triethylamine (106.0 mg, 1.05 mmol), and 30 mL of tetrahydrofuran were added sequentially. Triphosgene (104.0 mg, 0.349 mmol) was added under ice bath conditions. The mixture was heated to reflux for 2 h, and the solid was removed by filtration. 2e (179.0 mg, 0.872 mmol) and sodium methoxide (57.0 mg, 1.05 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation (acetonitrile / water = 45%) to obtain compound 26, a white powder solid (150 mg, yield 37.35%, ee% = 79%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 3.854 min).

[0742] 1 H NMR(400MHz,DMSO-d6)δ7.95(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),1.8 4–1.77(m,1H),1.62–1.55(m,1H),1.52–1.41(m,2H),1.38(s,6H),1.30–1.10(m,3H),1.0 4(d,3H),0.85–0.76(m,1H); LCMS m / z(ESI)=443.20[M+l].

[0743] Example 27

[0744] (S)-N-(((5-(1-cyclopentylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide

[0745] (S)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0746]

[0747] first step:

[0748] (S)-5-(1-cyclopentylethyl)-2,3-dihydro-1H-indan-4-amine (27A)

[0749] (S)-5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-amine

[0750] In a 500 mL autoclave, 26B (2.1 g, 9.24 mmol) and dichloromethane (30 mL) were added, followed by the catalyst [(S)-(-)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (1.5 g, 1.83 mmol). After the addition was complete, the autoclave was tightly sealed. The air inside the autoclave was purged three times with nitrogen, and then three times with hydrogen. Hydrogen was then introduced. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give compound 27A, a pale yellow oil (1 g, yield 47.17%).

[0751] 1 H NMR(400MHz,DMSO-d6)δ6.78(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),1.53– 1.38(m,4H),1.29–1.17(m,1H),1.07(d,3H),1.02–0.91(m,1H); LCMS m / z(ESI)=2 30.2[M+l].

[0752] Step Two:

[0753] (R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 27)

[0754] (R)-N-((5-(1-cyclopentylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonamide

[0755] In a 100 mL round-bottom flask, under nitrogen protection, compound 27A (200 mg, 0.872 mmol), triethylamine (106.0 mg, 1.05 mmol), and 30 mL of tetrahydrofuran were added sequentially. Triphosgene (104.0 mg, 0.349 mmol) was added under ice bath conditions. The mixture was heated to reflux for 2 h, and the solid was removed by filtration. 2e (179.0 mg, 0.872 mmol) and sodium methoxide (57.0 mg, 1.05 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation (acetonitrile / water = 45%) to obtain compound 27, a white powder solid (145 mg, yield 36.1%, ee% = 77.8%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 5.005 min).

[0756] 1 H NMR (400MHz, DMSO-d6) δ = 7.96 (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,3H),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),0.86–0.74(m,1H). LCMS m / z(ESI)=443.20[M+l].

[0757] Example 28

[0758] N-((5-(cyclopentylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 28)

[0759] N-((5-(cyclopentylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0760]

[0761] first step:

[0762] (4-Amino-2,3-dihydro-1H-indenyl-5-yl)(cyclopentyl)methanol (28A)

[0763] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopentyl)methanol

[0764] In a 250 mL three-necked flask, compound 26A (5.0 g, 21.80 mmol) was dissolved in ethanol (80 mL), and sodium borohydride (3.5 g, 92.51 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC until it was complete. The mixture was then quenched with water and filtered to obtain the crude product. The crude product was then slurried with ethyl acetate / petroleum ether = 1:100 to obtain 28A (5 g, yield 99.13%).

[0765] LCMS m / z(ESI)=214.1[M-17].

[0766] Step Two:

[0767] 5-(cyclopentylmethyl)-2,3-dihydro-1H-indan-4-amine (28B)

[0768] 5-(cyclopentylmethyl)-2,3-dihydro-1H-inden-4-amine

[0769] In a 250 mL three-necked flask, compound 28A (5.0 g, 21.61 mmol) was dissolved in DCM (60 mL). Triethylsilane (12.6 g, 108.36 mmol) and trifluoroacetic acid (4.9 g, 49.99 mmol) were added under ice bath conditions. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was poured into water, and the pH was adjusted to neutral with saturated sodium bicarbonate. The mixture was extracted with DCM (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to give compound 28B (3.0 g, 64.46%).

[0770] LCMS m / z(ESI) = 216.1[M+l].

[0771] Step 3:

[0772] N-((5-(cyclopentylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 28)

[0773] N-((5-(cyclopentylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[0774] In a 100 mL round-bottom flask, under nitrogen protection, 28B (500 mg, 2.32 mmol), triethylamine (282.0 mg, 2.79 mmol), and 30 mL of tetrahydrofuran were added sequentially. Triphosgene (276.0 mg, 0.929 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (1.48 g, 2.32 mmol) and sodium methoxide (151.0 mg, 2.79 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation (acetonitrile / water = 45%) to give compound 28 as a white powder solid (350 mg, yield 33.76%).

[0775] 1 H NMR (400MHz, DMSO-d6) δ = 7.81 (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),1.15–1.04(m,2H); LCMS m / z(ESI)=429.1[M+l].

[0776] Example 29

[0777] (R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl-7-d)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 29)

[0778] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-hydroxy propan-2-yl)furan-2-sulfonamide

[0779]

[0780] first step:

[0781] (R)-7-bromo-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-amine (29A)

[0782] (R)-7-bromo-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0783] In a 100 mL round-bottom flask under nitrogen protection, intermediate 8 (2.0 g, 9.95 mmol) and dichloromethane (50 mL) were added sequentially. Pyridinium tribromide (3.5 g, 10.9 mmol) was then slowly added under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. At the end of the reaction, the reaction mixture was quenched with an aqueous sodium sulfite solution. Extraction was performed with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, 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 (2.7 g, pale yellow oil, 97% yield).

[0784] 1 H NMR (400MHz, DMSO-d6) δ = 7.05 (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),0.17–0.16(m,1H),0.09–0.05(m,1H); LCMS m / z=281.2[M+l].

[0785] Step Two:

[0786] (R)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-Indan-7-d-4-amine (29B)

[0787] (R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-7-d-4-amine

[0788] In a 100 mL round-bottom flask, under nitrogen protection, 29A (1.5 g, 5.4 mmol), sodium deuterate (0.75 g, 10.8 mmol), tris(dibenzylacetone)dipalladium (247 mg, 0.27 mmol), tri-tert-butylphosphine (109 mg, 0.54 mmol), and 30 mL of dimethyl sulfoxide were added sequentially. The mixture was heated to 80 °C and reacted for 8 h. After the reaction was complete, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, 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, a pale yellow solid (1 g, yield 8.5%).

[0789] 1 H NMR (400MHz, DMSO-d6) δ = 6.92 (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),0.33–0.28(m,1H),0.15–0.10(m,1H),0.04–0.01(m,1H); LCMS m / z=203.2[M +l].

[0790] Step 3:

[0791] (R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl-7-d)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 29)

[0792] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-hydroxy propan-2-yl)furan-2-sulfonamide

[0793] In a 100 mL round-bottom flask, under nitrogen protection, compound 29B (201 mg, 1.0 mmol), triethylamine (121 mg, 1.2 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (118.4 mg, 0.4 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (205 mg, 1.0 mmol) and sodium methoxide (108 mg, 2.0 mmol) were added to the filtrate. The mixture was reacted at 60 °C for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with 100 mL of water. Extraction was performed with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The organic solvent was removed, and the crude product was purified by high-pressure preparation to obtain compound 29, a white solid (100 mg, yield 23.1%, ee%: 98.64%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 12.342 min).

[0794] 1 H NMR (400MHz, DMSO-d6) δ = 7.63 (s, 1H), 7.15 (s, 2H), 5.10 (s, 1H), 2.81 (t, 2H), 2.77 (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),0.52–0.43(m,1H),0.27–0.19(m,1H),0.14–0.07(m,1H),0.04–0.01(m,1H); LCMS m / z(ESI)=434.2[M+l].

[0795] Example 30

[0796] (S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl-7-d)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 30)

[0797] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-hydroxy propan-2-yl)furan-2-sulfonamide

[0798]

[0799] first step:

[0800] (S)-7-bromo-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-amine (30a)

[0801] (S)-7-bromo-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0802] In a 100 mL round-bottom flask under nitrogen protection, intermediate 9 (2.0 g, 9.95 mmol) and dichloromethane (50 mL) were added sequentially, followed by slow addition of pyridinium tribromide (3.5 g, 10.9 mmol) under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. Upon completion of the reaction, the reaction mixture was quenched with an aqueous sodium sulfite solution. The mixture was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, 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 30A (2.7 g, pale yellow oil, 97% yield).

[0803] 1 H NMR (400MHz, DMSO-d6) δ = 7.05 (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),0.17–0.16(m,1H),0.09–0.05(m,1H); LCMS m / z=281.2[M+l].

[0804] Step Two:

[0805] (S)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-Indan-7-d-4-amine (30B)

[0806] (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-7-d-4-amine

[0807] In a 100 mL round-bottom flask under nitrogen protection, 30A (1.5 g, 5.4 mmol), sodium deuterate (0.75 g, 10.8 mmol), tris(dibenzylacetone)dipalladium (247 mg, 0.27 mmol), tri-tert-butylphosphine (109 mg, 0.54 mmol), and 30 mL of dimethyl sulfoxide were added sequentially. The mixture was heated to 80 °C and reacted for 8 h. After the reaction was complete, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, 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 30B (778 mg, pale yellow solid, yield 71.9%).

[0808] 1 H NMR (400MHz, DMSO-d6) δ = 6.92 (s, 1H), 4.43 (s, 1H), 2.74 (t, 2H), 2.60 (t, 2H), 2 .25–2.21(m,1H),2.01–1.90(m,2H),1.13(d,3H),1.08–0.93(m,1H),0.49–0.41 (m,1H),0.33–0.26(m,1H),0.15–0.10(m,1H),0.05–0.01(m,1H); LCMS m / z=203.2 [M+l].

[0809] Step 3:

[0810] (S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl-7-d)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 30)

[0811] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-hydroxy propan-2-yl)furan-2-sulfonamide

[0812] In a 100 mL round-bottom flask under nitrogen protection, compound 30B (201 mg, 1.0 mmol), triethylamine (121 mg, 1.2 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (118.4 mg, 0.4 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 2e (205 mg, 1.0 mmol) and sodium methoxide (108 mg, 2.0 mmol) were added to the filtrate. The mixture was reacted at 60 °C for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by high-pressure preparation to give compound 30, a white solid (100 mg, yield 23.1%, ee%: 98.92%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 10.332 min).

[0813] 1 H NMR(400MHz,DMSO-d6)δ7.68(s,1H),7.12(s,2H),5.05(s,1H),2.81(t,2H),2.67(t,2H),2.17(m,1H),1.99–1.86(m,2H) ,1.37(s,6H),1.10(d,3H),0.93(m,1H),0.50–0.41(m,1H),0.25–0.16(m,1H),0.12–0.07(m,1H),0.04–0.01(m,1H); LCMS m / z(ESI) =434.2[M+l].

[0814] Example 31

[0815] (R S ,R C )- and (S S ,R C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl-7-d)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide amide (31-1 and 31-2)

[0816] (R S ,R C )-and(S S ,R C)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbam oyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0817]

[0818] Compounds 31-1 and 31-2 were prepared by referring to compounds 21-1 and 21-2. Compound 31-1 (57 mg, yield 75%, ee%: 97.02%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 14.234 min) and compound 31-2 (53 mg, yield 75%, ee%: 99.54%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 18.033 min).

[0819] Compound 31-1: 1 H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.67(d,1H),7.62(s,2H),7.12(s,1H),6.97(s,1H),5.07(s,1H),2.82(t,2H),2.67(t,2 H),2.25–2.21(m,1H),1.95–1.91(m,2H),1.37(s,6H),1.11(d,3H),0.96–0.91(m,1H),0.46–0.41(m,1H),0.21–0.16(m,1H), 0.11–0.07(m,1H),0.04–0.01(m,1H); LCMS m / z(ESI)=433.1[M+1].

[0820] Compound 31-2: 1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.67(d,1H),7.64(s,2H),7.12(s,1H),6.97 (s,1H),5.08(s,1H),2.82(t,2H),2.67(t,2H),2.25–2.21(m,1H),1.95–1.91(m, 2H),1.37(s,6H),1.11(d,3H),0.96–0.91(m,1H),0.49–0.43(m,1H),0.25–0.21(m,1H), 0.14–0.10(m,1H),0.06–0.02(m,1H); LCMS m / z(ESI)=433.1[M+1].

[0821] Example 32

[0822] (R S ,S C )- and (S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl-7-d)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide amide (32-1 and 32-2)

[0823] (R S ,S C )-and(S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbam oyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0824]

[0825] Compounds 32-1 and 32-2 were prepared by referring to compounds 21-1 and 22-2. Compound 32-1 (194 mg, yield 71.6%, ee%: 99.29%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 14.980 min) and compound 32-2 (164 mg, yield 71.6%, ee%: 99.20%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 19.398 min).

[0826] Compound 32-1: 1 H NMR (400MHz, DMSO-d6)δ=8.23(s,1H),7.67(d,1H),7.62(s,2H),7.12(s,1H),6.97(s,1H),5.07(s,1H),2.82(t,2H),2.67(t, 2H),2.25–2.21(m,1H),1.95–1.91(m,2H),1.37(s,6H),1.11(d,3H),0.96–0.91(m,1H),0.46–0.41(m,1H),0.21–0.16(m,1H), 0.11–0.07(m,1H),0.04–0.01(m,1H); LCMS m / z(ESI)=433.1[M+1].

