Amide derivatives and their applications

Abstract

An amide derivative and its use in medicine, specifically an amide derivative of formula (I) or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof, and a pharmaceutical composition comprising the above compound, wherein the above compound or composition can be used as an NLRP3 inhibitor, and the definition of each substituent in formula (I) is the same as that in the specification,

Description

Technical Field

[0001] The present application relates to an amide derivative or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated derivatives thereof, a pharmaceutical composition comprising the above-mentioned compound and use thereof in the preparation of an NLRP3 inhibitor. Background Art

[0002] NOD-Like Receptors (NLRs) with nucleotide-binding oligomerization domain (NOD) are a type of pattern recognition receptors (PRRs) located in the cytoplasm of mammalian cells, playing a very important role in the innate immune response. NLRs are a group of cytoplasmic proteins with signal transduction functions, which are widely involved in the body's inflammatory response. The NLRs family includes NODs, NALPs (NLRPs), CIITA (NLRA) and IPAF (NLRC), among which NLRPs and NLRC subfamilies are the two main types of NOD-like receptors (NLRs), and NLRPs can be 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 a variety of pathogenic microorganisms and stress-related endogenous signaling molecules. The classic NLRP3 inflammasome activation is activated by two signals. The first signal activates the TLR4 (Toll like receptor 4) signaling pathway, promotes the nuclear transcription factor κBN, and induces 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, that is, when activated, it aggregates with apoptosis-associated speck-like protein (ASC) containing caspase activation and recruitment domains. ASC then interacts with cysteineprotease caspase-1 to form a complex called inflammasome. The precursor form of caspase (pro-caspase-1) is self-cleaved into an activated form (Wen, H., Miao, EA & Ting, JP Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432-441 (2013)). The activated caspase-1 cleaves the precursor form of pro-inflammatory cytokines IL-1β and IL-18, converting them into active forms of IL-1β and IL-18 and releasing them into the extracellular space, recruiting inflammatory cells to aggregate and amplifying the inflammatory response.ASC speck-like proteins can also recruit and activate caspase-8, cleave precursor forms of IL-Iβ and IL-18 to convert them into mature forms and induce cell pyroptosis. Non-classical NLRP3 inflammasome activation does not depend on TLR4 signaling pathway activation. It is directly recognized by caspase-11 in the cell, which activates NLRP3 inflammasome activation, promotes the activation and release of Gasdermin D, and thus mediates cell death. (Lamkanfi, M. & Dixit, VM Mechanisms and functions of inflammasomes. Cell 157, 1013-1022 (2014).).

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

[0004] Current drugs for treating NLRP3-related diseases include recombinant IL-1 receptor antagonist anakinra, neutralizing IL-1β antibody canakinumab, and soluble IL-1 receptor trap rilonacept, all of which are biological products. In recent years, Rebecca CColl et al. reported a new sulfonylurea small molecule NLRP3 inhibitor compound MCC950, which inhibited NLRP3 inflammasome activity at the nanomolar level. Other small molecule compounds have been shown to inhibit NLRP3 inflammasomes, such as glibenclamide, parthenolide, 3,4-methylenedioxy-β-nitrostyrene (He, Y. et al. 3,4-Methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J. Biol. Chem. 289, 1142-1150 (2014)) and dimethyl sulfoxide (DMSO). However, the above drugs or small molecules still have problems such as 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] The purpose of the present application is to provide a novel amide derivative or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated derivatives thereof, a pharmaceutical composition thereof and a use thereof in the preparation of an NLRP3 inhibitor.

[0006] One or more embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated derivatives thereof:

[0007]

[0008] in

[0009] Q is a 5-membered heteroaryl group, the 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from N, O and S, the 5-membered heteroaryl group is optionally substituted by 1 cyano group or C 1-6 Alkyl substitution;

[0010] L is -(CR a R b )-;

[0011] R a C 1-6 alkyl;

[0012] R b C 1-6 alkyl, and the C 1-6 The alkyl group is substituted with 1 OH group;

[0013] W is O or NH;

[0014] Y is -(CR d R e )-;

[0015] R d , R e Each independently is H or C 1-6 alkyl;

[0016] R and R1 are each independently H, halogen, cyano, C 1-6 Alkyl, C 1-6 an alkoxyl group, a 3- to 10-membered carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the 4- to 10-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, wherein the C 1-6 The alkyl, 3- to 10-membered carbocyclyl or 4- to 10-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 groups selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Substitution by substituents of alkoxy, 3- to 6-membered carbocyclic group and 5- to 6-membered heterocyclic group;

[0017] Alternatively, R and the atom to which R1 is attached together form a 4- to 6-membered ring;

[0018] C is a 3- to 5-membered cycloalkyl group;

[0019] R2 is H or halogen;

[0020] G1, G2, and G3 are each independently N or CH;

[0021] r, q are each independently 0, 1 or 2;

[0022] n is 0, 1, 2 or 3.

[0023] In one or more embodiments:

[0024] Q is furanyl, thiazolyl or thienyl, wherein the furanyl, thiazolyl or thienyl is optionally substituted with 1 cyano group;

[0025] L is -(CR a R b )-;

[0026] R a C 1-3 alkyl;

[0027] R b C 1-3 alkyl, and the C 1-3 The alkyl group is substituted with 1 OH group;

[0028] W is O or NH;

[0029] Y is -(CR d R e )-;

[0030] R d , R e Each independently is H or C 1-3 alkyl;

[0031] R and R1 are each independently H, halogen, cyano, C 1-3 Alkyl or pyridyl, the C 1-3 The alkyl or pyridyl group is optionally substituted by 1 to 4 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and 3- to 5-membered cycloalkyl substituents;

[0032] Alternatively, R and the atom to which R1 is attached together form a 4- to 5-membered ring;

[0033] C is a 3- to 5-membered cycloalkyl group;

[0034] R2 is H;

[0035] G1, G2, and G3 are each independently N or CH;

[0036] r and q are each independently 0, 1 or 2.

[0037] In one or more embodiments:

[0038] for

[0039] for

[0040] W is O or NH.

[0041] In one or more embodiments:

[0042] Q is furanyl, thiazolyl or thienyl, wherein the furanyl, thiazolyl or thienyl is optionally substituted with 1 cyano group;

[0043] L is -(CR a R b )-;

[0044] R a C 1-3 alkyl;

[0045] R b C 1-3 alkyl, and the C 1-3 The alkyl group is substituted with 1 OH group;

[0046] W is O or NH;

[0047] Y is -(CR d R e )-;

[0048] R d , R e Each independently is H or C 1-3 alkyl;

[0049] R and R1 are each independently H or halogen; or, R and R1 together with the atom to which they are attached form a 4- to 5-membered ring;

[0050] C is a 3- to 5-membered cycloalkyl group;

[0051] R2 is H;

[0052] G1, G2, and G3 are each independently CH;

[0053] r and q are each independently 0 or 1.

[0054] In one or more embodiments:

[0055] for

[0056] for or

[0057] In one or more embodiments, the compound is:

[0058]

[0059] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated derivatives thereof and one or more pharmaceutically acceptable carriers and / or excipients.

[0060] One or more embodiments of the present application provide the use of the compound of the present application or its pharmaceutically acceptable salt or all its stereoisomers, tautomers and deuterated products thereof or the pharmaceutical composition of the present application in the preparation of drugs for treating inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine system diseases or central nervous system diseases.

[0061] One or more embodiments of the present application provide the use of the compound of the present application or its pharmaceutically acceptable salt or all its stereoisomers, tautomers and deuterated products thereof or the pharmaceutical composition of the present application in the preparation of a medicament for treating cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout or chronic kidney disease.

[0062] One or more embodiments of the present application provide the use of the compound of the present application or its pharmaceutically acceptable salt or all its stereoisomers, tautomers and deuterated substances thereof or the pharmaceutical composition of the present application in the preparation of NLRP3 inhibitors.

[0063] One or more embodiments of the present application provide a compound of general formula (I'), or a stereoisomer thereof:

[0064]

[0065] in:

[0066] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group may contain 1 to 2 heteroatoms selected from N, O or S, and the heteroaryl group may be substituted by 0 or 1 cyano group;

[0067] L is selected from -(CR a R b )-;

[0068] R a Selected from C 1-6 alkyl;

[0069] R b Selected from C 1-6 Alkyl, and the alkyl is further substituted with 1 OH;

[0070] w is selected from O or NH;

[0071] Y is selected from -(CR d R e )-;

[0072] R d , R e Each independently selected from H or C 1-6 alkyl;

[0073] R and R1 are each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10 membered carbocyclic group or 4 to 10 membered heterocyclic group, the heterocyclic group may contain 1 to 3 heteroatoms selected from N, O or S, wherein the alkyl, carbocyclic ring or heterocyclic ring may be further substituted by 1 to 4 halogen, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy group, a 3- to 6-membered carbocyclic group, or a 5- to 6-membered heterocyclic group;

[0074] Alternatively, R and R1 may be taken together with the atoms to which they are attached to form a 4- to 6-membered ring;

[0075] C is selected from 3 to 5 membered cycloalkyl;

[0076] R2 is selected from H or halogen;

[0077] G1, G2, and G3 are each independently selected from N or CH;

[0078] q, r are selected from 0, 1 or 2;

[0079] n is selected from 0, 1, 2 or 3.

[0080] In one or more embodiments:

[0081] Q is selected from furanyl, thiazolyl or thienyl, and Q may be further substituted by cyano;

[0082] L is selected from -(CR a R b )- or 3 to 4-membered cycloalkyl, and said L is optionally further substituted with 0 to 2 -OH;

[0083] R a , R b Each independently selected from H or C 1-3 alkyl;

[0084] W is selected from O or NH;

[0085] Y is selected from -(CR d R e )-;

[0086] R d , R e Each independently selected from H or C 1-3 alkyl;

[0087] R and R1 are each independently selected from H, halogen, cyano, C 1-3 Alkyl or pyridyl, the C 1-3 The alkyl or pyridyl group may be further substituted with 1 to 4 halogen, cyano, C 1-3 Alkyl, C 1-3 substituted by an alkoxy group or a 3- to 5-membered cycloalkyl group;

[0088] Alternatively, R and R1 may be taken together with the atoms to which they are attached to form a 4- to 5-membered ring;

[0089] C is selected from 3 to 5 membered cycloalkyl;

[0090] R2 is selected from H;

[0091] G1, G2, and G3 are each independently selected from N or CH;

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

[0093] n is selected from 0, 1, 2 or 3.

[0094] In one or more embodiments:

[0095] Selected from or

[0096] Selected from or

[0097] W is selected from O or NH.

[0098] In one or more embodiments, the compound is:

[0099] or

[0100] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound of the present application or a stereoisomer thereof and one or more pharmaceutically acceptable carriers and / or excipients.

[0101] One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application or the compound of the present application or its stereoisomer in the preparation of an NLRP3 inhibitor.

[0102] In one or more embodiments, the disease associated with NLRP3 includes: inflammatory disease, autoimmune disease, cardiovascular disease, cancer, renal disease, gastrointestinal disease, respiratory disease, endocrine disease or central nervous system disease.

[0103] In one or more embodiments, diseases associated with NLRP3 include: cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, and chronic kidney disease.

[0104] One or more embodiments provide the compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated substances and compositions thereof, which are used as drugs.

[0105] One or more embodiments provide a compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated substances and compositions thereof, for use in a method for treating a disease associated with NLRP3.

[0106] One or more embodiments provide the compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated substances and compositions thereof, which are used as NLRP3 inhibitors.

[0107] One or more embodiments provide a compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof and a composition thereof, which are used for treating inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine system diseases or central nervous system diseases.

[0108] One or more embodiments provide a compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof and a composition thereof, which are used to treat cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout or chronic kidney disease.

[0109] One or more embodiments provide a method for treating / preventing a disease associated with NLRP3, comprising administering the compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated derivatives thereof, or the composition of the present application to a subject in need thereof.

[0110] One or more embodiments provide a method for treating / preventing a disease, comprising administering the compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof, or a composition of the present application to a subject in need thereof, wherein the disease is an inflammatory disease, an autoimmune disease, a cardiovascular disease, a cancer, a renal disease, a gastrointestinal disease, a respiratory disease, an endocrine system disease or a central nervous system disease.

[0111] One or more embodiments provide a method for treating / preventing a disease, comprising administering a compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated derivatives thereof, or a composition of the present application to a subject in need thereof, wherein the disease is cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset 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.

[0112] One or more embodiments provide a method for inhibiting NLRP3, comprising administering the compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated substances thereof, or the composition of the present application to a subject in need thereof.

[0113] Unless stated to the contrary, 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 application include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in this application are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0115] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally 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-hexyloxy, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

[0117] "Alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, and further preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propene-2-yl, butene-2-yl, butene-2-yl, pentene-2-yl, pentene-4-yl, hexene-2-yl, hexene-3-yl, heptene-2-yl, heptene-3-yl, heptene-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

[0118] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, preferably an alkynyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably an alkynyl group of 2 to 8 carbon atoms, and further preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyne-3-yl, nonyn-3-yl, decyn-4-yl, undecyne-3-yl, dodecyne-4-yl. The alkynyl may optionally be further substituted with one or more substituents.

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

[0120] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5-8 membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. Heteroaryl can be connected to a heteroatom or a carbon atom, and can be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted by one or more substituents.

[0121] "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl" above; when it is a non-aromatic ring, it 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 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclic group" or "carbocycle" is optionally further substituted by one or more substituents.

[0122] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3-8 membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be connected to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thiidine, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiazole, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridine ... 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, oxazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 .1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

[0123] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a 3-10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4-12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic ring system, and the ring carbon atoms are preferably 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0124] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which may be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3-8 membered heterocyclic ring. 1, 2 or 3 N, S optionally substituted in the ring of "heterocycloalkyl" may be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or a carbon atom; "heterocycloalkyl" may be a bridged ring or a spiro ring. Non-limiting examples of “heterocycloalkyl” include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.

[0125] When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups 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 2-6 Alkynyl, -NR q4 Rq5 , =NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, 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 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, and wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, 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 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or R is replaced by a substituent of =O q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq2 , R q3 Select from H or C 1-6 Alkyl; wherein R q4 , R q5 Selected from H, C 1-6 Alkyl, -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 , where the C 1-6 The alkyl group is optionally further substituted with one or more groups 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 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0126] Halogens include F, Cl, Br and I.

[0127] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present application that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0128] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, 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.

[0129] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0130] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0131] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0132] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group. BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Figure 1 The colon-plasma drug distribution of Control Example 1 is shown.

[0134] Figure 2 The colon-plasma drug distribution of compound 7-1 is shown. DETAILED DESCRIPTION

[0135] The following embodiments describe the technical solution of the present application in detail, but the protection scope of the present application includes but is not limited to this.

[0136] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (dMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0137] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0138] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0139] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0140] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

[0141] The known starting materials of the present application can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology;

[0142] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1L;

[0143] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L;

[0144] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times;

[0145] Unless otherwise specified in the examples, the reactions were carried out under a nitrogen atmosphere;

[0146] Unless otherwise specified in the examples, solution refers to aqueous solution;

[0147] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the most suitable reaction temperature is 20°C-30°C;

[0148] DCM: dichloromethane;

[0149] EA: ethyl acetate;

[0150] HCl: hydrochloric acid;

[0151] THF: tetrahydrofuran;

[0152] DMF: N,N-dimethylformamide;

[0153] PE: petroleum ether;

[0154] TLC: thin layer chromatography;

[0155] SFC: supercritical fluid chromatography;

[0156] NCS: N-chlorosuccinimide;

[0157] Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0158] AD-mix-β: Hydroquinidine 1,4-naphthylidene ether mixture;

[0159] (dHQD)2AQN: Hydroquinidine (anthraquinone-1,4-diyl) diether.

[0160] Intermediate 1

[0161] (R)-5-(1-Cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 1)

[0162] (R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0163]

[0164] first step:

[0165] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone (1b)

[0166] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone

[0167] Under nitrogen protection, in a 500mL three-necked flask, compound 1a (20.0g, 150.16mmol) was dissolved in 1,2-dichloroethane (200mL), cooled to 0°C in an ice-salt bath, and a dichloromethane solution of boron trichloride (150mL, 1M, 150.16mmol) was slowly added dropwise. After the addition was complete, the temperature was maintained for 10min, and then aluminum chloride (22.0g, 165.20mmol) and cyclopropylnitrile (15.1g, 225.24mmol) were added; the reaction system was heated to 80°C for 4h, cooled to room temperature, 160mL (2MHCl) was added in an ice bath, and the temperature was refluxed for 1h after the addition was complete. 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 2 M sodium hydroxide solution, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound 1b as a white solid (17.1 g, yield 57.2%).

[0168] 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).

[0169] LCMS m / z (ESI) = 202.1 [M+1].

[0170] Step 2:

[0171] 5-(1-Cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine (1c)

[0172] 5-(1-Cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine

[0173] Under nitrogen protection, in a 500mL three-necked flask, the compound methyl triphenylphosphonium bromide (24.8g, 69.6mmol) was dissolved in THF (300mL), and the temperature was cooled to 0°C in an ice-salt bath. Potassium tert-butoxide (7.8g, 69.6mmol) was slowly added, and the temperature was maintained for 30min. Then, compound 1b (7.0g, 34.8mmol) was added and reacted at room temperature for 4h. After the reaction was completed, water was added to quench the reaction, and EA (100mL×3) was used for extraction. The mixture 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 = 30:1) to obtain compound 1c as a light yellow oil (6.4g, yield 92.3%).

