Amide derivatives and their use

Abstract

Provided are an amide derivative of formula (I) or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof, and a pharmaceutical composition comprising the above compound, which can be used as an NLRP3 inhibitor. In formula (I), the definitions of the substituents are the same as those in the specification

Description

Technical Field

[0001] This application belongs to the field of medicinal chemistry, and more specifically, relates to amide derivatives 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)). 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 or 2 R atoms. q0 replace;

[0010] Each R q0 Whether they are the same or different, each is independently C. 1-6 Alkyl or cyano, wherein the C 1-6 The alkyl group is optionally substituted with one or more OH groups;

[0011] W is either O or NH;

[0012] Y is -(CR) a R b )-;

[0013] R a R b Each independently is H or C 1-6 alkyl;

[0014] R and R1 are each independently H, halogen, cyano, or C. 1-6 Alkyl, 3- to 10-membered carbocyclic, or 4- to 10-membered heterocyclic, wherein the 4- to 10-membered heterocyclic comprises one or two heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, 3- to 10-membered carbocyclic or 4- to 10-membered heterocyclic groups are optionally surrounded by 1, 2, 3 or 4 groups selected from F, Cl, Br, I, cyano, C 1-6 Alkyl, C 1-6 Substitution with alkoxy or OH groups;

[0015] Alternatively, R and R1 together with the atoms they are attached to form a 4- or 5-membered ring;

[0016] C is a 3- to 5-membered cycloalkyl group;

[0017] R2 is a halogen or OH;

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

[0019] q and r are each independently 0, 1, or 2;

[0020] n can be 0, 1, 2, or 3.

[0021] In one or more implementations:

[0022] Q is

[0023] for

[0024] W can be O or NH.

[0025] In one or more implementations:

[0026] Q is selected from furanyl, thiazolyl, or thiopheneyl, wherein the furanyl, thiazolyl, or thiopheneyl group can be substituted by one R. q0 replace;

[0027] R q0 Selected from C 1-3 Alkyl, the C 1-3 The alkyl group can be further substituted by one or more OH substituents;

[0028] W is selected from NH;

[0029] Y is selected from -CH(CH3)-;

[0030] R and R1 are each independently selected from H or halogens; or, R and R1 can form a 4- or 5-membered ring together with the atoms they are attached to.

[0031] C is selected from 3- to 5-membered cycloalkyl groups;

[0032] R2 is selected from H;

[0033] G1, G2, and G3 are each independently selected from CH;

[0034] q and r are selected from 0 or 1.

[0035] In one or more implementations:

[0036] Q is selected from

[0037] Selected from

[0038] In one or more embodiments: the compounds of this application have the following structures:

[0039]

[0040]

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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 NLRP3 inhibitors.

[0045] One or more embodiments of this application provide compounds of general formula (I') or their stereoisomers:

[0046]

[0047] in:

[0048] 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 contain 1 or 2 R atoms. q0 replace;

[0049] R q0 They can be the same or different, and each can be independently selected from C. 1-6 Alkyl or cyano, wherein the C 1-6The alkyl group can be further substituted by one or more OH substituents;

[0050] W is selected from O or NH;

[0051] Y is selected from -(CR) d R e )-;

[0052] R d R e Each can be independently selected from H or C 1-6 alkyl;

[0053] R and R1 are each independently selected from H, halogen, cyano, and C. 1-6 Alkyl, 3- to 10-membered carbocyclic, or 4- to 10-membered heterocyclic groups, wherein the heterocyclic group may contain 1 to 2 heteroatoms selected from N, O, or S, and wherein the alkyl, carbocyclic, or heterocyclic group may be further surrounded by 1 to 4 F, Cl, Br, I, cyano, C... 1-6 Alkyl or C 1-6 Substituents of alkoxy groups;

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

[0055] C is selected from 3- to 5-membered cycloalkyl groups;

[0056] R2 is selected from H, halogen, or OH;

[0057] G1, G2, and G3 are each independently selected from N or CH;

[0058] q and r are selected from 0, 1, or 2;

[0059] n can be selected from 0, 1, 2, or 3.

[0060] In one or more implementations:

[0061] Q is selected from

[0062] Selected from

[0063] W is selected from O or NH.

[0064] In one or more embodiments, the compounds of this application are selected from one of the following structures:

[0065]

[0066]

[0067] 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.

[0068] Use of one or more embodiments of this application, the pharmaceutical composition of this application, or the compound or stereoisomer thereof of this application in the preparation of an NLRP3 inhibitor.

[0069] In one or more implementations, 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.

[0070] In one or more implementations, 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0081] 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.

[0082] "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.

[0083] "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.

[0084] "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.

[0085] "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.

[0086] "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.

[0087] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heteroaryl group can be attached to a heteroatom or a carbon atom. The heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furanyl, thiophene, pyranyl, pyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted with one or more substituents.

[0088] "Carbocyclic group" or "carbocyclic" refers to a saturated or unsaturated aromatic ring or non-aromatic ring. When it is an aromatic ring, its definition is the same as that of "aryl" above; when it is a non-aromatic ring, it can be a monocyclic ring of 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or a tricyclic system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members). It can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The “carbocyclic group” or “carbocyclic” may optionally be further replaced by one or more substituents.

[0089] "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.

[0090] "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.

[0091] "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.

[0092] 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 group, -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.

[0093] Halogens include F, Cl, Br and I.

[0094] "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.

[0095] "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.

[0096] "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.

[0097] "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.

[0098] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0099] "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. Attached Figure Description

[0100] Figure 1 This indicates the drug concentration in brain tissue of compound 15-1 and control example 1. Detailed Implementation

[0101] 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.

[0102] 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).

[0103] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0104] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0105] 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.

[0106] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0107] 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.

[0108] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0109] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0110] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0111] Unless otherwise specified in the examples, the reaction was carried out under a nitrogen atmosphere;

[0112] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0113] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the optimal reaction temperature is 20℃-30℃.

[0114] DCM: Dichloromethane;

[0115] EA: Ethyl acetate;

[0116] HCl: hydrochloric acid;

[0117] THF: Tetrahydrofuran;

[0118] DMF: N,N-dimethylformamide;

[0119] PE: Petroleum ether;

[0120] TLC: Thin-layer chromatography;

[0121] SFC: Supercritical Fluid Chromatography;

[0122] NCS: N-chlorosuccinimide;

[0123] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;

[0124] AD-mix-β: A mixture of hydrogenated quinidine 1,4-diazanaphthalene diether;

[0125] (dHQD)2AQN: Hydrogenated quinidine (anthraquinone-1,4-dimethyl) diether.

[0126] Example

[0127] intermediate int-1

[0128] (R)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-inden-4-amine (Intermediate int-1)

[0129] (R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0130]

[0131] first step:

[0132] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methyl ketone (int-1b)

[0133] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone

[0134] Under nitrogen protection, in a 500 mL three-necked flask, compound int-1a (20.0 g, 150.16 mmol) was dissolved in 200 mL of 1,2-dichloroethane. The mixture was cooled to 0 °C in an ice-salt bath, and a dichloromethane solution of boron trichloride (150 mL, 1 M, 150.16 mmol) was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature for 10 min. Then, aluminum trichloride (22.0 g, 165.20 mmol) and cyclopropyl nitrile (15.1 g, 225.24 mmol) were added. The reaction mixture was heated to 80 °C and reacted for 4 h. After cooling to room temperature, 160 mL of 2 M HCl was added in an ice bath. After the addition was complete, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (200 mL × 3). The organic phase was washed with 160 mL of 2 M sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound int-1b as a white solid (17.1 g, yield 57.2%).

[0135] 1 H NMR(400MHz, DMSO-d6)δ=7.87(d,1H),6.90(br,2H),6.54(d,1H),2.84(t, 2H),2.80-2.74(m,1H),2.67(t,2H),2.06-1.98(m,2H),0.96-0.87(m,4H).

[0136] LC-MS m / z(ESI)=202.1[M+1].

[0137] Step Two:

[0138] 5-(1-Cyclopropylvinyl)-2,3-Dihydro-1H-indene-4-amine (int-1c)

[0139] 5-(1-Cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine

[0140] Under nitrogen protection, in a 500 mL three-necked flask, compound methyltriphenylphosphine bromide (24.8 g, 69.6 mmol) was dissolved in THF (300 mL). The mixture was cooled to 0 °C in an ice-salt bath, and potassium tert-butoxide (7.8 g, 69.6 mmol) was slowly added. The reaction was maintained at this temperature for 30 min, and then compound int-1b (7.0 g, 34.8 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with EA (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 30:1) to give compound int-1c, a pale yellow oil (6.4 g, yield 92.3%).

[0141] 1 H NMR(400MHz, DMSO-d6)δ=6.64(d,1H),6.45(d,1H),5.15(d,1H),4.78(d,1H),4.37(br,2H),2.77 (t,2H),2.64(t,2H),2.02-1.96(m,2H),1.62-1.57(m,1H),0.69-0.64(m,2H),0.40-0.36(m,2H).

[0142] LC-MS m / z(ESI)=200.1[M+1].

[0143] Step 3:

[0144] (R)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-inden-4-amine (Intermediate int-1)

[0145] (R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0146] The intermediate int-1 was prepared according to patent CN108017559. In a 500 mL autoclave, int-1c (8.3 g, 41.7 mmol) and dichloromethane (90 mL) were added, followed by the catalyst [(R)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (1.8 g, 2.09 mmol). After the addition was complete, the autoclave was tightly sealed, purged with hydrogen three times, and then filled with hydrogen. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to give intermediate int-1, a pale yellow oil (8.2 g, yield 97.8%, 97.74% ee, chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35 °C; mobile phase: methanol / n-hexane = 15 / 85; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start and stop wavelength: 200–400 nm; RT = 3.295 min).

[0147] 1 H NMR (400MHz, DMSO-d6) δ = 6.92 (d, 1H), 6.45 (d, 1H), 4.43 (s, 2H), 2.75 (t, 2H), 2.62 (t, 2H), 2.26-2.20 (m, 1H), 2.00-1. 92(m,2H),1.14(d,3H),1.02-0.96(m,1H),0.50-0.44(m,1H),0.34-0.28(m,1H),0.17-0.11(m,1H),0.06-0.00(m,1H).

[0148] LC-MS m / z(ESI)=202.1[M+1].

[0149] intermediate int-2

[0150] (S)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-inden-4-amine (intermediate int-2)

[0151] (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0152]

[0153] The intermediate int-2 was prepared according to patent CN108017559. In a 500 mL autoclave, int-1c (7.3 g, 36.7 mmol) and dichloromethane (80 mL) were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (1.54 g, 1.83 mmol). After the addition was complete, the autoclave was tightly sealed and purged with hydrogen three times. The pressure gauge on the autoclave showed a pressure of 12 atm. The reaction was carried out at room temperature for 30 h. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to give intermediate int-2, a pale yellow oil (7.1 g, yield 96.3%, 98.18% ee, chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35 °C; mobile phase: methanol / n-hexane = 15 / 85; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector starting wavelength: 200–400 nm; RT = 2.802 min).

[0154] 1 H NMR (400MHz, DMSO-d6) δ = 6.92 (d, 1H), 6.46 (d, 1H), 4.43 (s, 2H), 2.75 (t, 2H), 2.63 (t, 2H), 2.26-2.20 (m, 1H), 2.00-1. 93(m,2H),1.15(d,3H),1.02-0.96(m,1H),0.50-0.44(m,1H),0.36-0.28(m,1H),0.17-0.11(m,1H),0.06-0.01(m,1H).