[0827] Compound 32-2: 1 H NMR (400MHz, DMSO-d6)δ=8.25(s,1H),7.67(d,1H),7.64(s,2H),7.12(s,1H),6.97(s,1H),5.08(s,1H),2.82(t,2H),2.67(t, 2H),2.25–2.21(m,1H),1.95–1.91(m,2H),1.37(s,6H),1.11(d,3H),0.96–0.91(m,1H),0.49–0.43(m,1H),0.25–0.21(m,1H), 0.14–0.10(m,1H),0.06–0.02(m,1H); LCMS m / z(ESI)=433.1[M+1].

[0828] Example 33

[0829] N-((3-(cyclobutylmethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide(33)

[0830] N-((3-(cyclobutylmethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0831]

[0832] first step:

[0833] 2-(2,6-Dibromophenyl)ethane-1-ol (33B)

[0834] 2-(2,6-dibromophenyl)ethan-1-ol

[0835] In a 1L three-necked flask, 33A (60.0 g, 0.2 mol) and anhydrous tetrahydrofuran (300 mL) were added. Under nitrogen protection, a borane tetrahydrofuran solution (300 mL, 1 M) was slowly added dropwise at 0 °C. After the addition was complete, the temperature was raised to 80 °C and the reaction was allowed to proceed for 1 h. The reaction was monitored by TLC until complete and then cooled to room temperature. Water (150 mL) was added in an ice-water bath, and the reaction was quenched with dilute hydrochloric acid (20 mL, 2 N). Part of the reaction solution was concentrated under reduced pressure, and then extracted with ethyl acetate (100 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give 33B as a white solid (50.0 g, yield 88%).

[0836] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.94 (t, 1H), 3.88 (t, 2H), 3.33 (t, 2H).

[0837] Step Two:

[0838] 1,3-Dibromo-2-(2-bromoethyl)benzene (33C)

[0839] 1,3-dibromo-2-(2-bromoethyl)benzene

[0840] In a 1L round-bottom flask, 33B (50.0 g, 0.18 mol), N-bromosuccinimide (38.0 g, 0.2 mmol), and dichloromethane (400 mL) were added sequentially. After stirring until dissolved, the flask was placed in an ice-water bath, and triphenylphosphine (65 g, 0.2 mol) was slowly added. After the addition was complete, the flask was moved to room temperature and reacted for 24 h. The reaction was monitored by TLC until complete. Tert-butyl hydroperoxide (8 mL) was added and reacted for 2 h to remove excess triphenylphosphine. The reaction was quenched by adding saturated sodium bisulfite solution (200 mL), extracted with dichloromethane (200 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated until a large amount of solid precipitated. Hexane was added to slurry the mixture, and the mixture was filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain 33C, a white solid (60.0 g, yield 98%).

[0841] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.97 (t, 1H), 3.63–3.43 (m, 4H).

[0842] Step 3:

[0843] 2-Bromobicyclo[4.2.0]oct-1(6),2,4-triene(33D)

[0844] 2-bromobicyclo[4.2.0]octa-1(6),2,4-triene

[0845] In a 250 mL three-necked flask, 33C (5.0 g, 15 mmol) and anhydrous tetrahydrofuran (150 mL) were added sequentially. Under nitrogen protection, n-butyllithium (5.5 mL, 2.5 M) was slowly added dropwise at -68 °C. After the addition was complete, the reaction was carried out at -68 °C for 2 h. The reaction was monitored by UP LC until complete. The reaction was quenched by slowly adding water (20 mL). The mixture was extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain compound 33D, a pale yellow oil (2.5 g, 90% yield).

[0846] Step 4:

[0847] tert-Butylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamate (33E)

[0848] tert-butyl bicyclo[4.2.0]octa-1(6),2,4-trien-2-ylcarbamate

[0849] In a 250 mL round-bottom flask, 33D (2.3 g, 0.013 mol), dioxane (50 mL), tert-butyl carbamate (2.2 g, 0.019 mol), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (476 mg, 1 mmol), and cesium carbonate (8.0 g, 0.025 mol) were added sequentially. Palladium acetate (132 mg, 6 mmol) was added under nitrogen protection. The mixture was heated to 100 °C and reacted for 2 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, 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 obtain 33E (2.3 g, brown oil, yield 83%).

[0850] 1 H NMR (400MHz, CDCl3) δ = 7.27 (d, 1H), 7.13 (t, 1H), 6.76 (d, 1H), 6.31 (s, 1 H), 3.27–3.16 (m, 2H), 3.16–3.06 (m, 2H), 1.52 (s, 9H).

[0851] Step 5:

[0852] Bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(33F)

[0853] bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0854] In a 100 mL round-bottom flask, 33E (2.3 g, 10.5 mmol), dichloromethane (40 mL), and trifluoroacetic acid (6 mL) were added sequentially. The mixture was reacted at room temperature for 7 h. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated sodium bicarbonate solution (40 mL). The mixture was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 33F, a brown oily substance (1.0 g, yield 80%).

[0855] 1 H NMR (400MHz, CDCl3) δ = 7.02 (dd, 1H), 6.51 (dd, 2H), 3.11 (dd, 2H), 3.04 (dd, 2H).

[0856] Step 6:

[0857] (2-Aminobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(cyclobutyl) ketone (33G)

[0858] (2-aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclobutyl)methanone

[0859] In a 100 mL three-necked flask, 33F (1.0 g, 8.4 mmol) and dichloroethane (10 mL) were added sequentially. After dissolving, the flask was placed in an ice-water bath. Under nitrogen protection, boron trichloride toluene solution (10 mL, 1 M) was slowly added dropwise. After 10 min, anhydrous aluminum trichloride (1.3 g, 10 mmol) was added, followed by slow dropwise addition of cyclobutyl nitrile (1.2 mL, 12.6 mmol). After the addition was complete, the mixture was reacted at 90 °C for 7 h. After cooling to room temperature, dilute hydrochloric acid solution (10 mL, 2 N) was added, and the mixture was refluxed for 30 min. The organic phase was separated, washed with saturated sodium bicarbonate (20 mL) until weakly acidic, extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 33 G, a brown oily substance (800 mg, yield 47%).

[0860] 1 H NMR(400MHz, CDCl3)δ7.51(d,1H),6.45(d,1H),4.05–3.91(m,1H),3.06 (d,2H),3.02(d,2H),2.47–2.35(m,2H),2.29-2.20(m,2H),2.05(ddd,1H),1.87(ddd,1H).

[0861] Step 7:

[0862] (2-Aminobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(cyclobutyl)methanol(33H)

[0863] (2-aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclobutyl)methanol

[0864] In a 50 mL round-bottom flask, 33G (800 mg, 4 mmol), anhydrous methanol (20 mL), and sodium borohydride (227 mg, 6 mmol) were added sequentially. The mixture was reacted at room temperature for 8 h. The reaction was monitored by TLC until complete. The reaction was quenched by slowly adding water (20 mL). The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give 33H, a brown oily substance (600 mg, yield 75%).

[0865] LCMS m / z(ESI)=186.1[M-17].

[0866] Step 8:

[0867] 3-(cyclobutylmethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(33I)

[0868] 3-(cyclobutylmethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0869] In a 50 mL round-bottom flask, 33H (600 mg, 3 mmol), dichloromethane (20 mL), triethylsilane (1.4 mL, 9 mmol), and trifluoroacetic acid (1.1 mL, 15 mmol) were added sequentially. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction was quenched by slowly adding saturated sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10.1) to obtain 33I (150 mg, brown oil, yield 32%).

[0870] 1 H NMR (400MHz, CDCl3) δ=6.88(d,1H),6.50(d,1H),3.08(d,2H),3.06–3.01(m,2H),2.69–2.55(m,3H),2.09(ddd,2H),1.88(ddd,2H),1.74(dt,2H).

[0871] Step 9:

[0872] N-((3-(cyclobutylmethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 33)

[0873] N-((3-(cyclobutylmethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0874] Under nitrogen protection, 33I (170 mg, 0.9 mmol), triethylamine (152 μL, 1.0 mmol), and tetrahydrofuran (10 mL) were added sequentially to a 100 mL round-bottom flask. Triphosgene (118 mg, 0.4 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 2e (143 mg, 0.7 mmol) and sodium methoxide (97 mg, 1.8 mmol) were added to the filtrate. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to give compound 33 as a white solid (25 mg, yield 8%).

[0875] 1 H NMR (400MHz, DMSO-d6) δ = 7.90 (s, 1H), 7.67 (s, 1H), 7.05 (s, 1H), 6.91 (d, 1H),6.73(d,1H),5.07(s,1H),3.00(dd,2H),2.93(d,2H),2.57(d,2H),2.47–2.35(m,1 H),1.96–1.85(m,2H),1.77(tt,2H),1.70–1.55(m,2H),1.37(s,6H); LCMS m / z(ESI)= 401.1[M-17]

[0876] Example 34

[0877] R S -and S S -N-((3-(cyclobutylmethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 34-1 and 34-2)

[0878] R S -and

[0879] S S -N-((3-(cyclobutylmethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0880]

[0881] Compounds 34-1 and 34-2 were prepared according to compounds 21-1 and 21-2. Compound 34-1 (40 mg, ee%: 99.88%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 10.722 min) and compound 34-2 (33 mg, ee%: 99.16%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 12.380 min).

[0882] Compound 34-1: 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.70(d,2H),7.01(d,1H),6.88(d,1H),6.73(d,1H),5.10(s,1H),2.95(t ,4H),2.63(dd,2H),2.49–2.41(m,1H),1.94–1.87(m,2H),1.83–1.72(m,2H),1.63(dt,2H),1.39(s,6H); LCMS m / z=418.2[M+1].

[0883] Compound 34-2: 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.78–7.62(m,2H),7.01(d,1H),6.88(d,1H),6.73(d,1H),5.10(s,1H),2 .95(s,4H),2.63(dd,2H),2.45(dd,1H),1.99–1.86(m,2H),1.77(tt,2H),1.69–1.56(m,2H),1.39(s,6H); LCMS m / z=418.2[M+1].

[0884] Example 35

[0885] (S)-N-(((3-(1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 35)

[0886] (S)-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0887]

[0888]

[0889] first step:

[0890] (2-Aminobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(cyclopropyl)methyl ketone(35A)

[0891] (2-aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclopropyl)methanone

[0892] In a 25 mL three-necked flask, 33F (100 mg, 0.84 mmol) and dichloroethane (5 mL) were added sequentially. After dissolving, the flask was placed in an ice-water bath. Under nitrogen protection, boron trichloride toluene solution (900 μL, 1 M) was slowly added dropwise. After 10 min, anhydrous aluminum trichloride (123 mg, 0.9 mmol) was added, followed by slow dropwise addition of cyclobutyronitrile (74 μL, 1 mmol). After the addition was complete, the mixture was reacted at 90 °C for 3 h. After cooling to room temperature, dilute hydrochloric acid solution (1 mL, 2 N) and water (5 mL) were added, and the mixture was refluxed for 30 min. The organic phase was separated, washed with saturated sodium bicarbonate (10 mL) until weakly acidic, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 35A, a brown oily substance (60 mg, yield 38%).

[0893] 1 H NMR (400MHz, CDCl3) δ = 7.91 (d, 1H), 6.51 (d, 1H), 3.12–3.05 (m, 2H), 3.0 4–2.95(m,2H),2.67–2.54(m,1H),1.19–1.10(m,2H),1.00–0.87(m,2H).

[0894] Step Two:

[0895] 3-(1-Cyclopropylvinyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(35B)

[0896] 3-(1-cyclopropylvinyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0897] In a 25 mL three-necked flask, triphenylmethylphosphine bromide (8 g, 22 mmol) and anhydrous tetrahydrofuran (40 mL) were added sequentially. After dissolving, the mixture was placed in an ice-water bath. Under nitrogen protection, potassium tert-butoxide (2.5 g, 22 mmol) was added. After 40 min, a tetrahydrofuran solution of 35A (1.4 g, 7.5 mmol) (20 mL) was added. After 10 min, the mixture was reacted at room temperature for 2 h. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, 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 35B (1.2 g, brown oil, yield 85%).

[0898] 1 H NMR (400MHz, CDCl3) δ=6.87(d,1H),6.49(d,1H),5.17(d,1H),4.91(d,1 H),3.09(dd,2H),3.03(dd,2H),1.63(tt,1H),0.77–0.67(m,2H),0.54–0.44(m,2H).

[0899] Step 3:

[0900] (S)-3-(1-Cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(35C)

[0901] (S)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0902] In a 500 mL autoclave, 35B (500 mg, 2.7 mmol) and dichloromethane (50 mL) were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (113 mg, 0.14 mmol). After the addition was complete, the autoclave was tightly sealed, purged three times with hydrogen, and then purged with hydrogen. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 5 h. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 35C, a pale yellow oil (360 mg, yield 72%).

[0903] 1H NMR (400MHz, MeOD) δ = 7.04 (d, 1H), 6.43 (d, 1H), 3.00 (s, 4H), 2.31–2.1 4(m,1H),1.24(d,3H),1.09–0.94(m,1H),0.62–0.46(m,1H),0.36(dt,1H),0.15(dt,1H), 0.06(dt,1H).

[0904] Step 4:

[0905] (S)-N-(((3-(1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 35)

[0906] (S)-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0907] Under nitrogen protection, in a 100 mL round-bottom flask, 35C (100 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (165 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (103 μL, 0.75 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The solution was then dissolved in tetrahydrofuran (10 mL), and intermediate 2e (82 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to obtain compound 35, a yellow solid (56 mg, yield 26.7%, UPLC: 95.6%, ee%: 98.12%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 10.052 min).

