Amide derivatives and their use

Abstract

This provides amide derivatives and their pharmaceutical applications, specifically relating to amide derivatives of formula (I) or pharmaceutically acceptable salts thereof, or all their stereoisomers, tautomers, and deuterated derivatives, and pharmaceutical compositions comprising the above compounds, wherein the compounds or compositions may act as NLRP3 inhibitors.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, specifically to amide derivatives or their pharmaceutically acceptable salts or all their stereoisomers, tautomers and deuterated derivatives, pharmaceutical compositions comprising the above compounds and their use in the preparation of NLRP3 inhibitors. Background Technology

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

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

[0004] Current drugs for treating NLRP3-related diseases include the recombinant IL-1 receptor antagonist anakinra, the IL-1β neutralizing antibody canakinumab, and the soluble IL-1 receptor trap rilonacept, all of which are biological products. In recent years, Rebecca CColl et al. reported a novel sulfonylurea small-molecule NLRP3 inhibitor compound, MCC950, which inhibits NLRP3 inflammasome activity at nanomolar levels. Other small-molecule compounds have shown inhibitory effects on the NLRP3 inflammasome, 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, these drugs or small molecules still suffer from low specificity or poor activity. Therefore, it is necessary to develop a new generation of small molecule NLRP3 inhibitors with high specificity and activity for the treatment of autoimmune diseases caused by NLRP3 mutations. Summary of the Invention

[0005] The purpose of this application is to provide novel amide derivatives or pharmaceutically acceptable salts thereof or all their stereoisomers, tautomers and deuterated derivatives thereof, pharmaceutical compositions thereof and their use in the preparation of NLRP3 inhibitors.

[0006] One or more embodiments of this application provide compounds of formula (I) or pharmaceutically acceptable salts thereof, or all stereoisomers, tautomers and their deuterated derivatives thereof:

[0007]

[0008] in

[0009] Q is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group comprises 1, 2, or 3 heteroatoms selected from N, O, and S, and the 5-membered heteroaryl group is optionally surrounded by 1 R. q replace;

[0010] R q It is cyano or C 1-6 alkyl;

[0011] L is C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more OH groups;

[0012] W is either O or NH;

[0013] Y1 and Y2 are each independently -(CR) a R b )-;

[0014] R a R b Each independently is H or C 1-6 alkyl;

[0015] C1 and C2 are each independently a 3- to 5-membered cycloalkyl group;

[0016] Each R is the same or different, and each is independently represented by C. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted with one, two, or three halogens;

[0017] R1 and R2 are each independently H or halogen;

[0018] G1, G2, and G3 are each independently N or CH;

[0019] m can be 0, 1, or 2.

[0020] In one or more embodiments, the compound of this application has the structure of formula (II):

[0021]

[0022] in

[0023] Q is furanyl, thiazolyl, or thiophene, and Q is optionally substituted with one cyano group;

[0024] W is either O or NH;

[0025] Y1 and Y2 are each independently -CH2- or -CH(CH3)-;

[0026] G1, G2, and G3 are each independently N or CH;

[0027] R is either -CH3 or -CF3;

[0028] m is 0, 1, or 2;

[0029] n is 1 or 2.

[0030] In one or more implementations:

[0031] for

[0032] for

[0033] W can be O or NH.

[0034] In one or more implementations:

[0035] Q is selected from furanyl, thiazolyl, or thiopheneyl;

[0036] W is selected from O or NH;

[0037] Y1 and Y2 are selected from -CH(CH3)-;

[0038] G1, G2, and G3 are each independently selected from CH;

[0039] n is selected from 1.

[0040] In one or more embodiments, the compounds of this application are:

[0041]

[0042] One or more embodiments of this application provide pharmaceutical compositions comprising a compound of this application or a pharmaceutically acceptable salt thereof or all of its stereoisomers, tautomers and their deuterated derivatives, and one or more pharmaceutically acceptable carriers and / or excipients.

[0043] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt or all its stereoisomers, tautomers and their deuterated derivatives or pharmaceutical compositions thereof in the preparation of a medicament for treating inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases or central nervous system diseases.

[0044] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and their deuterated derivatives or pharmaceutical compositions thereof in the preparation of a medicament for the treatment of cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout or chronic kidney disease.

[0045] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt or all its stereoisomers, tautomers and their deuterated derivatives or pharmaceutical compositions thereof in the preparation of an NLRP3 inhibitor.

[0046] One or more embodiments of this application provide compounds of general formula (I') or their stereoisomers:

[0047]

[0048] in:

[0049] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group may contain 1 to 3 heteroatoms selected from N, O, or S, and the heteroaryl group may have 0 or 1 R atoms. q replace;

[0050] R q Selected from cyano;

[0051] L is selected from C 1-6 Alkyl group, wherein the alkyl group is optionally further substituted with one or more OH substituents;

[0052] W is selected from O or NH;

[0053] Y1 and Y2 are selected from -(CR) a R b )-;

[0054] R a Rb Each can be independently selected from H or C 1-6 alkyl;

[0055] C1 and C2 are each independently selected from 3- to 5-membered cycloalkyl groups;

[0056] R can be the same or different, and each is independently selected from C. 1-6 Alkyl group, wherein the alkyl group may be further substituted with 1 to 3 halogens;

[0057] R1 and R2 are each independently selected from H or halogens;

[0058] G1, G2, and G3 are each independently selected from N or CH;

[0059] m can be selected from 0, 1, or 2.

[0060] In one or more embodiments, the compounds of this application are selected from those represented by general formula (II'):

[0061]

[0062] in:

[0063] Q is selected from furanyl, thiazolyl, or thiopheneyl, and Q may be further substituted with cyano;

[0064] W is selected from O or NH;

[0065] Y1 and Y2 are selected from -CH2- or -CHCH3-;

[0066] G1, G2, and G3 are each independently selected from N or CH;

[0067] R is selected from -CH3 or -CF3;

[0068] m is selected from 0, 1, or 2;

[0069] n can be either 1 or 2.

[0070] In one or more embodiments, wherein:

[0071] Selected from

[0072] Selected from

[0073] W is selected from O or NH.

[0074] In one or more embodiments, the compounds of this application are selected from one of the following structures:

[0075]

[0076] One or more embodiments of this application provide pharmaceutical compositions comprising a compound of this application or a stereoisomer thereof and one or more pharmaceutically acceptable carriers and / or excipients.

[0077] One or more embodiments of this application provide the use of the pharmaceutical composition of this application or the compound of this application or its stereoisomer in the preparation of an NLRP3 inhibitor.

[0078] In one or more embodiments, diseases associated with NLRP3 include: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

[0079] In one or more embodiments, diseases associated with NLRP3 include: cryptothermal protein-associated cycle syndrome (CAPS), Muker-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, and chronic kidney disease.

[0080] One or more embodiments provide the compounds of this application or their pharmaceutically acceptable salts or all of their stereoisomers, tautomers and their deuterated derivatives and compositions, which are used as pharmaceuticals.

[0081] One or more embodiments provide a method of using the compound of this application or a pharmaceutically acceptable salt thereof or all of its stereoisomers, tautomers and their deuterated derivatives and compositions for treating diseases associated with NLRP3.