[0155] LCMS m / z(ESI) = 202.1[M+1].

[0156] intermediate int-3

[0157] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide amide (intermediate int-3)

[0158] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0159]

[0160] first step:

[0161] Ethyl furan-3-carboxylate (int-3b)

[0162] Ethyl furan-3-carboxylate

[0163] Compound int-3a (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 int-3b, a light brown oil (38.1 g, yield 61%).

[0164] Step Two:

[0165] 4-Ethyl carbamate-2-sulfonyl chloride furan (int-3c)

[0166] Ethyl furan-2-sulfonyl chloride-4-formate

[0167] Compound int-3b (22.00 g, 0.157 mol) was dissolved in 250 mL of DCM at room temperature. The mixture was cooled to -15 °C in an ice-salt bath, and sulfonyl chloride (23.31 g, 0.173 mol) was slowly added dropwise while maintaining the temperature below -10 °C. After the addition was complete, the mixture was allowed to react at room temperature for 12 h. Then, pyridine (13.66 g, 0.173 mol) was slowly added dropwise after the mixture was cooled to below -15 °C in an ice-salt bath, followed by phosphorus pentachloride (36.00 g, 0.137 mol) in portions while maintaining the temperature below -10 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. The reaction was monitored 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 compound int-3c, a brown oily substance (33.00 g, 90% yield), which was directly added to the next step without purification.

[0168] Step 3:

[0169] Ethyl furan-2-sulfonamide-4-carboxylate (int-3d)

[0170] Furan-2-sulfonamide-4-ethyl formate

[0171] Compound int-3c (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 int-3d as a brown solid powder (23 g, 77% yield).

[0172] 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).

[0173] LCMS m / z = 218.2 [Ml].

[0174] Step 4:

[0175] 4-(2-Hydroxypropyl)furan-2-sulfonamide (int-3e)

[0176] 4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide

[0177] Compound int-3d (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 int-3e, a white solid powder (16 g, yield 76%).

[0178] LCMS m / z = 204.2 [Ml].

[0179] Step 5:

[0180] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl)furan-2-sulfonamide (int-3f)

[0181] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

[0182] Compound int-3e (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) was added (50 mL). 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 int-3f as a white solid (5.1 g, yield 66%).

[0183] 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).

[0184] LCMS m / z = 320.2[M+1].

[0185] Step 6:

[0186] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide amide (intermediate int-3)

[0187] N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0188] 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 a solution of int-3f (3.6 g, 11.29 mmol) in dichloromethane (10 mL) was added dropwise. After the addition was complete, the mixture was kept at 0 °C and reacted for another 30 min. Ammonia was then introduced into the reaction system for 15 min. The mixture was allowed to return to room temperature and reacted 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 obtain intermediate int-3, a white solid (816 mg, yield 23%).

[0189] 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).

[0190] LCMS m / z = 319.2 [M+1].

[0191] intermediate int-4

[0192] (R)-3-(1-Cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (intermediate int-4)

[0193] (R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0194]

[0195]

[0196] first step:

[0197] 2-(2,6-Dibromophenyl)ethane-1-ol (int-4b)

[0198] 2-(2,6-Dibromophenyl)ethan-1-ol

[0199] In a 1L three-necked flask, int-4a (60.0 g, 0.2 mol) and anhydrous tetrahydrofuran (300 mL) were added. Under nitrogen protection, a borane tetrahydrofuran solution (300 mL, 1 M) was slowly added dropwise at 0 °C. After the addition was complete, the temperature was raised to 80 °C and the reaction was allowed to proceed for 1 h. The reaction was monitored by TLC until complete and then cooled to room temperature. Water (150 mL) was added in an ice-water bath, and the reaction was quenched with dilute hydrochloric acid (20 mL, 2 N). A portion of the reaction solution was concentrated under reduced pressure, and then extracted with ethyl acetate (100 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give int-4b, a white solid (50.0 g, yield 88%).

[0200] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.94 (t, 1H), 3.88 (t, 2H), 3.33 (t, 2H).

[0201] Step Two:

[0202] 1,3-Dibromo-2-(2-bromoethyl)benzene (int-4c)

[0203] 1,3-Dibromo-2-(2-bromoethyl)benzene

[0204] In a 1L round-bottom flask, int-4b (50.0 g, 0.18 mol), N-bromosuccinimide (38.0 g, 0.2 mmol), and dichloromethane (400 mL) were added sequentially. After stirring until dissolved, the flask was placed in an ice-water bath, and triphenylphosphine (65 g, 0.2 mol) was slowly added. After the addition was complete, the flask was moved to room temperature and reacted for 24 h. The reaction was monitored by TLC until complete. Tert-butyl hydroperoxide (8 mL) was added and reacted for 2 h to remove excess triphenylphosphine. The reaction was quenched by adding saturated sodium bisulfite solution (200 mL), extracted with dichloromethane (200 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated until a large amount of solid precipitated. Hexane was added to slurry the mixture, and the mixture was filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain int-4c, a white solid (60.0 g, yield 98%).

[0205] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.97 (t, 1H), 3.63-3.43 (m, 4H).

[0206] Step 3:

[0207] 2-Bromobicyclo[4.2.0]oct-1(6),2,4-triene(int-4d)

[0208] 2-Bromobicyclo[4.2.0]octa-1(6),2,4-triene

[0209] In a 250 mL three-necked flask, int-4c (5.0 g, 15 mmol) and anhydrous tetrahydrofuran (150 mL) were added sequentially. Under nitrogen protection, n-butyllithium (5.5 mL, 2.5 M) was slowly added dropwise at -68 °C. After the addition was complete, the reaction was carried out at -68 °C for 2 h. The reaction was monitored by UPLC until complete. The reaction was quenched by slowly adding water (20 mL). The mixture was extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain int-4d, a pale yellow oil (2.5 g, 90% yield).

[0210] Step 4:

[0211] tert-Butylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamate (int-4e)

[0212] Tert-butyl bicyclo[4.2.0]octa-1(6),2,4-trien-2-ylcarbamate

[0213] In a 250 mL round-bottom flask, int-4d (2.3 g, 0.013 mol), dioxane (50 mL), tert-butyl carbamate (2.2 g, 0.019 mol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (476 mg, 1 mmol), and cesium carbonate (8.0 g, 0.025 mol) were added sequentially. Palladium acetate (132 mg, 6 mmol) was added under nitrogen protection. The mixture was moved to 100 °C and reacted for 2 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain int-4e (2.3 g, brown oil, yield 83%).

[0214] 1 H NMR (400MHz, CDCl3) δ = 7.27 (d, 1H), 7.13 (t, 1H), 6.76 (d, 1H), 6.31 (s, 1H), 3.27-3.16 (m, 2H), 3.16-3.06 (m, 2H), 1.52 (s, 9H).

[0215] Step 5:

[0216] Bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (int-4f)

[0217] Bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0218] In a 100 mL round-bottom flask, int-4e (2.3 g, 10.5 mmol), dichloromethane (40 mL), and trifluoroacetic acid (6 mL) were added sequentially. The mixture was reacted at room temperature for 7 h. The reaction was monitored by TLC until it was complete. The reaction was quenched by adding saturated sodium bicarbonate solution (40 mL). The mixture was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain int-4f, a brown oily substance (1.0 g, yield 80%).

[0219] 1 H NMR (400MHz, CDCl3) δ = 7.02 (dd, 1H), 6.51 (dd, 2H), 3.11 (dd, 2H), 3.04 (dd, 2H).

[0220] Step 6:

[0221] (2-Aminobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(cyclopropyl)methyl ketone (int-4g)

[0222] (2-Aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclopropyl)methanone

[0223] In a 25 mL three-necked flask, int-4f (100 mg, 0.84 mmol) and dichloroethane (5 mL) were added sequentially. After dissolving, the flask was placed in an ice-water bath. Under nitrogen protection, boron trichloride toluene solution (900 μL, 1 M) was slowly added dropwise. After 10 min, anhydrous aluminum trichloride (123 mg, 0.9 mmol) was added, followed by slow dropwise addition of cyclobutyl nitrile (74 μL, 1 mmol). After the addition was complete, the mixture was reacted at 90 °C for 3 h. After cooling to room temperature, dilute hydrochloric acid solution (1 mL, 2 N) and water (5 mL) were added, and the mixture was refluxed for 30 min. The organic phase was separated, washed with saturated sodium bicarbonate (10 mL) until weakly acidic, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain int-4g, a brown oily substance (60 mg, yield 38%).

[0224] 1H NMR (400MHz, CDCl3) δ = 7.91 (d, 1H), 6.51 (d, 1H), 3.12-3.05 (m, 2H), 3.04-2.95 (m, 2H), 2.67-2.54 (m, 1H), 1.19-1.10 (m, 2H), 1.00-0.87 (m, 2H).

[0225] Step 7:

[0226] 3-(1-Cyclopropylvinyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (int-4h)

[0227] 3-(1-Cyclopropylvinyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0228] In a 25 mL three-necked flask, triphenylmethylphosphine bromide (8 g, 22 mmol) and anhydrous tetrahydrofuran (40 mL) were added sequentially. After dissolving, the flask was placed in an ice-water bath. Under nitrogen protection, potassium tert-butoxide (2.5 g, 22 mmol) was added. After 40 min, a tetrahydrofuran solution of int-4 g (1.4 g, 7.5 mmol) (20 mL) was added. After 10 min, the reaction was carried out at room temperature for 2 h. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain int-4 h (1.2 g, brown oil, yield 85%).

[0229] 1 H NMR (400MHz, CDCl3) δ = 6.87 (d, 1H), 6.49 (d, 1H), 5.17 (d, 1H), 4.91 (d, 1H), 3. 09(dd,2H),3.03(dd,2H),1.63(tt,1H),0.77-0.67(m,2H),0.54-0.44(m,2H).

[0230] Step 8:

[0231] (R)-3-(1-Cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (intermediate int-4)

[0232] (R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0233] In a 500 mL autoclave, int-4h (500 mg, 2.7 mmol) and dichloromethane (50 mL) were added, followed by the catalyst [(R)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (113 mg, 0.14 mmol). After the addition was complete, the autoclave was tightly sealed and purged with hydrogen three times. The pressure gauge on the autoclave showed 14 atm. The reaction was carried out at room temperature for 5 h. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate int-4, a pale yellow oil (470 mg, yield 94%).

[0234] 1 H NMR (400MHz, DMSO) δ = 6.95 (d, 1H), 6.30 (d, 1H), 2.88 (s, 4H), 2.2 (m, 1H), 1.23 (d,3H),0.97(m,1H),0.46(m,1H),0.29(dt,1H),0.12(dt,1H),0.01(dt,1H).

[0235] intermediate int-5

[0236] (S)-3-(1-Cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (intermediate int-5)

[0237] (S)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0238]

[0239] In a 500 mL autoclave, int-4h (500 mg, 2.7 mmol) and dichloromethane (50 mL) were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (113 mg, 0.14 mmol). After the addition was complete, the autoclave was tightly sealed and purged three times with hydrogen gas. The pressure gauge on the autoclave showed 12 atm. The reaction was carried out at room temperature for 5 h. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate int-5, a pale yellow oil (360 mg, yield 72%).