[0174] 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).

[0175] LC-MS m / z(ESI)=200.1[M+1].

[0176] Step 3:

[0177] (R)-5-(1-Cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 1)

[0178] (R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0179] The synthesis of intermediate 1 was prepared according to patent CN108017559. 1c (8.3 g, 41.7 mmol) and dichloromethane (90 mL) were added to a 500 mL autoclave, and the catalyst [(R)-2,2′-bis(diphenylphosphine)-1,11-binaphthyl] diacetic acid ruthenium (1.8 g, 2.09 mmol) was added. After the addition, the autoclave was tightened and sealed, replaced with hydrogen three times, and filled with hydrogen. The pressure gauge on the autoclave showed 12 atm, and the reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain intermediate 1, a light yellow oil (8.2 g, yield 97.8%, 97.74% ee). Chiral HPLC (chiral column: CHIRALPAK AY-3 (4.6×100 mm); mobile phase: methanol; column temperature: 35°C; mobile phase: methanol / n-hexane=15 / 85; column pressure: 2000psi; flow rate: 2mL / min; detector signal channel: 215nm@4.8nm; diode array detector start and end wavelengths: 200~400nm; RT=3.295min).

[0180] 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,1H),0.50-0.44(m,1H),0.34-0.28(m,1H),0.17-0.11(m,1H),0.06-0.00(m,1H).

[0181] LCMS m / z (ESI) = 202.1 [M+1].

[0182] Intermediate 2

[0183] (S)-5-(1-Cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (Intermediate 2)

[0184] (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0185]

[0186]

[0187] The synthesis of intermediate 2 was prepared according to patent CN108017559. 1c (7.3 g, 36.7 mmol) and dichloromethane (80 mL) were added to a 500 mL autoclave, and the catalyst [(S)-2,2′-bis(diphenylphosphine)-1,11-binaphthyl] diacetic acid ruthenium (1.54 g, 1.83 mmol) was added. After the addition, the autoclave was tightened and sealed, replaced with hydrogen three times, and filled with hydrogen. The pressure gauge on the autoclave showed 12 atm, and the reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain intermediate 2, a light yellow oil (7.1 g, yield 96.3%, 98.18% ee). Chiral HPLC (chiral column: CHIRALPAK AY-3 (4.6×100 mm); mobile phase: methanol; column temperature: 35°C; mobile phase: methanol / n-hexane=15 / 85; column pressure: 2000psi; flow rate: 2mL / min; detector signal channel: 215nm@4.8nm; diode array detector starting wavelength: 200~400nm; RT=2.802min).

[0188] 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(m,2H),1.15(d,3H),1.02-0.96(m,1H),0.50-0.44(m,1H),0.36-0.28(m,1H),0.17-0.11(m,1H),0.06-0.01(m,1H).

[0189] LCMS m / z (ESI) = 202.1 [M+1].

[0190] Intermediate 3

[0191] N-(tert-Butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (Intermediate 3)

[0192] N-(Tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0193]

[0194] first step:

[0195] Ethyl furan-3-carboxylate (3b)

[0196] Ethyl furan-3-carboxylate

[0197] Compound 3a (50 g, 0.446 mol) was dissolved in 300 mL of anhydrous ethanol under ice bath, and thionyl chloride (65 mL, 0.892 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to reflux for reaction for 2 hours. TLC monitored the complete reaction, and after 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), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:50-1:10) to obtain compound 3b, a light brown oil (38.1 g, yield 61%).

[0198] Step 2:

[0199] 4-Ethyl formate-2-sulfonyl chloride furan (3c)

[0200] Ethyl furan-2-sulfonyl chloride-4-formate

[0201] Compound 3b (22.00 g, 0.157 mol) was dissolved in 250 mL DCM at room temperature, cooled to -15°C in an ice-salt bath, and sulfonyl chloride (23.31 g, 0.173 mol) was slowly added dropwise while controlling the temperature not to exceed -10°C. After the addition was complete, the mixture was reacted at room temperature for 12 h. After the mixture was cooled to below -15°C in an ice-salt bath, pyridine (13.66 g, 0.173 mol) was slowly added dropwise, and phosphorus pentachloride (36.00 g, 0.137 mol) was added in batches while controlling the temperature not to exceed -10°C. After the addition was complete, the mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until it was complete, and the reaction solution was quenched by adding 200 mL of ice water, 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 to obtain compound 3c as a brown oil (33.00 g, yield 90%), which was used in the next step without purification.

[0202] Step 3:

[0203] Ethyl furan-2-sulfonamide-4-carboxylate (3d)

[0204] Furan-2-sulfonamide-4-ethyl formate

[0205] Compound 3c (33.00 g, 0.138 mol) was dissolved in 350 mL of acetone at room temperature, and a saturated aqueous solution of ammonium bicarbonate (49.74 g, 0.553 mol) was added dropwise at room temperature. The reaction was allowed to proceed for 3 h at room temperature. TLC monitored the reaction to be 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 to obtain compound 3d as a brown solid powder (23 g, yield 77%).

[0206] 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).

[0207] LCMS m / z=218.2[M-1].

[0208] Step 4:

[0209] 4-(2-Hydroxypropyl)furan-2-sulfonamide (3e)

[0210] 4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide

[0211] Compound 3d (23 g, 0.105 mol) was dissolved in 500 mL of dry THF at room temperature, cooled to -15°C in an ice-salt bath, and methylmagnesium bromide (140 mL, 0.418 mol) was slowly added dropwise while keeping the temperature below 0°C. After the addition was complete, the reaction was allowed to proceed for 4 h at room temperature. The reaction was monitored by TLC until complete. The reaction solution was poured into 200 mL of ice water to quench, 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. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4 to 1:1) to obtain compound 3e as a white solid powder (16 g, yield 76%).

[0212] LCMS m / z=204.2[M-1].

[0213] Step 5:

[0214] N-(tert-Butyldimethylsilyl)-4-(2-hydroxypropyl)furan-2-sulfonamide (3f)

[0215] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0216] Compound 3e (5.0 g, 24.39 mmol) was dissolved in 50 mL of dry THF at room temperature, cooled to -10°C in an ice-salt bath, sodium hydride (0.9 g, 36.58 mmol) was slowly added to control the temperature below -10°C, and then a solution of tert-butyldimethylsilyl chloride (4.8 g, 31.70 mmol) in THF (50 mL) was added, and the reaction was allowed to proceed at room temperature for 12 h. The reaction was monitored by TLC to be complete. The reaction solution was poured into 20 mL of ice water to quench, 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 separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2 to 2:1) to obtain compound 3f as a white solid (5.1 g, yield 66%).

[0217] 1 H NMR (400MHz, CDCl3) δ = 7.85 (s, 1H), 7.68 (s, 1H), 6.93 (s, 1H), 5.07 (s, 1H), 1.38 (s, 6H), 0.88 (s, 9H), 0.16 (s, 6H).

[0218] LCMS m / z=320.2 [M+1].

[0219] Step 6:

[0220] N-(tert-Butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimideamide (Intermediate 3)

[0221] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0222] In a 250mL three-necked flask, under nitrogen protection, DCM (100mL) and triphenylphosphine dichloride (11.3g, 33.86mmol) were added, cooled to 0℃ in an ice bath, and diisopropylethylamine (5.8g, 45.16mmol) was slowly added dropwise. After the addition was completed, the mixture was returned to room temperature for reaction for 10min. The reaction system was cooled to 0℃, and a solution of 3f (3.6g, 11.29mmol) in dichloromethane (10mL) was added dropwise. After the addition was completed, the mixture was kept at 0℃ for further reaction for 30min. Ammonia was passed into the reaction system for 15min. The mixture was returned to room temperature for reaction for 2h. The reaction was monitored by TLC, and the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 3 as a white solid (816mg, yield 23%).

[0223] 1H NMR (400MHz, DMSO-d6) δ = 7.56 (s, 1H), 6.86 (s, 2H), 6.73 (s, 1H), 5.01 (s, 1H), 1.37 (s, 6H), 0.85 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H).

[0224] LCMS m / z=319.2 [M+1].

[0225] Intermediate 4

[0226] N-(tert-butyldimethylsilyl)-2-(-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Intermediate 4)

[0227] N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0228]

[0229] first step:

[0230] 1-((tert-Butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol (4b)

[0231] 1-((Tert-butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol

[0232] Compound 4a (50.48 g, 0.31 mol) was dissolved in 1 L dry THF at room temperature, and the temperature was lowered to -78 ° C under nitrogen protection. 2.5 M n-BuLi in n-hexane solution (136 mL, 0.34 mol) was slowly added dropwise and the temperature was kept below -70 ° C. After the addition was complete, the mixture was stirred and reacted for 1 h. Then 1-(tert-butyldimethylsilyloxy)-2-propanone (70 g, 0.37 mol) was slowly added dropwise and reacted for 1 h. The reaction was monitored by TLC to be complete. Saturated NH4Cl solution was added to the reaction system to quench the reaction, and EA was used for extraction (200 mL × 3). The organic phases were combined. The organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The black residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:30 to 1:20) to obtain compound 4b, a light yellow oil (50 g, yield 59%).

[0233] 1H NMR (400MHz, DMSO-d6) δ7.70(s,1H),7.56(s,1H),5.26(s,1H),3.34-3.69(m,2H),1.47(s,3H),0.84(s,6H),0.79(s,9H),0.15(s,6H).

[0234] LCMS m / z=274.1 [M+1].

[0235] Step 2:

[0236] 2-(1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide (4c)

[0237] 2-(1-((Tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

[0238] Compound 4b (7 g, 25.6 mmol) was dissolved in 200 mL of dry THF at room temperature, and the temperature was lowered to -78°C under nitrogen protection. A 2.5 M n-BuLi solution in n-hexane (21.5 mL, 53.8 mmol) was slowly added dropwise while keeping the temperature below -70°C. After the addition was complete, the mixture was reacted for 1 h. Then 1,4-diazabicyclo[2.2.2]octane-1,4-diamine-1,4-disulfinic acid (9.2 g, 38.4 mmol) was added and the mixture was reacted for 1 h. The dry ice bath was removed and stirred at room temperature for 2 h. Add 200 mL of saturated NH4Cl solution to the reaction system to quench the reaction, extract the aqueous phase with EA (100 mL × 2), add the aqueous phase to a 500 mL three-necked flask, cool to -10 ° C, add potassium acetate (10.05 g, 102.4 mmol), hydroxylamine sulfonic acid (11.6 g, 102.4 mmol) in sequence, and then naturally heat the reaction overnight. Extract with EA (200 mL × 5), and combine the organic phases. The organic phase is washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is separated and purified by silica gel column chromatography to obtain compound 4c, a light yellow oil (2.8 g, yield 46%).

[0239] LCMS m / z=239 [M+1].

[0240] Step 3:

[0241] N-(tert-Butyldimethylsilyl)-2-(1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide (4d)

[0242] N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

[0243] Under nitrogen protection and 0°C, sodium hydride (1.92 g, 60%, 48 mmol) was added in batches to a 50 mL tetrahydrofuran solution of 4c (3.80 g, 16.0 mmol), and stirring was continued for 30 minutes. Tert-butyldimethylsilyl chloride (5.79 g, 38.4 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. TLC monitored the reaction to be complete, and 200 mL of water was added under ice bath cooling, and ethyl acetate (100 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 6:1) to obtain 4d as a brown-yellow oil (4.72 g, yield 63.2%).

[0244] 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),8.00(s,1H),6.15(s,1H),3.74-3.67 (m,2H),1.46(s,3H),0.88(s,9H),0.79(s,9H),0.15(s,6H),0.05(s,6H). LC-MS m / z(ESI)=467.2[M+1].

[0245] Step 4:

[0246] N-(tert-butyldimethylsilyl)-2-(-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Intermediate 4)

[0247] N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0248] In a 100mL round-bottom flask, triphenylphosphine (1.58g, 6.02mmol), hexachloroethane (1.67g, 7.05mmol) and chloroform 25mL were added in sequence under nitrogen protection, and refluxed at 85℃ for 30 minutes. TLC monitored the complete conversion and cooled to room temperature. Further cooled to -30℃, N,N-diisopropylethylamine (1.14g, 8.82mmol) was slowly added dropwise. Stir for 10min, and 4d (2.35g, 5.03mmol) dissolved in chloroform (5mL) was slowly added dropwise under ice bath, and stirred for 3h. Ammonia was passed at -30℃ for 1h, and the temperature was slowly raised to room temperature for overnight reaction. TLC monitored the complete reaction and the reaction was over. The reaction solution was poured into water, the organic phase was extracted, and then extracted with dichloromethane (100mL×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 = 10:1 to 4:1) to obtain intermediate 4 as a light yellow solid (873 mg, yield 37.3%).

[0249] LC-MS m / z(ESI)=467.2[M+1].

[0250] Intermediate 5

[0251] N-(tert-butyldimethylsilyl)-2-(-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Intermediate 5)

[0252] N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0253]

[0254] first step:

[0255] 2-(1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide (5a)

[0256] 2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

[0257] 5a was synthesized by referring to the method of 4c using 4b as the starting material.

[0258] Step 2:

[0259] N-(tert-Butyldimethylsilyl)-2-(1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide (5b)

[0260] N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

[0261] 5b was synthesized by referring to the method of 4d using 5a as the starting material.

[0262] Step 3:

[0263] N-(tert-butyldimethylsilyl)-2-(-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Intermediate 5)

[0264] N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0265] Intermediate 5 was synthesized by referring to the method of Intermediate 4 using 5b as raw material to obtain 1.0 g of light yellow solid.

[0266] LC-MS m / z(ESI)=467.2[M+1].

[0267] Intermediate 6-1 and Intermediate 6-2

[0268] (S)-N′-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimide amide and

[0269] (R)-N′-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (Intermediate 6-1 and Intermediate 6-2)

[0270] (S)-N′-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide and

[0271] (R)-N′-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0272]

[0273]

[0274] first step:

[0275] 2-Isopropenylthiazole (6b)

[0276] 2-(Prop-1-en-2-yl)thiazole

[0277] In a 500mL three-necked flask, add 300mL of anhydrous tetrahydrofuran and methyltriphenylphosphonium bromide (56.2g, 157.3mmol), protect with nitrogen, cool to -15℃, add potassium tert-butoxide (17.6g, 157.3mmol), naturally warm to room temperature and stir for 1.5h, add 6a (10g, 78.6mmol), react at room temperature for 2h, the reaction is complete according to TLC, add 100mL of water to quench the reaction, extract with EA (100mL×2), combine the organic phases, wash with saturated brine (100mL×2), dry the organic phases over anhydrous sodium sulfate, filter, and remove the organic solvent under reduced pressure. The residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-6:1) to obtain 6b, a light yellow oil (4.5g, yield 45.9%).

[0278] 1 HNMR (400MHz, DMSO-d6) δ 8.08 (s, 1H), 8.00 (s, 1H), 5.33 (s, 1H), 4.96 (s, 1H), 2.12 (s, 3H).

[0279] Step 2:

[0280] (S)-2-(Thiazol-2-yl)propane-1,2-diol (6c)

[0281] (S)-2-(thiazol-2-yl)propane-1,2-diol

[0282] At room temperature, in a 2L three-necked flask, add 600mL of tert-butyl alcohol, 600mL of tetrahydrofuran, 600mL of water, and then add AD-mix-β mixture (448g, 320mmol), methylsulfonamide (30.4g, 0.32mol), (DHQD)2AQN catalyst (11.0g, 0.0128mol). Cool to 0°C, add 6b (40g, 0.32mol) and naturally warm to room temperature and stir for 24h. TLC monitors the reaction to complete, add EA to extract (500mL×2) times, combine the organic phases, wash with saturated brine (200mL×2), dry the organic phase over anhydrous sodium sulfate, filter, and remove the organic solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol = 100: 1-20: 1) to obtain a crude product, which was recrystallized again using ethyl acetate (70 mL), petroleum ether (210 mL), and methanol (5 mL) to obtain a white solid 6c (45 g, yield 70%, RT = 7.506 min, 99.8% ee). Chiral HPLC (AS) 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 and end wavelength: 200-400 nm.

[0283] 1 H NMR (400MHz, DMSO-d6) δ7.70(s,1H),7.53(s,1H),5.78(s,1H),4.80(s,1H),3.52-3.60(m,2H),1.48(s,3H).

[0284] LC-MS m / z(ESI)=160.2[M+1].

[0285] Step 3:

[0286] (S)-1-((tert-Butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol (6d)

[0287] (S)-1-((tert-butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol

[0288] In a 500mL three-necked flask, add 160mL of anhydrous tetrahydrofuran and 6c (8.6g, 0.054mol), protect with nitrogen, cool to -5℃, add sodium hydride (2.6g, 0.108mol) and stir for 0.5h, then add tert-butyldimethylsilyl chloride (10g, 0.0648mol), react at room temperature for 2h, and the reaction is complete by TLC, add 100mL of water to quench the reaction, extract with EA (100mL×2), combine the organic phases, wash with saturated brine (100mL×2), dry the organic phases with anhydrous sodium sulfate, filter, and remove the organic solvent under reduced pressure. The residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-6:1) to obtain 6d (12.6g, yield 85.7%).