[0082] One or more embodiments provide the compounds of this application or their pharmaceutically acceptable salts or all of their stereoisomers, tautomers and their deuterated derivatives and compositions thereof, which are used as NLRP3 inhibitors.

[0083] One or more embodiments provide a method for treating inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases with respect to the compound of this application or its pharmaceutically acceptable salt or all stereoisomers, tautomers, deuterated derivatives and compositions thereof.

[0084] One or more embodiments provide the compounds of this application or their pharmaceutically acceptable salts or all stereoisomers, tautomers and their deuterated derivatives and compositions thereof for use in treating cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.

[0085] One or more embodiments provide a method for treating / preventing diseases associated with NLRP3, comprising giving a subject in need a compound of the present application or a pharmaceutically acceptable salt thereof or all of its stereoisomers, tautomers and their deuterated derivatives or compositions thereof.

[0086] 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 their deuterated derivatives thereof or a composition thereof to a subject in need of treatment, wherein the disease is an inflammatory disease, an autoimmune disease, a cardiovascular disease, cancer, a renal disease, a gastrointestinal disease, a respiratory disease, an endocrine disease or a central nervous system disease.

[0087] 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 their deuterated derivatives thereof, or a composition thereof, to a subject in need of the disease, which is cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.

[0088] One or more embodiments provide a method for inhibiting NLRP3, comprising giving a desired object a compound of the present application or a pharmaceutically acceptable salt thereof or all of its stereoisomers, tautomers and their deuterated derivatives or compositions thereof.

[0089] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0090] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I mentioned in the groups and compounds described in this application include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen mentioned in the groups and compounds described in this application may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0091] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0092] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The definition of alkyl is the same as that of "alkyl" as described above.

[0093] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, composed of 2 to 20 carbon atoms, preferably alkenyl groups with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably alkenyl groups with 2 to 8 carbon atoms, and even more preferably alkenyl groups with 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may optionally be further replaced by one or more substituents.

[0094] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, composed of 2 to 20 carbon atoms, preferably an alkynyl group with 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group with 2 to 8 carbon atoms, and even more preferably an alkynyl group with 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, penyn-1-yl, penyn-2-yl, hexyn-1-yl, 1-heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyn-3-yl, decanyn-4-yl, undecyn-3-yl, and dodecanyn-4-yl. The ethynyl group may optionally be further substituted with one or more substituents.

[0095] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl and naphthyl. The aryl group may optionally be further substituted by one or more substituents.

[0096] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heteroaryl group can be attached to a heteroatom or a carbon atom. The heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furanyl, thiophenyl, pyranyl, pyrrolidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted with one or more substituents.

[0097] "Carbocyclic group" or "carbocyclic" refers to a saturated or unsaturated aromatic ring or non-aromatic ring. When it is an aromatic ring, its definition is the same as that of "aryl" above; when it is a non-aromatic ring, it can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a tricyclic system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members). It can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The “carbocyclic group” or “carbocyclic” may optionally be further substituted by one or more substituents.

[0098] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of the "heterocyclic group" or "heterocycle" include epoxyethyl, epoxypropyl, azirropropyl, oxacyclobutyl, azirrobutyl, thioheterobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxhexacycloyl, azirroheptyl, oxacycloheptyl, thioheterobutyl, oxazorphinyl, diazorphinyl, thioazorphinyl, pyridinyl, piperidinyl, homopiperidinyl, and furan. Thiophene, pyranyl, N-alkylpyrrole, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylalkyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentanecycloyl, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidyl Azolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3] [1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. The “heterocyclic group” or “heterocycle” may optionally be further substituted with one or more substituents.

[0099] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a polycyclic system of 10 to 20 members (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 members), preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cyclohepttrienyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0100] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The 1, 2, or 3 N or S atoms selectively substituted in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocyclic alkyl” include epoxide ethyl, aziridine propyl, oxacyclobutyl, aziridine butyl, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine heptyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, aziridine[5.2.0]nonyl, oxacyclo[5.3.1.1]dodecyl, aziridine, and oxaspiro[3.3]heptyl.

[0101] When the terms "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclic", "carbocyclic", "heterocyclic", "cycloalkyl", "heterocyclic", or "heterocyclic" mentioned above are substituted, they may be further replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 Rq5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further surrounded by one to three elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or replaced by the =O substituent; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq2 R q3 Selected from H or C 1-6 Alkyl; wherein, R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 The alkyl group may optionally be further influenced by one or more elements selected from OH, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 The N atom forms a 3- to 8-membered heterocycle, which may contain one or more heteroatoms selected from N, O or S.

[0102] Halogens include F, Cl, Br and I.

[0103] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of this application retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0104] "Pharmaceutical composition" means a mixture of one or more compounds described in this application, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" means pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0105] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0106] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0107] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0108] "Optional," "optionally," "selectively," or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "selectively alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0109] The following embodiments illustrate the technical solutions of this application in detail, but the scope of protection of this application includes, but is not limited to, these embodiments.

[0110] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (dMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0111] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0112] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0113] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0114] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0115] The known starting materials used in this application can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0116] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0117] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0118] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0119] Unless otherwise specified in the examples, the reaction was carried out under a nitrogen atmosphere;

[0120] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0121] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the optimal reaction temperature is 20℃-30℃.

[0122] DCM: Dichloromethane;

[0123] EA: Ethyl acetate;

[0124] HCl: hydrochloric acid;

[0125] THF: Tetrahydrofuran;

[0126] DMF: N,N-dimethylformamide;

[0127] PE: Petroleum ether;

[0128] TLC: Thin-layer chromatography;

[0129] SFC: Supercritical Fluid Chromatography;

[0130] NCS: N-chlorosuccinimide;

[0131] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;

[0132] AD-mix-β: A mixture of hydrogenated quinidine 1,4-diazanaphthalene diether;

[0133] (dHQD)2AQN: Hydrogenated quinidine (anthraquinone-1,4-diyl) diether.

[0134] Example

[0135] Intermediate 1

[0136] 2,6-Bis((S)-1-cyclopropylethyl)aniline (Intermediate 1)

[0137] 2,6-Bis((S)-1-cyclopropylethyl)aniline

[0138]

[0139] first step:

[0140] 2,6-Bis(1-cyclopropylvinyl)aniline (1c)

[0141] 2,6-Bis(1-cyclopropylvinyl)aniline

[0142] In a 250 mL three-necked flask, 1a (10.0 g, 40 mmol) and 1,4-dioxane (150 mL) were added, followed by 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 1b (17.1 g, 88 mmol). Cesium carbonate (39.1 g, 120 mmol) dissolved in 30 mL of water was added to the flask. The mixture was activated at room temperature under nitrogen protection for 10 minutes. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.9 g, 4 mmol) was added. After the addition was complete, the mixture was heated to 100 °C and reacted for 5 hours. The reaction was monitored by TLC until complete, and then cooled to room temperature. Water (50 mL) was added in an ice-water bath, and the reaction was quenched with dilute hydrochloric acid (10 mL, 2N). The reaction mixture was concentrated under reduced pressure, then extracted with ethyl acetate (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 (100% PE) to give 1c, a pale yellow oil (4.7 g, yield 52.2%).