[0240] 1H NMR(400MHz,MeOD)δ=7.04(d,1H),6.43(d,1H),3.00(s,4H),2.31-2.14(m,1H),1.24(d ,3H),1.09-0.94(m,1H),0.62-0.46(m,1H),0.36(dt,1H),0.15(dt,1H),0.06(dt,1H).

[0241] Example 1

[0242] (R)-4-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Compound 1)

[0243] (R)-4-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[0244]

[0245] first step:

[0246] 3-Amino-1-isopropyl-1H-pyrazole-4-carboxynitrile (1B)

[0247] 3-Amino-1-isopropyl-1H-pyrazole-4-carbonitrile

[0248] Under nitrogen protection, in a 500 mL round-bottom flask, 1A (40.0 g, 370 mmol), 200 mL DMF, and potassium carbonate (102.3 g, 740 mmol) were added sequentially. Bromoisopropane (123.0 g, 50 mmol) was added with stirring, and the reaction was carried out at 80 °C for 16 h. After cooling in an ice bath, 500 mL of water and ethyl acetate (200 mL × 3) were added for extraction. The organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain 56.6 g of crude product. 95 mL of ethyl acetate and 190 mL of petroleum ether were added to the crude product, and the mixture was heated to 80 °C and refluxed. After the solid dissolved completely, it was allowed to cool naturally to room temperature. The mixture was filtered, and the filter cake was washed with 50 mL of solvent (petroleum ether:ethyl acetate = 2:1) and dried to obtain 1B, a white solid (21.4 g, yield 38.5%).

[0249] 1H NMR (400MHz, DMSO-d6) δ = 8.10 (s, 1H), 5.54 (s, 2H), 4.23 (hept, 1H), 1.33 (d, 6H).

[0250] LC-MS m / z(ESI)=151.1[M+1].

[0251] Step Two:

[0252] 4-Cyano-1-isopropyl-1H-pyrazole-3-sulfonamide (1C)

[0253] 4-Cyano-1-isopropyl-1H-pyrazole-3-sulfonamide

[0254] Concentrated HCl (31 mL, 12 mol / L) was added to 6.42 g (42.7 mmol) of 3-amino-1-isopropyl-1H-pyrazole-4-carboxynitrile 1B at room temperature, and the mixture was cooled to -5 °C in an ice bath. 1 mL of an aqueous solution of sodium nitrite (3.54 g, 51.3 mmol) was slowly added dropwise, maintaining the internal temperature below 0 °C. After the addition was complete, the mixture was stirred at low temperature for 1 h to obtain intermediate A solution. 16.9 mL of thionyl chloride was slowly added dropwise to 100 mL of water pre-cooled with ice-salt water, maintaining the internal temperature below 0 °C. After the addition was complete in 30 min, the mixture was cooled to -10 °C in an ice-salt bath, and cuprous chloride (231 mg, mmol) was added and stirred until dissolved. Then, intermediate A solution was added dropwise, maintaining the internal temperature below 0 °C. After the addition was complete in 40 min, a solid gradually precipitated out, accompanied by the release of gas. The reaction was maintained at 0℃ for 1 hour, filtered, the filter cake was washed twice with water, dissolved in DCM, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow solid sulfonyl chloride. The obtained solid was dissolved in 100 mL of DCM, cooled to -20℃, and ammonia gas was introduced while stirring. The mixture was allowed to rise naturally to room temperature, and the reaction was continued with stirring for 1 hour. The reaction endpoint was monitored by TLC, and the reaction solution was evaporated to dryness to obtain 1C (6.5 g, yield 71.0%).

[0255] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),7.94(s,2H),4.63(hept,1H),1.45(d,6H).

[0256] LC-MS m / z(ESI)=215.0[M+1].

[0257] Step 3:

[0258] (R)-4-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Compound 1)

[0259] (R)-4-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[0260] In a 100 mL round-bottom flask under nitrogen protection, intermediate int-1 (201 mg, 1.0 mmol), triethylamine (118 mg, 1.2 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (118 mg, 0.40 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 1C (205 mg, 1.0 mmol) and sodium methoxide (108 mg, 2.0 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed by filtration, and the residue was purified by medium-pressure preparation to give compound 1 as a yellow solid (164 mg, yield 37.2%).

[0261] 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.55(s,1H),7.08(d,1H),6.99(d,1H),4.53(hept,1H),2.79(t,2H),2.62(t,2H),2.32-2.20(m,1H),1 .96-1.81(m,2H),1.41(d,6H),1.08(d,3H),1.00-0.80(m,1H),0.49- 0.36(m,1H),0.24-0.12(m,1H),0.12-0.04(m,1H),0.03-0.06(m,1H).

[0262] LC-MS m / z(ESI)=442.20[M+1].

[0263] Example 2

[0264] (S)-4-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Compound 2)

[0265] (S)-4-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[0266]

[0267] In a 100 mL round-bottom flask under nitrogen protection, intermediate int-2 (100 mg, 0.50 mmol), triethylamine (59 mg, 0.6 mmol), and 10 mL of tetrahydrofuran were added sequentially. Triphosgene (59 mg, 0.20 mmol) was added under ice bath conditions, and the mixture was refluxed for 2 h. The solid was removed by filtration, and 103 mg (0.5 mmol) and sodium methoxide (54 mg, 1.0 mmol) were added to the filtrate. The mixture was reacted at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (100 mL), extracted with DCM (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed by filtration, and the residue was purified by medium-pressure preparation to give compound 2 as a yellow solid (100 mg, yield 45.3%).

[0268] 1 H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.73(s,1H),7.11(d,1H),7.03(d,1H),4.55(hept,1H),2.60(t,2H),2.63(t,2H),2.26-2.18(m,1H),2. 00-1.84(m,2H),1.41(d,6H),1.09(d,3H),1.00-0.80(m,1H),0.49-0. 40(m,1H),0.25-0.13(m,1H),0.13-0.035(m,1H),0.024-0.10(m,1H).

[0269] LC-MS m / z(ESI)=442.20[M+1].

[0270] Example 3

[0271] 4-Cyano-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonylimide (compounds 3-1 and 3-2)

[0272] 4-Cyano-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbam-oyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

[0273]

[0274] first step:

[0275] N-(tert-butyldimethylsilyl)-4-cyano-1-isopropyl-1H-pyrazole-3-sulfonamide (3A)

[0276] N-(tert-butyldimethylsilyl)-4-cyano-1-isopropyl-1H-pyrazole-3-sulfonamide

[0277] In a 100 mL three-necked flask, 1C (2.00 g, 7.46 mmol), 50 mL of dichloromethane, and imidazole (1.2 g, 14.92 mmol) were added sequentially. Under nitrogen protection, tert-butyldimethylchlorosilane (1.35 g, 8.96 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 h, and the reaction was monitored by TLC until complete. Water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to give 3A, a pale yellow solid (2.2 g, yield 90.1%).

[0278] Step Two:

[0279] N'-(tert-butyldimethylsilyl)-4-cyano-1-isopropyl-1H-pyrazole-3-sulfonylimide (3B)

[0280] N'-(tert-butyldimethylsilyl)-4-cyano-1-isopropyl-1H-pyrazole-3-sulfonimidamide

[0281] In a 100 mL round-bottom flask, under nitrogen protection, triphenylphosphine (1.92 g, 7.31 mmol), hexachloroethane (2.02 g, 8.52 mmol), and chloroform (20 mL) were added sequentially, and the mixture was refluxed at 85 °C for 30 min. The conversion was monitored by TLC until complete, and the mixture was cooled to room temperature. The mixture was further cooled to -30 °C, and N,N-diisopropylethylamine (1.38 g, 10.65 mmol) was slowly added dropwise. The mixture was stirred for 10 min, and 3A (2.00 g, 6.09 mmol) dissolved in chloroform (5 mL) was slowly added dropwise under ice bath conditions. The mixture was stirred for 3 h. Ammonia was purged at -30 °C for 1 h, and the mixture was slowly brought to room temperature and reacted overnight. The reaction was monitored by TLC until complete, at which point the reaction was considered finished. The reaction mixture was poured into water, and the organic phase was extracted, followed by extraction with dichloromethane (100 mL × 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, remove organic solvent under reduced pressure, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 4:1 to 3:1) to give 3B, a white solid (1.28 g, yield 64.2%).

[0282] Step 3:

[0283] 4-Cyano-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonylimide (3C)

[0284] 4-Cyano-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

[0285] In a 25 mL round-bottom flask, under nitrogen protection, intermediate int-1 (156 mg, 0.774 mmol), 3 mL of dry tetrahydrofuran, and 2,2,2-trichloroethyl chloroformate (197 mg, 0.93 mmol) were added sequentially. The mixture was stirred for 30 min, and TLC was used to monitor complete conversion. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. 3 mL of dry tetrahydrofuran was added to dissolve the mixture to form solution A. In another 50 mL three-necked flask, 3B (300 mg, 0.774 mmol) and 3 mL of dry tetrahydrofuran were added. Sodium hydride (37 mg, 60%, 0.925 mmol) was added under ice bath conditions, and the mixture was stirred for 1 h. Solution A was slowly added dropwise under ice bath conditions, and the reaction was allowed to proceed at room temperature for 1 h. LC-MS was used to monitor complete reaction, and triethylamine trihydrofluoride (124 mg, 0.774 mmol) was slowly added dropwise. The reaction was carried out overnight at room temperature. The reaction was monitored by TLC until it ended. The reaction solution was poured into water, and ethyl acetate (20 mL × 2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium-pressure preparation (acetonitrile / water = 30 / 70) to obtain 3C, a pale yellow solid (290 mg, yield 85.0%).

[0286] LC-MS m / z(ESI)=441.2[M+1].

[0287] Step 4:

[0288] 4-Cyano-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonylimide (compounds 3-1 and 3-2)

[0289] 4-Cyano-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbam-oyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

[0290] 3C (270 mg, 0.613 mmol) was resolved by SFC to give compound 3-1 (134 mg, yield 49.6%, RT = 10.108 min, 100% ee) and compound 3-2 (135 mg, yield 50.0%, RT = 13.733 min, 100% ee). Chiral HPLC (AD) 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.

[0291] Compound 3-1: 1 H NMR(400MHz,DMSO)δ8.78(s,1H),8.23(s,1H),7.80(s,2H),7.11(d,1H),7 .03(d,1H),4.62(hept,1H),2.80(t,2H),2.71-2.52(m,2H),2.28-2.16(m, 1H),1.98-1.82(m,2H),1.45(dd,6H),1.09(d,3H),1.00-0.87(m,1H),0.5 0-0.38(m,1H),0.22-0.113(m,1H),0.11-0.021(m,1H),0.00-0.10(m,1H).

[0292] LCMS m / z(ESI) = 441.2[M+1].

[0293] Compound 3-2: 1 H NMR(400MHz,DMSO)δ8.77(s,1H),8.25(s,1H),7.80(s,2H),7.11(d,1H),7. 03(d,1H),4.61(hept,1H),2.80(t,2H),2.70-2.55(m,2H),2.29-2.17(m,1 H),1.98-1.83(m,2H),1.44(dd,6H),1.04(d,3H),1.00-0.88(m,1H),0.50- 0.39(m,1H),0.26-0.156(m,1H),0.142-0.053(m,1H),0.053-0.036(m,1H).

[0294] LCMS m / z(ESI) = 441.2[M+1].