[0289] 1 H NMR (400MHz, DMSO-d6) δ7.69(d,1H),7.56(d,1H),5.26(s,1H),3.70(d,2H),1.47(s,3H),0.84(s,6H),0.79(s,9H): LC-MS m / z(ESI)=274.4[M+1].

[0290] Step 4:

[0291] (S)-2-(1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonylimideamide (6e)

[0292] (S)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

[0293] In a 100mL three-necked flask, add 40mL of anhydrous tetrahydrofuran and 6d (2.0g, 7.31mmol) under nitrogen protection. Cool to -78℃, slowly add n-butyl lithium (6.14mL, 15.3mmol) dropwise, react at -78℃ for 2h, then add tert-butoxy-N-sulfoxide (1.18g, 8.772mmol), naturally warm to room temperature and react for 12h after addition. The reaction is complete by TLC, add 30mL of water to quench the reaction, extract with EA (50mL×2) times, combine the organic phases, wash with saturated brine (100mL×2), dry the organic phases over anhydrous sodium sulfate, filter, and remove the organic solvent under reduced pressure. The residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-2:1) to obtain 6e, a white solid (1.6g, yield 64.1%).

[0294] LC-MS m / z(ESI)=353.5[M+1].

[0295] Step 5:

[0296] (S)-N-(tert-Butyldimethylsilyl)-2-(1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropane-2-yl)thiazole-5-sulfonylimideamide (6f)

[0297] (S)-N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

[0298] Under nitrogen protection, sodium hydride (1.2 g, 60%, 24 mmol) was added in batches to a 50 mL tetrahydrofuran solution of 6e (4.0 g, 11.3 mmol) at 0°C, and stirred for 30 minutes after addition. Tert-butyldimethylsilyl chloride (2.4 g, 4.08 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 h. TLC monitored the reaction to be complete, and 100 mL of water was added under ice-bath cooling, and ethyl acetate (100 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 6:1) to obtain 6f, a light yellow oil (4.72 g, yield 63.2%).

[0299] 1 H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.85(s,1H),5.61(s,1H),3.64-3.55 (m,2H),1.31(s,3H),0.73(s,9H),0.63(s,9H),0.15(s,6H),0.05(s,6H).

[0300] LC-MS m / z(ESI)=467.2[M+1].

[0301] Step 6:

[0302] (S)-N′-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (Intermediate 6)

[0303] (S)-N′-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0304] Under nitrogen protection, at -10°C, 6f (8.0 g, 21.4 mmol) was dissolved in 50 mL of dichloroethane, then added to the freshly prepared triphenylphosphine dichloride-dichloroethane solution (32.1 mmol) and stirred for 2 h. TLC monitored the reaction to be complete, then S-1-(4-methoxyphenyl)ethane-1-amine (3.88 g, 25.68 mmol) was added, and stirred at room temperature for 3 h. After the reaction was complete, 100 mL of water was added, and dichloromethane (100 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 20:1) to obtain compound intermediate 6-1, light yellow oil (3.0 g, yield 30%) and intermediate 6-2 (3.5 g, yield 35%).

[0305] Intermediate 6-1: 1 H NMR(400MHz,DMSO-d6)δ7.50(s,1H),7.07(d,2H),6.72(d,2H),5.91(s,1H),4.39-4.32(m,1H),3.68(s,3H),3.61( s,2H),1.37(s,3H),1.22(d,3H),0.89(s,9H),0.80(s,9H),0.06(s,3H),0.03(s,3H),-0.04(s,3H),-0.06(s,3H).

[0306] LC-MS m / z(ESI)=600.2[M+1].

[0307] Intermediate 6-2: 1H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.19-6.94(m,2H),6.70(s,2H),5.83(s,1H),4.61-4.11(m,1H),3.58(s,3H),3 .51(s,2H),1.32(s,3H),1.20(d,3H),0.88(s,9H),0.81(s,9H),0.78(s,3H),0.20(s,3H),0.16(s,3H),0.06(s,3H).

[0308] LC-MS m / z(ESI)=600.2[M+1].

[0309] Intermediates 7-1 and 7-2

[0310] (S)-N′-(tert-butyldimethylsilyl)-2-((R)-1-(tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-(S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimide

[0311] (R)-N′-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-(S)-(S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimide (Intermediate 7-1 and Intermediate 7-2)

[0312] (S)-N′-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0313] (R)-N′-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0314] Prepare intermediates 7-1 and 7-2 by referring to the synthetic methods of intermediates 6-1 and 6-2

[0315]

[0316] Example 1

[0317] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Compounds 1-1 and 1-2)

[0318] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0319]

[0320]

[0321] first step:

[0322] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (1A)

[0323] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0324] In a 25mL round-bottom flask, add intermediate 2 (129mg, 0.644mmol), 3mL of dry tetrahydrofuran, diisopropylethylamine (166mg, 1.29mmol) and 2,2,2-trichloroethyl chloroformate (163mg, 0.77mmol) in sequence under nitrogen protection, stir and react for 30min, and monitor the complete conversion by TLC. Add 5mL of water to the reaction solution, extract with ethyl acetate (10mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry. Add 3mL of dry tetrahydrofuran to dissolve as solution B. Add intermediate 4 (300mg, 0.644mmol) and 3mL of dry tetrahydrofuran to another 50mL three-necked flask, add sodium hydride (31mg, 60%, 0.77mmol) under ice bath, and stir and react for 1h. Solution B was slowly added dropwise under ice bath, and the mixture was heated to room temperature for 1 h. After the reaction was complete as monitored by LC-MS, triethylamine trihydrofluoride (103 mg, 0.644 mmol) was slowly added dropwise. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain 1A as a light yellow solid (200 mg, yield 66.8%).

[0325] LC-MS m / z(ESI)=465.2[M+1].

[0326] Step 2:

[0327] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Compounds 1-1 and 1-2)

[0328] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0329] 1A (180 mg, 0.387 mmol) was separated by SFC to give compound 1-1 (72 mg, yield 40.0%, RT = 20.010 min, 100% ee) and compound 1-2 (85 mg, yield 47.2%, RT = 24.571 min, 100% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; 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 and end wavelength: 200 ~ 400 nm.

[0330] Compound 1-1: 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),8.05(s,1H),7.82(s,2H),7.12(d,1H),7.04 (d,1H),6.11(s,1H),5.00(t,1H),3.54(d,2H),2.82(t,2H),2.73-2.62(m,2H),2 .29-2.10(m,1H),2.00-1.86(m,2H),1.44(s,3H),1.08(d,3H),1.00-0.88(m,1H) ,0.49-0.40(m,1H),0.270-0.160(m,1H),0.15-0.08(m,1H),0.075-0.02(m,1H).

[0331] LCMS m / z (ESI) = 465.2 [M+1].

[0332] Compound 1-2: 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.04(s,1H),7.82(s,2H),7.13(d,1H),7.04 (d,1H),6.10(s,1H),5.00(t,1H),3.55(d,2H),2.82(t,2H),2.78-2.57(m,2H),2 .27-2.16(m,1H),2.00-1.855(m,2H),1.44(s,3H),1.10(d,3H),0.98-0.85(m,1H ),0.47-0.36(m,1H),0.23-0.13(m,1H),0.12-0.026(m,1H),0.023-0.085(m,1H).

[0333] LCMS m / z (ESI) = 465.2 [M+1].

[0334] Example 2

[0335] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Compounds 2-1 and 2-2)

[0336] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0337]

[0338] first step:

[0339] 2-(2,6-Dibromophenyl)ethan-1-ol (2B)

[0340] 2-(2,6-Dibromophenyl)ethan-1-ol

[0341] In a 1L three-necked flask, add 2A (60.0g, 0.2mol) and anhydrous tetrahydrofuran (300mL), under nitrogen protection, slowly add borane tetrahydrofuran solution (300mL, 1M) at 0℃. After the addition is complete, heat to 80℃ for 1h, monitor the reaction to be complete by TLC, and cool to room temperature. Add water (150mL) and dilute hydrochloric acid (20mL, 2N) to quench the reaction in an ice-water bath. Concentrate part of the reaction solution under reduced pressure, then add ethyl acetate (100mL×3) for extraction, dry over anhydrous sodium sulfate, filter, remove the organic solvent under reduced pressure, and purify the residue by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 2B as a white solid (50.0g, yield 88%).

[0342] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.94 (t, 1H), 3.88 (t, 2H), 3.33 (t, 2H).

[0343] Step 2:

[0344] 1,3-Dibromo-2-(2-bromoethyl)benzene(2C)

[0345] 1,3-Dibromo-2-(2-bromoethyl)benzene

[0346] In a 1L round-bottom flask, 2B (50.0 g, 0.18 mol), N-bromosuccinimide (38.0 g, 0.2 mmol) and dichloromethane (400 mL) were added in sequence. After stirring and dissolving, the mixture was placed in an ice-water bath, and triphenylphosphine (65 g, 0.2 mol) was slowly added. After the addition was complete, the mixture was moved to room temperature for reaction for 24 h. The reaction was monitored by TLC. Tert-butyl hydroperoxide (8 mL) was added to react for 2 h to remove excess triphenylphosphine. Saturated sodium bisulfite solution (200 mL) was added to quench the reaction. The mixture was 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, and the mixture was filtered. After the filtrate was concentrated, it was purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain 2C as a white solid (60.0 g, yield 98%).

[0347] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.97 (t, 1H), 3.63-3.43 (m, 4H).

[0348] Step 3:

[0349] 2-Bromobicyclo[4.2.0]oct-1(6),2,4-triene(2D)

[0350] 2-Bromobicyclo[4.2.0]octa-1(6),2,4-triene

[0351] In a 250 mL three-necked flask, 2C (5.0 g, 15 mmol) and anhydrous tetrahydrofuran (150 mL) were added in sequence. Under nitrogen protection, n-butyl lithium (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 completed as monitored by UPLC. Water (20 mL) was slowly added dropwise to quench the reaction. 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 2D as a light yellow oil (2.5 g, yield 90%).

[0352] Step 4:

[0353] Tert-butyl bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamate (2E)

[0354] Tert-butyl bicyclo[4.2.0]octa-1(6), 2,4-trien-2-ylcarbamate

[0355] In a 250 mL round-bottom flask, 2D (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 in sequence. Palladium acetate (132 mg, 6 mmol) was added under nitrogen protection, and the mixture was moved to 100 ° C for 2 h. The reaction was complete after TLC monitoring. After cooling to room temperature, saturated sodium bicarbonate (50 mL) was added to quench the reaction, and 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 2E (2.3 g, brown oil, yield 83%).

[0356] 1 H NMR (400MHz, CDCl3) δ = 7.27 (d, 1H), 7.13 (t, 1H), 6.76 (d, 1H), 6.31 (s, 1H), 3.27-3.16 (m, 2H), 3.16-3.06 (m, 2H), 1.52 (s, 9H).

[0357] Step 5:

[0358] Bicyclo[4.2.0]octan-1(6),2,4-trien-2-amine (2F)

[0359] Bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0360] In a 100 mL round-bottom flask, 2E (2.3 g, 10.5 mmol), dichloromethane (40 mL), and trifluoroacetic acid (6 mL) were added in sequence. The reaction was allowed to react at room temperature for 7 h. The reaction was completed after monitoring by TLC. Saturated sodium bicarbonate solution (40 mL) was added to quench the reaction. 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 2F as a brown oil (1.0 g, yield 80%).

[0361] 1 H NMR (400MHz, CDCl3) δ = 7.02 (dd, 1H), 6.51 (dd, 2H), 3.11 (dd, 2H), 3.04 (dd, 2H).

[0362] Step 6:

[0363] (2-aminobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(cyclopropyl)methanone (2G)

[0364] (2-Aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclopropyl)methanone

[0365] 2F (100 mg, 0.84 mmol) and dichloroethane (5 mL) were added to a 25 mL three-necked flask in sequence. After dissolving, the mixture was placed in an ice-water bath. Boron trichloride toluene solution (900 μL, 1 M) was slowly added dropwise under nitrogen protection. After 10 min, anhydrous aluminum trichloride (123 mg, 0.9 mmol) was added, and then cyclobutane nitrile (74 μL, 1 mmol) was slowly added dropwise. After the addition was completed, the mixture was reacted at 90 ° C for 3 h, cooled to room temperature, and a dilute hydrochloric acid solution (1 mL, 2N) and water (5 mL) were added. The mixture was refluxed for 30 min, and the organic phase was separated. The mixture was washed with saturated sodium bicarbonate (10 mL) until it was 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 obtain 2G, a brown oil (60 mg, yield 38%).

[0366] 1 H NMR (400MHz, CDCl3) δ = 7.91 (d, 1H), 6.51 (d, 1H), 3.12-3.05 (m, 2H), 3.04-2.95 (m, 2H), 2.67-2.54 (m, 1H), 1.19-1.10 (m, 2H), 1.00-0.87 (m, 2H).

[0367] Step 7:

[0368] 3-(1-Cyclopropylvinyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (2H)

[0369] 3-(1-Cyclopropylvinyl)bicyclo[4.2.0]octa-1(6), 2,4-trien-2-amine

[0370] Triphenylmethylphosphonium bromide (8 g, 22 mmol) and anhydrous tetrahydrofuran (40 mL) were added to a 25 mL three-necked flask in sequence. After dissolving, the mixture was placed in an ice-water bath. Potassium tert-butoxide (2.5 g, 22 mmol) was added under nitrogen protection. After 40 min, a tetrahydrofuran solution (20 mL) of 2G (1.4 g, 7.5 mmol) was added. After 10 min, the mixture was reacted at room temperature for 2 h. Water (20 mL) was added to quench the mixture. The mixture was 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 obtain 2H (1.2 g, brown oil, yield 85%).

[0371] 1 H NMR (400MHz, CDCl3) δ = 6.87 (d, 1H), 6.49 (d, 1H), 5.17 (d, 1H), 4.91 (d, 1H), 3. 09(dd,2H),3.03(dd,2H),1.63(tt,1H),0.77-0.67(m,2H),0.54-0.44(m,2H).

[0372] Step 8:

[0373] (R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (2I)

[0374] (R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0375] In a 500mL autoclave, 2H (500mg, 2.7mmol) and dichloromethane (50mL) were added, and the catalyst [(R)-2,2′-bis(diphenylphosphine)-1,11-binaphthyl] diacetic acid ruthenium (113mg, 0.14mmol) was added. After the addition was completed, the autoclave was sealed and replaced with hydrogen three times. The pressure gauge on the autoclave showed a pressure of 14atm, and the reaction was carried out at room temperature for 5h. 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 obtain 2I (470mg, light yellow oil, yield 94%).

[0376] 1 H NMR (400MHz, DMSO) δ = 6.95 (d, 1H), 6.30 (d, 1H), 2.88 (s, 4H), 2.2 (m, 1H), 1.23 (d,3H),0.97(m,1H),0.46(m,1H),0.29(dt,1H),0.12(dt,1H),0.01(dt,1H).

[0377] Step 9

[0378] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (2J)

[0379] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0380] In a 25mL round-bottom flask, 2I (133mg, 0.71mmol), 3mL of dry tetrahydrofuran, diisopropylethylamine (191mg, 1.48mmol) and 2,2,2-trichloroethyl chloroformate (177mg, 0.84mmol) were added in sequence under nitrogen protection, and the reaction was stirred for 30min. The conversion was monitored by TLC. 5mL of water was added to the reaction solution, and ethyl acetate was extracted (10mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and spun dry. 3mL of dry tetrahydrofuran was added to dissolve as solution C. In another 50mL three-necked flask, intermediate 4 (300mg, 0.644mmol) and 3mL of dry tetrahydrofuran were added, and sodium hydride (31mg, 60%, 0.77mmol) was added under ice bath, and the reaction was stirred for 1h. Solution C was slowly added dropwise under ice bath, and the reaction was carried out at room temperature for 1 h. After the reaction was completed by LC-MS monitoring, triethylamine trihydrofluoride (309 mg, 1.92 mmol) was slowly added dropwise. The reaction was carried out at room temperature overnight. After the reaction was completed by TLC monitoring, the reaction solution was poured into water, ethyl acetate (20 mL×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain 2J as a white solid (244 mg, yield 84.1%). LCMS m / z(ESI)=451.1[M+1].

[0381] Step 10:

[0382] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Compounds 2-1 and 2-2)

[0383] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0384] 2J (210 mg, 0.466 mmol) was separated by SFC to give compound 2-1 (100 mg, yield 47.6%, RT = 19.828 min, 98.44% ee) and compound 2-2 (95 mg, yield 45.2%, RT = 18.351 min, 100% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; 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 and end wavelength: 200 ~ 400 nm.

[0385] Compound 2-1: 1 H NMR(600MHz,DMSO)δ8.28(s,1H),8.05(s,1H),7.85(s,2H),7.16(d,1H),6.84(d,1H),6.12(s,1H),5.01(t,1H),3.54(d,2H),3.03-2.89(m,3H ),2.41-2.27(m,1H),1.44(s,3H),1.12(d,3H),0.95-0.88(m,1H),0.48 -0.39(m,1H),0.27-0.18(m,1H),0.11-0.05(m,1H),0.04-0.00(m,1H).

[0386] Compound 2-2: 1 H NMR(600MHz,DMSO)δ8.29(s,1H),8.05(s,1H),7.87(s,2H),7.17(d,1H),6.84(d,1H),6.14(s,1H),5.02(t,1H),3.53(d,2H),2.98(d,3H),2 .36-2.27(m,1H),1.44(s,3H),1.09(d,3H),1.00-0.88(m,1H),0.50- 0.42(m,1H),0.28-0.19(m,1H),0.19-0.07(m,1H),0.05-0.01(m,1H).