[0143] 1 H NMR (400MHz, CDCl3) δ = 7.07 (d, 2H), 6.70-6.64 (m, 1H), 5.50 (s, 2H), 5.13 (d, 2H), 5.03 (d, 2H), 1.37-1.32(m,2H), 0.48-0.43(m,2H), 0.33-0.29(m,2H), 0.13-0.09(m,2H), 0.03-0.01(m,2H).

[0144] Step Two:

[0145] 2,6-Bis((S)-1-cyclopropylethyl)aniline (Intermediate 1)

[0146] 2,6-Bis((S)-1-cyclopropylethyl)aniline

[0147] In a 250 mL hydrogenation reactor, 1c (1.0 g, 4.4 mmol), [(S)-(-)-2,2'-bis(diphenyl)-1,1'-naphthyl]ruthenium (185.2 mg, 0.22 mmol) and dichloromethane (50 mL) were added sequentially. Hydrogen gas (1.5 MPa) was introduced, and the reaction was allowed to proceed overnight for 16 h. The reaction was monitored by TLC until it was complete. After concentration, the product was purified by column chromatography (PE:EA = 80:1) to obtain intermediate 1, a pale yellow solid (500 mg, yield 50%).

[0148] 1 H NMR (400MHz, CDCl3) δ = 7.07 (d, 2H), 6.70-6.63 (m, 1H), 5.69 (s, 2H), 5.13 (d, 2H), 5.03 (d, 2H), 2.71-2.67 (m, 2H) ), 1.20(dd,6H),1.02-0.98(m,2H),0.50-0.46(m,2H),0.39-0.35(m,2H),0.15-0.11(m,2H),0.09-0.01(m,2H).

[0149] LC-MS m / z(ESI)=230.15[M+1].

[0150] Intermediate 2

[0151] 2,6-Bis((R)-1-cyclopropylethyl)aniline (Intermediate 2)

[0152] 2,6-Bis((R)-1-cyclopropylethyl)aniline

[0153]

[0154] In a 250 mL hydrogenation reactor, 1c (1.0 g, 4.4 mol), [(R)-(-)-2,2'-bis(diphenyl)-1,1'-naphthyl]ruthenium (185.2 mg, 0.22 mmol), and dichloromethane (50 mL) were added sequentially. Hydrogen gas (15 MPa) was introduced, and the reaction was allowed to proceed overnight for 16 h. The reaction was monitored by TLC until it was complete. After concentration, the intermediate was purified by column chromatography (PE:EA = 80:1) to obtain intermediate 2, a pale yellow solid (500 mg, yield 50%).

[0155] 1H NMR (400MHz, CDCl3) δ = 7.09 (d, 2H), 6.68-6.63 (m, 1H), 5.71 (s, 2H), 5.15 (d, 2H), 5.03 (d, 2H), 2.73-2.68 (m, 2H) ), 1.20(dd,6H),1.02-0.99(m,2H),0.50-0.44(m,2H),0.39-0.33(m,2H),0.16-0.10(m,2H),0.09-0.01(m,2H).

[0156] LC-MS m / z(ESI)=230.15[M+1].

[0157] Intermediate 3

[0158] 2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)aniline (intermediate 3)

[0159] 2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)aniline

[0160]

[0161] first step:

[0162] (2-Amino-3-bromophenyl)(cyclopropyl)methyl ketone (3b)

[0163] (2-Amino-3-bromophenyl)(cyclopropyl)methanone

[0164] Add 20 g (116.27 mmol) of 3a to a 1 L three-necked flask and dissolve it in 250 mL of DCE. Under nitrogen protection and an ice bath (0 °C), slowly add 139.5 mL (1 M) of boron trichloride toluene solution. After about 10 minutes, the solution will become clear. Then add anhydrous aluminum trichloride (18.6 g, 139.52 mmol). Stir at room temperature for about 10 minutes, and the solution will turn yellow and clear. Add 13.2 mL of propionitrile (13.2 M) toluene solution under an ice bath (0 °C). L (174.40 mmol), after which the toluene solvent was added, the mixture was refluxed at 100 °C to distill off. After distillation, the reaction was continued at 100 °C for about 6 h. A product was observed on the TLC (PE:EA = 10:1). 50 mL of water was slowly added under ice bath, and the mixture was heated to 80 °C. Heating was stopped after the reaction solution became clear. After cooling to room temperature, the mixture was extracted with DCM (300 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 3b (7.5 g, 27% yield).

[0165] 1 H NMR (400MHz, CDCl3) δ7.96(dd,1H),7.58(dd,1H),6.59(t,1H),2.69-2.52(m,1H),1.23-1.16(m,2H),1.04-0.94(m,2H).

[0166] LC-MS m / z(ESI)=239.99[M+l].

[0167] Step Two:

[0168] 2-Bromo-6-(1-Cyclopropylvinyl)aniline (3c)

[0169] 2-Bromo-6-(1-cyclopropylvinyl)aniline

[0170] Methyltriphenylphosphine bromide (33.5 g, 93.71 mmol) and potassium tert-butoxide (10.5 g, 93.71 mmol) were added to a 250 mL three-necked flask. Under nitrogen protection and an ice bath (0 °C), 100 mL of THF was added and stirred for 40 min. 3b (7.5 g, 31.24 mmol) was dissolved in a small amount of THF and added back to the three-necked flask. The mixture was stirred for 10 min and then moved to room temperature for 4 h. The reaction was monitored by TLC (PE:EA = 10:1). After the reaction was completed, the reaction solution was quenched with water (50 mL) and then extracted with EA (100 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 3c (6.8 g, yield 91%).

[0171] 1 H NMR(400MHz,DMSO-d6)δ7.31(dd,1H),6.85(dd,1H),6.51(t,1H),5.22(s,2H),4. 86(d,1H),4.73(s,1H),1.67-1.59(m,1H),0.74-0.65(m,2H),0.45-0.32(m,2H).

[0172] LC-MS m / z(ESI)=238.02[M+l].

[0173] Step 3:

[0174] (S)-2-bromo-6-(1-cyclopropylethyl)aniline (3d)

[0175] (S)-2-bromo-6-(1-cyclopropylethyl)aniline

[0176] In a 250 mL hydrogenation reactor, 3c (9.0 g, 37.98 mmol), [(S)-(-)-2,2'-bis(diphenyl)-1,1'-naphthyl]ruthenium (1.6 g, 1.9 mmol) and dichloromethane (90 mL) were added sequentially. Hydrogen gas (1.2 MPa) was introduced, and the reaction was allowed to proceed overnight for 16 h. The reaction was monitored by TLC until it was complete. After concentration, the product was purified by column chromatography (PE:EA = 80:1) to obtain 3d, a pale yellow solid (6.3 g, yield 67.3%).

[0177] 1 H NMR(400MHz,DMSO-d6)δ7.22(dd,1H),7.18(dd,1H),6.52(t,1H),4.91(s,2H),2.39 -2.23(m,1H),1.16(d,3H),1.07-1.00(m,1H),0.57-0.45(m,2H),0.39-0.31(m,2H).

[0178] LC-MS m / z(ESI)=240.03[M+1].