[0908] 1H NMR (400MHz, DMSO-d6) δ = 7.79 (s, 1H), 7.58 (s, 1H), 7.15 (d, 1H), 6.90 (s,1H),6.80(d,1H),5.03(s,1H),3.05–2.85(m,4H),2.25(dd,1H),1.36(s,6H),1.14( d,3H),0.96(tt,1H),0.47(dq,1H),0.26(tq,1H),0.10(dt,1H),0.04–-0.05(m,1H); LCM S m / z(ESI)=419.1[M+l].

[0909] Example 36

[0910] (R S ,S C )- and (S S ,S C )-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 36-1 and 36-2)

[0911] (R S ,S C )-and(S S ,S C )-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0912]

[0913] The synthesis of compounds 36-1 and 36-2 was performed in accordance with the procedures for compounds 21-1 and 22-2. Compound 36-1 (80 mg, ee%: 98.94%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 5.836 min) and compound 36-2 (100 mg, ee%: 98.74%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 8.054 min).

[0914] Compound 36-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.69 (d, 2H), 7.67 (s,1H),7.17(d,1H),6.99(s,1H),6.83(d,1H),5.09(s,1H),2.96(s,4H),2.33(dd,1H), 1.38(s,6H),1.10(d,3H),0.95(tt,1H),0.47(dt,1H),0.24(dt,1H),0.13(dd,1H),0.05 (dt, 1H); LCMS m / z (ESI) = 418.1 [M+l].

[0915] Compound 36-2: 1 H NMR (400MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.69 (d, 2H), 7.67 (s,1H),7.16(d,1H),6.99(d,1H),6.84(d,1H),5.09(s,1H),2.96(d,4H),2.35(dd,1H), 1.38(s,6H),1.13(d,3H),0.92(tt,1H),0.45(tq,1H),0.21(tq,1H),0.10(dq,1H),0.02 (dd, 1H); LCMS m / z (ESI) = 418.1 [M+l].

[0916] Example 37

[0917] (R)-N-(((3-(1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 37)

[0918] (R)-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0919]

[0920] first step:

[0921] (R)-3-(1-Cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(37A)

[0922] (R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0923] In a 500 mL autoclave, 35B (500 mg, 2.7 mmol) and dichloromethane (50 mL) were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (113 mg, 0.14 mmol). After the addition was complete, the autoclave was tightly sealed and purged with hydrogen three times. The pressure gauge on the autoclave showed a pressure of 14 atm. The reaction was carried out at room temperature for 5 h. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 37A (470 mg, pale yellow oil, yield 94%).

[0924] 1 H NMR (400MHz, DMSO) δ = 6.95 (d, 1H), 6.30 (d, 1H), 2.88 (s, 4H), 2.2 (m, 1 H),1.23(d,3H),0.97(m,1H),0.46(m,1H),0.29(dt,1H),0.12(dt,1H),0.01(dt,1H).

[0925] Step Two:

[0926] (R)-N-(((3-(1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 37)

[0927] (R)-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0928] Under nitrogen protection, in a 100 mL round-bottom flask, compound 37A (100 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (165 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (103 μL, 0.75 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and compound 2e (82 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol) were added. The reaction was carried out at 40 °C for 3 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to obtain compound 37 (50 mg, grayish-white solid, yield 22.4%, UPLC: 94.71%, ee% = 94.1%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 10.861 min). 1 H NMR (400MHz, D MSO-d6)δ=7.79(s,1H),7.58(s,1H),7.15(d,1H),6.90(s,1H),6.80(d,1H),5.03(s,1 H),3.05–2.85(m,4H),2.25(dd,1H),1.36(s,6H),1.14(d,3H),0.96(tt, 1H),0.47(dq,1H),0.26(tq,1H),0.10(dt,1H),0.04–-0.05(m,1H); LCMS m / z=419.1[M+l].

[0929] Example 38

[0930] Rs- and Ss-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compounds 38-1 and 38-2)

[0931] Rs-and Ss-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0932]

[0933] The synthesis of compounds 38-1 and 38-2 was performed in accordance with the synthesis of compounds 21-1 and 21-2. Compound 38-1 (105 mg, ee%: 99.67%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 3.900 min) and compound 38-2 (120 mg, ee%: 99.81%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 4.272 min).

[0934] Compound 38-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.79–7.63 (m, 2H), 7.17(d,1H),6.99(d,1H),6.83(d,1H),5.09(s,1H),2.96(s,4H),2.42–2.25(m,1H),1.3 8(s,6H),1.10(d,3H),0.95(tt,1H),0.56–0.43(m,1H),0.24(tt,1H),0.13(dq,1H),0.05(dt,1H); LCMS m / z(ESI)=418.1[M+l].

[0935] Compound 38-2:1 H NMR (400MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.74–7.62 (m, 2H), 7.16(d,1H),6.99(d,1H),6.84(d,1H),5.09(s,1H),2.96(d,4H),2.42–2.30(m,1H),1.3 8(s,6H),1.13(d,3H),0.98–0.85(m,1H),0.51-0.39(m,1H),0.28-0.16(m,1H),0.11(dd,1H),0.05–0.01(m,1H); LCMS m / z(ESI)=418.1[M+l].

[0936] Example 39

[0937] R S -and S S -N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl-7-d)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 39-1 and 39-2)

[0938] R S -and S S -N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl-7-d)carbamoyl)-4-(2-hy droxypropan-2-yl)furan-2-sulfonimidamide

[0939]

[0940] Compounds 39-1 and 39-2 were prepared according to compounds 31-1 and 32-2. Compound 39-1 (70 mg, ee%: 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 35.556 min) and compound 39-2 (70 mg, ee%: 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 39.131 min).

[0941] Compound 39-1: 1 H NMR (400MHz, Chloroform-d) δ = 7.48 (s, 1H), 7.09 (s, 1H), 6. 94 (s, 1H), 6.60 (s, 2H), 2.89 (t, 2H), 2.81 (t, 2H), 2.69–2.61 (m, 2H), 2.49 (dq, 1H), 2.02 (dp,4H),1.87–1.75(m,2H),1.75–1.62(m,2H),1.52(s,6H); LCMS m / z(ESI)=433.2 [M+1].

[0942] Compound 39-2: 1 H NMR (400MHz, Chloroform-d) δ = 7.45 (s, 1H), 7.08 (s, 1H), 6. 93 (s, 1H), 6.67 (d, 2H), 2.87 (t, 2H), 2.78 (t, 2H), 2.63 (d, 2H), 2.57–2.42 (m, 1H), 2.01 (tt,4H),1.92–1.73(m,2H),1.68(dt,2H),1.49(s,6H); LCMS m / z(ESI)=433.2[M+ 1].

[0943] Example 40

[0944] N-((5-(1-cyclopropylvinyl)-6-methyl-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 40)

[0945] N-((5-(1-cyclopropylvinyl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydro xypropan-2-yl)furan-2-sulfonamide

[0946]

[0947] first step:

[0948] N-(6-bromo-4-nitro-2,3-dihydro-1H-indan-5-yl)acetamide (40B)

[0949] N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

[0950] In a 3L round-bottom flask, compound 40A (50g, 198mmol) and acetic acid (130mL) were added sequentially. Under mechanical stirring and an ice bath, acetic acid:concentrated sulfuric acid = (1:1, 260mL) and concentrated sulfuric acid:concentrated nitric acid = (1:1, 260mL) were slowly added. After the reaction was completed, sodium hydroxide aqueous solution was added to the reaction system to adjust the pH to neutral. The mixture was filtered, and the solid was washed with water (200mL × 3) to obtain crude product 40B, a white solid (50g, yield 85.3%).

[0951] 1 H NMR (400MHz, DMSO-d6) δ = 9.98 (s, 1H), 7.86 (s, 1H), 2.99–2.93 (m, 4H), 2.09–2.05 (m, 2H), 2.00 (s, 3H); LCMS m / z = 301.2 [M+l].

[0952] Step Two:

[0953] N-(6-methyl-4-nitro-2,3-dihydro-1H-indan-5-yl)acetamide (compound 40C)

[0954] N-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

[0955] In a 1L round-bottom flask under nitrogen protection, compound 40B (30g, 106mmol), methyl borate (9g, 150mmol), and potassium carbonate (34.7g, 252mmol) were added sequentially. After the addition was complete, the mixture was stirred for 15 min, and then palladium dichlorobis(triphenylphosphine) (5g, 8.5mmol) was added. The mixture was then transferred to reflux (100℃). After the reaction was completed, the reaction system was adjusted to neutral with dilute hydrochloric acid, filtered, and slurried (petroleum ether: ethyl acetate = 10:1) to obtain the crude product compound 40C, a black powder (19.7g, yield 82.2%).

[0956] 1 HNMR (400MHz, DMSO-d6), δ = 9.66 (s, 1H), 7.40 (s, 1H), 2.93–2.91 (m, 4H), 2.20 (s, 3H), 2.09–2.05 (m, 2H), 2.00 (s, 3H); LCMS m / z (ESI) = 235.1 [M+l].

[0957] Step 3:

[0958] 6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-amine (Compound 40D)

[0959] 6-methyl-4-nitro-2,3-dihydro-1H-inden-5-amine

[0960] In a 500 mL round-bottom flask under nitrogen protection, compound 40C (20 g, 85.6 mmol), ethanol (90 mL), and hydrochloric acid (270 mL) were added sequentially. After the addition was complete, the mixture was transferred to reflux (100 °C). When the reaction was complete, sodium hydroxide aqueous solution was added to quench the reaction. The mixture was filtered, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 40D, a red powder (14 g, yield 83%).

[0961] 1 H NMR (400MHz, DMSO-d6) δ = 7.20 (s, 1H), 6.62 (s, 2H), 3.17-3.13 (t, 2H), 2.77-2.7 3 (t, 2H), 2.15 (s, 3H), 1.98-1.93 (m, 2H); LCMS m / z = 193.1 [M+l].

[0962] Step 4:

[0963] 5-Bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (Compound 40E)

[0964] 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene

[0965] In a 500 mL round-bottom flask under nitrogen protection and an ice-salt bath, compound 40D (14 g, 73 mmol), acetonitrile (525 mL), tert-butyl nitrite (15 g, 146 mmol), and cuprous bromide (20.9 g, 146 mmol) were added sequentially. After the addition was complete, the mixture was moved to room temperature for 30 min, and the reaction was allowed to proceed to completion in 4 h. The pH of the reaction system was adjusted to neutral by adding dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (200 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:1) to give compound 40E as a pale yellow solid (6.3 g, yield 34%).

[0966] 1 H NMR (400MHz, DMSO-d6) δ = 7.48 (s, 1H), 3.06–2.87 (m, 4H), 2.40 (s, 3H), 2.12–2.05 (m, 2H).

[0967] Step 5:

[0968] 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (Compound 40F)

[0969] 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine

[0970] In a 250 mL round-bottom flask, compound 40E (6.3 g, 24.7 mmol), an aqueous ethanol solution (4:1, 100 mL), and a saturated ammonium chloride solution (25 mL) were added sequentially. Reduced iron powder (4.2 g, 74.1 mmol) was slowly added. The reaction was carried out at room temperature for 4 h. After the reaction was complete, the mixture was filtered, extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered again, and the organic solvent was removed under reduced pressure to obtain compound 40F, a pale red oil (4.0 g, yield 72.7%).

[0971] 1 H NMR (400MHz, DMSO-d6) δ = 6.46 (s, 1H), 4.94 (s, 2H), 2.74–2.65 (m, 4H), 2.23 (s, 3H), 1.99–1.96 (m, 2H); LCMS m / z = 226.0, 228.0 [M+l].

[0972] Step 6:

[0973] 5-(1-Cyclopropylvinyl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Compound 40G)

[0974] 5-(1-cyclopropylvinyl)-6-methyl-2,3-dihydro-1H-inden-4-amine

[0975] In a 250 mL round-bottom flask under nitrogen protection, compound 40F (4.0 g, 17.8 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (6.9 g, 35.6 mmol), cesium carbonate (11.6 g, 35.6 mmol), dichlorobis(triphenylphosphine)palladium (1.4 g, 1.78 mmol), and a 1,4-dioxane / water mixed solvent (30 mL: 20 mL) were added sequentially. The reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 60:1) under medium pressure to obtain compound 40G, a pale yellow oil (2.2 g, yield 58.3%).

[0976] 1H NMR (400MHz, CDCl3) δ = 6.58 (s, 1H), 5.36 (d, 1H), 4.86 (d, 1H), 2.88–2.84 (t, 2H), 2.74–2.70(t,2H),2.17(s,3H),2.12–2.05(m,2H),1.67-1.63(m,1H),0.70–0.64(m,2H),0.41-0.32(m,2H); LCMS m / z=214.1[M+l].

[0977] Step 7:

[0978] N-((5-(1-cyclopropylvinyl)-6-methyl-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 40)

[0979] N-((5-(1-cyclopropylvinyl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydro xypropan-2-yl)furan-2-sulfonamide

[0980] Under nitrogen protection, in a 100 mL round-bottom flask, compound 40G (200 mg, 0.94 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (310 μL, 1.9 mmol), and 2,2,2-trichloroethyl chloroformate (260 μL, 1.9 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and compound 2e (164 mg, 0.8 mmol) and sodium hydride (60 mg, 1.5 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to obtain compound 40 as a yellow solid (150 mg, yield 36%, UPLC: 96%).

[0981] 1H NMR (400MHz, Chloroform-d) δ = 8.14 (s, 1H), 7.54 (s, 1H), 7.15 (s, 1H), 7.0 0(s,1H),5.34(d,1H),4.79(d,1H),2.88(q,2H),2.70(dt,1H),2.49(s,1H),2.22(s,3H ),2.09–2.01(m,1H),1.99–1.90(m,1H),1.64–1.58(m,1H),1.54(s,6H),0.72–0.56(m,2 H), 0.26 (dd, 2H); LCMS m / z (ESI) = 445.1 [M+l].