[0387] Example 3

[0388] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Compound 3)

[0389] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0390]

[0391]

[0392] first step:

[0393] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone (3B)

[0394] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone

[0395] 3A (40 g, 210.4 mmol) and dichloroethane (500 mL) were added to a 1L three-necked flask in sequence. After dissolving, the mixture was placed in an ice-water bath. Boron trichloride toluene solution (252.8 mL, 1 M) was slowly added dropwise under nitrogen protection. After 10 min, anhydrous aluminum trichloride (33.6 g, 252 mmol) was added, and then cyclobutane nitrile (59.2 mL, 632 mmol) was slowly added dropwise. After the addition was completed, the mixture was reacted at 90°C for 24 h, cooled to room temperature, and a dilute hydrochloric acid solution (30 mL, 2N) was added. The mixture was refluxed for 30 min, and the organic phase was separated. The mixture was washed with saturated sodium bicarbonate (50 mL) until weakly acidic, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the crude product 3B was removed under reduced pressure, a light yellow oil (4.8 g, yield 8.8%).

[0396] 1 H NMR(400MHz DMSO)δ=7.27(dd,1H),6.79(dd,1H),5.17(d,2H),4.14-4.10(m,1H),2.06-2.86(m,5H),1.82-1.68(m,1H)

[0397] Step 2:

[0398] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol(3C)

[0399] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol

[0400] In a 250 mL round-bottom flask, 3B (4.8 g, 17.3 mmol), anhydrous methanol (20 mL), and sodium borohydride (2.0 g, 51.9 mmol) were added in sequence. The reaction was allowed to react at room temperature for 2 h. The reaction was completed as monitored by TCL. 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 = 30: 1) to obtain 3C as a white powder (2.6 g, yield 54%).

[0401] 1 H NMR (400MHz DMSO) δ = 7.21 (dd, 1H), 6.94 (dd, 1H), 5.48 (d, 1H), 5.03 (s, 2H), 4.54 (dd, 1H), 2.74-2.62 (m, 2H), 1.98-1.68 (m, 6H).

[0402] Step 3:

[0403] 2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline (3D)

[0404] 2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline

[0405] In a 50 mL round-bottom flask, 3C (850 mg, 3 mmol), dichloromethane (20 mL), triethylsilane (1.4 mL, 9 mmol) and trifluoroacetic acid (1 mL, 9 mmol) were added in sequence and reacted at room temperature for 2 h. The reaction was completed after monitoring by TLC. Saturated sodium bicarbonate solution (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 = 10: 1) to obtain 3D as a brown oil (530 mg, yield 69%).

[0406] 1 H NMR(400MHz,Chloroform-d)δ7.06(dd,1H),6.70(dd,1H),3.36(s,2H),2.65( dq,1H),2.58(d,2H),2.22-2.07(m,2H),1.98-1.81(m,2H),1.83-1.63(m,2H).

[0407] Step 4:

[0408] 2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline (3E)

[0409] 2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline

[0410] In a 50mL round-bottom flask, 3D (500mg, 1.93mmol), dioxane (20mL), sodium carbonate (616mg, 5.8mmol) were added in sequence, and dichlorobis(triphenylphosphine)palladium (67.7mg, 0.0965mmol) and 2-methoxypyridine-4-boronic acid (383mg, 2.50mmol) were added under nitrogen protection and reacted at 80°C for 24h. The reaction was complete after TLC monitoring. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 3E, a brown oil (350mg, yield 63.3%).

[0411] LCMS m / z (ESI) = 287.2 [M+1].

[0412] Step 5:

[0413] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Compound 3)

[0414] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0415] In a 25mL round-bottom flask, 3E (221mg, 0.772mmol), 3mL of dry tetrahydrofuran, diisopropylethylamine (191mg, 1.48mmol) and 2,2,2-trichloroethyl chloroformate (191mg, 0.901mmol) were added in sequence under nitrogen protection, and the reaction was stirred for 30min. The conversion was complete under TLC monitoring. 5mL of water was added to the reaction solution, and ethyl acetate was extracted (10mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. 3mL of dry tetrahydrofuran was added to dissolve as solution C. In another 50mL three-necked flask, intermediate 4 (300mg, 0.644mmol) and 3mL of dry tetrahydrofuran were added, and sodium hydride (31mg, 60%, 0.77mmol) was added under ice bath, and the reaction was stirred for 1h. Solution C was slowly added dropwise under an ice bath, and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete as monitored by LC-MS, triethylamine trihydrofluoride (311 mg, 1.93 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction solution was poured into water, and ethyl acetate (20 mL × 2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain compound 3 as a white solid (311 mg, yield 87.9%).

[0416] 1 H NMR(400MHz,DMSO)δ8.27(s,1H),8.10(d,1H),7.92(s,1H),7.78(s,2H),7.10-7.03(m,1H),7.03-6.96(m,1H),6.90(s,1H),6.76(s,1 H),6.11(d,1H),5.06-4.95(m,1H),3.87(s,3H),3.55(t,2H),2.61(s,2H),1.97(s,2H),1.83-1.74(m,2H),1.66(s,2H),1.45(d,4H).

[0417] LCMS m / z (ESI) = 550.2 [M+1].

[0418] Example 4

[0419] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (Compounds 4-1 and 4-2)

[0420] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0421]

[0422]

[0423] first step:

[0424] N-((2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonylimideamide (4A)

[0425] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0426] In a 25mL round-bottom flask, 3E (221mg, 0.772mmol), 3mL of dry tetrahydrofuran, diisopropylethylamine (191mg, 148mmol) and 2,2,2-trichloroethyl chloroformate (191mg, 0.901mmol) were added in sequence under nitrogen protection, and the reaction was stirred for 30min. The conversion was complete under TLC monitoring. 5mL of water was added to the reaction solution, and ethyl acetate was extracted (10mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. 3mL of dry tetrahydrofuran was added to dissolve as solution C. In another 50mL three-necked flask, intermediate 5 (300mg, 0.644mmol) and 3mL of dry tetrahydrofuran were added, and sodium hydride (31mg, 60%, 0.77mmol) was added under ice bath, and the reaction was stirred for 1h. Solution C was slowly added dropwise under an ice bath, and the mixture was reacted at room temperature for 1 h. After the reaction was complete as monitored by LC-MS, triethylamine trihydrofluoride (311 mg, 1.93 mmol) was slowly added dropwise. The mixture was reacted at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction solution was poured into water, and ethyl acetate (20 mL × 2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain 4A as a white solid (177 mg, yield 50.0%).

[0427] LCMS m / z (ESI) = 550.2 [M+1].

[0428] Step 2:

[0429] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropane-2-yl)thiazole-5-sulfenamide (Compounds 4-1 and 4-2)

[0430] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0431] 4A (177 mg, 0.322 mmol) was separated by SFC to give compound 4-1 (79 mg, yield 44.6%, RT = 6.348 min, 99.54% ee) and compound 4-2 (68 mg, yield 38.4%, RT = 9.341 min, 98.42% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; column temperature: 35 ° C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm @ 48 nm; diode array detector start and end wavelength: 200 ~ 400 nm.

[0432] Compound 4-1: 1 H NMR(600MHz,DMSO)δ8.26(s,1H),8.13-8.05(m,1H),7.91(s,1H),7.77(s ,2H),7.06(dd,1H),7.03-6.97(m,1H),6.88(s,1H),6.76(s,1H),6.12(s, 1H),5.02(t,1H),3.87(s,3H),3.55(d,2H),2.66-2.59(m,2H),2.55(s,1 H),2.04-1.91(m,2H),1.84-1.75(m,2H),1.73-1.59(m,2H),1.45(s,3H).

[0433] Compound 4-2: 1H NMR(600MHz,DMSO)δ8.26(s,1H),8.10(d,1H),7.91(s,1H),7.76(br,2H),7.06(dd,1H),7.01(dd,1H),6.90(s,1H),6.76(s,1H),6.11(s,1H), 5.02(t,1H),3.86(s,3H),3.56(d,2H),2.62(d,2H),2.59-2.53(m,1H) ,2.03-1.91(m,2H),1.84-1.76(m,2H),1.72-1.60(m,2H),1.46(s,3H).

[0434] Example 5

[0435] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compounds 5-1 and 5-2)

[0436] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0437]

[0438] first step:

[0439] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (5A)

[0440] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0441] In a 25mL round-bottom flask, add intermediate 2 (133mg, 0.71mmol), 3mL of dry tetrahydrofuran, diisopropylethylamine (191mg, 1.48mmol) and 2,2,2-trichloroethyl chloroformate (177mg, 0.84mmol) in sequence under nitrogen protection, stir and react for 30min, and monitor the complete conversion by TLC. Add 5mL of water to the reaction solution, extract with ethyl acetate (10mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry. Add 3mL of dry tetrahydrofuran to dissolve as solution C. Add intermediate 4 (300mg, 0.644mmol) and 3mL of dry tetrahydrofuran to another 50mL three-necked flask, add sodium hydride (31mg, 60%, 0.77mmol) under ice bath, and stir and react for 1h. Solution C was slowly added dropwise under an ice bath, and the mixture was reacted at room temperature for 1 h. After the reaction was complete as monitored by LC-MS, triethylamine trihydrofluoride (309 mg, 1.92 mmol) was slowly added dropwise. The mixture was reacted at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain 5A as a white solid (76 mg, yield 26.2%).

[0442] LCMS m / z (ESI) = 451.1 [M+1].

[0443] Step 2:

[0444] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compounds 5-1 and 5-2)

[0445] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0446] 5A (76 mg, 0.168 mmol) was separated by SFC to give compound 5-1 (28 mg, yield 36.8%, RT = 6.298 min, 100% ee) and compound 5-2 (33 mg, yield 43.4%, RT = 8.351 min, 99.04% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; 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 and end wavelength: 200-400 nm.

[0447] Compound 5-1: 1 H NMR(600MHz,DMSO)δ8.29(s,1H),8.04(s,1H),7.82(s,2H),7.12(d,1H),7.04( d,1H),6.12(s,1H),5.02(t,1H),3.53(d,2H),2.82(t,2H),2.63(d,2H),2.26-2 .15(m,1H),1.99-1.87(m,2H),1.44(s,3H),1.23(s,1H),1.06(d,3H),0.99-0.9 0(m,1H),0.48-0.41(m,1H),0.24-0.16(m,1H),0.09(d,1H),0.05-0.00(m,1H).

[0448] Compound 5-2: 1 H NMR(600MHz,DMSO)δ8.27(s,1H),8.04(s,1H),7.81(s,2H),7.17-7.08(m,1H),7.04 (d,1H),6.10(s,1H),5.01(t,1H),3.54(d,2H),2.82(t,2H),2.71-2.59(m,2H),2.30 -2.16(m,1H),1.93(d,2H),1.44(s,3H),1.10(d,3H),0.98-0.89(m,1H),0.48-0.38 (m,1H),0.23-0.13(m,1H),0.10-0.03(m,1H),0.02-0.08(m,1H),0.00-0.07(m,1H).

[0449] Example 6

[0450] 3-cyano-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(1,2-dihydroxypropane-2-yl)thiophene-2-sulfonamide (Compounds 6-1 and 6-2)

[0451] 3-Cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[0452]

[0453] first step:

[0454] 4-Bromo-5-sulfamoylthiophene-2-carboxylic acid methyl ester (6B)

[0455] Methyl 4-bromo-5-sulfamoylthiophene-2-carboxylate

[0456] A mixture of chlorosulfonic acid (44.67 mL, 678.52 mmol) and thionyl chloride (14.78 mL, 203.56 mmol) of 6A (30.0 g, 135.70 mmol) was added in batches at 0°C. The mixture was stirred at 0°C for 20 minutes and then placed at 50°C for 1 hour. After the reaction was completed, it was cooled to room temperature, and 400 mL (1:1) of ammonium bicarbonate, water and acetone solution were added dropwise at 0°C and stirred overnight. TLC detected that the reaction was completed, filtered, and the solid was washed with ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL), and the organic phases were combined and concentrated to obtain a dark oil. Purification was obtained by slurrying with dichloromethane (200 mL) to obtain 6B, a light yellow solid (28 g, yield 68.74%).

[0457] LC-MS m / z(ESI)=300.03[M+1].

[0458] Step 2:

[0459] 3-Bromo-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (6C)

[0460] 3-Bromo-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[0461] Dissolve 6B (28 g, 93.29 mol) in 500 mL dry THF at room temperature, cool to -15°C in an ice-salt bath, slowly drop methylmagnesium bromide (155.48 mL, 466.45 mol) and keep the temperature below 0°C. After the dropwise addition, react at room temperature for 4 h. TLC monitors the reaction until complete. Pour the reaction solution into 200 mL ice water to quench, extract with EA (200 mL × 3), and combine the organic phases. Wash the organic phase with saturated brine (100 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent. The residue is treated with (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain 6C, a white solid powder (4.5 g, yield 47.4%).

[0462] LC-MS m / z(ESI)=300.0[M+1].

[0463] Step 3:

[0464] 3-Cyano-5-(prop-1-en-2-yl)thiophene-2-sulfonamide (6D)

[0465] 3-Cyano-5-(prop-1-en-2-yl)thiophene-2-sulfonamide

[0466] Under nitrogen protection, in a 50 mL round-bottom flask, 6C (4.0 g, 13.33 mmol) and cuprous cyanide (1.43 g, 15.99 mmol) were dissolved in N,N-dimethylformamide (40 mL), and the reaction was carried out at 150 ° C for 4 hours. The reaction was completed by TLC monitoring. 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 obtain 6D as a light yellow solid (1.0 g, yield 30.47%).

[0467] LC-MS m / z (ESI) = 229 [M+1].

[0468] Step 4:

[0469] (R)-3-Cyano-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(prop-1-en-2-yl)thiophene-2-sulfonamide (6E)

[0470] (R)-3-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(prop-1-en-2-yl)thiophene-2-sulfonamide

[0471] In a 25mL round-bottom flask, add intermediate 1 (1.31g, 6.51mmol), 50mL of dry tetrahydrofuran, diisopropylethylamine (1.53mg, 11.84mmol) and 2,2,2-trichloroethyl chloroformate (1.63g, 7.70mmol) in sequence under nitrogen protection, stir and react for 30min, and monitor the complete conversion by TLC. Add 50mL of water to the reaction solution, extract with ethyl acetate (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry. Add 3mL of dry tetrahydrofuran to dissolve as solution C. In another 50 mL three-necked flask, 6D (1.35 g, 5.92 mmol) and 3 mL of dry tetrahydrofuran were added, and sodium hydride (474 ​​mg, 60%, 11.84 mmol) was added under ice bath. The reaction was stirred for 1 h. The reaction was completed after monitoring by TLC. The reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 6E as a light yellow oil (1.35 g, yield 50.1%).

[0472] LCMS m / z (ESI) = 451.1 [M+1].

[0473] Step 5:

[0474] 3-Cyano-N-(((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (6F)

[0475] 3-Cyano-N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[0476] In a 250 mL round-bottom flask, 6E (1.35 g, 2.97 mmol) was dissolved in a mixed solvent of tert-butanol / acetone (45 mL / 45 mL), and NMO (696 mg, 5.94 mmol) was added under stirring. After stirring at room temperature for 10 min, an aqueous solution of potassium osmate dihydrate (109 mg, 0.297 mmol) (45 mL of water) was added dropwise. After the addition was completed, the reaction was allowed to react at room temperature. The reaction was monitored by TLC. The reaction was quenched with an aqueous sodium bisulfite solution, extracted with EA (100 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 (EA:PE=1:30-1.5:1) to obtain 6F as a yellow solid (240 mg, yield 16.5%).

[0477] LCMS m / z (ESI) = 490.1 [M+1].

[0478] Step 6:

[0479] 3-Cyano-N-(((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(1,2-dihydroxypropane-2-yl)thiophene-2-sulfonamide (Compounds 6-1 and 6-2)

[0480] 3-Cyano-N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[0481] 6F (240 mg, 0.491 mmol) was separated by SFC to give compound 6-1 (39 mg, yield 16.3%, RT = 8.630 min, 99.22% ee) and compound 6-2 (43 mg, yield 17.9%, RT = 15.807 min, 99.40% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; 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 and end wavelength: 200 ~ 400 nm.

[0482] Compound 6-1: 1H NMR(600MHz,DMSO)δ11.75(s,1H),9.46(s,1H),7.47(s,1H),7.22(d,1H),7.15 (d,1H),6.03(s,1H),5.20(t,1H),3.49-3.41(m,2H),2.87(t,2H),2.78(t,2H), 2.36-2.28(m,1H),2.03-1.98(m,2H),1.48(s,3H),1.21(d,3H),1.04-0.97(m,1 H),0.54-0.40(m,1H),0.33-0.24(m,1H),0.17-0.10(m,1H),0.07-0.04(m,1H).

[0483] Compound 6-2: 1 H NMR(600MHz,DMSO)δ11.74(s,1H),9.48(s,1H),7.47(s,1H),7.22(d,1H),7.16 (d,1H),6.03(s,1H),5.21(t,1H),3.48-3.39(m,2H),2.88(t,2H),2.78(t,2H), 2.37-2.29(m,1H),2.04-1.97(m,2H),1.49(s,3H),1.21(d,3H),1.04-0.97(m,1 H),0.54-0.40(m,1H),0.33-0.24(m,1H),0.18-0.11(m,1H),0.08-0.05(m,1H).