[0179] Step 4:

[0180] (S)-2-(1-Cyclopropylethyl)-6-(1-Cyclopropylvinyl)aniline (3e)

[0181] (S)-2-(1-cyclopropylethyl)-6-(1-cyclopropylvinyl)aniline

[0182] In a 250 mL three-necked flask, 3d (0.4 g, 1.67 mmol) and 1,4-dioxane (10 mL) were added, followed by 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.48 g, 2.51 mmol). Cesium carbonate (1.3 g, 4.19 mmol) dissolved in 5 mL of water was added to a 50 mL three-necked flask. The mixture was activated at room temperature under nitrogen protection for 10 min. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (62 mg, 0.08 mmol) was added. After the addition was complete, the mixture was heated to 100 °C and reacted for 2 h. The reaction was monitored by TLC until complete, and then cooled to room temperature. Water (20 mL) was added in an ice-water bath, and the reaction was quenched with dilute hydrochloric acid (10 mL, 2N). The reaction mixture was concentrated under reduced pressure, then 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 (PE:EA = 10:0) to obtain 3e, a pale yellow oil (371 mg, yield 98%).

[0183] 1H NMR(400MHz,DMSO-d6)δ7.09(dd,1H),6.65(dd,1H),6.56(t,1H),5.19(d,2H),4.80(d,1H),4.33(d,1H) ,2.30(dd,1H),1.69-1.56(m,1H),1.17(d,3H),1.09-0.97(m,1H),0.71-0.60(m,4H),0.39-0.29(m,4H).

[0184] LC-MS m / z(ESI)=228.17[M+l].

[0185] Step 5:

[0186] 2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)aniline (intermediate 3)

[0187] 2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)aniline

[0188] In a 250 mL hydrogenation reactor, 3e (1.5 g, 6.61 mmol), [(R)-(-)-2,2'-bis(diphenyl)-1,1'-naphthyl]ruthenium (5.5 g, 6.61 mmol), and dichloromethane (30 mL) were added sequentially. Hydrogen gas (1.2 MPa) was introduced, and the reaction was carried out overnight for 16 h. The reaction was monitored by TLC until it was complete. After concentration, the intermediate 3 (460 mg, yield 30.5%) was purified by column chromatography (PE:EA = 10:1).

[0189] 1 H NMR(400MHz,DMSO-d6)δ7.01(dd,1H),6.69(dd,1H),6.57(t,1H),4.35(s,2H),2.35 -2.23(m,2H),1.15(d,6H),1.04-0.97(m,2H),0.54-0.43(m,4H),0.38-0.29(m,4H).

[0190] LC-MS m / z(ESI)=230.18[M+l].

[0191] Intermediate 4

[0192] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide amide (intermediate 4)

[0193] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0194]

[0195] first step:

[0196] Ethyl furan-3-carboxylate (4b)

[0197] Ethyl furan-3-carboxylate

[0198] Compound 4a (50 g, 0.446 mol) was dissolved in 300 mL of anhydrous ethanol under ice bath conditions. Thionyl chloride (65 mL, 0.892 mol) was slowly added dropwise. After the addition was complete, the mixture was heated to reflux for 2 h. The reaction was monitored by TLC until complete. The solvent and excess thionyl chloride were removed by concentration under reduced pressure. Water (200 mL) and ethyl acetate were added for extraction (150 mL × 3). The organic phases were combined. The organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:10) to give compound 4b, a light brown oil (38.1 g, yield 61%).

[0199] Step Two:

[0200] 4-Ethyl formate-2-sulfonyl chloride furan (4c)

[0201] Ethyl furan-2-sulfonyl chloride-4-formate

[0202] 4b (22.00 g, 0.157 mol) was dissolved in 250 mL of DCM at room temperature. The mixture was cooled to -15 °C in an ice-salt bath, and sulfonyl chloride (23.31 g, 0.173 mol) was slowly added dropwise while maintaining the temperature below -10 °C. After the addition was complete, the mixture was allowed to react at room temperature for 12 h. Then, pyridine (13.66 g, 0.173 mol) was slowly added dropwise after the mixture was cooled to below -15 °C in an ice-salt bath, followed by the addition of phosphorus pentachloride (36.00 g, 0.137 mol) in portions while maintaining the temperature below -10 °C. The mixture was allowed to react at room temperature for 2 h after the addition was complete. The reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding compound 4c, a brown oily substance (33.00 g, 90% yield). This unpurified compound was directly added to the next step.

[0203] Step 3:

[0204] Ethyl furan-2-sulfonamide-4-carboxylate (4d)

[0205] Furan-2-sulfonamide-4-ethyl formate

[0206] Compound 4c (33.00 g, 0.138 mol) was dissolved in 350 mL of acetone at room temperature. A saturated aqueous solution of ammonium bicarbonate (49.74 g, 0.553 mol) was added dropwise at room temperature, and the reaction was carried out for 3 h at room temperature. The reaction was monitored by TLC until complete. The mixture was extracted with EA (200 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding compound 4d as a brown solid powder (23 g, 77% yield).

[0207] 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).

[0208] LC-MS m / z = 219.2 [Ml].

[0209] Step 4:

[0210] 4-(2-hydroxypropyl)furan-2-sulfonamide (4e)

[0211] 4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide

[0212] Compound 4d (23 g, 0.105 mol) was dissolved in 500 mL of dry THF at room temperature. The solution was cooled to -15 °C in an ice-salt bath, and methylmagnesium bromide (140 mL, 0.418 mol) was slowly added dropwise while maintaining the temperature below 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4 to 1:1) to give compound 4e, a white solid powder (16 g, yield 76%).

[0213] LC-MS m / z = 205.2 [Ml].

[0214] Step 5:

[0215] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl)furan-2-sulfonamide (4f)

[0216] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0217] Compound 4e (5.0 g, 24.39 mmol) was dissolved in 50 mL of dry THF at room temperature. The solution was cooled to -10 °C in an ice-salt bath, and sodium hydride (0.9 g, 36.58 mmol) was slowly added to maintain the temperature below -10 °C. Then, a THF solution of tert-butyldimethylchlorosilane (4.8 g, 31.70 mmol) in 50 mL was added. The reaction was carried out at room temperature for 12 h, and the reaction was monitored by TLC to ensure complete reaction. The reaction solution was quenched in 20 mL of ice water and extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2 to 2:1) to give compound 4f as a white solid (5.1 g, yield 66%).

[0218] 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).

[0219] LC-MS m / z = 321.2 [M+l].

[0220] Step 6:

[0221] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (Intermediate 4)

[0222] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0223] In a 250 mL three-necked flask under nitrogen protection, DCM (100 mL) and triphenyl diphosphine chloride (11.3 g, 33.86 mmol) were added. The mixture was cooled to 0 °C in an ice bath, and diisopropylethylamine (5.8 g, 45.16 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 10 min. The reaction system was then cooled to 0 °C, and 4f (3.6 g, 11.29 mmol) of dichloromethane (10 mL) solution was added dropwise. After the addition was complete, the mixture was kept at 0 °C and reacted for another 30 min. Ammonia gas was then introduced into the reaction system for 15 min. The reaction was allowed to return to room temperature for 2 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to give intermediate 4, a white solid (1.8 g, 50% yield).

[0224] 1 H 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).

[0225] LC-MS m / z = 319.2 [M+l].

[0226] Example 1

[0227] N-(((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (Compound 1)

[0228] N-((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0229]

[0230] Under nitrogen protection, intermediate 1 (110 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (165 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (103 μL, 0.75 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and 4e (82 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 30:70) to give compound 1, a white solid (130 mg, yield 56.5%, UPLC: 99.9%).