[0982] Example 41

[0983] (R)-N-(((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 41)

[0984] (R)-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hy droxypropan-2-yl)furan-2-sulfonamide

[0985]

[0986] first step:

[0987] (R)-5-(1-Cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine (Compound 41A)

[0988] (R)-5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine

[0989] Compound 41A was prepared according to patent CN108017559. In a 500 mL autoclave, 9 g (1.0 g, 4.60 mmol) and 20 mL of dichloromethane were added, followed by the catalyst [(R)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (194 mg, 0.23 mmol). After the addition was complete, the autoclave was tightly sealed, purged three times with hydrogen, and then purged with hydrogen. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give compound 41A, a pale yellow oil (798 mg, yield 79.8%, ee%: 97.50%, chiral HPLC (2 mL_10B4_C2); 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 2.050 min).

[0990] LCMS m / z(ESI) = 220.1[M+l].

[0991] Step Two:

[0992] (R)-N-(((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 41)

[0993] (R)-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hy droxypropan-2-yl)furan-2-sulfonamide

[0994] Under nitrogen protection, compound 41A (150 mg, 0.685 mmol), triethylamine (84 mg, 0.822 mmol), and 20 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (82 mg, 0.274 mmol) was added under ice bath conditions. The mixture was heated to reflux for 2 h. The solid was removed by filtration. 2e (140 mg, 0.685 mmol) and sodium methoxide (74 mg, 1.37 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to obtain compound 41, a yellow solid (140 mg, yield 45.4%, ee%: 96.06%, chiral HPLC (OZ2); 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 16.260 min).

[0995] 1 H NMR (400MHz, DMSO-d6)δ=7.71(br,1H),7.55(s,1H),6.89(br,1H),6.86(d,1H), 6.84(s,1H),4.96(s,1H),2.75(t,2H),2.55(t,2H),2.06–2.05(m,1H),1.96–1.84(m,2H), 1.28(d,6H),1.00(d,3H),0.95–0.80(m,1H),0.40–0.33(m,1H),0.16–0.11(m,1H),0.06– 0.02(m,1H),0.01–0.11(m,1H); 19 F NMR δ = 120.22; LCMS m / z = 451.2 [M+l].

[0996] Example 42

[0997] (R S ,R C )- and (R S ,R C )-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 42-1 and 42-2)

[0998] (R S ,RC )-and(R S ,R C )-N-((5-(cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0999]

[1000] The synthesis of compounds 42-1 and 42-2 was carried out in accordance with the preparation of compounds 21-1 and 22-2. Compound 42-1 (118 mg, yield 47.9%, ee%: 97.0%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 12.006 min) and compound 42-2 (113 mg, yield 45.9%, ee%: 95.56%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 12.910 min).

[1001] Compound 42-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.23 ​​(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),0.23–0.20(m,1H),0.13–0.10(m,1H),0.06–0.0(m,1H); LCMS m / z(ESI) = 450.1[M+1].

[1002] Compound 42-2: 1H NMR (400MHz, DMSO-d6)δ=8.24(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),0.23–.20(m,1H),0.13–0.10(m,1H),0.06–-0.05(m,1H); LCMS m / z(ESI) = 450.1[M+1].

[1003] Example 43

[1004] (S)-N-(((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 43)

[1005] (S)-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hyd roxypropan-2-yl)furan-2-sulfonamide

[1006]

[1007] first step:

[1008] (R)-5-(1-Cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine (Compound 43A)

[1009] (R)-5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-amine

[1010] Compound 43A was prepared according to patent CN108017559. In a 500 mL autoclave, 9 g (1.3 g, 5.99 mmol) and 40 mL of dichloromethane were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (253 mg, 0.299 mmol). After the addition was complete, the autoclave was tightly sealed, purged three times with hydrogen, and then purged with hydrogen. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give compound 43A, a pale yellow oil (1.2 g, yield 91.4%, ee%: 98.76%, chiral HPLC (2 mL_10B4_C2); 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 2.325 min).

[1011] LCMS m / z(ESI) = 220.1[M+l].

[1012] Step Two:

[1013] (S)-N-(((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 43)

[1014] (S)-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hyd roxypropan-2-yl)furan-2-sulfonamide

[1015] Under nitrogen protection, in a 100 mL round-bottom flask, compound 43A (100 mg, 0.46 mmol) and triethylamine (62.5 mg, 0.55 mmol) were dissolved in 10 mL THF. Triphosgene (50.1 mg, 0.18 mmol) was added under ice bath conditions. The mixture was heated to 80 °C and refluxed for 1 h. The solid was removed by filtration. Intermediate 2e (94.0 mg, 0.46 mmol) and sodium methoxide (49.8 mg, 0.91 mmol) were added to the filtrate. The mixture was then reacted at 80 °C for 1 h. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, followed by extraction with EA (40 mL × 3), washing the organic phase with saturated brine, drying with anhydrous sodium sulfate, removing the organic solvent under reduced pressure, and purifying the crude product under medium pressure to obtain compound 43, a white solid (34 mg, purity 97.59%, yield 16.7%, ee%: 99.40%, chiral HPLC (2 mL 10B4 C2); mobile phase: ethanol / n-hexane = 10:90; column temperature: 35°C; mobile phase (%): 15; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 14.133 min).

[1016] 1 H NMR (400MHz, DMSO): δ = 8.51 (s, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 6.86 (d, 1H), 6.58 (s,1H),4.91(s,1H),2.82(t,2H),2.70(t,2H),2.34–2.23(m,1H),1.96(dd,2H),1.35(s,6H), 1.09(d,3H),0.99–0.85(m,1H),0.44–0.38(m,1H),0.31–0.16(m,1H),0.09–0.00(m,2H); 19 F NMR (377MHz, DMSO): δ = 121.99; LCMS m / z (ESI) = 451.2 [M+l].

[1017] Example 44

[1018] (R S ,R C )- and (R S ,R C )-N-((5-(1-cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 44-1 and 44-2)

[1019] (R S ,R C )-and(R S ,R C )-N-((5-(cyclopropylethyl)-7-fluoro-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[1020]

[1021] The synthesis of compounds 44-1 and 44-2 was carried out in accordance with the preparation of compounds 21-1 and 21-2. Compound 44-1 (71 mg, yield 44.9%, ee%: 99.80%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 18.855 min) and compound 44-2 (63 g, yield 39.6%, ee%: 99.07%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 14.178 min).

[1022] Compound 44-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.68 (d, 1H), 7.62 (s, 2H), 6.97 (s, 1H), 6 .93(d,1H),5.08(s,1H),2.85(t,2H),2.7–2.62(m,2H),2.28–2.15(m,1H),2.05 –1.89(m,2H),1.38(s,6H),1.10(d,3H),0.99–0.89(m,1H),0.46(dd,1H),0.26–0.15(m,1H), 0.15–0.06(m,1H),0.05–0.00(m,1H); 19 F NMRδ-121.99(s); LCMS m / z=450.2[M+l].

[1023] Compound 44-2:1 H NMR (400MHz, DMSO-d6)δ=8.24(s,1H),7.68(d,1H),7.62(s,2H),6.97(s,1H),6.93(d,1H),5.08(s,1H),2.85(t,2H),2.78–2 .62(m,2H),2.28–2.15(m,1H),2.05–1.89(m,2H),1.38(s,6H),1.10(d,3H),0.95(dd,1H),0.50–0.40(m,1H),0.26–0.15(m, 1H),0.09–0.06(m,1H),0.05–0.00(m,1H); 19 F NMR (377MHz, DMSO) δ121.99(s); LCMSm / z=450.2.

[1024] Example 45

[1025] (R)-N-(((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 45)

[1026] (R)-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hyd roxypropan-2-yl)furan-2-sulfonamide

[1027]

[1028] first step:

[1029] (R)-7-amino-6-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-carboxynitrile (Compound 45A)

[1030] (R)-7-amino-6-(1-cyclopropylethyl)-2,3-dihydro-1H-indene-4-carbonitrile

[1031] In a 100 mL three-necked flask under nitrogen protection, compound 29A (803 mg, 2.88 mmol), potassium ferrocyanide (486.3 mg, 1.15 mmol), tetrakis(triphenylphosphine)palladium (166 mg, 0.144 mmol), 1,8-diazabicycloundec-7-ene (110 mg, 0.72 mmol), and a tert-butanol / water mixed solvent (10 / 10 mL) were added sequentially. The mixture was heated to 85 °C and reacted for 5 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give 45A, a pale yellow oil (429 mg, yield 66.0%, ee%: 97.62%), by chiral HPLC (CHIRALPAK). AY-3 (4.6×100mm); Mobile phase: methanol; Column temperature: 35℃; Mobile phase (%): 15; Column pressure: 2000psi; Flow rate: 2mL / min; Detector signal channel: 215nm@4.8nm; Diode array detector start wavelength: 200nm; Diode array detector stop wavelength: 400nm: RT=10.082min).

[1032] LCMS m / z(ESI) = 227.1[M+l].

[1033] Step Two:

[1034] (R)-N-(((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 45)

[1035] (R)-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hyd roxypropan-2-yl)furan-2-sulfonamide

[1036] Under nitrogen protection, compound 45A (100 mg, 0.44 mmol), triethylamine (60.5 mg, 0.53 mmol), and 20 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (52.4 mg, 0.18 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 2e (90.7 mg, 0.44 mmol) and sodium methoxide (47.8 mg, 0.88 mmol) were added to the filtrate. The mixture was then reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to obtain compound 45, a yellow solid (32.1 mg, yield 15.8%; ee%: 98.73%). The reaction was carried out by 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 9.662 min).

[1037] 1 H NMR (400MHz, DMSO-d6) δ = 7.83 (s, 1H), 7.51 (s, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 6.57 (s, 1H) ),4.91(s,1H),2.95(t,2H),2.75(t,2H),2.35(dd,1H),2.06–1.90(m,2H),1.35(s,6H), 1.12(d,3H),1.04–0.89(m,1H),0.57–0.38(m,1H),0.31–0.20(m,1H),0.12(m,1H),0.08–0.01 (m,1H); LCMS m / z(ESI)=458.2[M+l].

[1038] Example 46

[1039] (R S ,R C )- and (S S ,R C )-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 46-1 and 46-2)

[1040] (R S ,R C)-and(S S ,R C )-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[1041]

[1042] Compounds 46-1 and 46-2 were prepared according to the same procedures as compounds 21-1 and 21-2. Compound 46-1 (30 mg, yield 38.5%, ee%: 99.99%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 36.665 min) and compound 46-2 (32 mg, yield 41.0%, ee%: 99.99%, chiral HPLC (OZ); mobile phase: n-hexane / ethanol = 90 / 10; column temperature: 35°C) were prepared using 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm: RT = 29.353 min).

[1043] Compound 46-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.61 (s, 1H), 7.68 (d, 3H), 7.59 (s, 1H), 6.98 (s, 1H), 5 .06(s,1H),2.98(t,2H),2.75(t,2H),2.29(dq,1H),2.09–1.93(m,2H),1.36(s, 6H),1.14-1.05(d,3H),1.04-0.92(m,1H),0.53-0.46(m,1H),0.30-0.25((m,1H),0.17-0.12(m,1H),0.06-0.02(m,1H).; LCMS m / z=457.2[M+l].

[1044] Compound 46-2: 1H NMR (400MHz, DMSO-d6) δ = 8.61 (s, 1H), 7.68 (d, 3H), 7.59 (s, 1H), 6.98 (s, 1H), 5 .09(s,1H),2.98(t,2H),2.74(t,2H),2.29(dq,1H),2.07–1.91(m,2H),1.38(s, 6H),1.16-1.08(d,3H),1.05–0.94(m,1H),0.55-0.47(m,1H),0.29-0.21((m,1H),0.15-0.10(m,1H),0.06-0.01(m,1H); LCMS m / z=457.2[M+l].

[1045] Example 47

[1046] (S)-N-(((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 47)

[1047] (S)-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hyd roxypropan-2-yl)furan-2-sulfonamide

[1048]

[1049] first step:

[1050] (S)-7-amino-6-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-carboxynitrile (Compound 47A)

[1051] (S)-7-amino-6-(1-cyclopropylethyl)-2,3-dihydro-1H-indene-4-carbonitrile

[1052] In a 100 mL three-necked flask under nitrogen protection, compound 30A (1.43 g, 5.12 mmol), potassium ferrocyanide (866 mg, 2.05 mmol), tetrakis(triphenylphosphine)palladium (297 mg, 0.256 mmol), 1,8-diazabicycloundec-7-ene (196 mg, 1.28 mmol), and a tert-butanol / water mixed solvent (10 / 10 mL) were added sequentially. The mixture was heated to 85 °C and reacted for 5 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give 47A, a pale yellow oil (910 mg, yield 78.4%, ee%: 98.06%). Chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35 °C; mobile phase (%): 15; column pressure: 910 mg / mL). 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm: RT = 9.513 min).

[1053] LCMS m / z(ESI) = 227.1[M+l].

[1054] Step Two:

[1055] (S)-N-(((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 47)

[1056] (S)-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hyd roxypropan-2-yl)furan-2-sulfonamide

[1057] Under nitrogen protection, compound 47A (100 mg, 0.44 mmol), triethylamine (60.5 mg, 0.53 mmol), and 20 mL of tetrahydrofuran were added sequentially to a 100 mL round-bottom flask. Triphosgene (52.4 mg, 0.18 mmol) was added under ice bath conditions. The mixture was heated to reflux for 2 h. The solid was removed by filtration. 2e (90.7 mg, 0.44 mmol) and sodium methoxide (47.8 mg, 0.88 mmol) were added to the filtrate. The mixture was then reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to obtain compound 47, a yellow solid (90 mg, yield 40.9%; ee%: 99.30%, chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35; mobile phase (%): 15; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 9.150 min)).