[0484] Example 7

[0485] 3-Cyano-N-(((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(1,2-dihydroxypropane-2-yl)thiophene-2-sulfonamide (Compounds 7-1 and 7-2)

[0486] 3-Cyano-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[0487]

[0488]

[0489] first step:

[0490] (R)-3-Cyano-N-(((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(prop-1-en-2-yl)thiophene-2-sulfonamide (7A)

[0491] (R)-3-cyano-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(prop-1-en-2-yl)thiophene-2-sulfonamide

[0492] In a 25mL round-bottom flask, add 2I (1.1g, 5.76mmol), 50mL of dry tetrahydrofuran, diisopropylethylamine (1.4g, 10.48mmol) and 2,2,2-trichloroethyl chloroformate (1.45g, 6.81mmol) in sequence under nitrogen protection, stir and react for 30min, and monitor the complete conversion by TLC. Add 50mL of water to the reaction solution, extract with ethyl acetate (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry. Add 3mL of dry tetrahydrofuran to dissolve as solution C. In another 50 mL three-necked flask, 6D (1.2 g, 5.24 mmol) and 3 mL of dry tetrahydrofuran were added, and sodium hydride (420 mg, 60%, 10.48 mmol) was added under ice bath. The reaction was stirred for 1 h. The reaction was completed after monitoring by TLC. The reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain 7A as a light yellow oil (1.14 g, yield 49.4%).

[0493] LCMS m / z (ESI) = 442.1 [M+1].

[0494] Step 2:

[0495] 3-Cyano-N-(((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (7B)

[0496] 3-Cyano-N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[0497] In a 250 mL round-bottom flask, 7A (442 mg, 1 mmol) was dissolved in a mixed solvent of tert-butanol / acetone (25 mL / 25 mL), and NMO (235 mg, 2.0 mmol) was added under stirring. After stirring at room temperature for 10 min, an aqueous solution (45 mL) of potassium osmate dihydrate (37 mg, 0.10 mmol) was added dropwise. After the addition was completed, the reaction was allowed to react at room temperature. The reaction was monitored by TLC. The reaction was quenched with an aqueous sodium bisulfite solution, extracted with EA (100 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 (EA:PE=1:30-1.5:1) to obtain 7B as a yellow solid (210 mg, yield 44.2%).

[0498] LCMS m / z (ESI) = 476.1 [M+1].

[0499] Step 3:

[0500] 3-Cyano-N-(((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(1,2-dihydroxypropane-2-yl)thiophene-2-sulfonamide (Compounds 7-1 and 7-2)

[0501] 3-Cyano-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

[0502] 7B (210 mg, 0.442 mmol) was separated by SFC to give compound 7-1 (76 mg, yield 36.2%, RT = 5.568 min, 100% ee) and compound 7-2 (93 mg, yield 44.2%, RT = 12.071 min, 100% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; 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 and end wavelength: 200 ~ 400 nm.

[0503] Compound 7-1: 1H NMR(600MHz,DMSO)δ9.87(s,1H),7.48(s,1H),7.26(d,1H),6.93(d,1H),6.03(s,1H),5.21(t,1H),3.47-3.38(m,2H),3.16(d,2H),3.03(t,2H ),2.41-2.33(m,1H),1.48(d,3H),1.25(d,3H),1.11-1.02(m,1H),0.60 -0.49(m,1H),0.37-0.30(m,1H),0.19-0.11(m,1H),0.09-0.02(m,1H).

[0504] Compound 7-2: 1 H NMR(600MHz,DMSO)δ9.84(s,1H),7.28(d,1H),7.00-6.84(m,1H),5.96(s,1H),5.21(s,1H),3.52-3.46(m,2H),3.20(d,2H),3.07(s,2H),2 .49-2.42(m,1H),1.54(s,3H),1.29(d,3H),1.12-1.06(m,1H),0.62- 0.54(m,1H),0.40-0.32(m,1H),0.26-0.19(m,1H),0.17-0.09(m,1H).

[0505] Example 8

[0506] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 8)

[0507] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0508]

[0509] first step:

[0510] Tert-butyl (6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)carbamate (8B)

[0511] Tert-butyl(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0512] 8A (25 g, 162.75 mmol), tert-butyl carbamate (28.7 g, 244.12 mmol), X-phos (7.8 g, 16.3 mmol), palladium acetate (1.83 g, 8.14 mmol), cesium carbonate (105.8 g, 325.5 mmol) and 1,4-dioxane (400 mL) were added in sequence into a 500 mL three-necked flask, and the mixture was reacted at 100 °C for 6 h under nitrogen protection. The reaction was completed by TLC monitoring, and 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 crude product was slurried with ethyl acetate (60 mL) to obtain 8B as a light yellow solid (24.1 g, yield 62.7%).

[0513] LC-MS m / z(ESI)=235.3[M+1].

[0514] Step 2:

[0515] Tert-butyl (3-bromo-6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)carbamate (8C)

[0516] Tert-butyl(3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0517] 8B (24 g, 102.13 mmol), NBs (27.3 g, 153.2 mmol) and acetonitrile (200 mL) were added in sequence to a 500 mL round-bottomed tube, reacted at 60 °C for 8 h, and the reaction was completed after monitoring by TLC. The mixture was cooled to room temperature, quenched with sodium bisulfite, 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 column chromatography (EA:PE=1:10-1:2) to obtain 8C as a light yellow solid (35.2 g, yield 81.3%).

[0518] 1 H NMR (400MHz, DMSO) δ9.18(s,1H),8.41(s,1H),2.89(t,2H),2.82(t,2H),2.10-1.98(m,2H),1.46(d,9H).

[0519] LC-MS m / z(ESI)=314.2[M+1].

[0520] Step 3:

[0521] Tert-butyl (3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (8D)

[0522] Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0523] Under nitrogen protection, 8C (25 g, 79.87 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.6 g, 95.85 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (8.8 g, 11.98 mmol), potassium phosphate (33.9 g, 159.74 mmol) and 1,4-dioxane / water mixed solvent (200 mL / 50 mL) were added in sequence to a 500 mL round-bottomed container, and the reaction was carried out at 100° C. for 8 h. The reaction was completed after monitoring by TLC. The reaction 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 crude product was purified by column chromatography (EA:PE=1:30-1:5) to obtain 8D as a white solid (15.2 g, yield 63.3%).

[0524] LC-MS m / z(ESI)=301.2[M+1].

[0525] Step 4:

[0526] Tert-butyl (3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (8E)

[0527] Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0528] 8D (15 g, 49.83 mmol) and dichloromethane (150 mL) were added in sequence to a 500 mL round-bottom container, and boron trifluoride etherate (28.4 g, 200 mmol) was slowly added dropwise. After the addition was completed, the reaction was allowed to react at room temperature. The reaction was monitored by TLC to be complete. Water was added to quench the reaction, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The reaction was extracted with DCM (100 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 (EA:PE=1:30-1:3) to obtain 8E as a brown oil (3 g, yield 30%).

[0529] LC-MS m / z(ESI)=201.1[M+1].

[0530] Step 5:

[0531] (S)-5-(1-Cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine (8F)

[0532] (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0533] The synthesis of 8F was prepared by referring to patent CN108017559. In a 250mL autoclave, 8E (820mg, 4.1mmol) and dichloromethane (30mL) were added, and the catalyst [(S)-2,2′-bis(diphenylphosphine)-1,11-binaphthyl] diacetic acid ruthenium (346mg, 0.41mmol) was added. After the addition, the autoclave was tightened and sealed, replaced with hydrogen three times, and filled with hydrogen. The pressure gauge on the autoclave showed 30atm, and the reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dCM / MeOH=30:1-15:1) to obtain 8F, a light yellow oil (343mg, yield 41.5%, 92.70%ee). Chiral HPLC (CHIRALPAK AY-3 (4.6×100 mm); mobile phase: methanol; column temperature: 35°C; mobile phase: methanol / n-hexane=15 / 85; column pressure: 2000psi; flow rate: 2mL / min; detector signal channel: 215nm@4.8nm; diode array detector start and end wavelengths: 200~400nm; RT=8.765min).

[0534] 1 H NMR(400MHz,DMSO)δ7.88(s,1H),5.40(s,2H),2.70(t,2H),2.62(t,2H),2.22-2.18(m,1H),2.00-1.94(m,2H) ,1.17(d,3H),1.11-1.00(m,1H),0.54-0.45(m,1H),0.40-0.29(m,1H),0.19-0.09(m,1H),0.07-0.00(m,1H).

[0535] LCMS m / z (ESI) = 202.1 [M+1].

[0536] Step 6:

[0537] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 8)

[0538] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0539] In a 25mL round-bottom flask, add 8F (144mg, 0.708mmol), 50mL of dry tetrahydrofuran, diisopropylethylamine (167mg, 1.288mmol) and 2,2,2-trichloroethyl chloroformate (164mg, 0.773mmol) in sequence under nitrogen protection, stir and react for 30min, and monitor the complete conversion by TLC. Add 50mL of water to the reaction solution, extract with ethyl acetate (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry. Add 3mL of dry tetrahydrofuran to dissolve as solution C. In another 50 mL three-necked flask, intermediate 4 (300 mg, 0.644 mmol) and 3 mL of dry tetrahydrofuran were added, and sodium hydride (52 mg, 60%, 1.288 mmol) was added under ice bath, and the reaction was stirred for 1 h. After the reaction was completed under TLC monitoring, the reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain compound 8 as a light yellow solid (92 mg, yield 30.7%).

[0540] 1 H NMR(600MHz,DMSO)δ8.61(s,1H),8.27(s,1H),8.05(d,1H),7.78(s,2H),6.14( d,1H),5.06-4.98(m,1H),3.54(t,2H),2.84(t,2H),2.74-2.61(m,2H),2.31-2. 21(m,1H),2.06-1.90(m,2H),1.44(s,3H),1.22-1.10(m,3H),1.07-0.95(m,1H ),0.53-0.38(m,1H),0.31-0.18(m,1H),0.18-0.07(m,1H),0.04--0.00(m,1H).

[0541] LCMS m / z (ESI) = 466.2 [M+1].

[0542] Example 9

[0543] (N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compounds 9-1 and 9-2)

[0544] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0545]

[0546] first step:

[0547] (R)-N′-(tert-Butyldimethylsilyl)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (9A)

[0548] (R)-N′-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0549] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 2 (3.1 g, 15.4 mmol), triethylamine (1.87 g, 18.5 mmol) and tetrahydrofuran 100 mL were added in sequence, triphosgene (1.83 g, 6.2 mmol) was added under ice bath, the temperature was raised and refluxed for 2 h, the solid was filtered to remove, intermediate 3 (4.9 g, 15.4 mmol) and sodium methoxide (1.66 g, 30.8 mmol) were added to the filtrate, and the reaction was carried out at room temperature for 12 h. The reaction was complete when monitored by TLC, and the reaction was completed to obtain compound 9A, which was directly used for the next step without purification.

[0550] LCMS m / z (ESI) = 546.3 [M+1].

[0551] Step 2:

[0552] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (9B)

[0553] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0554] Tetrabutylammonium fluoride (6.2 mL, 61.6 mmol, 1 M inTHF) was added to the reaction system for synthesizing compound 9A in the previous step, and the reaction was allowed to react overnight at room temperature. The reaction was completed by monitoring with TLC. The reaction solution was poured into water, extracted with ethyl acetate (100 mL×3), and 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 obtain 9B as a transparent solid (1.2 g, yield 18.2%).

[0555] LCMS m / z (ESI) = 432.2 [M+1].

[0556] Step 3:

[0557] N-(((5-1-Cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (9C)

[0558] N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0559] The racemic compound 9B was resolved by SFC to give 9C (537 mg, yield 44.8%, 98.80% ee, RT = 14.041 min), 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 starting wavelength: 200 nm; diode array detector ending wavelength: 400 nm.

[0560] 1H 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),2.3 3-2.19(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).

[0561] LCMS m / z (ESI) = 432.2 [M+1].

[0562] Step 4:

[0563] (S)-N-(((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (9D)

[0564] (S)-N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0565] Under nitrogen protection, 9C (2.0 g, 4.63 mmol) was dissolved in tetrahydrofuran (40 mL) in a 100 mL single-mouth bottle, cooled to 0°C in an ice bath, and Burgess reagent (2.2 g, 9.26 mmol) was slowly added. After maintaining this temperature for 10 min, the reaction system was returned to room temperature for 2 h. After the reaction was completed, ethyl acetate (50 mL × 3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 60: 1) to obtain 9D as a white solid (1.0 g, yield 52.1%).

[0566] LCMS m / z(ESI)=414.20[M+1].

[0567] Step 5:

[0568] (S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (9E)

[0569] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0570] Under nitrogen protection, in a 100 mL single-mouth bottle, 9D (1.0 g, 2.42 mmol) was dissolved in tert-butanol:acetone (10 mL:10 mL), cooled to 0 ° C in an ice-salt bath, 4-methylmorphine-N-oxide (566 mg, 4.84 mmol) was added, and an aqueous solution (10 mL) of potassium osmate monohydrate (88 mg, 0.24 mmol) was slowly added dropwise. After the addition was completed, the temperature was maintained for 10 min, and the reaction system was restored to room temperature for 1 h. After the reaction was completed, it was cooled to room temperature and quenched with a saturated aqueous sodium bisulfite solution. The reaction was extracted with ethyl acetate (50 mL×3), and the organic phase was washed with a saturated aqueous salt solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=30:1) to obtain 9E as a white solid (0.5 g, yield 46.2%).

[0571] Step 6:

[0572] (N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compounds 9-1 and 9-2)

[0573] N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0574] 9E (500 mg, 1.116 mmol) was separated by SFC to give compound 9-1 (200 mg, yield 40.0%, RT = 6.441 min, 99.02% ee) and compound 9-2 (205 mg, yield 40.1%, RT = 5.036 min, 100% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; 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 and end wavelength: 200-400 nm.

[0575] Compound 9-1: 1 H NMR(400MHz, Methanol-d4)δ7.58(s,1H),7.16(d,1H),7.06(d,1H),7.00(s,1H),3.60-3.45(m,2H),2.89-2.83(t,2H),2.80-2.73(m,2H),2.3 3-2.26(m,1H),2.05-1.98(m,2H),1.44(s,3H),1.21-1.19(d,3H),1.01 -0.93(m,1H),0.59-0.47(m,1H),0.33-0.27(m,1H),0.19-0.05(m,2H).

[0576] LCMS m / z(ESI)=448.20[M+1].

[0577] Compound 9-2: 1 H NMR(400MHz, Methanol-d4)δ7.59(s,1H),7.16(d,1H),7.06(d,1H),7.00(s,1H),3.55-3.46(m,2H),2.89-2.83(t,2H),2.81-2.73 (m,2H),2.33-2.26(m,1H),2.07-1.96(m,2H),1.45(s,3H),1.20(d,3H),1.00-0.92(m,1H),0.55-0.47(m,1H),0.22-0.07(m,2H).

[0578] LCMS m / z(ESI)=448.20[M+1].

[0579] Example 10

[0580] N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compounds 10-1 and 10-2)

[0581] N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0582]

[0583]

[0584] first step:

[0585] (S)-N′-(tert-Butyldimethylsilyl)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (10A)

[0586] (S)-N′-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0587] In a 100 mL round-bottom flask, under nitrogen protection, intermediate 1 (2.6 g, 12.9 mmol), triethylamine (1.57 g, 15.5 mmol) and tetrahydrofuran 100 mL were added in sequence, triphosgene (1.54 g, 5.2 mmol) was added under ice bath, the temperature was raised and refluxed for 2 h, the solid was filtered to remove, intermediate 3 (4.1 g, 12.9 mmol) and sodium methoxide (1.4 g, 25.8 mmol) were added to the filtrate, and the reaction was carried out at room temperature for 12 h. The reaction was complete when monitored by TLC, and the reaction was completed to obtain compound 10A, which was directly used for the next step without purification.

[0588] LCMS m / z (ESI) = 546.3 [M+1].

[0589] Step 2:

[0590] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (10B)

[0591] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0592] Tetrabutylammonium fluoride (5.2 mL, 51.7 mmol, 1 M / THF) was added to the reaction system for synthesizing compound 10A in the previous step, and the reaction was allowed to react overnight at room temperature. The reaction was completed by monitoring with TLC. 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 obtain racemate 10B as a transparent solid (2.6 g, yield 46.6%).

[0593] LCMS m / z (ESI) = 432.2 [M+1].

[0594] Step 3:

[0595] N-(((5-1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (10C)

[0596] N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-Sulfonimidamide

[0597] The racemate 10B was separated by SFC to give 10C (1.17 g, yield 45%, 99.70% ee, RT = 14.463 min). 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 starting wavelength: 200 nm; diode array detector ending wavelength: 400 nm; RT = 14.463 min.

[0598] 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),6.97(br,1H),5.09(s,1H),2.82(t,2H),2.74-2.66(m,2H),2.2 8-2.19(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),0.04-0.01(m,1H).

[0599] LCMS m / z (ESI) = 432.2 [M+1].

[0600] Step 4:

[0601] (R)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonylimideamide (10D)

[0602] (R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide

[0603] Under nitrogen protection, 10C (3.0 g, 6.96 mmol) was dissolved in tetrahydrofuran (40 mL) in a 100 mL single-mouth bottle, cooled to 0°C in an ice bath, and p-toluenesulfonic acid monohydrate (2.6 g, 13.92 mmol) was slowly added. After maintaining this temperature for 10 min, the reaction system was returned to room temperature for 2 h. After the reaction was completed, ethyl acetate (50 mL × 3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 60: 1) to obtain 10D as a white solid (1.8 g, yield 62.4%).