[0231] 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.68(d,1H),7.63(d,2H),7.26(s,3H),6.95(s,1H),2.25-2.17(m,2H) ,1.35(s,6H),1.19-1.04(m,6H),0.98-0.90(m,2H),0.5-0.43(m,2H),0.21-0.14(m,2H),0.10-0.05(m,4H).

[0232] LC-MS m / z(ESI)=461.20[M+l].

[0233] Example 2

[0234] N-(((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 2-1 and 2-2)

[0235] N-((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0236]

[0237]

[0238] first step:

[0239] N-(((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compound 2)

[0240] N-((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0241] Under nitrogen protection, intermediate 1 (345 mg, 1.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (534 μL, 3.0 mmol), and 2,2,2-trichloroethyl chloroformate (234 μL, 1.65 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and intermediate 4 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, and the reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride (4 mL, 1 M) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed. The crude product was purified by medium-pressure preparation (acetonitrile:water = 40:60) to give compound 2, a white solid (500 mg, yield 72.6%).

[0242] Step Two:

[0243] N-(((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 2-1 and 2-2)

[0244] N-((2,6-bis((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0245] Compound 2 (500 mg) was resolved by SFC to give compound 2-1 (212 mg, yield 42.4%, RT = 1.723 min, 99.59% ee) and compound 2-2 (221 mg, yield 44.2%, RT = 2.335 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: 200~400nm.

[0246] Compound 2-1: 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.66(d,1H),7.63(d,2H),7.20(s,3H),6.95(s,1H),5.07(s,1H),2.21-2.17( m,2H),1.38(s,6H),1.15-1.04(m,6H),0.99-0.93(m,2H),0.5-0.46(m,2H),0.21-0.16(m,2H),0.13-0.09(m,4H).

[0247] LC-MS m / z(ESI)=460.20[M+l].

[0248] Compound 2-2: 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.68(d,1H),7.65(d,2H),7.22(s,3H),6.95(s,1H),5.07(s,1H),2.21-2.15( m,2H),1.38(s,6H),1.13-1.04(m,6H),0.98-0.92(m,2H),0.5-0.46(m,2H),0.21-0.16(m,2H),0.13-0.09(m,4H).

[0249] LC-MS m / z(ESI)=460.20[M+l].

[0250] Example 3

[0251] N-(((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 3)

[0252] N-((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0253]

[0254] first step:

[0255] N-(((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 3)

[0256] N-((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0257] Under nitrogen protection, intermediate 2 (115 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (165 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (103 μL, 0.75 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The solution was then dissolved in tetrahydrofuran (10 mL), and 4e (82 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 40:60) to give compound 3, a white solid (110 mg, yield 47.8%, UPLC: 99.52%).

[0258] 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.69(d,1H),7.63(d,2H),7.26(s,3H),6.95(s,1H),2.29-2.19(m,2H) ,1.39(s,6H),1.20-1.14(m,6H),0.98-0.90(m,2H),0.5-0.43(m,2H),0.21-0.14(m,2H),0.10-0.03(m,4H).

[0259] LC-MS m / z(ESI)=461.20[M+l].

[0260] Example 4:

[0261] N-(((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 4-1 and 4-2)

[0262] N-((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0263]

[0264]

[0265] first step:

[0266] N-(((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compound 4)

[0267] N-((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0268] Under nitrogen protection, intermediate 2 (345 mg, 1.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (534 μL, 3.0 mmol), and 2,2,2-trichloroethyl chloroformate (234 μL, 1.65 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and intermediate 4 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, and the reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride (4 mL, 1 M) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 40:60) to give compound 4, a white solid (440 mg, yield 63.9%).

[0269] Step Two:

[0270] N-(((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 4-1 and 4-2)

[0271] N-((2,6-bis((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0272] Compound 4 (440 mg) was resolved by SFC to give compound 4-1 (205 mg, yield 46.6%, RT = 1.664 min, 100% ee) and compound 4-2 (197 mg, yield 44.8%, RT = 2.341 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 stop wavelengths: 200–400 nm.

[0273] Compound 4-1: 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.66(d,1H),7.63(d,2H),7.20(s,3H),6.95(s,1H),5.07(s,1H),2.21-2.17( m,2H),1.38(s,6H),1.15-1.04(m,6H),0.99-0.93(m,2H),0.5-0.46(m,2H),0.21-0.16(m,2H),0.13-0.09(m,4H).

[0274] LC-MS m / z(ESI)=460.20[M+l].

[0275] Compound 4-2: 1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.68(d,1H),7.65(d,2H),7.22(s,3H),6.95(s,1H),5.07(s,1H),2.21-2.15( m,2H),1.38(s,6H),1.13-1.04(m,6H),0.98-0.92(m,2H),0.5-0.46(m,2H),0.21-0.16(m,2H),0.13-0.09(m,4H).

[0276] LC-MS m / z(ESI)=460.20[M+l].

[0277] Example 5:

[0278] N-((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 5)

[0279] N-((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0280]

[0281] Under nitrogen protection, intermediate 3 (115 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (165 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (103 μL, 0.75 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and 4e (125 mg, 0.5 mmol) and sodium hydride (24 mg, 0.6 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 30:70) to give compound 5, a white solid (100 mg, yield 16.2%).

[0282] Compound 5 was prepared by medium pressure (100 mg, yield 26.5%, RT = 2.197 min, 97.04% 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 stop wavelength: 200–400 nm.

[0283] 1 H NMR (40MHz, DMSO-d6)δ=7.39(d,1H),7.37(d,2H),7.14(t,1H),6.67(s,1H),6.64(d,1H),5.82(s,1H),3.3 8(s,1H),1.78-1.74(m,2H),1.39(d,6H),1.19(d,6H),0.75(q,2H),0.66-0.56(m,4H),0.24-0.13(m,4H).

[0284] LC-MS m / z(ESI)=461.20[M+l].

[0285] Example 6:

[0286] N-(((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 6-1 and 6-2)

[0287] N-((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0288]

[0289]

[0290] first step:

[0291] N-(((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compound 6)

[0292] N-((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0293] Under nitrogen protection, intermediate 3 (345 mg, 1.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (534 μL, 3.0 mmol), and 2,2,2-trichloroethyl chloroformate (234 μL, 1.65 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and intermediate 4 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, and the reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride (4 mL, 1 M) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 40:60) to give compound 6, a white solid (440 mg, yield 63.9%).

[0294] Step Two:

[0295] N-(((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 6-1 and 6-2)

[0296] N-((2-((R)-1-cyclopropylethyl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0297] Compound 6 was resolved by SFC to yield compound 6-1 (185 mg, yield 20.9%, RT = 2.333 min, 100% ee) and compound 6-2 (176 mg, yield 21.2%, RT = 1.709 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 stop wavelengths: 200–400 nm.

[0298] Compound 6-1: 1 H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.51(d,2H),7.45(d,1H)7.01(t,1H),6.60(d,1H),5.84(s,1H),3.2 7(s,1H),2.71-2.67(m,2H),1.35(d,6H),1.23(d,6H),1.01(q,2H),0.54-0.49(m,4H),0.44-0.40(m,4H).