[0295] Example 4

[0296] 4-Cyano-N'-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonylimide (compounds 4-1 and 4-2)

[0297] 4-Cyano-N'-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbam-oyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

[0298]

[0299] first step:

[0300] 4-Cyano-N'-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonylimide (4A)

[0301] 4-Cyano-N'-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbam-oyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

[0302] The synthesis of 4A was carried out by replacing intermediate 1 with intermediate int-2, following the same synthesis method as 3C.

[0303] Step Two:

[0304] 4-Cyano-N'-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonylimide (compounds 4-1 and 4-2)

[0305] 4-Cyano-N'-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbam-oyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

[0306] 4A was resolved by SFC to yield compounds 4-1 (RT = 26.856 min, 100% ee) and 4-2 (RT = 30.435 min, 100% ee). Chiral HPLC (AS) mobile phase: n-hexane / ethanol = 95 / 5; column temperature: 35℃; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start and end wavelengths: 200–400 nm.

[0307] Compound 4-1: 1H NMR(400MHz,DMSO)δ8.76(s,1H),8.24(s,1H),7.78(s,2H),7.11(d,1H),7 .02(d,1H),4.60(hept,1H),2.80(t,2H),2.66-2.56(m,2H),2.28-2.17(m, 1H),1.97-1.83(m,2H),1.44(d,6H),1.05(d,3H),1.00-0.87(m,1H),0.50- 0.39(m,1H),0.25-0.16(m,1H),0.145-0.057(m,1H),0.054-0.030(m,1H).

[0308] LCMS m / z(ESI) = 441.2[M+1].

[0309] Compound 4-2: 1 H NMR(400MHz,DMSO)δ8.78(s,1H),8.22(s,1H),7.79(s,2H),7.11(d,1H),7 .03(d,1H),4.61(hept,1H),2.81(t,2H),2.70-2.54(m,2H),2.27-2.14(m, 1H),1.98-1.83(m,2H),1.45(dd,6H),1.09(d,3H),0.98-0.87(m,1H),0.5 0-0.37(m,1H),0.22-0.12(m,1H),0.11-0.023(m,1H),-0.08-0.11(m,1H).

[0310] LCMS m / z(ESI) = 441.2[M+1].

[0311] Example 5

[0312] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 5-1 and 5-2)

[0313] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0314]

[0315] first step:

[0316] (6,7-Dihydro-5H-cyclopentyl[b]pyridin-4-yl)tert-butyl carbamate (5B)

[0317] Tert-butyl(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0318] In a 500 mL three-necked flask, 5A (25 g, 162.75 mmol), tert-butyl carbamate (28.7 g, 244.12 mmol), X-phos (CAS: 564483-18-7) (7.8 g, 16.3 mmol), palladium acetate (1.83 g, 8.14 mmol), cesium carbonate (105.8 g, 325.5 mmol), and 1,4-dioxane (400 mL) were added sequentially. The mixture was reacted at 100 °C for 6 h under nitrogen protection. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was slurried with ethyl acetate (60 mL) to give 5B, a pale yellow solid (24.1 g, yield 62.7%).

[0319] LC-MS m / z(ESI)=235.3[M+1].

[0320] Step Two:

[0321] (3-Bromo-6,7-dihydro-5H-cyclopentan[b]pyridin-4-yl)tert-butyl carbamate (5C)

[0322] Tert-butyl(3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0323] 5B (24 g, 102.13 mmol), NBS (27.3 g, 153.2 mmol), and acetonitrile (200 mL) were added sequentially to a 500 mL round-bottom container. The reaction was carried out at 60 °C for 8 h. The reaction was monitored by TLC until completion. The container was cooled to room temperature, quenched with sodium bisulfite, extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:10 to 1:2) to give compound 5C as a pale yellow solid (35.2 g, yield 81.3%).

[0324] 1H NMR (400MHz, DMSO) δ9.18(s,1H),8.41(s,1H),2.89(t,2H),2.82(t,2H),2.10-1.98(m,2H),1.46(d,9H).

[0325] LC-MS m / z(ESI)=314.2[M+1].

[0326] Step 3:

[0327] (3-(1-Cyclopropylvinyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-4-yl)tert-butyl carbamate (5D)

[0328] Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0329] Under nitrogen protection, 5C (25 g, 79.87 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (18.6 g, 95.85 mmol), Pd(dppf)Cl2 (8.8 g, 11.98 mmol), potassium phosphate (33.9 g, 159.74 mmol), and a 1,4-dioxane / water mixed solvent (200 mL / 50 mL) were added sequentially to a 500 mL round-bottom container. The reaction was carried out at 100 °C for 8 h. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:30 to 1:5) to give 5D, a white solid (15.2 g, yield 63.3%).

[0330] LC-MS m / z(ESI)=301.2[M+1].

[0331] Step 4:

[0332] (3-(1-Cyclopropylvinyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-4-yl)tert-butyl carbamate (5E)

[0333] Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

[0334] 5D (15 g, 49.83 mmol) and DCM (150 mL) were added sequentially to a 500 mL round-bottom container. Boron trifluoride ether (28.4 g, 200 mmol) was then slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC until it was complete. The mixture was quenched with water, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with DCM (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:30 to 1:3) to obtain 5E, a brown oily substance (3 g, yield 30%).

[0335] LC-MS m / z(ESI)=201.1[M+1].

[0336] Step 5:

[0337] (S)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-Indene-4-amine (5F)

[0338] (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0339] The synthesis of 5F was carried out with reference to patent CN108017559. In a 250 mL autoclave, 820 mg (4.1 mmol) of 5E and 30 mL of dichloromethane were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (346 mg, 0.41 mmol). After the addition was complete, the autoclave was tightly sealed, purged three times with hydrogen, and then purged with hydrogen. The pressure gauge on the autoclave showed 30 atm. The reaction was carried out at room temperature for 30 h. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 30:1 to 15:1) to give 5F, a pale yellow oil (343 mg, yield 41.5%, 92.70% ee, chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35 °C; mobile phase: methanol / n-hexane = 15 / 85; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start and stop wavelength: 200–400 nm; RT = 8.765 min).

[0340] 1H NMR (400MHz, DMSO) δ7.88(s,1H),5.40(s,2H),2.70(t,2H),2.62(t,2H),2.22-2.18(m,1H),2.00-1.94(m,2H) ,1.17(d,3H),1.11-1.00(m,1H),0.54-0.45(m,1H),0.40-0.29(m,1H),0.19-0.09(m,1H),0.07-0.00(m,1H).

[0341] LCMS m / z(ESI) = 202.1[M+1].

[0342] Step 6:

[0343] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopentan[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (5G)

[0344] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0345] Under nitrogen protection, in a 100 mL round-bottom flask, 5F (230 mg, 1 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (356 μL, 2.0 mmol), and 2,2,2-trichloroethyl chloroformate (156 μL, 1.2 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The solution was then dissolved in tetrahydrofuran (10 mL), and intermediate int-3 (340 mg, 1 mmol) and sodium hydride (36 mg, 1.5 mmol) were added, and the reaction was carried out at room temperature for 2 h. Triethylamine hydrofluoric acid (326 mg, 2 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 to give 5 G of white solid (110 mg, yield 16.9%).

[0346] Step 7:

[0347] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 5-1 and 5-2)

[0348] N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0349] 5G (110 mg) was resolved by SFC to yield compound 5-1 (48 mg, yield 43.6%, RT = 5.426 min, 100% ee) and compound 5-2 (44 mg, yield 40.0%, RT = 6.372 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.

[0350] Compound 5-1: 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.21(s,1H),8.12(s,1H),7.55(s,1H),6.39(s,1H),5.08(s,1H),3 .77(m,2H),2.59(m,1H),2.53(m,2H),1.38(s,6H),1.20(dd,3H),1.02(m,1H),0.40(m,2H),0.15(m,2H).

[0351] Compound 5-2: 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.21(s,1H),8.12(s,1H),7.55(s,1H),6.39(s,1H),5.08(s,1H),3 .77(m,2H),2.59(m,1H),2.53(m,2H),1.38(s,6H),1.20(dd,3H),1.02(m,1H),0.40(m,2H),0.15(m,2H).

[0352] Example 6

[0353] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 6-1 and 6-2)

[0354] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0355]

[0356]

[0357] first step:

[0358] 2-Cyclopentadienylmalononitrile (6B)

[0359] 2-Cyclopentylidenemalononitrile

[0360] In a 500 mL round-bottom flask, cyclopentanone 6A (50 g, 594.38 mmol) and malononitrile (39.3 g, 594.38 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 6 h. The reaction was confirmed by TLC. The mixture was then cooled to room temperature to give compound 6B, a brown oily substance (81.3 g, yield 103%), which could be used directly in the next step without purification.

[0361] LCMS m / z(ESI) = 133.2[M+1].

[0362] Step Two:

[0363] 2-(2-(((dimethylamino)methylene)cyclopentadiene)malononitrile(6C)

[0364] 2-(2-((Dimethylamino)methylene)cyclopentylidene)malononitrile

[0365] In a 500 mL round-bottom flask, 6B (80 g, 606.1 mmol), acetic anhydride (40 mL), and DMF-DMA (50 mL) were added sequentially. The mixture was reacted at room temperature for 30 min. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then slurried with ethyl acetate and petroleum ether to obtain 6C, a yellow solid (59 g, yield 52%).

[0366] LCMS m / z(ESI) = 188.1[M+1].

[0367] Step 3:

[0368] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-onitrile (6D)

[0369] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile

[0370] In a 500 mL round-bottom flask, 6C (58 g, 310.16 mmol), dioxane hydrochloride solution (4 N, 120 mL), and acetic acid (30 mL) were added sequentially. The mixture was reacted at 55 °C for 4 h. The reaction was stopped by TLC. The mixture was cooled to room temperature, quenched with water, and the pH was adjusted to neutral with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain the crude product. The crude product was then slurried with ethyl acetate and petroleum ether to obtain 6D, a gray solid (35 g, yield 63.4%).

[0371] LCMS m / z(ESI) = 179.0[M+1].

[0372] Step 4:

[0373] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxamide (6E)

[0374] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxamide

[0375] 6D (33 g, 185.39 mmol), sodium hydroxide (31.1 g, 556.18 mmol), and 150 mL of water were added sequentially to a 500 mL three-necked flask. The mixture was heated to reflux and reacted for 2 h. The reaction was stopped by TLC. The mixture was cooled to room temperature, and the pH was adjusted to neutral with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was slurried with ethyl acetate and petroleum ether to obtain 6E, a grayish-white solid (20 g, 54.7%).

[0376] LCMS m / z(ESI) = 197.0[M+1].

[0377] Step 5:

[0378] 3-Chloro-6,7-dihydro-5H-cyclopentane[c]pyridine-4-amine (6F)

[0379] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-amine

[0380] In a 250 mL three-necked flask, 6E (10 g, 51.02 mmol), NBS (45.4 g, 255.1 mmol), potassium hydroxide (57.1 g, 102.0 mmol), and 150 mL of methanol were added sequentially. The mixture was heated to reflux until the reaction was complete, cooled to room temperature, and the reaction was quenched with sodium bisulfite. The mixture was extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (MeOH:DCM = 50:1–10:1) to give 6F, a yellow solid (5.9 g, yield 68.6%).

[0381] LCMS m / z(ESI) = 169.1[M+1].