[0604] LCMS m / z(ESI)=414.20[M+1].

[0605] Step 5:

[0606] (S)-N-(((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (10E)

[0607] (S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0608] Under nitrogen protection, in a 100 mL single-mouth bottle, 10D (1.8 g, 4.36 mmol) was dissolved in tert-butanol:acetone (18 mL:18 mL), cooled to 0°C in an ice-salt bath, 4-methylmorphine-N-oxide (1.02 g, 8.72 mmol) was added, and an aqueous solution (10 mL) of potassium osmate monohydrate (161.9 mg, 0.44 mmol) was slowly added dropwise. After the addition was completed, the temperature was maintained for 10 min, and the reaction system was restored to room temperature for 1 h. After the reaction was completed, the reaction was cooled to room temperature and quenched with a saturated aqueous sodium bisulfite solution. The reaction was extracted with ethyl acetate (50 mL×3), and the organic phase was washed with a saturated aqueous salt solution, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=30:1) to obtain 10E as a white solid (0.9 g, yield 45.8%).

[0609] LCMS m / z(ESI)=448.20[M+1].

[0610] Step 6:

[0611] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compounds 10-1 and 10-2)

[0612] N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0613] 10E (900 mg, 2.008 mmol) was separated by SFC to give compound 10-1 (290 mg, yield 32.2%, RT = 6.220 min, 99.06% ee) and compound 10-2 (270 mg, yield 40.1%, RT = 4.909 min, 98.09% ee). Chiral HPLC (AS) 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 and end wavelength: 200 ~ 400 nm.

[0614] Compound 10-1: 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.68-7.63(m,3H),7.12(d,1H),7.04(d,1H), 6.96(s,1H),5.04(s,1H),4.87(t,1H),3.35(d,2H),2.83-2.78(t,2H),2.74-2.61( m,2H),2.28-2.19(m,1H),1.94-1.88(m,2H),1.33(s,3H),1.11(d,3H),1.04-0.84( m,1H),0.46-0.40(m,1H),0.31-0.15(m,1H),0.13-0.07(m,1H),0.01-0.07(m,1H).

[0615] LCMS m / z(ESI)=448.20[M+1].

[0616] Compound 10-2: 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.60-7.53(m,3H),7.02(d,1H),6.94( d,1H),6.86(s,1H),4.90(s,1H),4.73(t,1H),2.74-2.69(t,2H),2.62-2.5 2(m,2H),2.17-2.12(m,1H),1.86-1.80(m,2H),1.23(s,3H),1.02(d,3H),0 .87-0.79(m,1H),0.38-0.30(m,1H),0.11-0.07(m,1H),0.06-0.11(m,1H).

[0617] LCMS m / z(ESI)=448.20[M+1].

[0618] Embodiment 11

[0619] N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonylimideamide (Compounds 11-1 and 11-2)

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

[0621]

[0622] first step:

[0623] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanone (11B)

[0624] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanone

[0625] Under nitrogen protection, compound 11A (5.0 g, 37.54 mmol) was dissolved in 1,2-dichloroethane (50 mL) in a 500 mL three-necked flask, 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 temperature was maintained for 10 min, and aluminum chloride (5.5 g, 41.3 mmol) and cyclobutanenitrile (4.55 g, 56.3 mmol) were added. The reaction system was heated to 80°C for 4 h, cooled to room temperature, and 40 mL (2 M HCl) was added in an ice bath. After the addition was complete, the temperature was raised to reflux 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 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 obtain compound 11B as a white solid (2.6 g, yield 32.2%).

[0626] 1 H NMR(400MHz, CDCl3)δ=7.45(d,1H),6.56(d,1H),2.91(t,2H),2.70(t,2H),2.44- 2.3(m,3H),2.25(m,2H),2.14-2.08(m,2H),2.07-2.00(m,1H),1.90-1.81(m,1H).

[0627] LC-MS m / z(ESI)=216.1[M+1].

[0628] Step 2:

[0629] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol(11C)

[0630] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl) methanol

[0631] In a 50 mL round-bottom flask, under nitrogen protection, ethanol (20 mL) and compound 11B (2.0 g, 9.30 mmol) were added, the temperature was cooled to 0°C in an ice bath, sodium borohydride (703 mg, 18.60 mmol) was slowly added, and the temperature was restored to room temperature after the addition was completed to react for 1 h; after the reaction was completed, the system was cooled to 0°C, 20 mL of water was added dropwise to quench the reaction, and DCM (30 mL×3) was used for extraction, 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 obtain compound 11C, a colorless oil (1.8 g, yield 89%).

[0632] LCMS m / z(ESI)=200.1[M-17].

[0633] Step 3:

[0634] 5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine (11D)

[0635] 5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine

[0636] Under nitrogen protection, 11C (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 completed, the reaction was allowed to react at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate water, and extracted with DCM (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain 11D as a colorless oil (1.0 g, yield 83.1%).

[0637] 1H NMR(400MHz, CDCl3)δ=6.83(d,1H),6.66(d,1H),2.89(t,2H),2.74(t,2H),2.66-2 .62(m,1H),2.59(d,2H),2.13-2.07(m,4H),1.88-1.83(m,2H),1.77-1.70(m,2H).

[0638] LC-MS m / z(ESI)=201.1[M+1].

[0639] Step 4:

[0640] N-(tert-Butyldimethylsilyl)-N′-((5-(cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (11E)

[0641] N-(Tert-butyldimethylsilyl)-N′-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0642] Under nitrogen protection, 11D (1.5 g, 7.46 mmol), triethylamine (11.02 g, 8.95 mmol) and tetrahydrofuran 10 mL were added in sequence in a 100 mL round-bottom flask, triphosgene (103 mg, 0.40 mmol) was added under ice bath, the temperature was raised and refluxed for 2 h, the solid was removed by filtration, intermediate 3 (1.1 g, 2.98 mmol) and sodium methoxide (806 mg, 14.9 mmol) were added to the filtrate, and the reaction was carried out at room temperature for 12 h. The reaction was completed and used directly in the next step without purification. TLC monitored the complete reaction, the reaction solution was quenched with water (50 mL), extracted with DCM (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the organic solvent was removed, and the crude product was purified by thin layer chromatography to obtain 11E, a light yellow oily solid (1.43 g, yield 44.0%).

[0643] LCMS m / z (ESI) = 546.3 [M+1].

[0644] Step 5:

[0645] N-((5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamidoamide (11F)

[0646] N-((5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0647] Under nitrogen protection, tetrabutylammonium fluoride (15 mL, 1 Min THF, 15 mmol) was slowly added dropwise to the reaction system of compound 11E synthesized in the previous step. After the addition was completed, the temperature was restored to room temperature and the reaction was continued for 2 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (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 medium pressure preparation (acetonitrile / water = 50%) to obtain 11F as a white solid (1.43 g, yield 44.0%).

[0648] LCMS m / z (ESI) = 432.2 [M+1].

[0649] Step 6:

[0650] N-((5-(Cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamidoamide (11G)

[0651] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-y l )furan-2-sulfonimidamide

[0652] The racemate 11F was separated by SFC to give 11G (680 mg, 99.45% ee, RT = 10.896 min). 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 starting wavelength: 200 nm; diode array detector end wavelength: 400 nm.

[0653] 1H 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),5.09(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,6H).

[0654] LCMS m / z (ESI) = 432.2 [M+1].

[0655] Step 7:

[0656] (S)-N-(((5-(Cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonylimideamide (11H)

[0657] (S)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide

[0658] Under nitrogen protection, 11G (1.0 g, 2.32 mmol) was dissolved in tetrahydrofuran (40 mL) in a 100 mL single-mouth bottle, cooled to 0°C in an ice bath, and p-toluenesulfonic acid monohydrate (788 mg, 4.64 mmol) was slowly added. After maintaining this temperature for 10 min, the reaction system was returned to room temperature for 2 h. After the reaction was completed, ethyl acetate (50 mL × 3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 60: 1) to obtain 11H as a white solid (0.6 g, yield 62.5%).

[0659] LCMS m / z(ESI)=414.20[M+1].

[0660] Step 8:

[0661] (S)-N-(((5-(Cyclobutylmethyl)-2,3-dihydro-1H-indan-4-yl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (11I)

[0662] (S)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0663] Under nitrogen protection, in a 100 mL single-mouth bottle, 11H (0.6 g, 1.45 mmol) was dissolved in tert-butanol: acetone (6 mL: 6 mL), cooled to 0 ° C in an ice-salt bath, 4-methylmorphine-N-oxide (339 mg, 2.90 mmol) was added, and an aqueous solution (6 mL) of potassium osmate monohydrate (55.2 mg, 0.15 mmol) was slowly added dropwise. After the addition was completed, the temperature was maintained for 10 min, and the reaction system was restored to room temperature for 1 h. After the reaction was completed, it was cooled to room temperature and quenched with saturated sodium bisulfite aqueous solution. The reaction was extracted with ethyl acetate (50 mL×3), and the organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 30: 1) to obtain compound 11I as a white solid (0.3 g, yield 46.2%).

[0664] LCMS m / z(ESI)=448.20[M+1].

[0665] Step 9:

[0666] N-(((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonylimideamide (Compounds 11-1 and 11-2)

[0667] N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide

[0668] 11I (300 mg, 0.669 mmol) was separated by SFC to give compound 11-1 (105 mg, yield 35.0%, RT = 12.374 min, 98.60% ee) and compound 11-2 (99 mg, yield 33.0%, RT = 7.388 min, 98.32% ee). Chiral HPLC (AS), 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 and end wavelength: 200-400 nm.

[0669] Compound 11-1: 1 H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.65(d,1H),7.60(s,2H),6.98-6.92(m,2H),6.86(d,1H),5.00(s,1H),4.83(t,1H),2.80(t,2 H),2.68-2.64(m,1H),2.59-2.55(d,2H),2.53-2.51(m,1H),1.94-1.88(m,4H),1.81-1.73(m,2H),1.66-1.58(m,2H),1.33(s,3H).

[0670] LCMS m / z(ESI)=448.20[M+1].

[0671] Compound 11-2: 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.66(d,1H),7.60(s,2H),6.98-6.92(m,2H),6.86(d,1H),5.00(s,1H),4.83(t,1H),2.80(t,2 H),2.76-2.60(m,1H),2.59-2.56(d,2H),2.51-2.48(m,1H),1.94-1.88(m,4H),1.83-1.73(m,2H),1.66-1.60(m,2H),1.33(s,3H).

[0672] LCMS m / z(ESI)=448.20[M+1].

[0673] Example 12

[0674] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropane-2-yl)thiazole-4-sulfonylimideamide (Compounds 12-1 and 12-2)

[0675] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide

[0676]

[0677] first step:

[0678] 3,5-Bis(cyclobutylmethyl)pyridin-4-amine (12B)

[0679] 3,5-Bis(cyclobutylmethyl)pyridin-4-amine

[0680] In a 100 mL three-necked flask, 12A (1.0 g, 6.13 mmol), potassium cyclobutylmethyl trifluoroborate (4.3 g, 24.54 mmol), potassium carbonate (5.1 g, 36.78 mmol), Ruphos Pd-G3 (775 mg, 0.919 mmol) and toluene / water mixed solvent (40 mL / 10 mL) were added in sequence, and the temperature was raised to reflux for reaction for 5 h. The reaction was completed when detected by TLC. The mixture was cooled to room temperature, quenched with water, 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 (EA:PE=1:20-1:5) to obtain 12B as a light yellow oil (1 g, yield 36%).

[0681] Step 2:

[0682] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropane-2-yl)thiazole-4-sulfonylimideamide (12C)

[0683] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide

[0684] Under nitrogen protection, 12B (115 mg, 0.5 mmol), tetrahydrofuran (10 mL), N, N-diisopropylethylamine (177 μL, 1.0 mmol) and 2,2,2-trichloroethyl chloroformate (234 μL, 1.5 mmol) were added to a 100 mL round-bottom flask in sequence and reacted at room temperature for 1 h. Water (10 mL) was added to quench, ethyl acetate (20 mL × 3) was extracted, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, dissolved in tetrahydrofuran (10 mL), intermediate 4 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, and reacted at room temperature for 2 h. Triethylamine hydrofluoride (484 mg, 3 mmol) was added and reacted at room temperature for 5 h. The reaction was completed under the control of TLC. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mL×3). 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=60%) to obtain 12C as a light yellow oil (420 mg, yield 75.3%).

[0685] Step 3:

[0686] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropane-2-yl)thiazole-4-sulfonylimideamide (Compounds 12-1 and 12-2)

[0687] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide

[0688] 12C (120 mg) was separated by SFC to give compound 12-1 (48 mg, yield 40%, RT = 3.376 min, 100% ee) and compound 12-2 (52 mg, yield 43.3%, RT = 4.446 min, 100% ee). Chiral HPLC (AS) 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 and end wavelength: 200-400 nm.

[0689] LC-MS m / z(ESI)=493.18.

[0690] Compound 12-1: 1H NMR(400MHz,DMSO-d6)δ8.18(s,2H),8.06(s,1H),7.92(s,2H),6.11(s,1H),5.06(s,1H),3.53(d,2H),2. 59-2.54(m,4H),2.48-2.42(m,2H),1.90-1.83(m,4H),1.76-1.71(m,4H),1.65-1.58(m,4H),1.46(s,3H).

[0691] Compound 12-2: 1 H NMR(400MHz,DMSO-d6)δ8.14(s,2H),8.08(s,1H),7.91(s,2H),6.11(s,1H),5.00(s,1H),3.53(d,2H),2. 59-2.56(m,4H),2.49-2.45(m,2H),1.90-1.82(m,4H),1.76-1.71(m,4H),1.61-1.55(m,4H),1.44(s,3H).

[0692] Embodiment 13

[0693] (R)-N-(((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compound 13)

[0694] (R)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0695]

[0696] first step:

[0697] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone (13B)

[0698] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone

[0699] 13A (40 g, 210.4 mmol) and dichloroethane (500 mL) were added to a 1L three-necked flask in sequence. After dissolving, the mixture was placed in an ice-water bath. Boron trichloride toluene solution (252.8 mL, 1 M) was slowly added dropwise under nitrogen protection. After 10 min, anhydrous aluminum trichloride (33.6 g, 252 mmol) was added, and then cyclobutane nitrile (59.2 mL, 632 mmol) was slowly added dropwise. After the addition was completed, the mixture was reacted at 90°C for 24 h, cooled to room temperature, and a dilute hydrochloric acid solution (30 mL, 2N) was added. The mixture was refluxed for 30 min, and the organic phase was separated. The mixture was washed with saturated sodium bicarbonate (50 mL) until weakly acidic, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the crude product 13B was removed under reduced pressure as a light yellow oil (4.8 g, yield 8.8%).

[0700] 1 H NMR (400MHz DMSO) δ = 7.27 (dd, 1H), 6.79 (dd, 1H), 5.17 (d, 2H), 4.14-4.10 (m, 1H), 2.06-2.86 (m, 5H), 1.82-1.68 (m, 1H).

[0701] Step 2:

[0702] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol(13C)

[0703] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol

[0704] In a 250 mL round-bottom flask, 13B (4.8 g, 17.3 mmol), anhydrous methanol (20 mL), and sodium borohydride (2.0 g, 51.9 mmol) were added in sequence and reacted at room temperature for 2 h. The reaction was completed after monitoring by TCL. 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 = 30:1) to obtain 13C as a white powder (2.6 g, yield 54%).

[0705] 1 H NMR (400MHz DMSO) δ=7.21 (dd, 1H), 6.94 (dd, 1H), 5.48 (d, 1H), 5.03 (s, 2H), 4.54 (dd, 1H), 2.74-2.62 (m, 2H), 1.98-1.68 (m, 6H).

[0706] Step 3:

[0707] 2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline (13D)

[0708] 2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline

[0709] In a 50 mL round-bottom flask, 13C (850 mg, 3 mmol), dichloromethane (20 mL), triethylsilane (1.4 mL, 9 mmol) and trifluoroacetic acid (1 mL, 9 mmol) were added in sequence and reacted at room temperature for 2 h. The reaction was completed after monitoring by TLC. Saturated sodium bicarbonate solution (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 = 10:1) to obtain 13D as a brown oil (530 mg, yield 69%).

[0710] 1 H NMR (400MHz, Chloroform-d) δ7.06 (dd, 1H), 6.70 (dd, 1H), 3.36 (s, 2H), 2.65 ( dq, 1H), 2.58 (d, 2H), 2.22-2.07 (m, 2H), 1.98-1.81 (m, 2H), 1.83-1.63 (m, 2H).

[0711] Step 4:

[0712] 2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline (13E)

[0713] 2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline

[0714] In a 50 mL round-bottom flask, 13D (500 mg, 1.93 mmol), dioxane (20 mL), sodium carbonate (616 mg, 5.8 mmol) were added in sequence, and dichlorobis(triphenylphosphine)palladium (67.7 mg, 0.0965 mmol) and 2-methoxypyridine-4-boronic acid (383 mg, 2.50 mmol) were added under nitrogen protection and reacted at 80°C for 24 h. The reaction was complete after TLC monitoring. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 13E, a brown oil (350 mg, yield 63.3%).