[1058] 1 H NMR (400MHz, DMSO-d6)δ=7.72(1H,s),7.39(1H,s),7.25(1H,d,J 0.8),6.47(1H,d,J 0.8),4.79(1H,s),2.83(t,2H),2.63(t,2H),2.25(dd,1H),1.87(dd,2H),1.23(s,6H),1.00(d,3H), 0.92–0.80(m,1H),0.40–0.30(m,1H),0.16-0.08(m,1H),0.07-0.04(m,1H),0.03-0.01(m,1H); LCMS m / z(ESI)=458.2[M+l].

[1059] Example 48

[1060] (R S ,S C )- and (S S ,S C )-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 48-1 and 48-2)

[1061] (R S ,S C)-and(S S ,S C )-N-((7-cyano-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[1062]

[1063] The synthesis of compounds 48-1 and 48-2 was performed according to the method for compounds 21-1 and 21-2; Compound 48-1 (75 mg, yield 25%, ee%: 99.99%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 33.584 min) and Compound 48-2 ...); and compound 48-2 (75 mg, yield 25%, ee%: 99.99%, 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. g, yield 25%, ee%: 99.22%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm; RT = 43.523 min).

[1064] Compound 48-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.58 (s, 1H), 7.68 (s, 1H), 7.66–7.60 (m, 1H), 7.59 (s ,1H),7.57–7.51(m,1H),6.96(s,1H),5.08(d,1H),2.98(t,2H),2.75(t,2H), 2.35–2.23(m,1H),2.02(dd,2H),1.38(s,6H),1.16-1.06(d,3H),1.05–0.95(m,1H ),0.55-0.44(m,1H),0.31-0.18(m,1H),0.18-0.07(m,1H),0.05-0.01(m,1H); LCMS m / z = 457.2[M+l].

[1065] Compound 48-2: 1H NMR (400MHz, DMSO-d6) δ = 8.58 (s, 1H), 7.68 (s, 1H), 7.66–7.61 (m, 1H), 7.59 (s ,1H),7.58-7.53(m,1H),6.98(s,1H),5.07(d,1H),2.98(t,2H),2.76(t,2H), 2.32–2.27(m,1H),2.03(dd,2H),1.38(s,6H),1.12-1.09(d,3H),1.02–0.95(m,1H ),0.56-0.42(m,1H),0.32-0.16(m,1H),0.15-0.06(m,1H),0.05-0.01(m,1H); LCMS m / z = 457.2[M+l].

[1066] Example 49

[1067] (R S ,S C )- and (S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonamide (49-1 and 49-2)

[1068] (R S ,S C )-and(S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4 -(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonimidamide

[1069]

[1070] first step:

[1071] 5-(N-(tert-butyldimethylsilyl)aminosulfonyl)furan-3-carboxylic acid ethyl ester (49A)

[1072] ethyl 5-(N-(tert-butyldimethylsilyl)sulfamoyl)furan-3-carboxylate

[1073] Under nitrogen protection, compound 2d (15.0 g, 68.42 mmol) was dissolved in dry THF in a 500 mL round-bottom flask. Sodium hydride (4.1 g, 102.64 mmol) was added under ice bath conditions, and the reaction was carried out at 0 °C for 30 min after the addition was complete. After 30 min, a THF (100 mL) solution of tert-butyldimethylchlorosilane (12.0 g, 82.10 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 h after the addition was complete. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with EA (100 mL × 3). The product was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography to give compound 49A, a pale yellow oil (10.6 g, yield 46.5%).

[1074] LCMS m / z(ESI) = 334.1[M+l].

[1075] Step Two:

[1076] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropane-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonamide (49B)

[1077] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonamide

[1078] In a 250 mL three-necked flask under a nitrogen atmosphere, 49A (10 g, 29.99 mmol) was dissolved in THF (100 mL). The mixture was cooled to -15 °C, and deuterated methyl magnesium iodide (100 mL, 100 mmol, 1.0 mol / L in THF) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was completed, ammonium chloride was added and quenched in ice water (100 mL). The mixture was extracted with EA (300 mL × 3), and the organic phases were combined. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography (EA / PE (v / v) = 10% - 30%) yielded 49B (8 g, yield 81.95%).

[1079] 1 H NMR (400MHz, DMSO-d6) δ7.86 (s, 1H), 7.67 (d, 1H), 6.93 (d, 1H), 5.05 (s, 1H), 0.88 (s, 9H), 0.15 (s, 6H); LCMS m / z (ESI) = 326.2 [M+l].

[1080] Step 3:

[1081] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropane-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonamide (49C)

[1082] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonimida mide

[1083] In a 250 mL three-necked flask under a nitrogen atmosphere, triphenylphosphine (7.1 g, 27.03 mmol) and hexachloroethane (6.4 g, 27.03 mmol) were dissolved in chloroform (100 mL) and refluxed for 2 h. After 2 h, the mixture was cooled to -10 °C, and diisopropylethylamine (4.8 g, 36.86 mmol) was added dropwise. After the addition was complete, the mixture was reacted at this temperature for 10 min. Then, a chloroform solution of 49B (8.0 g, 24.58 mmol) was slowly added dropwise, and the mixture was reacted at -10 °C for 30 min. After 30 min, ammonia was introduced at this temperature for 30 min. After 30 min, the mixture was heated to room temperature and reacted overnight by TLC. After the reaction was completed, the mixture was quenched with water, extracted with DCM (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (ethyl acetate / petroleum ether (v / v) = 15%-20%) to obtain product 49C (2). 4g, yield 30.09%.

[1084] 1 H NMR (400MHz, DMSO-d6) δ7.65–7.61(m,1H),7.60–7.54(m,2H),6.88(s, 1H),5.01(d,1H),0.85(d,9H),0–-0.6(m,6H); LCMS m / z(ESI)=325.2[M+l].

[1085] Step 4:

[1086] N'-(tert-butyldimethylsilyl)-N-(((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl-1,1,1,1,3,3,3-d6)furan-2-sulfonamide (49D)

[1087] N'-(tert-butyldimethylsilyl)-N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)c arbamoyl)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonimidamide

[1088] In a 100 mL round-bottom flask under nitrogen protection, compound 49C (300 mg, 1.49 mmol), triethylamine (180.96 mg, 1.79 mmol), and 30 mL of tetrahydrofuran were added sequentially. Triphosgene (176.88 mg, 0.60 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h. The solid was removed by filtration, and intermediate 9 (532.0 mg, 1.64 mmol) and sodium methoxide (80.51 mg, 1.49 mmol) were added to the filtrate. The mixture was reacted at 60 °C for 2 h. The reaction was monitored by TLC until complete. The reaction yielded compound 49D, which could be directly added to the next step without further purification.

[1089] LCMS m / z(ESI)=552.10[M+l].

[1090] Step 5:

[1091] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonamide (49E)

[1092] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonimidamide

[1093] Tetrabutylammonium fluoride (5.1 mL, 5.1 mmol, 1 M / THF) was added to the previous reaction system, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until completion. The reaction mixture was poured into water and extracted with ethyl acetate (80 mL × 3). The organic phases were combined. The mixture was washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give 49E as a white solid (120 mg, yield 46.3%).

[1094] Step 6:

[1095] (R S ,S C )- and (S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonamide (49-1 and 49-2)

[1096] (R S ,S C )-and(S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-h ydroxypropan-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonimidamide

[1097] Compound 49-1 (194 mg, yield 71.6%, ee%: 99.99%, chiral HPL C(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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 15.264 min) and compound 49-2 (164 mg, yield 71.6%, ee%: 99.99%) were obtained by SFC resolution. 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; Diode array detector start wavelength: 200 nm; Diode array detector stop wavelength: 400 nm; RT = 19.522 min).

[1098] Compound 49-1: 1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.64(s,1H),7.12(d,1 H),7.03(d,1H),6.91(s,1H),5.03(s,1H),2.82(t,2H),2.76–2.64(m,2H),2.30–2.21(m, 1H),1.98–1.89(m,2H),1.02(t,4H),0.47–0.39(m,1H),0.23–0.15(m,1H),0.12–0.06 (m,1H),0.05–0.00(m,1H); LCMS m / z(ESI)=438.20[M+l].

[1099] Compound 49-2: ¹H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, ¹H), 7.67 (d, ¹H), 7.12 (d, ¹H), 7.04 (d, ¹H), 6.96 (s, ¹H), 5.05 (s, ¹H), 2.82 (t, 2H), 2.70–2.64 (m, 2H), 2.27–2.20 (m, ¹H), 1.95–1.89 (m, 2H), 1.09 (d, 3H), 0.97–0.92 (m, ¹H), 0.49–0.43 (m, ¹H), 0.24–0.17 (m, ¹H), 0.14–0.08 (m, ¹H), 0.07–0.01 (m, ¹H); LCMS m / z(ESI) = 438.20[M+l].

[1100] Example 50

[1101] R S -and S S -N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonylimide (50-1 and 50-2)

[1102] R S -and S S -N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydrox ypropan-2-yl-1,1,1,3,3,3-d6)furan-2-sulfonimidamide

[1103]

[1104] The synthesis of compounds 50-1 and 50-2 was carried out in accordance with the preparation of compounds 21-1 and 21-2; Compound 50-1 (194 mg, yield 41.6%, ee%: 99.01%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 11.797 min) and Compound 50-2 (164 mg, yield 44.6%, ee%: 99.99%, 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); Diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm: RT = 1 8.146min).

[1105] Compound 50-1: 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.69–7.64(m,3H), 7.03–6.93(m,2H),6.86(d,1H),5.06(s,1H),2.80(t,2H),2.71–2.62(m,2H),2.59(d,2H),2.54 –2.51(m,1H),1.98–1.87(m,4H),1.82–1.73(m,2H),1.68–1.58(m,2H); LCMS m / z(ESI) =438.20[M+l].

[1106] Compound 50-2: 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.71–7.62(m,3H), 7.02–6.92(m,2H),6.86(d,1H),5.05(s,1H),2.80(t,2H),2.72–2.63(m,2H),2.58(d,2H),2.54 –2.51(m,1H),1.97–1.87(m,4H),1.82–1.73(m,2H),1.67–1.58(m,2H); LCMS m / z(ESI)=438.20[M+l].

[1107] Example 51

[1108] (R S ,S C )- and (S S ,SC )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonylimide (compounds 51-1 and 51-2)

[1109] (R S ,S C )-and(S S , S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydroxypropan-2 -yl)thiophene-2-sulfonimidamide

[1110]

[1111] first step:

[1112] 5-Aminosulfonylthiophene-2-carboxylic acid methyl ester (51B)

[1113] methyl 5-sulfamoylthiophene-2-carboxylate

[1114] Compound 51A (10.0 g, 70.34 mmol) was dissolved in 150 mL of DCM at room temperature. The mixture was cooled to -15 °C in an ice-salt bath, and sulfonyl chloride (12.3 g, 105.51 mmol) was slowly added dropwise while maintaining the temperature below -10 °C. After the addition was complete, the mixture was reacted at 40 °C for 4 h. The mixture was then cooled to -15 °C in an ice-salt bath, and phosphorus pentachloride (29.3 g, 140.68 mmol) was added in batches while maintaining the temperature below -10 °C. After the addition was complete, the mixture was reacted at 40 °C for 4 h. The reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a crude product. The crude product was dissolved in 200 mL of acetone at room temperature, and a saturated aqueous solution of ammonium bicarbonate (49.7 g, 0.553 mol) was added dropwise at room temperature. The reaction was carried out overnight at room temperature, and the reaction was monitored for completion by TLC. The mixture was extracted with EA (200 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding compound 51B as a brown solid powder (23.0 g, 77% yield).

[1115] 1H NMR (400MHz, DMSO-d6) δ = 7.95 (br, 2H), 7.77 (d, 1H), 7.58 (d, 1H), 4.32 (dd, 2H), 1.30 (t, 3H); LCMS m / z = 236.0 [M+l].

[1116] Step Two:

[1117] 5-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (51C)

[1118] 5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1119] Compound 51B (10.5 g, 52.55 mmol) was dissolved in 100 mL of dry THF at room temperature. The solution was cooled to -15 °C in an ice-salt bath, and methylmagnesium bromide (71 mL, 212.77 mmol, 3 M) was slowly added dropwise while maintaining the temperature below 0 °C. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored for completeness by TLC. The reaction solution was quenched in 200 mL of ice-saturated ammonium chloride and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4–1.5:1) to give compound 51C as a pale yellow solid (8.8 g, yield 88.2%).

[1120] 1 H NMR (400MHz, DMSO-d6) δ = 7.54 (br, 2H), 7.35 (d, 1H), 6.90 (d, 1H), 5.75 (s, 1H), 1.50 (s, 6H); LCMS m / z = 220.0 [M+l].

[1121] Step 3:

[1122] N-(tert-butyldimethylsilyl)-5-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (51D)

[1123] N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1124] Compound 51C (6.7 g, 30.28 mmol) was dissolved in 50 mL of dry THF at room temperature. The solution was cooled to -10 °C in an ice-salt bath, and sodium hydride (1.8 g, 45.42 mmol) was slowly added to maintain the temperature below -10 °C. Then, a solution of tert-butyldimethylchlorosilane (5.5 g, 36.33 mmol) in THF (50 mL) was added. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC to ensure complete reaction. The reaction solution was quenched in 100 mL of ice water and extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:4) to give compound 51D, a pale yellow oil (9.3 g, yield 9.2%).

[1125] LCMS m / z = 336.1 [M+l].