[0382] Step 6:

[0383] 3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopentane[c]pyridine-4-amine (6G)

[0384] 3-(Cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-amine

[0385] Under nitrogen protection, 6F (550 mg, 3.26 mmol), potassium cyclobutylmethyltrifluoroborate (1.15 g, 6.52 mmol), potassium carbonate (1.35 g, 9.78 mmol), RuPhos Pd-G3 (CAS: 1445085-77-7) (277 mg, 0.33 mmol), and toluene / water mixed solvent (40 mL / 10 mL) were added sequentially to a 100 mL three-necked flask. 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 (DCM:MeOH = 50:1–20:1) to give 6G, a pale yellow solid (261 mg, yield 39.6%).

[0386] LC-MS m / z(ESI)=203.1[M+1].

[0387] Step 7:

[0388] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (6H)

[0389] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0390] Under nitrogen protection, in a 100 mL round-bottom flask, 6 G (230 mg, 1 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (356 μL, 2.0 mmol), and 2,2,2-trichloroethyl chloroformate (156 μL, 1.2 mmol) were added sequentially, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The solution was then dissolved in tetrahydrofuran (10 mL), and intermediate int-3 (340 mg, 1 mmol) and sodium hydride (36 mg, 1.5 mmol) were added, and the reaction was carried out at room temperature for 2 h. Triethylamine hydrofluoric acid (322 mg, 2 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 to give 6H, a white solid (130 mg, yield 20.1%).

[0391] Step 8:

[0392] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 6-1 and 6-2)

[0393] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0394] Compound 6-1 (110 mg, yield 38.6%, RT = 4.884 min, 100% ee) and compound 6-2 (115 mg, yield 41.8%, RT = 6.252 min, 100% ee) were obtained by SFC resolution of 6H (130 mg). 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.

[0395] Compound 6-1: 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.12(s,1H),7.55(s,1H),6.98(s,1H),5.08(s,1H),2.85(t,J=7.4H z,2H),2.77(d,2H),2.66(s,3H),1.96(m,1H),1.92(m,2H),1.83-1.72(m,2H),1.65(m,2H),1.38(s,6H).

[0396] Compound 6-2: 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.12(s,1H),7.55(s,1H),6.98(s,1H),5.08(s,1H),2.85(t,2 H),2.77(d,2H),2.66(s,3H),1.96(m,1H),1.92(m,2H),1.8-1.72(m,2H),1.65(m,2H),1.38(s,6H).

[0397] Example 7

[0398] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 7-1 and 7-2)

[0399] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0400]

[0401] first step:

[0402] Diethyl 2-hydroxy-2-(2-oxocyclopentyl)malonate (7B)

[0403] Diethyl 2-hydroxy-2-(2-oxocyclopentyl)malonate

[0404] In a 250 mL round-bottom flask, 7A (25 g, 143.55 mmol) and cyclopentanone (12.1 g, 143.55 mmol) were added sequentially, and the mixture was heated to 100 °C and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature and purified by column chromatography (EA:PE = 1:100 to 1:30) to obtain 7B, a pale yellow oil (29 g, yield 78.1%).

[0405] LC-MS m / z(ESI)=259.2[M+1].

[0406] Step Two:

[0407] 3-Hydroxy-6,7-dihydro-5H-cyclopentadiazine-4-carboxylic acid ethyl ester (7C)

[0408] Ethyl 3-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-carboxylate

[0409] In a 50 mL round-bottom flask, 7B (5.0 g, 19.36 mmol) and 20 mL of acetic acid were added sequentially. The mixture was heated to 100 °C and reacted for 3 h. The reaction was monitored by TLC until it ended. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:10 to 1:5) to give 7C, a pale yellow solid (2.1 g, yield 52.1%).

[0410] LC-MS m / z(ESI)=209.1[M+1].

[0411] Step 3:

[0412] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-carboxylic acid ethyl ester (7D)

[0413] Ethyl 3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-carboxylate

[0414] In a 50 mL round-bottom flask, 7C (2.1 g, 10.08 mmol), phosphorus oxychloride (3.1 g, 20.17 mmol), and 1,4-dioxane (20 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled to room temperature, the organic solvent was removed under reduced pressure, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:10 to 1:6) to give 7D, a pale yellow solid (1.2 g, yield 52.6%).

[0415] 1 H NMR (400MHz, DMSO) δ12.88(s,1H),4.30-4.22(m,2H),2.87(t,2H),2.73(t,2H),2.08-1.93(m,2H),1.27(t,3H).

[0416] LC-MS m / z(ESI)=227.1[M+1].

[0417] Step 4:

[0418] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-carboxylic acid (7E)

[0419] 3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-carboxylic acid

[0420] In a 50 mL round-bottom flask, 7D (1.2 g, 5.31 mmol) and lithium hydroxide (254 mg, 10.62 mmol) were dissolved in a THF / H2O mixed solvent (10 mL / 10 mL). The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, water was added to quench the reaction, and the pH was adjusted to acidic with dilute hydrochloric acid. The mixture was then filtered to obtain 7E, a white solid (764 mg, yield 72.7%).

[0421] 1 H NMR (400MHz, DMSO) δ14.45(s,1H),3.13(t,2H),3.04(t,2H),2.21-2.06(m,2H).

[0422] LC-MS m / z(ESI)=199.0[M+1].

[0423] Step 5:

[0424] (3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-yl)tert-butyl carbamate (7F)

[0425] Tert-butyl(3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridazin-4-yl)carbamate

[0426] In a 50 mL round-bottom flask, 7E (764 mg, 3.85 mmol), triethylamine (777 mg, 7.69 mmol), diphenyl azidophosphate (1.17 g, 4.24 mmol), and tert-butanol (10 mL) were added sequentially. The mixture was heated to 80 °C and the reaction was stopped by TLC. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (EA:PE = 10:1) to give 7F, a pale yellow solid (733 mg, yield 69.8%).

[0427] 1 H NMR (400MHz, DMSO) δ9.58(s,1H),3.10(t,2H),2.86(t,2H),2.17-2.00(m,2H),1.48(d,9H).

[0428] LC-MS m / z(ESI)=270.1[M+1].

[0429] Step 6:

[0430] (3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-yl) tert-butyl carbamate (7G)

[0431] Tert-butyl(3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazin-4-yl)carbamate

[0432] Under nitrogen protection, 7F (733 mg, 2.72 mmol), potassium cyclobutylmethyltrifluoroborate (957 mg, 5.44 mmol), potassium carbonate (797 mg, 5.44 mmol), Ruphos-Pd-G3 (CAS: 1445085-77-7) (340 mg, 0.41 mmol), and toluene / water mixed solvent (40 mL / 10 mL) were added sequentially to a 100 mL three-necked flask. 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 obtain 7G, a pale yellow oil (531 mg, yield 64.4%).

[0433] 1 H NMR(400MHz,DMSO)δ9.19(s,1H),3.11-2.96(m,4H),2.77(t,2H),2.73-2.58(m,1H),2. 09-1.98(m,2H),1.98-1.90(m,2H),1.85-1.75(m,2H),1.75-1.62(m,2H),1.46(s,9H).

[0434] LC-MS m / z(ESI)=304.2[M+1].

[0435] Step 7:

[0436] 3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopentane[c]pyridazine-4-amine(7H)

[0437] 3-(Cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazin-4-amine

[0438] In a 50 mL round-bottom flask, 7 g (733 mg, 2.42 mmol) was dissolved in DCM (10 mL), and TFA (1 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. Once the reaction was complete, water was added to quench the reaction, and the pH was adjusted to neutral with saturated sodium bicarbonate. The mixture was then extracted with DCM (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 100:1 to 15:1) to give 7H, a white solid (330 mg, yield 67.1%).

[0439] LC-MS m / z(ESI)=204.1[M+1].

[0440] Step 8:

[0441] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (7I)

[0442] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0443] In a 25 mL round-bottom flask, under nitrogen protection, 7H (330 mg, 1.63 mmol), diisopropylethylamine (421 mg, 3.26 mmol), 10 mL of dry tetrahydrofuran, and 2,2,2-trichloroethyl chloroformate (414 mg, 1.95 mmol) were added sequentially. The mixture was stirred for 30 min, and the conversion was monitored by TLC until complete. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. 5 mL of dry tetrahydrofuran was added to dissolve the mixture to form solution B. In another 50 mL three-necked flask, intermediate int-3 (519 mg, 1.63 mmol) and 5 mL of dry tetrahydrofuran were added. Sodium hydride (130 mg, 60%, 3.26 mmol) was added under ice bath conditions, and the mixture was stirred for 1 h. Solution B was slowly added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 1 hour. The reaction was monitored to be complete by LC-MS. Triethylamine trihydrofluoride (525 mg, 3.26 mmol) was then slowly added dropwise. The reaction was carried out overnight at room temperature, and the reaction was monitored to be complete by TLC. The reaction solution was poured into water, and ethyl acetate (20 mL × 2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium-pressure preparation (acetonitrile / water = 30 / 70) to give 7I, a pale yellow solid (117 mg, yield 16.5%).

[0444] LC-MS m / z(ESI)=434.2[M+1].

[0445] Step 9:

[0446] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazine-4-yl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 7-1 and 7-2)

[0447] N-((3-(cyclobutylmethyl)-6,7-dihydro-5H-cyclopenta[c]pyridazin-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0448] 7I (117 mg, 0.27 mmol) was resolved by SFC to give compound 7-1 (52 mg, yield 44.4%, RT = 5.373 min, 99.24% ee) and compound 7-2 (56 mg, yield 47.9%, RT = 6.068 min, 98.05% ee). Chiral HPLC (AD) 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.

[0449] Compound 7-1: 1 H NMR(600MHz,DMSO)δ8.98(s,1H),7.76(s,2H),7.72(s,1H),7.04(s,1H),5.12(s,1H),3.01(t,2H),2 .97(s,1H),2.79-2.57(m,4H),2.02-1.87(m,5H),1.82-1.73(m,2H),1.69-1.61(m,2H),1.39(s,7H).

[0450] LCMS m / z(ESI)=434.2[M+1].

[0451] Compound 7-2: 1 H NMR(600MHz,DMSO)δ8.97(s,1H),7.71(s,1H),7.64(s,2H),7.03(s,1H),5.11(s,1H),3.01(t,2H),2 .97(s,1H),2.73-2.64(m,3H),2.02-1.89(m,4H),1.85-1.77(m,2H),1.70-1.61(m,2H),1.39(s,6H).

[0452] LCMS m / z(ESI)=434.2[M+1].

[0453] Example 8

[0454] N-(((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (compounds 8-1 and 8-2)

[0455] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0456]

[0457] first step:

[0458] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl) ketone (8B)

[0459] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone

[0460] In a 1L three-necked flask, 8A (40g, 210.4mmol) and dichloroethane (500mL) were added sequentially. After dissolving completely, the flask was placed in an ice-water bath. Under nitrogen protection, boron trichloride toluene solution (252.8mL, 1M) was slowly added dropwise. After 10 min, anhydrous aluminum trichloride (33.6g, 252mmol) was added, followed by slow dropwise addition of cyclobutyronitrile (59.2mL, 632mmol). After the addition was complete, the reaction was carried out at 90℃ for 24 h. After cooling to room temperature, dilute hydrochloric acid solution (30mL, 2N) was added, and the mixture was refluxed for 30 min. The organic phase was separated, washed with saturated sodium bicarbonate (50mL) until weakly acidic, extracted with dichloromethane (50mL × 3), dried over anhydrous sodium sulfate, filtered, and the crude product 8B (4.8g, yield 8.8%) was removed under reduced pressure.