[0715] LCMS m / z (ESI) = 287.2 [M+1].

[0716] Step 5:

[0717] N-(((2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (13F)

[0718] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0719] Under nitrogen protection, 13E (429 mg, 1.5 mmol), tetrahydrofuran (10 mL), triphosgene (177.6 mg, 0.6 mmol) and triethylamine (181.8, 1.8 mmol) were added in sequence in a 100 mL round-bottom flask, reacted at room temperature for 1 h, filtered, intermediate 3 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, and reacted at room temperature for 2 h. Triethylamine hydrofluoride (484 mg, 3 mmol) was added and reacted at room temperature for 1 h. TLC monitored the complete reaction, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the organic solvent was removed, and the crude product was purified by medium pressure preparation (acetonitrile / water=30%) to obtain chemical 13F as a white solid (260 mg, yield 30.1%).

[0720] Step 6:

[0721] N-(((2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (13G)

[0722] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0723] 13F (260 mg) was separated by SFC to give 13G (110 mg, yield 38.6%, RT = 3.786 min, 100% ee). Chiral HPLC (AS) 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 and end wavelengths: 200-400 nm.

[0724] LC-MS m / z(ESI)=516.18.

[0725] 13G: 1 H NMR (400MHz, DMSO-d6) δ8.20 (s, 1H), 8.15 (d, 1H), 7.66 (s, 1H), 7.63 (s, 2H), 7.09 (dd, 1H), 7.00 (dd, 1H) , 6.94(s, 1H), 6.74(s, 1H), 5.09(s, 1H), 3.88(s, 3H), 2.62-2.59(m, 2H), 1.99-1.91(m, 2H), 1.83-1.80(m 2H), 1.73-1.67(m, 2H), 1.38(s, 6H).

[0726] Step 7:

[0727] N-(((2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonylimideamide (13H)

[0728] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide

[0729] Under nitrogen protection, 13G (60 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL) in a 100 mL single-mouth bottle, cooled to 0°C in an ice bath, and Burgess reagent (88 g, 0.36 mmol) was slowly added. After maintaining this temperature for 10 min, the reaction system was returned to room temperature for 2 h. After the reaction was completed, ethyl acetate (10 mL × 3) was extracted, the organic phase was washed with saturated brine, 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 = 20%) to obtain 13H as a white solid (37 mg, yield 61.7%).

[0730] LCMS m / z(ESI)=498.17[M+1].

[0731] Step 8:

[0732] N-(((2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compound 13)

[0733] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0734] Under nitrogen protection, in a 100 mL single-mouth bottle, 13H (40 mg, 0.08 mmol) was dissolved in tert-butanol: acetone (2 mL: 2 mL), and the mixture was cooled to 0 ° C in an ice-salt bath. 4-Methylmorphine-N-oxide (18.7 mg, 0.16 mmol) was added, and an aqueous solution (2 mL) of potassium osmate monohydrate (4.4 mg, 0.012 mmol) was slowly added dropwise. After the addition was completed, the temperature was maintained for 10 min, and the reaction system was restored to room temperature for 1 h. After the reaction was completed, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bisulfite solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated aqueous salt solution, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain compound 13 as a white solid (10 mg, yield 25.8%).

[0735] LCMS m / z(ESI)=532.18[M+1].

[0736] Embodiment 14

[0737] N-(((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compound 14)

[0738] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0739]

[0740]

[0741] first step:

[0742] 4-(2-Amino-3-(cyclobutylmethyl)-5-fluorophenyl)pyridinecarbonitrile (14A)

[0743] 4-(2-Amino-3-(cyclobutylmethyl)-5-fluorophenyl)picolinonitrile

[0744] In a 100 mL three-necked flask, 13D (1.5 g, 5.8 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinol (2.01 g, 8.6 mmol), 1,4-dioxane (30 mL), cesium carbonate (1.54 g, 14.5 mmol) and catalyst [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (424 mg, 0.58 mmol) were added. The mixture was protected by nitrogen and refluxed at 90°C for 8 h. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (PE:EA=8:1) to obtain 14A as a green solid (520 mg, yield 94%).

[0745] 1 H NMR (400MHz, DMSO-d6) δ8.15 (d, 1H), 7.66 (s, 2H), 7.62 (s, 1H) 7.63 (m, 2H), 7.05 (dd, 1H), 7.01 (dd, 1H), 2.62-2.60(m, 2H), 2.53-2.51(m, 1H) 1.99-1.95(m, 2H), 1.83-1.80(m, 2H), 1.73-1.67(m, 2H).

[0746] LC-MS m / z(ESI)=281.13.

[0747] Step 2:

[0748] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (14B)

[0749] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0750] Under nitrogen protection, 14A (429 mg, 1.5 mmol), tetrahydrofuran (10 mL), triphosgene (177.6 mg, 0.6 mmol) and triethylamine (181.8, 1.8 mmol) were added in sequence to a 100 mL round-bottom flask, reacted at room temperature for 1 h, filtered, intermediate 3 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, reacted at room temperature for 2 h, triethylamine hydrofluoride (484 mg, 3 mmol) was added, and reacted at room temperature for 1 h. The reaction was completed by TLC monitoring. 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, filtered, and the organic solvent was removed. The crude product was quenched, extracted with ethyl acetate (30 mL×3), and 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 (acetonitrile / water=30%) to obtain 14B as a white solid (220 mg, yield 28.6%).

[0751] Step 3:

[0752] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonylimideamide (14C)

[0753] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobuty, lmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0754] 14B (220 mg) was separated by SFC to give 14C (85 mg, yield 38.6%, RT = 2.463 min, 100% ee). Chiral HPLC (AS) 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 and end wavelength: 200-400 nm;

[0755] LC-MS m / z (ESI) = 511.17;

[0756] 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 1H), 8.15 (d, 1H), 7.66 (s, 1H), 7.63 (s, 2H), 7.05 (dd, 1H), 7.01 (d d, 1H), 6.94 (s, 1H), 6.78 (s, 1H), 5.09 (s, 1H), 2.62-2.55 (m, 2H), 1.99-1.95 (m, 2H), 1.83-1.80 (m 2H), 1.73-1.67(m, 2H), 1.38(s, 6H).

[0757] Step 4:

[0758] N-(((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl-4-(prop-1-en-2-yl)furan-2-sulfonylimideamide (14D)

[0759] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide

[0760] Under nitrogen protection, in a 100 mL single-mouth bottle, compound 14C (60 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C in an ice bath, and Burgess reagent (88 g, 0.36 mmol) was slowly added. After maintaining this temperature for 10 min, the reaction system was returned to room temperature for 2 h. After the reaction was completed, ethyl acetate (10 mL × 3) was extracted, the organic phase was washed with saturated brine, 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 = 20%) to obtain compound 14D as a white solid (40 mg, yield 66.7%).

[0761] LCMS m / z(ESI)=493.16[M+1].

[0762] Step 5:

[0763] N-(((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropane-2-yl)furan-2-sulfonylimideamide (Compound 14)

[0764] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide

[0765] Under nitrogen protection, in a 100 mL single-mouth bottle, compound 14D (40 mg, 0.08 mmol) was dissolved in tert-butanol: acetone (2 mL: 2 mL), cooled to 0 ° C in an ice-salt bath, 4-methylmorphine-N-oxide (18.7 mg, 0.16 mmol) was added, and an aqueous solution (2 mL) of potassium osmate monohydrate (4.4 mg, 0.012 mmol) was slowly added dropwise. After the addition was completed, the temperature was maintained for 10 min, and the reaction system was restored to room temperature for 1 h. After the reaction was completed, the reaction was cooled to room temperature and quenched with saturated sodium bisulfite aqueous solution. The reaction was extracted with ethyl acetate (10 mL×3), and the organic phase was washed with saturated saline solution, 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=40%) to obtain compound 14 as a white solid (10 mg, yield 25.2%).

[0766] LCMS m / z(ESI)=527.16[M+1].

[0767] Embodiment 15

[0768] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 15)

[0769] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihvdroxypropan-2-yl)thiazole-5-sulfonimidamide

[0770]

[0771]

[0772] first step:

[0773] 2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (15A)

[0774] 2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0775] Intermediate 6-1 (2.0 g, 3.3 mmol) was dissolved in 32 mL of acetonitrile and 8 mL of water, and formic acid (607 mg, 13.3 mmol) was added dropwise at room temperature, and then stirred for 2 h. TLC monitored the reaction to be complete, saturated sodium bicarbonate solution was added to adjust the pH to neutral, and ethyl acetate (50 mL × 3) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1 to 20: 1) to obtain 15A, a light yellow oil (1.34 g, yield 84%).

[0776] 1 H NMR (400MHz, DMSO-d6) δ7.50 (s, 1H), 7.07 (d, 2H), 6.72 (d, 2H), 5.91 (s, 1H), 4.39-4.32 (m, 1H) , 3.68(s, 3H), 3.61(s, 2H), 1.37(s, 3H), 1.22(d, 3H), 0.89(s, 9H), 0.03(s, 3H), -0.06(s, 3H).

[0777] LC-MS m / z(ESI)=486.2[M+1].

[0778] Step 2:

[0779] 2-((S)-1-((tert-butyldimethylsilyloxy)-2-hydroxypropan-2-yl)-N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (15B)

[0780] 2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0781] In a 25mL round-bottom flask, add intermediate 1 (201mg, 1mmol), 5mL of dry tetrahydrofuran, diisopropylethylamine (258.5mg, 2mmol) and 2,2,2-trichloroethyl chloroformate (254.3mg, 1.2mmol) in sequence under nitrogen protection, stir and react for 30min, and monitor the complete conversion by TLC. Add 5mL of water to the reaction solution, extract with dichloromethane (10mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and spin dry. Add 3mL of dry tetrahydrofuran to dissolve as solution B. Add 15A (437mg, 0.9mmol) and 8mL of dry tetrahydrofuran to another 50mL three-necked flask, add sodium hydride (120mg, 60%, 3.0mmol) under ice bath, and stir and react for 1h. Solution B was slowly added dropwise under an ice bath, and the temperature was raised to room temperature to react for 1 h. The reaction was completed after monitoring by LC-MS. The reaction solution was poured into water, and dichloromethane (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 15B as a light yellow solid (264 mg, yield 63.1%).

[0782] LC-MS m / z(ESI)=714.0[M+1].

[0783] Step 3:

[0784] N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropane-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (15C)

[0785] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0786] In a 50 mL three-necked flask, 15B (200 mg, 0.28 mmol) and 3 mL of dry tetrahydrofuran were added, triethylamine trihydrofluoride (225 mg, 1.4 mmol) was slowly added dropwise, and the temperature was raised to 40°C for 2 h. The reaction was completed after monitoring by TLC. The reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 15C as a light yellow solid (104 mg, yield 62.1%).

[0787] 1 H NMR (400MHz, DMSO-d6) δ8.37 (s, 1H), 7.76 (s, 1H), 7.19 (d, 2H), 7.15 (d, 1H), 7.06 (d, 1 H), 6.79(d, 2H), 6.04(s, 1H), 4.95(t, 1H), 4.52(d, 1H), 3.71(s, 3H), 3.48(d, 2H), 2.8 4(t, 3H), 2.80-2.61(m, 2H), 2.30(m, 1H), 2.10-1.88(m, 2H), 1.38(s, 3H), 1.29(d, 3H) , 1.15(d, 4H), 0.96(s, 1H), 0.45(d, 1H), 0.22(d, 1H), 0.18-0.07(m, 1H), -0.00(s, 2H).

[0788] Step 4:

[0789] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 15)

[0790] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0791] In a 50 mL three-necked flask, 15B (100 mg, 0.167 mmol) and 3 mL of dry dichloromethane were added, and triethylsilane (100 mg, 0.835 mmol) and trifluoroacetic acid (1.8 mL) were added at room temperature, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into 10 mL of water, ethyl acetate (20 mL×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain compound 15 as a white solid (60 mg, yield 77.3%).

[0792] 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 1H), 8.01 (s, 1H), 7.72 (s, 2H), 7.12 (d, 1H), 7.04 (d, 1H), 6.09 (s, 1H), 5.00 (t, 1H), 3.53 (d, 3H), 2.82 (t , 3H), 2.66 (s, 2H), 2.32-2.16 (m, 1H), 1.94 (m, 2H), 1.44 (s, 4H), 1.08 (d, 4H), 0.94 (m, 1H), 0.54-0.38 (m, 1H), 0.20 (m, 1H), 0.10 (m, 1H);

[0793] LC-MS m / z(ESI)=465.6[M+1].

[0794] Example 16

[0795] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 16)

[0796] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0797]

[0798]

[0799] first step:

[0800] 2-((S)-1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (16A)

[0801] 2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0802] The intermediate 6-2 (2.0 g, 3.3 mmol) was dissolved in 32 mL of acetonitrile and 8 mL of water, and formic acid (607 mg, 13.3 mmol) was added dropwise at room temperature and stirred for 2 h. The reaction was monitored by TLC. A saturated sodium bicarbonate solution was added to adjust the pH to neutral, and ethyl acetate (50 mL × 3) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1 to 20: 1) to obtain 16A, a light yellow oil (1.37 g, yield 85.9%).

[0803] 1 H NMR (400MHz, DMSO-d6) δ7.55 (s, 1H), 7.19-6.94 (m, 2H), 6.70 (s, 2H), 5.83 (s, 1H), 4.61-4.11 (m , 1H), 3.58 (s, 3H), 3.51 (s, 2H) 1.32 (s, 3H), 1.20 (d, 3H), 0.88 (s, 9H), 0.20 (s, 3H), 0.16 (s, 3H).

[0804] LC-MS m / z (ESI) = 486.2 [M+1].

[0805] Step 2:

[0806] 2-((S)-1-((tert-butyldimethylsilyloxy)-2-hydroxypropan-2-yl)-N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (16B)

[0807] 2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0808] In a 25mL round-bottom flask, add intermediate 1 (603mg, 3mmol), 5mL of dry tetrahydrofuran, diisopropylethylamine (775mg, 6mmol) and 2,2,2-trichloroethyl chloroformate (762.6mg, 3.6mmol) in sequence under nitrogen protection, stir and react for 30min, and monitor the complete conversion by TLC. Add 10mL of water to the reaction solution, extract with dichloromethane (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and spin dry. Add 10mL of dry tetrahydrofuran to dissolve as solution B. Add 16A (1.31g, 2.7mmol) and 20mL of dry tetrahydrofuran to another 50mL three-necked flask, add sodium hydride (360mg, 60%, 8.1mmol) under ice bath, and stir and react for 1h. Solution B was slowly added dropwise under an ice bath and the mixture was heated to room temperature for 1 h. The reaction was completed after monitoring by LC-MS. The reaction solution was poured into water and dichloromethane (50 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 16B as a light yellow solid (1.2 g, yield 56.1%).

[0809] LC-MS m / z(ESI)=714.0[M+1].

[0810] Step 3:

[0811] N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropane-2-yl)N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (16C)

[0812] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0813] 16B (300 mg, 0.42 mmol) and 3 mL of dry tetrahydrofuran were added to a 50 mL three-necked flask, triethylamine trihydrofluoride (338.5 mg, 2.1 mmol) was slowly added dropwise, the temperature was raised to 40 °C and the reaction was allowed to react for 2 h. The reaction was completed by monitoring by TLC. The reaction solution was poured into water, ethyl acetate (40 mL × 2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 16C as a light yellow solid (180 mg, yield 71.7%).

[0814] 1 H NMR (400MHz, DMSO-d6) δ8.42 (d, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.16-7.08 (m, 2H), 7.04 (d, 1H), 6.72 (d, 2H), 5.99 (s, 1H), 4.93 (t, 1H), 4.51 (s, 1H), 3 .68(s, 3H), 2.82(t, 2H), 2.65(s, 2H), 2.23(s, 1H), 2.07-1.85(m, 2H), 1.3 6(m, 6H), 1.07(d, 3H), 0.94(s, 1H), 0.44(s, 1H), 0.21(s, 1H), 0.12(s, 1H).

[0815] Step 4:

[0816] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 16)

[0817] N′-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0818] 16C (100 mg, 0.167 mmol) and 3 mL of dry dichloromethane were added to a 50 mL three-necked flask, and triethylsilane (100 mg, 0.835 mmol) and trifluoroacetic acid (1.8 mL) were added at room temperature. The reaction was stirred at room temperature for 1 h. LC-MS monitored the completion of the reaction. The reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain compound 16 as a white solid (55 mg, yield 55.1%).

[0819] 1 HNMR (400MHz, DMSO-d6) δ8.24 (s, 1H), 8.01 (s, 1H), 7.72 (s, 2H), 7.12 (d, 1H), 7.04 (d, 1H), 6.09 (s, 1H), 5.00 (t, 1H), 3.53 (d, 2H), 2.82 (t, 2H) ,2.66(s,2H),2.31-2.16(m,1H),1.94(m2H),1.44(s,3H),1.08(d,3H), 0.94 (m, 1H), 0.55-0.38 (m, 1H), 0.20 (m, 1H), 0.10 (m, 1H), 0.02 (d, 2H).

[0820] LC-MS m / z(ESI)=465.6[M+1].