[0299] LCMS m / z(ESI)=460.22[M+l].

[0300] Compound 6-2: 1 H NMR(40MHz,DMSO-d6)δ9.10(s,1H),7.49(d,2H),7.43(d,1H),7.02(t,1H),6.81(d,1H),6.00(s,1H),3.3 7(s,1H),2.73-2.68(m,2H),1.40(d,6H),1.25(d,6H),0.99(q,2H),5.55-0.50(m,4H),0.46-0.41(m,4H).

[0301] LCMS m / z(ESI)=460.22[M+l].

[0302] Example 7:

[0303] N-(((4,6-bis(R)-1-cyclopropylethyl)pyrimidin-5-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 7)

[0304] N-((4,6-bis((R)-1-cyclopropylethyl)pyrimidin-5-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0305]

[0306] first step:

[0307] 4,6-Bis(1-cyclopropylvinyl)pyrimidin-5-amine (7B)

[0308] 4,6-Bis(1-cyclopropylvinyl)pyrimidin-5-amine

[0309] Under nitrogen protection, compound 7A (3.26 g, 20 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (8 g, 42 mmol), and 1,4-dioxane (50 mL) were added sequentially to a 250 mL three-necked flask. Cesium carbonate (15.8 g, 50 mmol) and catalyst [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.48 g, 2 mmol) were added. The mixture was refluxed at 95 °C for 5 h. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed. The mixture was then passed through a column (PE:EA = 5:1) to give product compound 7B (700 mg, 16%).

[0310] LC-MS m / z(ESI)=227.14[M+1].

[0311] Step Two:

[0312] 4,6-Bis((R)-1-cyclopropylethyl)pyrimidin-5-amine (7C)

[0313] 4,6-Bis((R)-1-cyclopropylethyl)pyrimidin-5-amine

[0314] In a 500 mL autoclave, compound 7B (700 mg, 3.08 mmol) and dichloromethane (50 mL) were added, followed by the catalyst [(R)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (247 mg, 0.25 mmol). After the addition was complete, the autoclave was tightly sealed and purged with hydrogen three times. The pressure gauge on the autoclave showed a pressure of 1.2 MPa. The reaction was carried out at room temperature for 5 h. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain compound 7C, a pale yellow oil (520 mg, yield 72%).

[0315] 1H NMR (400MHz, DMSO) δ = 8.59 (s, 1H), 5.82 (s, 2H), 2.68-2.63 (m, 2H), 1.22 (d, 6H), 1.02-0 .98(m,2H),0.50-0.4(m,2H),0.39-0.35(m,2H),0.15-0.11(m,2H),0.09-0.01(m,2H).

[0316] LC-MS m / z(ESI)=231.17[M+1].

[0317] Step 3:

[0318] N-(((4,6-bis(R)-1-cyclopropylethyl)pyrimidin-5-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 7)

[0319] N-((4,6-bis((R)-1-cyclopropylethyl)pyrimidin-5-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0320] Under nitrogen protection, compound 7C (115 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (165 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (103 μL, 0.75 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and 4e (82 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 30:70) to give compound 7, a white solid (85 mg, yield 36.9%).

[0321] 1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.53(s,1H),7.66(s,1H),6.96(s,1H),5.07(s,1H),2.30-2.25(m,2H),1.38(s,6 H),1.17-1.15(m,6H),1.07-1.04(m,2H),0.46-0.40(m,2H),0.20-0.15(m,2H),0.13-0.09(m,2H),0.08-0.01(m,2H).

[0322] LC-MS m / z(ESI)=463.19[M+1].

[0323] Example 8:

[0324] N-(((4,6-bis(-1-cyclopropylethyl)pyrimidin-5-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 8)

[0325] N-((4,6-bis(1-cyclopropylethyl)pyrimidin-5-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0326]

[0327] Under nitrogen protection, compound 7C (345 mg, 1.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (534 μL, 3.0 mmol), and 2,2,2-trichloroethyl chloroformate (234 μL, 1.65 mmol) were added sequentially to a 100 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and intermediate 4 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, and the reaction was carried out at room temperature for 2 h. Triethylamine hydrofluoric acid salt (484 mg, 3 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 40:60) to give compound 8, a white solid (520 mg, yield 75.3%).

[0328] 1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.53(s,1H),8.44(s,1H),7.66(s,1H),6.96(s,1H),5.07(s,1H),2.30-2.25(m,2H),1. 38(s,6H),1.17-1.12(m,6H),1.07-1.02(m,2H),0.46-0.39(m,2H),0.20-0.17(m,2H),0.13-0.08(m,2H),0.07-0.02(m,2H).

[0329] LC-MS m / z(ESI)=462.21[M+1].

[0330] Example 9:

[0331] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compounds 9-1 and 9-2)

[0332] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0333]

[0334] first step:

[0335] 3,5-Bis(cyclobutylmethyl)pyridine-4-amine (9B)

[0336] 3,5-Bis(cyclobutylmethyl)pyridin-4-amine

[0337] In a 100 mL three-necked flask, compound 9A (1.0 g, 6.13 mmol), potassium cyclobutylmethyltrifluoroborate (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 sequentially. The mixture was refluxed for 5 h, and the reaction was stopped 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 to 1:5) to give compound 9B, a pale yellow oil (1 g, yield 36%).

[0338] Step Two:

[0339] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 9)

[0340] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0341] Under nitrogen protection, in a 100 mL round-bottom flask, 9B (345 mg, 1.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (534 μL, 3.0 mmol), and 2,2,2-trichloroethyl chloroformate (234 μL, 1.65 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and intermediate 4 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added, and the reaction was carried out at room temperature for 2 h. Triethylamine hydrofluoric acid salt (484 mg, 3 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 30:70) to obtain compound 9, a white solid (260 mg, yield 56.5%).

[0342] LC-MS m / z(ESI)=461.21[M+1].

[0343] Step 3:

[0344] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compounds 9-1 and 9-2)

[0345] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0346] Compound 9 (260 mg) was resolved by SFC to give compound 9-1 (110 mg, yield 38.6%, RT = 5.535 min, 100% ee) and compound 9-2 (115 mg, yield 41.8%, RT = 6.397 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 stop wavelengths: 200–400 nm.

[0347] LC-MS m / z(ESI)=461.21[M+1].

[0348] Compound 9-1: 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.11(s,2H),7.68(s,1H),7.64(s,1H),6.98(s,1H),5.07(s ,1H),2.59(d,4H),2.49(s,2H)1.99-1.82(m,4H),1.76(tt,4H),1.69-1.55(m,4H),1.38(s,6H).

[0349] Compound 9-2: 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.13(s,2H),7.67(s,1H),7.62(s,1H),6.98(s,1H),5.09(s ,1H),2.59(d,4H),2.49(s,2H),1.99-1.85(m,4H),1.78(tt,4H),1.69-1.55(m,4H),1.38(s,6H).