[1126] Step 4:

[1127] N-(tert-butyldimethylsilyl)-5-(2-hydroxypropyl-2-yl)thiophene-2-sulfonylimide (51E)

[1128] N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

[1129] In a 250 mL three-necked flask under nitrogen protection, triphenylphosphine (8.0 g, 30.59 mmol) and hexachloroethane (8.6 g, 36.15 mmol) were dissolved in chloroform and the mixture was refluxed for 2 h. After 2 h, the mixture was cooled to -10 °C in an ice bath, and diisopropylethylamine (5.8 g, 44.50 mmol) was slowly added dropwise. The mixture was allowed to react at this temperature for 30 min after the addition was complete. After 30 min, the mixture was cooled to -10 °C, and a chloroform (100 mL) solution of 51D (9.3 g, 27.81 mmol) was added dropwise. The mixture was allowed to react at -10 °C for 30 min, and ammonia was introduced into the reaction system for 30 min. The mixture was allowed to return to room temperature and react for 2 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 51E, a pale yellow solid (7.4 g, yield 79.5%).

[1130] LCMS m / z = 335.1 [M+l].

[1131] Step 5:

[1132] (S)-N'-(tert-butyldimethylsilyl)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfinamide (51F)

[1133] (S)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)c arbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

[1134] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 9 (300 mg, 1.49 mmol), triethylamine (182 mg, 1.79 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (178 mg, 0.60 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 51E (500 mg, 1.49 mmol) and sodium hydride (120 mg, 2.99 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. 51F was obtained and directly added to the next step without purification.

[1135] LCMS m / z(ESI) = 562.3[M+l].

[1136] Step 6:

[1137] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonylimide (51G)

[1138] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydroxyprop an-2-yl)thiophene-2-sulfonimidamide

[1139] Tetrabutylammonium fluoride (6 mL, 6 mmol, 1 M) was added to the previous reaction system, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was poured into water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give 51 g of transparent solid (220 mg, two-step yield 32.8%).

[1140] LCMS m / z = 448.2[M+l].

[1141] Step 7:

[1142] (R S ,S)- and (S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonylimide (compounds 51-1 and 51-2)

[1143] (R S ,S)-and(S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

[1144] 51G was resolved by SFC to obtain compound 51-1 (106 mg, yield 48.2%, ee%: 99.99%, chiral HPL C(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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 19.784 min) and compound 51-2 (95 mg, yield 43.2%, ee%: 99.99%). 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; Diode array detector start wavelength: 200 nm; Diode array detector stop wavelength: 400 nm; RT = 21.782 min). Compound 51-1: 1H NMR(400MHz,D MSO-d6)δ=8.17(br,1H),7.58(br,2H),7.38(s,1H),7.12(d,1H),7.03(d,1H),6.90(d, 1H),5.71(s,1H),2.82(t,2H),2.69–2.67(m,2H),2.27–2.24(m,1H),1.94–1.91(m,2H), 1.49(s,6H),1.11(d,3H),0.93–0.89(m,1H),0.45–0.42(m,1H),0.20–0.17(m,1H),0.1 0–0.07(m,1H),0.06–-0.01(m,1H); LCMS m / z = 448.1 [M+1].

[1145] Compound 51-2: 1 H NMR (400MHz, DMSO-d6)δ=8.18(br,1H),7.57(br,2H),7.39(s,1H),7.12(d,1H),7.03(d,1H),6.91(d,1H),5.72(s,1H),2.82(t,2H),2.74–2.62 (m,2H),2.26–2.24(m,1H),1.94–1.91(m,2H),1.49(d,6H),1.08(d,3H),0.95–0.93(m ,1H),0.45–0.43(m,1H),0.21–0.20(m,1H),0.11–0.09(m,1H),0.05–0.01(m,1H); LCM S m / z = 448.1 [M+1].

[1146] Example 52

[1147] (R S ,S C )- and (S S ,S C )-N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 52-1 and 52-2)

[1148] (R S ,S C )-and(S S ,S C)-N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)- 4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[1149]

[1150]

[1151] first step:

[1152] (R)-N'-(tert-butyldimethylsilyl)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (52A)

[1153] (R)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)c arbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[1154] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 8 (300 mg, 1.49 mmol), triethylamine (182 mg, 1.79 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (178 mg, 0.60 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 51E (500 mg, 1.49 mmol) and sodium hydride (120 mg, 2.99 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. 52A was obtained and directly added to the next step without purification.

[1155] LCMS m / z(ESI) = 562.3[M+l].

[1156] Step Two:

[1157] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compound 52B)

[1158] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxyprop an-2-yl)furan-2-sulfonimidamide

[1159] Tetrabutylammonium fluoride (6 mL, 6.0 mmol, 1 M) was added to the previous reaction system, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was poured into water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give 52B, a pale yellow solid (210 mg, yield 31.3%).

[1160] LCMS m / z = 448.2[M+l].

[1161] Step 3:

[1162] (R S ,S C )- and (S S ,S C )-N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 52-1 and 52-2)

[1163] (R S ,S C )-and(S S ,S C )-N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)- 4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[1164] Compound 52-1 (81 mg, yield 38.5%, ee%: 99.81%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm; RT = 19.031 min) and compound 52-2 (74 mg, yield 35.2%, ee%: 99.99%, chiral HPLC (OZ); mobile phase: n-hexane / ethanol = 90 / 10; column temperature: 35°C; column pressure: 80 bar; flow rate: 1 mL / min) were obtained by SFC resolution. in; Detector signal channel: 215nm@4.8nm; Diode array detector start wavelength: 200nm; Diode array detector end wavelength: 400nm: RT=20.638min).

[1165] Compound 52-1: 1 H NMR (400MHz, DMSO-d6) δ = 8.17 (br, 1H), 7.57 (br, 2H), 7.3 9(s,1H),7.12(d,1H),7.04(d,1H),6.90(d,1H),5.72(s,1H),2.82(t,2H),2.67–2.50(m, 2H),2.30–2.20(m,1H),1.98–1.86(m,2H),1.50(s,6H),1.11(d,3H),0.97–0.87(m,1 H),0.48–0.42(m,1H),0.23–0.13(m,1H),0.12–0.04(m,1H),0.03–0.00(m,1H); LCMS m / z = 448.2[M+l].

[1166] Compound 52-2: 1H NMR (400MHz, DMSO-d6) δ = 8.08 (br, 1H), 7.47 (br, 2H), 7. 28(s,1H),7.02(d,1H),6.93(d,1H),6.80(d,1H),5.62(s,1H),2.72(t,2H),2.65–2.50(m, 2H),2.17–2.14(m,1H),1.84–1.81(m,2H),1.39(d,6H),0.99(d,3H),0.84–0.82(m,1 H),0.36–0.33(m,1H),0.12–0.09(m,1H),0.02–0.00(m,1H),0.01–-0.00(m,1H); LCM S m / z = 448.2[M+l].

[1167] Example 53

[1168] (R S )- and (S S )-N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 53-1 and 53-2)

[1169] (R S )-and(S S )-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydr oxypropan-2-yl)thiophene-2-sulfonimidamide

[1170]

[1171] Compounds 53-1 and 53-2 were synthesized following the procedures for compounds 21-1 and 21-2; Compound 53-1 (61 mg, yield 30.2%, ee%: 99.99%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 23.761 min) and Compound 53-2 (54 mg, yield 26.7%, ee%: 98.48%, 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; Diode array detector start wavelength: 200 nm; Diode array detector stop wavelength: 400 nm: RT = 28.959 min). Compound 53-1: 1 H NMR (400MHz, DMSO-d6)δ=8.22(br,1H),7.61(br,2H), 7.41(d,1H),6.94(d,1H),6.91(d,1H),6.85(d,1H),5.72(s,1H),2.81(t,2H),2.73–2.67 (m,2H),2.59(d,2H),2.46–2.44(m,1H),1.95–1.88(m,4H),1.80–1.72(m,2H),1.66–1.57(m,2H),1.49(d,6H); LCMS m / z=448.1[M+1].

[1172] Compound 53-2: 1 H NMR (400MHz, DMSO-d6) δ = 8.22 (br, 1H), 7.61 (br, 2H), 7.4 1(d,1H),6.94(d,1H),6.91(d,1H),6.85(d,1H),5.72(s,1H),2.80(t,2H),2.75–2.63(m, 2H),2.59(d,2H),2.48–2.41(m,1H),1.95–1.88(m,4H),1.80–1.74(m,2H),1.66–1.59 (m,2H),1.49(d,6H); LCMS m / z=448.1[M+1].

[1173]

[1174] Example 56

[1175] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 56)

[1176] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1177]

[1178] Step 1: N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 56)

[1179] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1180] In a 100 mL round-bottom flask, under nitrogen protection, compound 17B (200 mg, 0.993 mmol), triethylamine (120.64 mg, 1.19 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (117.92 mg, 0.4 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 51C (220 mg, 0.993 mmol) and sodium hydride (35.76 mg, 1.49 mmol) were added to the filtrate. The reaction was incubated at 60 °C for 2 h. The reaction was monitored by TLC until complete. Compound 56 (135 mg, 30.29%) was isolated by EA (50 mL × 3) under medium pressure.

[1181] 1H NMR (400MHz, DMSO-d6) δ = 10.89 (s, 1H), 7.81 (s, 1H), 7.49 (d, 1H), 6.99 (d, 1H), 6.90 (dd ,2H),5.74(s,1H),2.80(t,2H),2.57(t,2H),2.42–2.30(m,1H),1.96–1,79(m,4H),1.77 –1.65(m,2H),1.62–1.63(m,2H),1.49(s,6H),1.29-1.20(s,1H),0.89–0.81(m,1H); LCMS m / z(ESI)=449.20[M+l].

[1182] Example 57

[1183] (S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 57)

[1184] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydroxyprop an-2-yl)thiophene-2-sulfonamide

[1185]

[1186] Compound 57 was synthesized following the method used for compound 56. Compound 57 (136 mg, yield 30.52%, ee%: 99.99%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 25.788 min.

[1187] 1H NMR (400MHz, DMSO-d6)δ=7.72(s,1H),7.42(s,1H),7.12(d,1H),7.06d, 1H),6.92–6.87(m,1H),5.73(d,1H),2.81(t,2H),2.58–2.56(m,1H),2.35–2.20(m,1 H),2.17–2.08(m,1H),1.97–1.88(m,2H),1.49(d,6H),1.11(d,3H),0.96–0.86(m,1 H), 0.46–0.38(m,1H),0.22–0.13(m,1H),0.08–0.02(m,1H),0.04–0.10(m,1H); LCM S m / z(ESI)=449.20[M+l].

[1188] Example 58

[1189] (R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 58)

[1190] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydroxypro pan-2-yl)thiophene-2-sulfonamid

[1191]

[1192] Compound 58 was prepared according to the method for compound 56; Compound 58 (120 mg, yield 26.93%, ee%: 99.99%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 24.955 min.

[1193] 1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.42(s,1H),7.12(d,1H),7.06(d,1H),6.89( dd,1H),5.73(d,1H),2.81(t,2H),2.72–2.62(m,1H),2.35–2.19(m,1H),2.19–2.09 (m,1H),1.98–1.86(m,,2H),1.49(s,6H),1.08(d,3H),0.95–0.86(m,1H),0.50–0.39 (m,1H),0.22–0.09(m,1H),0.08–0.01(m,1H),0.03–0.11(m,1H); LCMS m / z(ESI) = 449.20[M+l].

[1194] Example 59

[1195] ((R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1-hydroxycyclopropyl)furan-2-sulfonamide (compound 59)

[1196] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1-hydroxycycl opropyl)furan-2-sulfonamide

[1197]

[1198] first step:

[1199] 4-(1-Hydroxycyclopropyl)furan-2-sulfonamide (Compound 59A)

[1200] 4-(1-hydroxycyclopropyl)furan-2-sulfonamide

[1201] In a 100 mL three-necked flask under nitrogen protection, 2 d (7.0 g, 31.9 mmol), tetraisopropyl titanate (4.48 g, 15.8 mmol), ethyl magnesium bromide (79.8 mL, 1 M, 79.8 mmol), and 150 mL tetrahydrofuran were added sequentially. After the reaction was completed, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 59A as a pale yellow solid (1.4 g, yield 21.4%).

[1202] 1 H NMR (400MHz, DMSO) δ = 7.68 (s, 2H), 7.66 (s, 1H), 6.74 (d, 1H), 6.04 (s, 1H),, 1.00–0.97 (m, 2H), 0.82–0.80 (m, 2H); LCMS m / z (ESI) = 204.3 [M+1].

[1203] Step Two:

[1204] ((R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1-hydroxycyclopropyl)furan-2-sulfonamide (compound 59)

[1205] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1-hydroxycycl opropyl)furan-2-sulfonamide

[1206] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 8 (100 mg, 0.497 mmol), triethylamine (60.32 mg, 0.596 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (58.96 mg, 0.2 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 59A (220 mg, 0.993 mmol) and sodium hydride (20 mg, 0.833 mmol) were added to the filtrate. The reaction was carried out at 60 °C for 2 h. The reaction was monitored by TLC until complete. Compound 59 (70 mg, 32.73% yield) was isolated by EA (50 mL × 3) under medium pressure.

[1207] 1H NMR(400MHz,DMSO-d6)δ7.68(d,1H),7.53(s,1H),7.10(d,1H),7.01(d, 1H),6.54(s,1H),5.95(s,1H),2.81(t,2H),2.69–2.57(m,2H),2.28–2.16(m,1H),1.97 –1.86(m,2H),1.16–1.05(m,3H),1.00–0.90(m,3H),0.78–0.70(m,2H),0.48–0.38(m, 1H),0.25–0.16(m,1H),0.12–0.04(m,1H),0.04–0.01(m,1H); LCMS m / z(ESI) = 431.20[M+l].