[0821] Embodiment 17

[0822] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 17)

[0823] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0824]

[0825]

[0826] first step:

[0827] 2-((S)-1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (17A)

[0828] 2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0829] 7G-1 (1.0 g, 1.67 mmol) was dissolved in 24 mL of acetonitrile and 6 mL of water, and formic acid (307 mg, 6.68 mmol) was added dropwise at room temperature and stirred for 2 h. The reaction was monitored by TLC. A saturated sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1 to 20: 1) to obtain 17A as a light yellow oil (650 mg, yield 81.5%).

[0830] 1 H NMR (400MHz, DMSO-d6) δ7.70 (s, 1H), 7.13 (d, 2H), 6.91-6.67 (m, 2H), 5.97 (s, 1H), 4.37 (m , 1H), 3.69(s, 3H), 3.64(s, 2H), 1.41(s, 3H), 1.17(d, 3H), 0.81(s, 9H), 0.12-0.36(d, 6H).

[0831] LC-MS m / z(ESI)=486.2[M+1].

[0832] Step 2:

[0833] 2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (17B)

[0834] 2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((3-((R)-1-cyclopropylethyl)bicyclo [4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0835] In a 25mL round-bottom flask, 2I (187mg, 1mmol), dry tetrahydrofuran (3mL), diisopropylethylamine (258.5mg, 2mmol) and 2,2,2-trichloroethyl chloroformate (254.3mg, 1.2mmol) were added in sequence under nitrogen protection, and the reaction was stirred for 30min. The conversion was complete under TLC monitoring. 5mL of water was added to the reaction solution, and dichloromethane was extracted (10mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and spun dry. 3mL of dry tetrahydrofuran was added to dissolve as solution B. 17A (440mg, 0.9mmol) and 3mL of dry tetrahydrofuran were added to another 50mL three-necked flask, and sodium hydride (120mg, 60%, 3.0mmol) was added under ice bath, and the reaction was stirred for 1h. Solution B was slowly added dropwise under an ice bath and the temperature was raised to room temperature to react for 1 h. The reaction was completed as monitored by LC-MS. The reaction solution was poured into water, and dichloromethane (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 17B as a light yellow solid (500 mg, yield 71.5%).

[0836] LC-MS m / z(ESI)=700.2[M+1].

[0837] Step 3:

[0838] N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (17C)

[0839] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0840] In a 50 mL three-necked flask, 17B (300 mg, 0.43 mmol) and 3 mL of dry tetrahydrofuran were added, triethylamine trihydrofluoride (311 mg, 1.93 mmol) was slowly added dropwise, and the temperature was raised to 40°C for 2 h. The reaction was completed after monitoring by TLC. The reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 17C as a light yellow solid (180 mg, yield 71.7%).

[0841] LC-MS m / z(ESI)=585.7[M+1].

[0842] Step 4:

[0843] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 17)

[0844] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-y l )thiazole-5-sulfonimidamide

[0845] 17C (180 mg, 0.31 mmol) and 3 mL of dry dichloromethane were added to a 50 mL three-necked flask, and triethylsilane (180 mg, 1.55 mmol) and trifluoroacetic acid (1.8 mL) were added at room temperature, and the mixture was stirred at room temperature for 1 h. The reaction was completed after LC-MS monitoring, and the reaction solution was poured into water, ethyl acetate (20 mL×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain compound 17 as a white solid (100 mg, yield 71.9%).

[0846] 1 H NMR (400MHz, DMSO-d6) δ8.26 (s, 1H), 8.05 (s, 1H), 7.84 (s, 2H), 7.16 (d, 1H), 6.84 (d, 1H), 6.11 (s, 1H), 5.00 (t, 1H), 3.54 (d, 2 H), 2.97(d, 4H), 2.45-2.25(m, 1H), 1.44(s, 3H), 1.12(d, 3H), 0.92(s, 1H), 0.44(m, 1H), 0.21(m, 1H), 0.09(m, 1H), 0.01(d, 1H)

[0847] LC-MS m / z (ESI) = 451.5 [M+1].

[0848] Embodiment 18

[0849] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 18)

[0850] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0851]

[0852]

[0853] first step:

[0854] 2-((S)-1-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (18A)

[0855] 2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-y l )-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0856] Intermediate 7-2 (1.2 g, 2.0 mmol) was dissolved in 24 mL of acetonitrile and 6 mL of water, and formic acid (368 mg, 8.0 mmol) was added dropwise at room temperature and stirred for 2 h. The reaction was monitored by TLC. A saturated sodium bicarbonate solution was added to adjust the pH to neutral, and ethyl acetate (50 mL × 3) was used for extraction. The organic phases were combined and washed with saturated brine (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1 to 20: 1) to obtain 18A, a light yellow oil (710 mg, yield 73.1%).

[0857] 1 HNMR (400MHz, DMSO-d6) δ7.75 (s, 1H), 7.18 (d, 2H), 6.96-6.73 (m, 2H), 5.95 (s, 1H), 4.42 (m, 1 H), 3.68 (s, 3H), 3.64 (s, 2H), 1.46 (s, 3H), 1.22 (d, 3H), 0.89-0.80 (s, 9H), 0.06-0.01 (d, 6H).

[0858] LC-MS m / z(ESI)=486.2[M+1].

[0859] Step 2:

[0860] 2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (18B)

[0861] 2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-y l )carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0862] In a 25mL round-bottom flask, 2I (400mg, 2.13mmol), 3mL of dry tetrahydrofuran, diisopropylethylamine (550.6mg, 4.26mmol) and 2,2,2-trichloroethyl chloroformate (541.3mg, 277mmol) were added in sequence under nitrogen protection, and the reaction was stirred for 30min. The conversion was complete under TLC monitoring. 5mL of water was added to the reaction solution, and dichloromethane was extracted (10mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and spun dry. 3mL of dry tetrahydrofuran was added to dissolve as solution B. 18A (937mg, 1.92mmol) and 10mL of dry tetrahydrofuran were added to another 50mL three-necked flask, and sodium hydride (260mg, 60%, 6.39mmol) was added under ice bath, and the reaction was stirred for 1h. Solution B was slowly added dropwise under an ice bath and the temperature was raised to room temperature to react for 1 h. The reaction was completed after monitoring by LC-MS. The reaction solution was poured into water, and dichloromethane (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 18B as a light yellow solid (1.06 g, yield 74.5%).

[0863] LC-MS m / z(ESI)=700.2[M+1].

[0864] Step 3:

[0865] N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonylimideamide (18C)

[0866] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

[0867] In a 50 mL three-necked flask, 18B (300 mg, 0.43 mmol) and 3 mL of dry tetrahydrofuran were added, triethylamine trihydrofluoride (311 mg, 1.93 mmol) was slowly added dropwise, and the temperature was raised to 40°C for 2 h. The reaction was completed after monitoring by TLC. The reaction solution was poured into water, and ethyl acetate (20 mL×2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water = 30%) to obtain 18C as a light yellow solid (150 mg, yield 59.8%).

[0868] LC-MS m / z(ESI)=585.7[M+1].

[0869] Step 4:

[0870] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropane-2-yl)thiazole-5-sulfonylimideamide (Compound 18)

[0871] N′-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0872] In a 50mL three-necked flask, 18C (180mg, 0.31mmol) and 3mL of dry dichloromethane were added, and triethylsilane (180mg, 1.55mmol) and trifluoroacetic acid (1.8mL) were added at room temperature, and the mixture was stirred at room temperature for 1h. The reaction was completed after LC-MS monitoring, and the reaction solution was poured into water, ethyl acetate (20mL×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium pressure preparation (acetonitrile / water=30%) to obtain compound 18 as a white solid (90mg, yield 64.8%).

[0873] 1H NMR (400MHz, DMSO-d6) δ8.27 (s, 1H), 8.05 (s, 1H), 7.85 (s, 1H), 7.17 (d,, 1H), 6.84 (d, 1H), 6.12 (s, 1H), 5.00 (t, 1H), 3.53 (d , 2H), 2.97(s, 4H), 2.32(s, 1H), 1.44(s, 3H), 1.09(d, 3H), 0.93(m, 1H), 0.46(m, 1H), 0.22(m, 1H), 0.11(m, 1H), 0.00(s, 2H).

[0874] LC-MS m / z(ESI)=451.5[M+1].

[0875] Biological test cases

[0876] 1.THP-1 Cell Culture

[0877] Human monocytic cell line THP-1 ( TIB-202TM) were cultured in RPMI-1640 medium containing 10% FBS, 1 mM pyruvate, 0.05 mM β-mercaptoethanol and 1% double antibody at 37°C and 5% CO2.

[0878] 2. THP-1 cell pyroptosis detection

[0879] By cell counting, 50,000 THP-1 cells per well were seeded in a 96-well plate, 20 nM PMA was added, and 5% CO2 was used to induce for 48 hours at 37°C. The culture medium was discarded, and 100 μL of serum-free RPMI-1640 culture medium containing 1 μg / mL LPS was added. 5 μL of compound or solvent control was added, starting with the highest dose of 10 μM, and a 3-fold gradient dilution was set, with a total of 10 gradient concentrations. Incubate at 37°C and 5% CO2 for 3 hours. After the incubation, centrifuge at 300g for 5 minutes, discard the culture medium, and perform pyroptosis analysis ( 1 Inflammasome Assay kit) for detailed steps, refer to the kit instructions. IC was calculated using GraphPad Prism7.0 software 50 , the results are shown in Table 1.

[0880] Table 1 Inhibition of pyroptosis of THP-1 cells by the compounds of the present application

[0881]

[0882]

[0883] Note: A≤0.1uM, 0.1uM<B≤0.5uM, 0.5uM<C≤1uM, D>1uM.

[0884] The results show that the compounds of the present application can effectively inhibit pyroptosis of the human monocytic cell line THP-1.

[0885] 3. Analysis of IL-1β Release from Human PBMC

[0886] 5 mL of human venous whole blood from a healthy donor was placed in a Li-heparin tube. After isolating PBMC using a PBMC isolation kit (sigma, 10771-100 mL), the cells were resuspended in RPMI-1640 medium containing 10% FBS and diluted to 2×10 6 / mL, placed in a culture dish and cultured overnight in a 37°C, 5% CO2 incubator. The next day, add culture medium containing 10ng / mL LPS and incubate in the incubator for 3 hours. 5 Cells were plated in 96-well plates at 100 μL / well. 25 μL of compound or solvent control was added to each well, starting from the highest dose of 10 μM, 3-fold gradient dilution, a total of 8 gradient concentrations were set, and incubated for 0.5 hours. 25 μL of 5 mM ATP was added to each well and incubated for 1 hour. After incubation, centrifuged at 1500 rpm for 20 minutes, and the supernatant was collected and the expression of IL-1β was detected by ELISA (BD, Human IL-1β ELISA Set II, Cat#557953). IC was calculated using GraphPad Prism7.0 software. 50 The results are shown in Table 2.

[0887] Table 2 Inhibition of IL-1β release by the compounds of the present application

[0888] Compound <![CDATA[IC 50 (nM)]]> 2-1 18.7 7-1 9.8 7-2 5.8

[0889] The results showed that the compounds of the present application can significantly inhibit the release of IL-1β from human PBMC.

[0890] 4. Analysis of TNFα Release from Human PBMC

[0891] 5 mL of human venous whole blood from a healthy donor was placed in a Li-heparin tube. After isolating PBMC using a PBMC isolation kit (sigma, 10771-100 mL), the cells were resuspended in RPMI-1640 medium containing 10% FBS and diluted to 2×10 6 / mL, placed in a culture dish and cultured overnight in a 37°C, 5% CO2 incubator. The next day, 1×10 5Cells were seeded in 96-well plates at 100 μg / well. Subsequently, 25 μL of compound or solvent control was added to each well, starting from the highest dose of 10 μM, with 5-fold gradient dilution, and a total of 9 gradient concentrations were set. Incubate at 37°C and 5% CO2 for 24 hours. 25 μL of LPS with a final concentration of 100 ng / mL was added to each well. 25 μL of ATP with a final concentration of 5 mM was added to each well and incubated for 1.5 hours. After the incubation, centrifuge at 1500 rpm for 20 minutes, collect the supernatant, and use ELISA (BD, Human TNFα ELISA Set II, Cat#555212) to detect the expression of TNFα. IC was calculated using GraphPad Prism7.0 software. 50 .

[0892] The results showed that the compound of the present application had no down-regulating effect on the expression of TNFα produced by PBMC induced by LPS.

[0893] 5. Compound plasma and colon tissue distribution test

[0894] Weigh an appropriate amount of the drug and prepare it into a 5 mg / mL solution using 5% DMSO and 30% HP-β-CD. After fasting overnight, healthy adult ICR mice were gavaged with the drug to be tested (50 mg / kg) or blank solvent. Blood was collected from the orbital venous plexus (anticoagulated with EDTA-K2) at four time points after administration: 0.5, 2, 4, and 8 h. The animals were then killed and the colon contents and colon tissues were collected. The blood samples were centrifuged at 4°C 2000g for 10 min to separate the plasma. The colon tissue was washed with ice-cold saline and dried. All samples were stored at -80°C for testing. The LC / MS / MS method was used to determine the drug concentrations in plasma and tissue, intestinal contents, and the colon tissue samples were homogenized before testing. The average drug concentration at each time point is as follows: Figure 1 and Figure 2 As shown, Figure 1 It shows that the colon-plasma drug distribution of Control Example 1, Figure 2 The colon-plasma drug distribution of compound 7-1 is shown. Comparative Example 1 is 1-(1,2,3,5,6,7-hexahydro-s-indan-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]urea, which is prepared by referring to the method of compound 1 in Synthetic Communications (2003), 33(12), 2029-2043.

[0895] The results show that the compounds of the present application have better gastrointestinal targeting than the control compounds.

[0896] The specification of this application describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as a limitation of the present application. For those skilled in the art, without departing from the principles of the present application, by making several improvements and modifications to the present application, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present application.

Claims

1. A compound of formula (I) or any stereoisomer or tautomer thereof: in Q is a 5-membered heteroaryl group, the 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from N, O and S, the 5-membered heteroaryl group is optionally substituted by 1 cyano group or C 1-6 Alkyl substitution; L is -(CR a R b )-; R a C 1-6 alkyl; R b C 1-6 alkyl, and the C 1-6 The alkyl group is substituted with 1 OH group; W is O or NH; Y is -(CR d R e )-; R d , R e Each independently is H or C 1-6 alkyl; R and R1 are each independently H, halogen, cyano, C 1-6 Alkyl, C 1-6 an alkoxyl group, a 3- to 10-membered carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the 4- to 10-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, wherein the C 1-6 The alkyl, 3- to 10-membered carbocyclyl or 4- to 10-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 groups selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Substitution by substituents of alkoxy, 3- to 6-membered carbocyclic group and 5- to 6-membered heterocyclic group; Alternatively, R and the atom to which R1 is attached together form a 4- to 6-membered ring; C is a 3- to 5-membered cycloalkyl group; R2 is H or halogen; G1, G2, and G3 are each independently N or CH; r, q are each independently 0, 1 or 2; n is 0, 1, 2 or 3.

2. The compound according to claim 1 or all of its stereoisomers or tautomers, wherein Q is furanyl, thiazolyl or thienyl, wherein the furanyl, thiazolyl or thienyl is optionally substituted with 1 cyano group; L is -(CR a R b )-; R a C 1-3 alkyl; R b C 1-3 alkyl, and the C 1-3 The alkyl group is substituted with 1 OH group; W is O or NH; Y is -(CR d R e )-; R d , R e Each independently is H or C 1-3 alkyl; R and R1 are each independently H, halogen, cyano, C 1-3 Alkyl or pyridyl, the C 1-3 The alkyl or pyridyl group is optionally substituted by 1 to 4 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and 3- to 5-membered cycloalkyl substituents; Alternatively, R and the atom to which R1 is attached together form a 4- to 5-membered ring; C is a 3- to 5-membered cycloalkyl group; R2 is H; G1, G2, and G3 are each independently N or CH; r and q are each independently 0, 1 or 2.

3. The compound according to claim 1 or all its stereoisomers or tautomers, wherein for for W is O or NH.

4. The compound according to claim 1 or all of its stereoisomers or tautomers, wherein Q is furanyl, thiazolyl or thienyl, wherein the furanyl, thiazolyl or thienyl is optionally substituted with 1 cyano group; L is -(CR a R b )-; R a C 1-3 alkyl; R b C 1-3 alkyl, and the C 1-3 The alkyl group is substituted with 1 OH group; W is O or NH; Y is -(CR d R e )-; R d , R e Each independently is H or C 1-3 alkyl; R and R1 are each independently H or halogen; or, R and R1 together with the atom to which they are attached form a 4- to 5-membered ring; C is a 3- to 5-membered cycloalkyl group; R2 is H; G1, G2, and G3 are each independently CH; r and q are each independently 0 or 1.

5. The compound according to claim 4 or all of its stereoisomers or tautomers, wherein for for or 6. The compound according to claim 1 or all of its stereoisomers or tautomers, wherein the compound is:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or all stereoisomers or tautomers thereof and one or more pharmaceutically acceptable carriers and / or excipients.

8. Use of the compound of any one of claims 1 to 6 or all of its stereoisomers or tautomers, or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancers, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases or central nervous system diseases associated with NLRP3.

9. A compound according to any one of claims 1 to 6 or all of its stereoisomers or tautomers, or a pharmaceutical composition according to claim 7, for use in the preparation of a medicament for treating NLRP3-associated cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset 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.

10. Use of the compound according to any one of claims 1 to 6 or all stereoisomers or tautomers thereof, or the pharmaceutical composition according to claim 7 in the preparation of an NLRP3 inhibitor.

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