[0461] 1 H NMR(400MHz DMSO)δ=7.27(dd,1H),6.79(dd,1H),5.17(d,2H),4.14-4.10(m,1H),2.06-2.86(m,5H),1.82-1.68(m,1H)

[0462] Step Two:

[0463] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol (8C)

[0464] (2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol

[0465] In a 250 mL round-bottom flask, 8B (4.8 g, 17.3 mmol), anhydrous methanol (20 mL), and sodium borohydride (2.0 g, 51.9 mmol) were added sequentially. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TCL until complete. The reaction was quenched by slowly adding water (20 mL) dropwise. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain 8C, a white powder (2.6 g, yield 54%).

[0466] 1 H NMR (400MHz DMSO) δ7.21(dd,1H),6.94(dd,1H),5.48(d,1H),5.03(s,2H),4.54(dd,1H),2.74-2.62(m,2H),1.98-1.68(m,6H).

[0467] Step 3:

[0468] 2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline (8D)

[0469] 2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline

[0470] In a 50 mL round-bottom flask, 8C (850 mg, 3 mmol), dichloromethane (20 mL), triethylsilane (1.4 mL, 9 mmol), and trifluoroacetic acid (1 mL, 9 mmol) were added sequentially. The mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction was quenched by slowly adding saturated sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 8D, a brown oily substance (530 mg, yield 69%).

[0471] 1 H NMR(400MHz,Chloroform-d)δ7.06(dd,1H),6.70(dd,1H),3.36(s,2H),2.65( dq,1H),2.58(d,2H),2.22-2.07(m,2H),1.98-1.81(m,2H),1.83-1.63(m,2H).

[0472] Step 4:

[0473] 2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline (8E)

[0474] 2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline

[0475] In a 50 mL round-bottom flask, 8D (500 mg, 1.93 mmol), dioxane (20 mL), and sodium carbonate (616 mg, 5.8 mmol) were added sequentially. Under nitrogen protection, palladium dichlorodi(triphenylphosphine)ide (67.7 mg, 0.0965 mmol) and 2-methoxypyridine-4-boronic acid (383 mg, 2.50 mmol) were added, and the reaction was carried out at 80 °C for 24 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 8E, a brown oil (350 mg, yield 63.3%).

[0476] LCMS m / z(ESI) = 287.2[M+l].

[0477] Step 5:

[0478] N-(((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (8F)

[0479] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0480] Under nitrogen protection, 8E (429 mg, 1.5 mmol), tetrahydrofuran (10 mL), triphosgene (177.6 mg, 0.6 mmol), and triethylamine (181.8 mg, 1.8 mmol) were added sequentially to a 100 mL round-bottom flask. The mixture was reacted at room temperature for 1 h, filtered, and intermediate int-3 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added. The mixture was reacted at room temperature for 2 h. Triethylamine hydrofluoric acid (484 mg, 3 mmol) was added, and the mixture was reacted at room temperature for 1 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 to give 8F as a white solid (260 mg, yield 30.1%).

[0481] Step 6:

[0482] N-(((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonylimide (compounds 8-1 and 8-2)

[0483] N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0484] 8F (260 mg) was resolved by SFC to yield compound 8-1 (110 mg, yield 38.6%, RT = 3.786 min, 100% ee) and compound 8-2 (115 mg, yield 41.8%, RT = 4.222 min, 100% ee). Chiral HPLC (AS) was performed with the following mobile phases: n-hexane / ethanol = 90 / 10; column temperature: 35 °C; column pressure: 80 bar; flow rate: 1 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start and stop wavelengths: 200–400 nm.

[0485] LC-MS m / z(ESI)=516.18[M+l].

[0486] Compound 8-1: 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.15(d,1H),7.66(s,1H),7.63(s,2H),7.09(dd,1H),7.00(dd,1H) ,6.94(s,1H),6.74(s,1H),5.09(s,1H),3.88(s,3H),2.62-2.59(m,2H),1.99-1.91(m,2H),1.83-1.80(m 2H),1.73-1.67(m,2H),1.38(s,6H).

[0487] Compound 8-2: 1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.17(d,1H),7.69(s,1H),7.63(s,2H),7.05(dd,1H),7.01(dd,1H) ,6.94(s,1H),6.78(s,1H),5.09(s,1H),3.88(s,3H),2.64-2.60(m,2H),1.99-1.90(m,2H),1.83-1.79(m 2H),1.73-1.65(m,2H),1.38(s,6H).

[0488] Example 9

[0489] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 9-1 and 9-2)

[0490] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0491]

[0492] first step:

[0493] 4-(2-Amino-3-(cyclobutylmethyl)-5-fluorophenyl)pyridinenitrile (9A)

[0494] 4-(2-Amino-3-(cyclobutylmethyl)-5-fluorophenyl)picolinonitrile

[0495] In a 100 mL three-necked flask, 8D (1.5 g, 5.8 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinium (2.01 g, 8.6 mmol), 1,4-dioxane (30 mL), cesium carbonate (1.54 g, 14.5 mmol), and catalyst [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (424 mg, 0.58 mmol) were added. Under nitrogen protection, the reaction was carried out under reflux at 90 °C for 8 h. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 8:1) to give 9A, a green solid (520 mg, yield 94%).

[0496] 1H NMR(400MHz,DMSO-d6)δ8.15(d,1H),7.66(s,2H),7.62(s,1H)7.63(m,2H),7.05(dd,1 H),7.01(dd,1H),2.62-2.60(m,2H),2.53-2.51(m,1H)1.99-1.95(m,2H),1.83-1.80(m 2H),1.73-1.67(m,2H).

[0497] LC-MS m / z(ESI) = 281.13.

[0498] Step Two:

[0499] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (9B)

[0500] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0501] Under nitrogen protection, in a 100 mL round-bottom flask, 9A (429 mg, 1.5 mmol), tetrahydrofuran (10 mL), triphosgene (177.6 mg, 0.6 mmol), and triethylamine (181.8 mg, 1.8 mmol) were added sequentially. The reaction was carried out at room temperature for 1 h, filtered, and intermediate int-3 (510 mg, 1.5 mmol) and sodium hydride (54 mg, 2.25 mmol) were added. The reaction was carried out at room temperature for 2 h. Triethylamine hydrofluoric acid (484 mg, 3 mmol) was added, and the reaction was carried out at room temperature for 1 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 to give compound 9B as a white solid (220 mg, yield 28.6%).

[0502] Step 3:

[0503] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 9-1 and 9-2)

[0504] N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0505] 9B (220 mg) was resolved by SFC to yield compounds 9-1 (85 mg, yield 38.6%, RT = 2.463 min, 100% ee) and 9-2 (92 mg, yield 41.8%, RT = 2.472 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.

[0506] LC-MS m / z(ESI)=511.17[M+l].

[0507] Compound 9-1: 1 H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.15(d,1H),7.66(s,1H),7.63(s,2H),7.05(dd,1H),7.01(d d,1H),6.94(s,1H),6.78(s,1H),5.09(s,1H),2.62-2.55(m,2H),1.99-1.95(m,2H),1.83-1.80(m 2H),1.73-1.67(m,2H),1.38(s,6H).

[0508] Compound 9-2: 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.15(d,1H),7.68(s,1H),7.63(s,2H),7.05(dd,1H),7.01(d d,1H),6.91(s,1H),6.78(s,1H),5.05(s,1H),2.65-2.57(m,2H),2.02-1.98(m,2H),1.83-1.80(m 2H),1.73-1.66(m,2H),1.35(s,6H).

[0509] Example 10

[0510] N-((2-(2-cyanopyridin-4-yl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 10-1 and 10-2)

[0511] N-((2-(2-cyanopyridin-4-yl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0512]

[0513]

[0514] first step:

[0515] (2-Amino-3-bromophenyl)(cyclopropyl)methyl ketone (10B)

[0516] (2-Amino-3-bromophenyl)(cyclopropyl)methanone

[0517] Add 20 g (116.27 mmol) of 10A 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 18.6 g (139.52 mmol) of aluminum trichloride. Stir at room temperature for about 10 minutes, and the solution will turn yellow and clear. Add 13.2 mL (174.40 mmol) of propionitrile toluene solution under an ice bath (0 °C). After adding the solvent (ol), the mixture was refluxed at 100°C to remove the toluene solvent. After evaporation, the reaction was continued at 100°C for about 6 hours. TLC (PE:EA = 10:1) showed that a product was formed. Then, 50 mL of water was added to boil the imine (80°C). After clarification, the boiling was complete. The mixture was then extracted with DCM (30 mL × 3). The organic phase was washed with saturated NaCl, dried with anhydrous NaSO4, filtered, concentrated, distilled under reduced pressure, mixed, and column chromatography (100% PE) was performed to obtain 10B, a pale yellow oil (7.5 g, 27% yield).

[0518] 1 H NMR (400MHz, CDCl3) δ7.96(dd,1H),7.58(dd,1H),6.59(t,1H),2.62(m,1H),1.20(m,4H),0.99(m,4H).

[0519] LCMS m / z(ESI)=238.99[M+l].

[0520] Step Two:

[0521] 2-Bromo-6-(1-Cyclopropylvinyl)aniline (10C)

[0522] 2-Bromo-6-(1-cyclopropylvinyl)aniline

[0523] 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. 10B (7.5 g, 31.24 mmol) was dissolved in a small amount of THF and added 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 (30 mL) and then extracted with EA (20 mL × 3). The organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, concentrated, distilled under reduced pressure, mixed, and column chromatography (100% PE) was performed to obtain 10C, a pale yellow oil (6.8 g, 91% yield).

[0524] 1 H NMR (400MHz, DMSO) δ7.31(dd,1H),6.85(dd,1H),6.51(t,1H),5.22(s,2H),4.86(d,1H),4.73(s,1H),1.63(m,1H),0.69(m,4H),0.39(m,4H).

[0525] LCMS m / z(ESI)=237.02[M+l].

[0526] Step 3:

[0527] (S)-2-bromo-6-(1-cyclopropylethyl)aniline (10D)

[0528] (S)-2-bromo-6-(1-cyclopropylethyl)aniline

[0529] Compound 10C (9.0 g, 37.98 mmol) was added to a 250 mL hydrogenation reactor along with 110 mL of DCM. Then, 1.6 g (5%) of [(S)-(-)-2,2'-bis(diphenyl)-1,1'-naphthyl]ruthenium was weighed out. After the addition was complete, the reactor was sealed, the gas in the hydrogenation reactor was replaced with nitrogen, and hydrogen gas was introduced at 1.2 MPa. The reaction was then carried out overnight at room temperature. TLC (PE:EA = 10:1) was used for monitoring. After the reaction was complete, silica gel powder was added to the reaction solution, and the mixture was evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product 10D, a pale yellow oil (6.29 g, 67.3% yield).

[0530] 1 H NMR (400MHz, DMSO-d6) δ7.22(dd,1H),7.18(dd,1H),6.52(t,1H),4.91(s,2H),2.32(dd,1H),1.16(d,3H),1.03(m,1H),0.50(m,4H),0.36(m,4H).

[0531] LCMS m / z(ESI)=239.03[M+l].