[1208] Example 60

[1209] ((S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1-hydroxycyclopropyl)furan-2-sulfonamide (Compound 60)

[1210] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1-hydroxycycl opropyl)furan-2-sulfonamide

[1211]

[1212] Compound 60 was prepared according to the method of compound 59; compound 60 (80 mg, yield 37.41%).

[1213] 1 H NMR(400MHz,DMSO-d6)δ7.41(s,1H),7.14(d,1H),7.07(d,1H),6.97(d, 1H),6.36(s,1H),5.90(s,1H),2.80(t,2H),2.65(t,2H),2.35–2.22(m,1H),1.97–1.85(m, 2H),1.16–1.06(m,3H),1.01–0.83(m,3H),0.75–0.69(m,2H),0.49–0.39(m,1H),0.25– 0.15(m,1H),0.12–0.02(m,2H); LCMS m / z(ESI)=431.20[M+l].

[1214] Example 61

[1215] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1-hydroxycyclopropyl)furan-2-sulfonamide (compound 61)

[1216] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1-hydroxycyclopro pyl)furan-2-sulfonamide

[1217]

[1218] Compound 61 was prepared following the same procedure as compound 59. Compound 61 (70 mg, yield 32.73%).

[1219] 1 H NMR(400MHz, DMSO-d6)δ=7.47(s,1H),7.39(s,1H),7.08–6,95(m,1H),6.82(d,1H),6.87 (d,1H),6.33(s,1H),5.88(s,1H),2.79(t,2H),2.67(t,2H),2.58(d,2H),2.48–2.43(m, 1H),1.97–1.85(m,4H),1.82–1.72(m,2H),1.67–1.57(m,2H),0.99–0.91(m,2H),0.75–0.68 (m,2H); LCMS m / z(ESI)=431.20[M+l].

[1220] Example 62

[1221] (R)-3-cyano-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (Compound 62)

[1222] (R)-3-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hyd roxypropan-2-yl)thiophene-2-sulfonamide

[1223]

[1224] first step:

[1225] 4-Bromo-5-aminosulfonylthiophene-2-carboxylic acid methyl ester (62B)

[1226] methyl 4-bromo-5-sulfamoylthiophene-2-carboxylate

[1227] A mixture of chlorosulfonic acid (44.67 mL, 678.52 mmol) and thionyl chloride (14.78 mL, 203.56 mmol) was added in portions at 0 °C (30.0 g, 135.70 mmol). The mixture was stirred at 0 °C for 20 minutes and then reacted at 50 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and 400 mL of a solution of ammonium bicarbonate and acetone (1:1) was added dropwise at 0 °C, with stirring overnight. The reaction was confirmed by TLC. The mixture was filtered, and the solid was washed with ethyl acetate (100 mL), extracted with ethyl acetate (200 mL) in aqueous phase, and the organic phases were combined and concentrated to give a dark oily substance. The purified compound 62B was obtained by slurrying with dichloromethane (200 mL) to give 28.0 g of a pale yellow solid (68.74% yield).

[1228] LC-MS m / z(ESI)=300.03[M+1].

[1229] Step Two:

[1230] 3-Bromo-5-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (62C)

[1231] 3-bromo-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1232] Compound 62B (28.0 g, 93.29 mol) was dissolved in 500 mL of dry THF at room temperature. The solution was cooled to -15 °C in an ice-salt bath, and methylmagnesium bromide (155.48 mL, 466.45 mol) was slowly added dropwise while maintaining the temperature below 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to give compound 62C, a white solid powder (18 g, yield 64.28%).

[1233] 1H NMR (400MHz, DMSO-d6) δ = 7.79 (s, 2H), 7.07 (s, 1H), 5.87 (s, 1H), 1.48 (s, 6H); LC-MS m / z (ESI) = 300.03 [M+1].

[1234] Step 3:

[1235] 3-Cyano-5-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (62D)

[1236] 3-cyano-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1237] Under nitrogen protection, compound 62C (4.0 g, 13.33 mmol) and cuprous cyanide (1.4 g, 15.99 mmol) were dissolved in N,N-dimethylformamide (40 mL) in a 50 mL round-bottom flask and reacted at 150 °C for 4 hours. The reaction was monitored by TLC until complete. The reaction solution was poured into a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (50 mL × 10), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:5) to give 62D as a white solid (1.0 g, yield 30.47%).

[1238] 1H NMR (400MHz, DMSO-d6) δ = 8.85 (d, 2H), 7.23 (s, 1H), 6.02 (s, 1H), 1.52 (s, 6H);

[1239] LC-MS m / z(ESI)=247.03[M+1].

[1240] Step 4:

[1241] (R)-3-cyano-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (Compound 62)

[1242] (R)-3-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hyd roxypropan-2-yl)thiophene-2-sulfonamide

[1243] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 8 (100 mg, 0.497 mmol), triethylamine (60.32 mg, 0.596 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (58.96 mg, 0.2 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 62D (123 mg, 0.497 mmol) and sodium hydride (20 mg, 0.833 mmol) were added to the filtrate. The reaction was carried out at 60 °C for 2 h. The reaction was monitored by TLC until complete. Compound 62 (70 mg, 30.8% yield) was isolated by EA (50 mL × 3) under medium pressure.

[1244] 1 H NMR (400MHz, DMSO-d6) δ = 11.63 (s, 1H), 9.53 (s, 1H), 7.55 (s, 1H), 7.23 (d, 1H), 7.18(d,1H),6.12(s,1H),2.89(t,2H),2.78(t,2H),2.32(m,1H),2.01(m,2H),1.54(s,6H) ,1.22(d,3H),1.08-0.97(m,1H),0.54-0.46(m,1H),0.34-0.26(m,1H),0.16-0.08(m,1H), 0.07-0.01(m,1H); LCMS m / z(ESI)=474.1[M+l].

[1245] Example 63

[1246] (S)-3-cyano-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (Compound 63)

[1247] (S)-3-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hyd roxypropan-2-yl)thiophene-2-sulfonamide

[1248]

[1249] Compound 63 was synthesized using the same method as compound 62.

[1250] 1H NMR (400MHz, DMSO) δ = 11.63 (s, 1H), 9.52 (s, 1H), 7.54 (s, 1H), 7.23 (d, 1H), 7.18 (d, 1H), 6.12 (s, 1H), 2.89 (t, 2H), 2.78 (t, 2 H),2.37–2.26(m,1H),2.07–1.92(m,2H),1.54(s,6H),1.22(d,3H),1.07–0.95(m,1H),0.56–0.44(m,1H),0.36–0.23(m,1H), 0.17–0.09(m,1H),0.08–0.02(m,1H); LCMS m / z(ESI)=474.1[M+l].

[1251] Example 64

[1252] (R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-3-fluoro-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 64)

[1253] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-3-fluoro-5-(2-hy droxypropan-2-yl)thiophene-2-sulfonamide

[1254]

[1255] first step:

[1256] 3-Bromo-N-(tert-butyldimethylsilyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (64A)

[1257] 3-bromo-N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1258] Compound 62C (4.0 g, 13.33 mmol) was dissolved in 40 mL of dry THF at room temperature. The solution was cooled to -10 °C in an ice-salt bath, and sodium hydride (1.6 g, 39.98 mmol) was slowly added to maintain the temperature below -10 °C. Then, a THF solution of tert-butyldimethylchlorosilane (2.41 g, 15.99 mmol) was added (20 mL). The reaction was carried out at room temperature for 12 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in 20 mL of ice water and extracted with EA (50 mL × 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. The residue was slurried with ethyl acetate:petroleum ether (1:10–1:5) to give compound 64A, a white solid (3.0 g, 54.32%).

[1259] 1 H NMR (400MHz, DMSO) δ = 8.05 (s, 1H), 7.06 (s, 1H), 5.88 (s, 1H), 1.48 (s, 6 H), 0.89 (s, 9H), 0.15 (s, 6H); LCMS m / z = 414.02 [M+l].

[1260] Step Two:

[1261] N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (64B)

[1262] N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[1263] Compound 64A (2.0 g, 4.83 mol) was dissolved in 20 mL of dry THF. The solution was cooled to -78 °C in an acetone bath on dry ice. Butyllithium (6.76 mL, 16.89 mmol, 2.5 M) was slowly added dropwise while maintaining the temperature below -50 °C. After the addition was complete, the reaction was maintained at this temperature for 1 h. Then, N-fluoro-N-(benzenesulfonyl)benzenesulfonamide (1.98 g, 6.27 mmol) was added, and the reaction was maintained at this temperature for 1 h. The reaction was monitored for completeness by TLC. The reaction solution was slowly quenched in 100 mL of ice water and extracted with EA (100 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (ethyl acetate: dichloromethane = 1:100–1:10) to give compound 64B, a dark oil (240 mg, yield 14.07%).

[1264] 1H NMR (400MHz, DMSO-d6) δ = 7.87 (s, 1H), 6.80 (d, 1H), 5.69 (s, 1H), 1.31 (s, 6H), 0.73 (s, 9H), 0.00 (s, 6H); LC-MS m / z (ESI) = 354.02 [M+1].

[1265] Step 3:

[1266] 5-(3-hydroxyoxetane-3-yl)thiophene-2-sulfonamide (64C)

[1267] 5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonamide

[1268] Under nitrogen protection, 64B (240 mg, 0.679 mmol) and THF (10 mL) were added sequentially to a 100 mL round-bottom flask. The mixture was cooled to 0 °C in an ice bath, and tetrabutylammonium fluoride (1.4 mL, 1 M / THF, 1.35 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 h. After the reaction was completed, the mixture was quenched with water and extracted with EA (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure to obtain the residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 64C, a pale yellow solid (120 mg, yield 73.6%).

[1269] LCMS m / z = 240.1 [M+l].

[1270] Step 4:

[1271] (R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-3-fluoro-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 64)

[1272] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-3-fluoro-5-(2-hy droxypropan-2-yl)thiophene-2-sulfonamide

[1273] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 8 (100 mg, 0.497 mmol), triethylamine (60.32 mg, 0.596 mmol), and 20 mL of tetrahydrofuran were added sequentially. Triphosgene (58.96 mg, 0.2 mmol) was added under ice bath conditions. The mixture was refluxed for 2 h, and the solid was removed by filtration. 64C (119 mg, 0.497 mmol) and sodium hydride (20 mg, 0.833 mmol) were added to the filtrate, and the mixture was reacted at 60 °C for 2 h. The reaction was monitored by TLC until complete. After the reaction, the mixture was extracted with EA (50 mL × 3), dried over anhydrous sodium sulfate, and the residue was prepared by medium-pressure separation to obtain compound 64 (73 mg, yield 31.2%).

[1274] 1 H NMR (400MHz, DMSO-d6)δ=7.60(s,1H),7.11(d,1H),7.03(d,1H),6.86(s,1H),5.74(s,1H),2.81(t,2H),2.61(t,2H),2.20-2.15(m,1H),1.93 -1.86(m,2H),1.44(s,6H),1.09(d,3H),0.94-0.88(m,1H),0.46-0.39 (m,1H),0.21-0.16(m,1H),0.09-0.04(m,1H),0.03-0.01(m,1H); LC-MS m / z(ESI)=467.2[M+1].

[1275] Example 65

[1276] N-(((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(3-hydroxyoxetane-3-yl)thiophene-2-sulfonylimide (compounds 65-1 and 65-2)

[1277] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(3-hydroxyoxet an-3-yl)thiophene-2-sulfonimidamide

[1278]

[1279] first step:

[1280] N'-(tert-butyldimethylsilyl)-5-(3-hydroxyoxetane-3-yl)thiophene-2-sulfinamide (65A)

[1281] N'-(tert-butyldimethylsilyl)-5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonimidamide

[1282] In a 250 mL three-necked flask under nitrogen protection, triphenylphosphine (3.64 g, 13.84 mmol) and hexachloroethane (3.88 g, 16.36 mmol) were dissolved in chloroform and the mixture was refluxed for 2 h. The mixture was then cooled to -10 °C in an ice bath, and diisopropylethylamine (2.6 g, 20.14 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at this temperature for 30 min. After 30 min, the mixture was cooled to -10 °C, and a chloroform (100 mL) solution of 34C (4.4 g, 12.58 mmol) was added dropwise. After the addition was complete, the mixture was allowed to react at -10 °C for another 30 min. Ammonia was then introduced into the reaction system for 30 min. The mixture was allowed to return to room temperature for 2 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 65A, a pale yellow solid (2.7 g, 61%).

[1283] LCMS m / z = 349.1 [M+l].

[1284] Step Two:

[1285] (N'-(tert-butyldimethylsilyl)-N-(((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(3-hydroxyoxetane-3-yl)thiophene-2-sulfonylimide (65B)

[1286] N'-(tert-butyldimethylsilyl)-N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)c arbamoyl)-5-(3-hydroxyoxetan-3-yl)thiophene-2-sulfonimidamide

[1287] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 9 (288 mg, 1.44 mmol), triethylamine (174 mg, 1.772 mmol), and tetrahydrofuran (20 mL) were added sequentially. Triphosgene (171 mg, 0.57 mmol) was added in an ice bath, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 65A (500 mg, 1.44 mmol) and sodium hydride (11.5 mg, 2.87 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete, yielding compound 65B, which could be directly added to the next step without further purification.

[1288] LCMS m / z(ESI) = 576.2 [M+l].

[1289] Step 3:

[1290] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonylimide (65C)

[1291] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(2-hydroxyprop an-2-yl)thiophene-2-sulfonimidamide

[1292] Tetrabutylammonium fluoride (6 mL, 6 mmol, 1 M) was added to the previous reaction system, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until it ended. The reaction solution was poured into water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed once with 1 M dilute HCl, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by medium-pressure preparation (acetonitrile / water = 50%) to give a 65C transparent solid (220 mg, two-step yield 32.8%).