[0350] Example 10

[0351] N-(((2,6-bis(cyclobutylmethyl)phenyl)carbamoyl)-3-cyano-5-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 10)

[0352] N-((2,6-bis(cyclobutylmethyl)phenyl)carbamoyl)-3-cyano-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[0353]

[0354] first step:

[0355] 4-Bromo-5-aminosulfonylthiophene-2-carboxylic acid methyl ester (10B)

[0356] Methyl 4-bromo-5-sulfamoylthiophene-2-carboxylate

[0357] A mixture of chlorosulfonic acid (44.67 mL, 678.52 mmol) and thionyl chloride (14.78 mL, 203.56 mmol) was added in portions at 0 °C (30.0 g, 135.70 mmol). The mixture was stirred at 0 °C for 20 minutes and then reacted at 50 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and 400 mL of a solution of ammonium bicarbonate and acetone (1:1) was added dropwise at 0 °C, with stirring overnight. The reaction was confirmed by TLC. The mixture was filtered, and the solid was washed with ethyl acetate (100 mL), extracted with ethyl acetate (200 mL) in aqueous phase, and the organic phases were combined and concentrated to give a dark oil. The oil was purified by beating with dichloromethane (200 mL) to give compound 10B as a pale yellow solid (28 g, yield 68.74%).

[0358] LC-MS m / z(ESI)=299.89[M+1].

[0359] Step Two:

[0360] 3-Bromo-5-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (10C)

[0361] 3-Bromo-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[0362] Compound 10B (28 g, 93.29 mol) was dissolved in 500 mL of dry THF at room temperature. The solution was cooled to -15 °C in an ice-salt bath, and methylmagnesium bromide (155.48 mL, 466.45 mol) was slowly added dropwise while maintaining the temperature below 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to give compound 10C as a white solid powder (18 g, yield 64.28%).

[0363] 1 H NMR (400MHz, DMSO-d6) δ = 7.79 (s, 2H), 7.07 (s, 1H), 5.87 (s, 1H), 1.48 (s, 6H);

[0364] LC-MS m / z(ESI)=299.89[M+1].

[0365] Step 3:

[0366] 3-Cyano-5-(prop-1-en-2-yl)thiophene-2-sulfonamide (10D)

[0367] 3-Cyano-5-(prop-1-en-2-yl)thiophene-2-sulfonamide

[0368] Under nitrogen protection, in a 50 mL round-bottom flask, compound 10C (4.0 g, 13.33 mmol) and cuprous cyanide (1.43 g, 15.99 mmol) were dissolved in N,N-dimethylformamide (40 mL) and reacted at 150 °C for 4 hours. The reaction was monitored by TLC until complete. The reaction solution was poured into a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (50 mL × 10), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:5) to give 10D, a pale yellow solid (1.0 g, yield 30.47%).

[0369] LC-MS m / z(ESI)=247.0[M+1].

[0370] Step 4:

[0371] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-3-cyano-5-(2-hydroxypropane-2-yl)furan-2-sulfonamide (compound 10)

[0372] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-3-cyano-5-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0373] Under nitrogen protection, in a 100 mL round-bottom flask, compound 9B (115 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (178 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (78 μL, 0.6 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and compound 10D (124 mg, 1.5 mmol) and sodium hydride (18 mg, 2.25 mmol) were added, and the reaction was carried out at room temperature for 2 h. Triethylamine hydrofluoric acid (161 mg, 1 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 25:75) to give compound 10, a white solid (25 mg, yield 10.9%, UPLC: 90.53%).

[0374] 1 H NMR(400MHz,DMSO-d6)δ8.13(s,2H),7.67(s,1H),7.62(s,1H),6.98(s,1H),5.09(s,1H), 2.59(d,4H),2.49(s,2H)1.99-1.85(m,4H),1.78(tt,4H),1.69-1.55(m,4H),1.38(s,6H).

[0375] LC-MS m / z(ESI)=462.21[M+1].

[0376] Example 11

[0377] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-3-cyano-4-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 11)

[0378] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-3-cyano-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[0379]

[0380] first step:

[0381] 4-Bromothiophene-3-carboxylic acid ethyl ester (11B)

[0382] Ethyl 4-bromothiophene-3-carboxylate

[0383] Compound 11A (25 g, 120.77 mmol) was dissolved in 300 mL of anhydrous ethanol under ice bath conditions. Thionyl chloride (22 g, 0.181 mol) was slowly added dropwise. After the addition was complete, the mixture was heated to reflux for 2 h. The reaction was monitored by TLC until complete. The solvent and excess thionyl chloride were removed by concentration under reduced pressure. Water (200 mL) and ethyl acetate were added for extraction (150 mL × 3). The organic phases were combined. The organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:10) to give compound 11B, a light brown oil (23.1 g, yield 81.6%).

[0384] Step Two:

[0385] 4-Bromo-5-aminosulfonylthiophene-3-carboxylic acid ethyl ester (11C)

[0386] Ethyl 4-bromo-5-sulfamoylthiophene-3-carboxylate

[0387] Compound 11B (10 g, 42.55 mol) was dissolved in 250 mL of DCM at room temperature. The mixture was cooled to -15 °C in an ice-salt bath, and sulfonyl chloride (5.9 g, 51.06 mol) was slowly added dropwise while maintaining the temperature below -10 °C. After the addition was complete, the mixture was allowed to react at room temperature for 12 h. Then, pyridine (4.4 g, 55.32 mmol) was slowly added dropwise after the mixture was cooled to below -15 °C in an ice-salt bath, followed by phosphorus pentachloride (12.4 g, 59.57 mmol) in portions while maintaining the temperature below -10 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were then combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding an intermediate crude product. This intermediate product was dissolved in 350 mL of acetone, and a saturated aqueous solution of ammonium bicarbonate (33.6 g, 425.5 mol) was added dropwise at room temperature. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until completion. The mixture was extracted with EA (200 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding compound 11C as a brown solid powder (10.2 g, yield 76.2%).

[0388] LC-MS m / z(ESI)=314.0[M+1].

[0389] Step 3:

[0390] 3-Bromo-4-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (11D)

[0391] 3-Bromo-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[0392] Compound 11C (10 g, 31.84 mol) was dissolved in 500 mL of dry THF at room temperature. The solution was cooled to -15 °C in an ice-salt bath, and methylmagnesium bromide (43 mL, 127.4 mmol) was slowly added dropwise while maintaining the temperature below 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in 200 mL of ice water and extracted with EA (200 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was treated with ethyl acetate:petroleum ether (ethyl acetate:petroleum ether = 1:20–1:10) to give compound 11D as a white solid powder (18 g, yield 64.28%).

[0393] LC-MS m / z(ESI)=299.93[M+1].

[0394] Step 4:

[0395] 3-Cyano-4-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (11E)

[0396] 3-Cyano-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

[0397] Under nitrogen protection, compound 11D (4.0 g, 13.33 mmol) and cuprous cyanide (1.43 g, 15.99 mmol) were dissolved in N,N-dimethylformamide (40 mL) in a 50 mL round-bottom flask and reacted at 150 °C for 4 h. The reaction was monitored by TLC until complete. The reaction solution was poured into a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (50 mL × 10), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:5) to give 11E as a pale yellow solid (1.0 g, yield 30.47%).

[0398] LC-MS m / z(ESI)=247.1[M+1].