[0532] Step 4:

[0533] (S)-4-(2-amino-3-(1-cyclopropylethyl)phenyl)pyridinium (10E)

[0534] (S)-4-(2-amino-3-(1-cyclopropylethyl)phenyl)picolinonitrile

[0535] Under nitrogen protection, in a 100 mL three-necked flask, 10D (500 mg, 2.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinium (727 mg, 3.14 mmol), 1,4-dioxane (30 mL), cesium carbonate (1.36 g, 4.18 mmol), and the catalyst [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (233 mg, 0.32 mmol) were added sequentially; the mixture was refluxed for 6 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. After filtration and removal of the organic solvent, the crude product was purified to give 10E, a light green solid (535 mg, yield 18.5%).

[0536] LCMS m / z = 263.14 [M+l].

[0537] Step 5:

[0538] N-((2-(2-cyanopyridin-4-yl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (10F)

[0539] N-((2-(2-cyanopyridin-4-yl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0540] Under nitrogen protection, in a 100 mL round-bottom flask, 10E (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 int-3 (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 (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 to obtain 10F, a pale yellow oil (420 mg, yield 56.3%).

[0541] Step 6

[0542] N-((2-(2-cyanopyridin-4-yl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 10-1 and 10-2)

[0543] N-((2-(2-cyanopyridin-4-yl)-6-((S)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0544] 10F (420 mg) was resolved by SFC to yield compound 10-1 (200 mg, yield 47.6%, RT = 8.738 min, 100% ee) and compound 10-2 (198 mg, yield 47.0%, RT = 9.394 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.

[0545] LC-MS m / z(ESI) = 493.14.

[0546] Compound 10-1: 1 H NMR(400MHz,DMSO-d6)δ8.71(dd,1H),8.41(s,1H),7.99(s,1H),7.66(s,1 H),7.62(d,1H),7.56(d,2H),7.38(t,1H),7.23(dd,1H),6.89(s,1H),5.06 (s,1H),2.31-2.28(m,1H),1.38(d,6H),1.19(dd,3H),1.04-1.01(m,1H),0 .50-0.47(m,1H),0.25-0.19(m,1H),0.15-0.10(m,1H),0.02-0.01(m,1H).

[0547] Compound 10-2: 1 H NMR(400MHz,DMSO-d6)δ8.73(d,1H),8.42(s,1H),7.98(s,1H),7.66(d,1H ),7.62(d,1H),7.55(d,2H),7.38(t,1H),7.23(dd,1H),6.89(s,1H),5.06 (s,1H),2.36-2.25(m,1H),1.37(d,6H),1.13(s,3H),1.04-0.99(m,1H),0 .51-0.47(m,1H),0.25-0.19(m,1H),0.17-0.13(m,1H),0.13-0.09(m,1H).

[0548] Example 11

[0549] N-((2-(2-cyanopyridin-4-yl)-6-((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 11-1 and 11-2)

[0550] N-((2-(2-cyanopyridin-4-yl)-6-((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0551]

[0552] first step:

[0553] (R)-2-bromo-6-(1-cyclopropylethyl)aniline (11A)

[0554] (R)-2-bromo-6-(1-cyclopropylethyl)aniline

[0555] 9.0 g (37.98 mmol) of 10C was added to a 250 mL hydrogenation reactor, followed by 110 mL of DCM. Then, 1.6 g (5%) of [(R)-(-)-2,2'-bis(diphenyl)-1,1'-naphthyl]ruthenium was weighed out. After the addition was complete, the reactor was sealed, the gas in the hydrogenation reactor was replaced with nitrogen, and hydrogen gas was introduced at 1.2 MPa. The reaction was then carried out overnight at room temperature. TLC (PE:EA = 10:1) was used for monitoring. After the reaction was complete, silica gel powder was added to the reaction solution, and the mixture was evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product 11A (5.29 g, 56.3% yield).

[0556] 1 H NMR (400MHz, DMSO) δ7.27-7.13(m,2H),6.52(t,1H),4.91(s,2H),2.39-2.25(m,1H),1.16(d,3H) ,1.08-0.97(m,1H),0.58-0.46(m,1H),0.38-0.32(m,1H),0.22-0.13(m,1H),0.10-0.01(m,1H).

[0557] LCMS m / z(ESI)=239.03[M+l].

[0558] Step Two:

[0559] (R)-4-(2-amino-3-(1-cyclopropylethyl)phenyl)pyridinenitrile (11B)

[0560] (R)-4-(2-amino-3-(1-cyclopropylethyl)phenyl)picolinonitrile

[0561] Under nitrogen protection, in a 100 mL three-necked flask, 11A (500 mg, 2.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinium (727 mg, 3.14 mmol), 1,4-dioxane (30 mL), cesium carbonate (1.36 g, 4.18 mmol), and catalyst [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (233 mg, 0.32 mmol) were added sequentially; the mixture was refluxed for 6 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. After filtration and removal of the organic solvent, the crude product was purified to give 11B, a light green solid (535 mg, yield 99.3%).

[0562] LC-MS m / z = 263.14 [M+l].

[0563] Step 3:

[0564] N-((2-(2-cyanopyridin-4-yl)-6-((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (11C)

[0565] N-((2-(2-cyanopyridin-4-yl)-6-((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0566] Under nitrogen protection, in a 100 mL round-bottom flask, 11B (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 int-3 (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 (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 to obtain 11C, a pale yellow oil (520 mg, yield 70.3%).

[0567] Step 4:

[0568] N-((2-(2-cyanopyridin-4-yl)-6-((R-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 11-1 and 11-2)

[0569] N-((2-(2-cyanopyridin-4-yl)-6-((R)-1-cyclopropylethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0570] 11C (520 mg) was resolved by SFC to yield compound 11-1 (241 mg, yield 46.3%, RT = 6.496 min, 100% ee) and compound 11-2 (238 mg, yield 45.8%, RT = 6.535 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.

[0571] LC-MS m / z(ESI) = 493.18.

[0572] Compound 11-1: 1 H NMR(400MHz,DMSO-d6)δ8.73(d,1H),8.42(s,1H),7.98(s,1H),7.66(d,1H),7.62(d,1H),7.55(d,2H),7.38(t,1H),7.23(dd,1H),6.91(s,1H),5. 06(s,1H),2.30(t,1H),1.37(s,6H),1.13(dd,3H),1.04-1.01(m,1H),0. 51-0.48(m,1H),0.25-0.19(m,1H),0.17-0.13(m,1H),0.12-0.08(m,1H).

[0573] Compound 11-2: 1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),8.40(s,1H),7.99(s,1H),7.66(s,1H ),7.62(d,1H),7.57(d,2H),7.38(t,1H),7.23(dd,1.5Hz,1H),6.89(s,1H) ,5.06(s,1H),2.28(t,1H),1.38(s,6H),1.19(dd,3H),1.03-0.99(m,1H),0 .50-0.46(s,1H),0.25-0.18(m,1H),0.16-0.13(m,1H),0.12-0.07(m,1H).

[0574] Example 12

[0575] (R)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide and (S)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 12-2 and 12-1)

[0576] (R)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0577] (S)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0578]

[0579]

[0580] first step:

[0581] 2-(cyclobutylmethyl)-6-cyclopropyl-4-fluoroaniline (12A)

[0582] 2-(Cyclobutylmethyl)-6-cyclopropyl-4-fluoroaniline

[0583] In a 50 mL round-bottom flask, 8D (512 mg, 2 mmol) and cesium carbonate (1.63 g, 5 mmol) suspended in dioxane (20 mL) were added sequentially. Then, under nitrogen protection, dichlorobis(triphenylphosphine)palladium (294 mg, 0.4 mmol) and cyclopropylboronic acid (258 mg, 3 mmol) were added to the system. After the addition was complete, the reaction was stirred at 100 °C for 5 h, and the reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to give 12A as a brown oil (90 mg, yield 30%).

[0584] LCMS m / z(ESI) = 220.1[M+l].

[0585] Step Two:

[0586] N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compound 12)

[0587] N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0588] Under nitrogen protection, intermediate 12A (90 mg, 0.41 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (136 μL, 0.82 mmol), and 2,2,2-trichloroethyl chloroformate (75 μL, 1.65 mmol) were added sequentially to a 100 mL round-bottom flask. After the additions were complete, the system was stirred at room temperature for 1 h. Once the reaction was complete, it was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The solution was then dissolved in tetrahydrofuran (10 mL), and intermediate int-3 (130 mg, 0.41 mmol) and sodium hydride (20 mg, 0.82 mmol) were added. The reaction was continued at room temperature for 2 h. Tetrabutylammonium fluoride (1 mL, 1 M) was then added, and the reaction was continued at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (3 mL), extracted with ethyl acetate (10 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 = 55:45) to give compound 12, a white solid (80 mg, yield 68.3%).

[0589] Step 3:

[0590] (R)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide and (S)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 12-1 and 12-2)

[0591] (R)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide and

[0592] (S)-N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0593] Compound 12 (500 mg) was resolved by SFC to give compound 12-1 (38 mg, yield 48.2%, RT = 11.624 min, 100% ee) and compound 12-2 (35 mg, yield 47.5%, RT = 16.382 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.

[0594] Compound 12-1: 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.78-7.56(m,3H),6.99(d,1H),6.71(dd,1H),6.45(dd,1H),5.09(s,1H),2. 57(d,2H),1.95(q,3H),1.86-1.72(m,2H),1.70-1.63(m,2H),1.38(d,6H),0.91-0.77(m,2H),0.62-0.50(m,2H).

[0595] LC-MS m / z(ESI) = 450.18.

[0596] Compound 12-2: 1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.91-7.53(m,3H),6.99(d,1H),6.71(dd,1H),6.45(dd,1H),5.09(s,1H),2. 61-2.52(m,2H),2.03-1.87(m,3H),1.83-1.76(m,2H),1.64(q,2H),1.38(d,6H),0.84(d,2H),0.59-0.51(m,2H).

[0597] LC-MS m / z(ESI)=450.18[M+l].

[0598] Example 13

[0599] (R)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazacyclobutane-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide and (S)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazacyclobutane-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 13-1 and 13-2)

[0600] (R)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazetidin-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide and

[0601] (S)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazetidin-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0602]

[0603] first step:

[0604] 2-(3-((tert-butyldimethylsilyl)oxy)azacyclobutane-1-yl)-6-(cyclobutylmethyl)-4-fluoroaniline (13A)

[0605] 2-(3-((Tert-butyldimethylsilyl)oxy)azetidin-1-yl)-6-(cyclobutylmethyl)-4-fluoroaniline

[0606] In a 50 mL round-bottom flask, 8D (256 mg, 1 mmol) and cesium carbonate (801 mg, 2.5 mmol) were added sequentially, suspended in dioxane (20 mL). Then, under nitrogen protection, palladium acetate (22.4 mg, 0.1 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (124 mg, 0.2 mmol) and 3-((tert-butyldimethylsilyl)oxy)azacyclobutane (187 mg, 1 mmol) were added sequentially. The reaction was carried out at 100 °C for 2 h, and TLC was used to monitor the reaction until complete. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to give 13A, a brown oil (170 mg, yield 52.0%).

[0607] LCMS m / z(ESI)=365.23[M+l].

[0608] Step Two:

[0609] N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazacyclobutane-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compound 13)

[0610] N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazetidin-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0611] Under nitrogen protection, intermediate 13A (180 mg, 0.5 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (177 μL, 1 mmol), and 2,2,2-trichloroethyl chloroformate (87 μL, 0.65 mmol) were added sequentially to a 50 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was dissolved in tetrahydrofuran (10 mL), and intermediate int-3 (156 mg, 0.5 mmol) and sodium hydride (24 mg, 1 mmol) were added, and the reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride (3 mL, 1 M) was added, and the reaction was carried out at 50 °C for 3 h. The reaction was monitored by TLC until complete. The reaction solution was quenched with water (3 mL), extracted with ethyl acetate (10 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 = 50:50) to give compound 13, a white solid (180 mg, yield 59.2%).