[1293] LCMS m / z(ESI) = 462.1[M+l].

[1294] Step 4:

[1295] (R S ,S C )- and (S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonylimide (compounds 65-1 and 65-2)

[1296] (R S ,S C )-and(S S ,S C )-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

[1297] Compound 65-1 (106 mg, yield 48.2%, ee%: 99.99%) was obtained by resolution of 65C via SFC. Chiral HCl PLC (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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm; RT = 19.784 min) and compound 65-2 (95 mg, yield 43.2%, ee%: 99.99%) were obtained. 99%, 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; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm); RT = 21.782 min.

[1298] Compound 65-1: 1 H NMR (400MHz, DMSO) δ = 8.21 (s, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 7.02 (s, 1H), 4.77 (d ,2H),4.67(d,2H),2.82(t,2H),2.74–2.62(m,2H),2.33(s,1H),2.29–2.18(m,1H),1.98–1.84(m,2H),1.06(d,3H),1.00 –0.88(m,1H),0.48–0.37(m,1H),0.25–0.16(m,1H),0.12–0.05(m,1H),0.05–0.01(m,1H).

[1299] Compound 65-2: 1H NMR (400MHz, DMSO-d6)δ=8.17(s,1H),7.59(s,1H),7.48(d,1H),7.25(d,1H),7.12(d,1H),7.04(d,2H),4.78(s,1H),4.7 7(s,1H),4.69(d,1H),4.67(d,1H),2.83(t,2H),2.77–2.61(m,2H),2.30–2.17(m,1H),2.02–1.83(m,2H),1.19–1.03(m, 3H),0.98–0.85(m,1H),0.48–0.35(m,1H),0.23–0.12(m,1H),0.11–0.02(m,1H),0.00 –0.07(m,1H).

[1300] Example 66

[1301] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 66)

[1302] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonamide

[1303]

[1304] Compound 66 was prepared by synthesizing compound 59. Compound 66 was a yellow solid (190 mg, yield 24.5%).

[1305] 1 H NMR (400MHz, DMSO-d6) δ = 7.60 (s, 1H), 7.49 (s, 1H), 7.10–7.00 (m, 4H), 6.26(s,1H),4.18(d,1H),4.10-4.06(m,3H),2.77-2.73(m,2H),2.66-2.60(m,2H),2.39(d ,1H),2.31-2.26(m,2H),1.92-1.88(m,2H),1.07(d,3H),0.93-0.88(m,1H),0.43-0.39(m, 1H), 0.20-0.16 (m, 1H), 0.08-0.04 (m, 1H), 0.03-0.00 (m, 1H); LCMS m / z (ESI) = 477. 1 [M+l].

[1306]

[1307] Example 70

[1308] R S -and S S -N-(((2-(cyclobutylmethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 70-1 and 70-2)

[1309] R S -and S S -N-((2-(cyclobutylmethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropan -2-yl)furan-2-sulfonimidamide

[1310]

[1311] first step:

[1312] (2-Amino-3-isopropylphenyl)(cyclobutyl) methyl ketone (70B)

[1313] (2-amino-3-isopropylphenyl)(cyclobutyl)methanone

[1314] In a 500 mL three-necked flask, 70A (5.2 g, 38.5 mmol) and dichloroethane (100 mL) were added sequentially. After dissolving, the flask was placed in an ice-water bath. Under nitrogen protection, boron trichloride toluene solution (46 mL, 1 M) was slowly added dropwise. After 10 min, anhydrous aluminum trichloride (6.1 g, 10 mmol) was added, followed by slow dropwise addition of cyclobutyronitrile (5.8 mL, 12.6 mmol). After the addition was complete, the mixture was reacted at 90 °C for 7 h. After cooling to room temperature, dilute hydrochloric acid solution (10 mL, 2 N) was added, and the mixture was refluxed for 30 min. The organic phase was separated, washed with saturated sodium bicarbonate (20 mL) until weakly acidic, extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 70B, a brown oily substance (1.2 g, yield 13%).

[1315] 1H NMR (400MHz, CDCl3)δ=7.50(d,1H),7.27(d,1H),6.65(t,1H),4.01(p,1 H),2.90(dt,1H),2.52–2.36(m,2H),2.33–2.19(m,2H),2.12–1.98(m,1H),1.87(ddd,1 H),1.27(d,6H).

[1316] Step Two:

[1317] (2-Amino-3-isopropylphenyl)(cyclobutyl)methanol (70°C)

[1318] (2-amino-3-isopropylphenyl)(cyclobutyl)methanol

[1319] In a 50 mL round-bottom flask, 70B (1.1 g, 5 mmol), anhydrous methanol (10 mL), and sodium borohydride (227 mg, 6 mmol) were added sequentially. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. Water (20 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 70C, a brown oily substance (1.1 g, yield 99%).

[1320] 1 H NMR(400MHz, DMSO)δ=6.92(d,1H),6.80(d,1H),6.50(t,1H),5.19(d,1 H),4.86(s,2H),4.44(dd,1H),2.98(dt,1H),2.78(dd,1H),1.98–1.86(m,2H),1.83–1.6 2(m,4H),1.14(d,6H).

[1321] Step 3:

[1322] 2-(cyclobutylmethyl)-6-isopropylaniline (70D)

[1323] 2-(cyclobutylmethyl)-6-isopropylaniline

[1324] In a 50 mL round-bottom flask, 70C (1.1 g, 5 mmol), dichloromethane (20 mL), triethylsilane (2.4 mL, 15 mmol), and trifluoroacetic acid (1.8 mL, 15 mmol) were added sequentially. The mixture was reacted at room temperature for 2 h, and the reaction was monitored by TL until complete. The reaction was quenched by slowly adding saturated sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 70D, a brown oily substance (820 mg, yield 78%).

[1325] 1 H NMR (400MHz, DMSO) δ = 6.88 (dd, 1H), 6.72 (dd, 1H), 6.50 (t, 1H), 4.46 (s, 2H), 3.0 0(dt,1H),2.69–2.58(m,1H),2.56(d,1H),2.51–2.48(m,1H),2.06–1.98(m,2H), 1.89–1.76(m,2H),1.72–1.63(m,2H),1.14(d,6H).

[1326] Step 4:

[1327] N-(((2-(cyclobutylmethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (70E)

[1328] N-((2-(cyclobutylmethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[1329] Under nitrogen protection, 70D (500 mg, 2.46 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (815 μL, 5 mmol), and 2,2,2-trichloroethyl chloroformate (508 μL, 3.6 mmol) were added sequentially to a 50 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (20 mL), and 2e (625 mg, 2 mmol) and sodium hydride (118 mg, 3 mmol) were added. The reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride tetrahydrofuran solution (4 mL, 1 M) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 70E as a pale yellow oil (380 mg, yield 36%).

[1330] Step 5:

[1331] R S -and S S -N-(((2-(cyclobutylmethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 70-1 and 70-2)

[1332] R S -and S S -N-((2-(cyclobutylmethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropan -2-yl)furan-2-sulfonimidamide

[1333] 70E was resolved by SFC to yield compounds 70-1 (40 mg, RT = 2.989 min, ee%: 99.99%) and 70-2 (40 mg, RT = 5.033 min, ee%: 96.76%). Chiral HPLC (OX-3) was performed using methanol as the mobile phase; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm.

[1334] Compound 70-1: 1H NMR (400MHz, DMSO-d6) δ = 8.17 (s, 1H), 7.74–7.62 (m, 3H), 7.13–7.04(m,2H),6.98(d,1H),6.95–6.91(m,1H),5.07(s,1H),3.09(q,1H),2.57(d,2 H), 2.00–1.93 (m, 2H), 1.83–1.75 (m, 2H), 1.65 (q, 2H), 1.38 (s, 6H), 1.28–1.15 (m, 1H), 1.07 (dd, 6H); LCMS m / z=434.2[M+1].

[1335] Compound 70-2: 1 H NMR (400MHz, DMSO-d6)δ=8.17(s,1H),7.74–7.62(m,3H), 7.17–7.04(m,2H),6.98(d,1H),6.93(dd,1H),5.07(s,1H),3.18–3.05(m,1H),2.57(d, 2H),1.98–1.94(m,2H),1.85–1.75(m,2H),1.72–1.55(m,2H),1.38(s,6H),1.26–1.1 5(m,1H),1.07(dd,6H); LCMS m / z=434.2[M+1].

[1336] Example 71

[1337] (S)-N-(((2-(1-cyclopropylethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 71)

[1338] (S)-N-((2-(1-cyclopropylethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl) furan-2-sulfonamide

[1339]

[1340] first step:

[1341] (2-Amino-3-isopropylphenyl)(cyclopropyl)methyl ketone (71A)

[1342] (2-amino-3-isopropylphenyl)(cyclopropyl)methanone

[1343] In a 500 mL three-necked flask, 70A (20 g, 148 mmol) and dichloroethane (200 mL) were added sequentially. After dissolving, the flask was placed in an ice-water bath. Under nitrogen protection, boron trichloride toluene solution (175 mL, 1 M) was slowly added dropwise. After 10 min, anhydrous aluminum trichloride (22 g, 177 mmol) was added, followed by slow dropwise addition of cyclobutyl nitrile (16.5 mL, 222 mmol). After the addition was complete, the mixture was reacted at 90 °C for 7 h. After cooling to room temperature, dilute hydrochloric acid solution (50 mL, 2 N) and water (50 mL) were added, and the mixture was refluxed for 30 min. The organic phase was separated, washed with saturated sodium bicarbonate (10 mL) until weakly acidic, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give 71A, a brown oily substance (7.2 g, yield 24%).

[1344] 1 H NMR (400MHz, CDCl3) δ = 7.89 (dd, 1H), 7.33–7.28 (m, 1H), 6.73 (t, 1H), 2. 90(dt,1H),2.73–2.59(m,1H),1.27(d,6H),1.20–1.14(m,2H),0.96(dq,2H).

[1345] Step Two:

[1346] 2-(1-Cyclopropylvinyl)-6-Isopropylaniline (71B)

[1347] 2-(1-cyclopropylvinyl)-6-isopropylaniline

[1348] In a 50 mL three-necked flask, triphenylmethylphosphine bromide (15.7 g, 44 mmol) and anhydrous tetrahydrofuran (20 mL) were added sequentially. After dissolving, the mixture was placed in an ice-water bath. Under nitrogen protection, potassium tert-butoxide (5.0 g, 44 mmol) was added. After 40 min, a tetrahydrofuran solution of 71A (3.0 g, 15 mmol) (10 mL) was added. After 10 min, the reaction was carried out at room temperature for 2 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 71B, a brown oily substance (2.1 g, yield 69%).

[1349] 1H NMR (400MHz, CDCl3) δ = 7.07 (dd, 1H), 6.83 (dd, 1H), 6.73 (t, 1H), 5.22 (d, 1H),4.94(d,1H),2.90(dt,1H),1.65(tt,1H),1.26(d,6H),0.76–0.66(m,2H),0.51–0.3 9(m,2H).

[1350] Step 3:

[1351] (S)-2-(1-Cyclopropylethyl)-6-Isopropylaniline (71C)

[1352] (S)-2-(1-cyclopropylethyl)-6-isopropylaniline

[1353] In a 500 mL autoclave, 71B (1.0 g, 5 mmol) and dichloromethane (100 mL) were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (209 mg, 0.25 mmol). After the addition was complete, the autoclave was tightly sealed, purged three times with hydrogen, and then purged with hydrogen. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 5 h. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 71C, a pale yellow oil (600 mg, yield 59%).

[1354] 1 H NMR(400MHz, CDCl3)δ7.15(d,1H),7.10–7.02(m,1H),6.83(t,1H),3.03– 2.89(m,1H),2.44–2.28(m,1H),1.30(d,3H),1.27(d,6H),1.14–1.03(m,1H),0.60–0.51(m,1H),0.48–0.41(m,1H),0.17–0.08(m,2H).

[1355] Step 4:

[1356] (S)-N-(((2-(1-cyclopropylethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 71)

[1357] (S)-N-((2-(1-cyclopropylethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl) furan-2-sulfonamide

[1358] Under nitrogen protection, 71C (100 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (165 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (103 μL, 0.75 mmol) were added sequentially to a 50 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL * 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and 2e (82 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by medium-pressure preparation to obtain compound 71, a yellow solid (46 mg, yield 21%, UPLC: 94.06%, ee%: 98.28%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 14.317 min).

[1359] 1 H NMR (400MHz, DMSO) δ = 11.11 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.22 (s, 1H),7.21(s,1H),7.13–7.06(m,1H),7.02(s,1H),5.05(s,1H),3.06–2.90(m,1H),2.11(s, 1H), 1.37 (d, 6H), 1.06 (s, 10H), 0.98–0.88 (m, 1H), 0.45 (s, 1H), 0.19 (s, 1H), 0.06 (s, 1H); LCMSm / z=435.2[M+1].

[1360] Example 72

[1361] N-(((2-((R)-1-cyclopropylethyl)-6-isopropylphenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (Compound 72)

[1362] N-((2-((R)-1-cy...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from one of the following structures:

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients.

3. Use of the pharmaceutical composition of claim 2 or the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an NLRP3 inhibitor or in the preparation of a medicament for treating NLRP3-related diseases.

4. The use according to claim 3, wherein the disease treated by the NLRP3 inhibitor or the disease related to NLRP3 is selected from: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

5. According to the use of claim 3, the disease treated by the NLRP3 inhibitor or a disease related to NLRP3 is selected from: cryptothermal protein-associated cycle syndrome (CAPS), Muker-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.

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