[0399] Step 5:

[0400] N-(((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-3-cyano-4-(2-hydroxypropane-2-yl)thiophene-2-sulfonamide (compound 11)

[0401] N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-3-cyano-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

[0402] Under nitrogen protection, in a 100 mL round-bottom flask, 9B (115 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (178 μL, 1.0 mmol), and 2,2,2-trichloroethyl chloroformate (78 μL, 0.6 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting solution was dissolved in tetrahydrofuran (10 mL), and compound 11E (124 mg, 1.5 mmol) and sodium hydride (18 mg, 2.25 mmol) were added, and the reaction was carried out at room temperature for 2 h. Triethylamine hydrofluoric acid (161 mg, 1 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the organic solvent, and the crude product was purified by medium-pressure preparation (acetonitrile:water = 25:75) to give compound 11, a white solid (25 mg, yield 10.9%, UPLC: 90.53%).

[0403] 1 H NMR(400MHz,DMSO-d6)δ8.13(s,2H),7.67(s,1H),7.62(s,1H),6.98(s,1H),5.09(s,1H), 2.59(d,4H),2.49(s,2H)1.99-1.85(m,4H),1.78(tt,4H),1.69-1.55(m,4H),1.38(s,6H).

[0404] LC-MS m / z(ESI)=462.21[M+1].

[0405] Biological test cases

[0406] 1. THP-1 cell culture

[0407] The human mononuclear cell line THP-1 ( TIB-202TM was cultured in RPMI-1640 medium containing 10% FBS, 1mM pyruvate, 0.05mM β-mercaptoethanol and 1% antibiotics at 37°C and 5% CO2.

[0408] 2. Detection of pyroptosis in THP-1 cells

[0409] Cell counting was performed, and 50,000 THP-1 cells were seeded per well in 96-well plates. 20 nM PMA was added, and the cells were induced at 37°C with 5% CO2 for 48 hours. The medium was discarded, and 100 μL of serum-free RPMI-1640 medium containing 1 μg / mL LPS was added. 5 μL of the compound or solvent control was added, starting with the highest dose of 10 μM and serially diluted 3-fold to establish 10 different concentrations. The cells were incubated at 37°C with 5% CO2 for 3 hours. After incubation, the cells were centrifuged at 300g for 5 minutes, the medium was discarded, and pyroptosis analysis was performed. 1. Follow the detailed steps for the Inflammasome Assay Kit, referring to the kit instructions. Calculate the IC50 using GraphPad Prism 7.0 software. 50 The results are shown in the table below.

[0410] compound <![CDATA[IC 50 ]]> 1 B 2-1 B 3 A 4-1 A 5 B 6-1 C 6-2 B Compare with Example 1 F Compare with Example 2 F

[0411] Note: A≤0.1uM, 0.1uM<B≤0.5uM, 0.5uM<C≤1uM, 1uM<D≤5uM, 5uM<E≤10uM, F>10uM. Comparative Examples 1 and 2 are compounds 92-1 and 92-2 of patent WO2021093820, and were obtained according to its preparation method.

[0412] The results showed that the compound of this application can effectively inhibit pyroptosis in the human mononuclear cell line THP-1.

[0413] 3. IL-1β Release Analysis in Human PBMCs

[0414] Five mL of whole blood from a healthy human venous donor was collected and placed in a Li-heparin tube. PBMCs were isolated using a PBMC isolation kit (Sigma, 10771-100 mL), and the cells were resuspended in RPMI-1640 medium containing 10% FBS and diluted to 2 × 10⁻⁶. 6 Cells / mL were placed in petri dishes and incubated overnight at 37°C in a 5% CO2 incubator. The next day, medium containing 10 ng / mL LPS was added, and the cells were incubated for 3 hours at a density of 1×10⁻⁶. 5Cells were seeded into 96-well plates. 25 μL of the compound or solvent control was added to each well, starting with the highest dose of 10 μM and serially diluted 3-fold for a total of 8 concentrations, incubating for 0.5 hours. 25 μL of 5 mM ATP was added to each well, and incubation was continued for 1 hour. After incubation, the cells were centrifuged at 1500 rpm for 20 minutes, and the supernatant was collected. IL-1β expression was detected using an ELISA (BD, Human IL-1β ELISA Set II, Cat#557953). The IC50 was calculated using GraphPad Prism 7.0 software. 50 .

[0415] The results showed that the compounds in this application could significantly inhibit the release of IL-1β from human PBMCs. Compound 3, in particular, had an IC50 value of [missing value]. 50 =14.2nM.

[0416] 4. Analysis of TNFα release from human PBMCs

[0417] Five mL of whole blood from a healthy human venous donor was collected and placed in a Li-heparin tube. PBMCs were isolated using a PBMC isolation kit (Sigma, 10771-100 mL), and the cells were resuspended in RPMI-1640 medium containing 10% FBS and diluted to 2 × 10⁻⁶. 6 Cells / mL were placed in petri dishes and incubated overnight at 37°C in a 5% CO2 incubator. The next day, cells were cultured at 1×10⁻⁶. 5 Cells were seeded per well in 96-well plates. Then, 25 μL of the compound or solvent control was added to each well, starting with the highest dose of 10 μM and serially diluted 5-fold for a total of 9 concentrations. The plates were incubated at 37°C with 5% CO2 for 24 hours. 25 μL of LPS (final concentration 100 ng / mL) was added to each well. 25 μL of ATP (final concentration 5 mM) was added to each well, and the plates were incubated for 1.5 hours. After incubation, the plates were centrifuged at 1500 rpm for 20 minutes, and the supernatant was collected. TNFα expression was detected using an ELISA (BD, Human TNFα ELISA Set II, Cat#555212). The IC50 was calculated using GraphPad Prism 7.0 software. 50 .

[0418] The results showed that the compound in this application did not downregulate the expression level of TNFα induced by LPS in PBMCs.

[0419] This application specification provides a detailed description of specific implementation schemes. Those skilled in the art should recognize that the above implementation schemes are exemplary and should not be construed as limiting this application. For those skilled in the art, without departing from the principles of this application, several improvements and modifications can be made to this application, and the resulting technical solutions also fall within the protection scope of the claims of this application.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof, or all its stereoisomers and their deuterated derivatives: (II) in Q is furanyl, thiazolyl, or thiopheneyl; W is either O or NH; Y1 and Y2 are each independently -CH(CH3)-; G1, G2, and G3 are each independently CH; R is either -CH3 or -CF3; m is 0, 1, or 2; n is 1.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, or all its stereoisomers and their deuterated derivatives, wherein... To ; To ; W can be O or NH.

3. The following compounds, or their pharmaceutically acceptable salts, or all their stereoisomers and deuterated derivatives: , , , , , , or .

4. A pharmaceutical composition comprising any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof and their deuterated derivatives, and one or more pharmaceutically acceptable carriers.

5. A pharmaceutical composition comprising any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof and their deuterated derivatives, and one or more excipients.

6. Use of the compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or any stereoisomer thereof or its deuterated derivative, or the pharmaceutical composition of claim 4 or 5, in the preparation of a medicament for treating diseases associated with NLRP3, said diseases being inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

7. Use of the compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or any stereoisomer thereof or its deuterated derivative, or the pharmaceutical composition of claim 4 or 5, in the preparation of a medicament for the treatment of cryptothermal protein-associated cycle syndrome (CAPS), Muker-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.

8. Use of the compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or any stereoisomer thereof or its deuterated derivative, or the pharmaceutical composition of claim 4 or 5, in the preparation of an NLRP3 inhibitor.

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