[0612] LC-MS m / z(ESI) = 481.18.

[0613] Step 3:

[0614] (R)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazacyclobutane-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide and (S)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazacyclobutane-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropane-2-yl)furan-2-sulfonylimide (compounds 13-1 and 13-2)

[0615] (R)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazetidin-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide and

[0616] (S)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(3-hydroxyazetidin-1-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0617] Compound 13 (180 mg) was resolved by SFC to yield compound 13-1 (85 mg, yield 48.2%, RT = 8.944 min, 100% ee) and compound 13-2 (87 mg, yield 47.5%, RT = 12.047 min, 97.42% 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.

[0618] Compound 13-1: 1 H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.67-7.64(m,1H),7.62(s,1H),6.97( d,1H),6.21(dd,1H),5.99(dd,1H),5.50(d,1H),5.09(s,1H),4.47-4.36(m, 1H),4.11-4.04(m,2H),3.59-3.51(s,2H),3.48-3.42(m,1H),2.47-2.38(m ,2H),1.99-1.88(m,2H),1.82-1.73(m,2H),1.68-1.51(m,2H),1.38(s,6H).

[0619] LC-MS m / z(ESI)=481.18[M+1].

[0620] Compound 13-2: 1 H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.65(s,1H),7.62(s,1H),6.97(s,1H),6.21(dd 1H),5.99(dd,1H),5.50(d,1H),5.09(s,1H),4.42(q,1H),4.15-4.08(m,2H),3.57-3.51(m,2H),3.48- 3.39(m,1H),2.47-2.40(m,2H),1.97-1.92(m,2H),1.79-1.69(m,2H),1.71-1.61(m,2H),1.38(s,6H).

[0621] LC-MS m / z(ESI)=481.18[M+1].

[0622] Example 14

[0623] (R)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide and (S)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide (compounds 14-1 and 14-2)

[0624] (R)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide and(S)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0625]

[0626] first step

[0627] 2-(2-Methyl-1,3-dioxolane-2-yl)thiazole (14B)

[0628] 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

[0629] Under nitrogen protection, 14A (50.0 g, 393.7 mmol) was dissolved in toluene (600 mL) in a 1 L three-necked flask. p-Toluenesulfonic acid monohydrate (7.48 g, 39.3 mmol) and ethylene glycol (50 mL) were added at room temperature, and the mixture was refluxed for 16 h. After the reaction was complete, the mixture was cooled to room temperature, washed with 200 mL of water, extracted with ethyl acetate (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give 14B, a pale yellow liquid (62 g, 92% yield).

[0630] 1H NMR (400MHz, CD3CN) δ=7.78(d,1H),7.47(d,1H),4.09-4.05(m,2H),4.01-3.97(m,2H),1.76(s,3H); LC-MS m / z(ESI)=172.0[M+1].

[0631] Step 2

[0632] 2-(2-Methyl-1,3-dioxolane-2-yl)thiazolyl-5-sulfonamide (14C)

[0633] 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide

[0634] Under nitrogen protection, 14B (10.0 g, 58.48 mmol) was dissolved in tetrahydrofuran (100 mL) in a 1 L three-necked flask. The mixture was cooled to -70 °C in a dry ice ethanol bath, and n-butyllithium (2.5 M in THF, 26 mL, 64.33 mmol) was slowly added dropwise. The mixture was kept at -70 °C for 30 min, and then DABCO·(SO2)2 (14.05 g, 58.48 mmol) was added. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 1 h. The mixture was then cooled to 0 °C, and NCS (23.43 g, 175.4 mmol) was slowly added. The mixture was reacted at room temperature for 4 h, and then cooled to below -10 °C. Ammonia was slowly and continuously introduced for 1 h. After the reaction was completed, the temperature was raised to room temperature, and 100 mL of water was added to wash the reaction solution. The mixture was extracted with DCM (100 mL × 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE:EA = 4:1) to obtain 14C, a yellow solid powder (6 g, yield 41%).

[0635] 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.94(s,2H),4.10-4.07(m,2H),3.99-3.96(m,2H),1.72(s,3H).

[0636] LC-MS m / z(ESI)=251.0[M+1].

[0637] Step 3

[0638] 2-Acetthiazole-5-sulfonamide (14D)

[0639] 2-Acetylthiazole-5-sulfonamide

[0640] Under nitrogen protection, 14C (6 g, 24.00 mmol) was dissolved in tetrahydrofuran (50 mL) in a 250 mL three-necked flask. Concentrated hydrochloric acid (2 mL) was added with stirring, and the mixture was refluxed in an oil bath for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction was quenched by slowly adding sodium bicarbonate aqueous solution (60 mL). The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give 1d, a pale yellow solid powder (4.4 g, 90% yield).

[0641] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.17(s,2H),2.65(s,3H).

[0642] LC-MS m / z(ESI)=207.0[M+1].

[0643] Step 4

[0644] 2-(2-hydroxypropyl-2-yl)thiazol-5-sulfonamide (14E)

[0645] 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

[0646] Under nitrogen protection, 14D (4.4 g, 21.35 mmol) was dissolved in tetrahydrofuran (50 mL) in a 100 mL three-necked flask. The mixture was cooled to -15 °C in an ice-salt bath, and methyl magnesium bromide (21 mL, 3 M, 64.08 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted overnight. When the reaction was complete, saturated ammonium chloride aqueous solution (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL × 3), and the combined organic phases were 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 = 2:1-1:2) to obtain 14E as a white solid powder (4 g, yield 85%).

[0647] 1 H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.83(s,2H),6.30(s,1H),1.50(s,6H).

[0648] LC-MS m / z(ESI)=223.0[M+1].

[0649] Step 5

[0650] N-(tert-butyldimethylsilyl)-2-(2-hydroxypropyl-2-yl)thiazolyl-5-sulfonamide (14F)

[0651] N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

[0652] 14E (3.1 g, 13.95 mmol) was dissolved in 40 mL of dry THF at room temperature. The solution was cooled to -10 °C in an ice-salt bath, and sodium hydride (1.12 g, 27.89 mmol) was slowly added to maintain the temperature below -10 °C. Then, tert-butyldimethylchlorosilane (25.3 g, 16.74 mmol) was added, and the reaction was carried out at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction solution was quenched in 20 mL of ice water and extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was slurried with ethyl acetate:petroleum ether (1:10–1:5) to give 14F, a white solid (4.3 g, yield 91.4%).

[0653] LCMS m / z = 337.1 [M+l].

[0654] Step 6

[0655] N-(tert-butyldimethylsilyl)-2-(2-hydroxypropyl-2-yl)thiazolyl-5-sulfonylimide (14G)

[0656] N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0657] In a 250 mL three-necked flask under nitrogen protection, triphenylphosphine (4.7 g, 17.62 mmol) and hexachloroethane (4.8 g, 20.46 mmol) were dissolved in chloroform and the mixture was refluxed for 2 h. After 2 h, the mixture was cooled to -10 °C in an ice bath, and diisopropylethylamine (3.0 g, 23.02 mmol) was slowly added dropwise. The mixture was allowed to react at this temperature for 30 min after the addition was complete. After 30 min, the mixture was cooled to -10 °C, and a chloroform (100 mL) solution of 14F (4.3 g, 12.79 mmol) was added dropwise. The mixture was allowed to react at -10 °C for another 30 min, and ammonia was then introduced into the reaction system for 30 min. The mixture was allowed to return to room temperature for 2 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 14G, a pale yellow solid (1.5 g, yield 34.9%).

[0658] LCMS m / z = 336.1 [M+l].

[0659] Step 7

[0660] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimide (compound 14)

[0661] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0662] Under nitrogen protection, intermediate int-4 (300 mg, 1.61 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (312 mg, 2.42 mmol), and 2,2,2-trichloroethyl chloroformate (410 mg, 1.93 mmol) were added sequentially to a 50 mL round-bottom flask, and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The extract was then dissolved in tetrahydrofuran (20 mL), and 14 G (540 mg, 1.61 mmol) and sodium hydride (129 mg, 3.22 mmol) were added, and the reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride tetrahydrofuran solution (3.2 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), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by column chromatography (PE:EA = 2:1) to give compound 14 as a white solid (356 mg, yield 50.9%).

[0663] Step 8

[0664] (R)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide and (S)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide (compounds 14-1 and 14-2)

[0665] (R)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide and(S)-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0666] Compound 14 was resolved by SFC to obtain compound 14-1 (120 mg, ee%: 94.01%, chiral HPLC (OZ); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 13.709 min) and compound 14-2 (100 mg, ee%: 96.44%, chiral HPLC (OZ); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 9.954 min).

[0667] Compound 14-1: 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.81(s,1H),7.58(s,1H),7.01(d,1H),6.63(d,1H),2.88(dd,2H),2.81(t,2H),2.29-2.1 9(m,1H),1.35(s,6H),1.02(d,3H),0.91-0.80(m,1H),0.39-0.28(m,1H),0.20-0.09(m,1H),0.00(t,1H),-0.05-0.13(m,1H).

[0668] Compound 14-2: 1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.79(s,1H),7.12(d,1H),6.76(d,1H),6.07(s,1H),3.05-2.81(m,4H),2.41-2.27(m,1 H),1.47(s,6H),1.11(d,3H),0.99-0.82(m,1H),0.51-0.34(m,1H),0.33-0.18(m,1H),0.18-0.07(m,1H),0.06-0.07(m,1H).

[0669] Example 15

[0670] (R)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide and (S)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide (compounds 15-1 and 15-2)

[0671] (R)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide and(S)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0672]

[0673] first step

[0674] (R)-5-bromo-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine(15A)

[0675] (R)-5-bromo-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0676] Under nitrogen protection, intermediate int-4 (300 mg, 1.60 mmol) and dichloromethane (10 mL) were added sequentially to a 100 mL round-bottom flask. Pyridinium tribromide (513 mg, 1.60 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature for 1 h. Upon completion of the reaction, an aqueous sodium sulfite solution was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (PE:EA = 50:1–20:1) to give 15A, a pale yellow oil (298 mg, yield 69.9%).

[0677] LCMS m / z = 266.0 [M+l].

[0678] Step Two:

[0679] N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimide (compound 15)

[0680] N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0681] Under nitrogen protection, in a 50 mL round-bottom flask, 15A (298 mg, 1.12 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (218 mg, 1.68 mmol), and 2,2,2-trichloroethyl chloroformate (287 mg, 1.35 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 (20 mL), and 14G (379 mg, 1.12 mmol) and sodium hydride (91 mg, 2.25 mmol) were added. The reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride tetrahydrofuran solution (2.2 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), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain 15, a white solid (345 mg, yield 62.7%).

[0682] Step 3

[0683] (R)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide and (S)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide (compounds 15-1 and 15-2)

[0684] (R)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide and(S)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0685] Compound 15 was resolved by SFC to obtain compound 15-1 (105 mg, ee%: 99.99%, chiral HPLC (OZ); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 10.733 min) and compound 15-2 (117 mg, ee%: 99.99%, chiral HPLC (OZ); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 13.613 min).

[0686] Compound 15-1: 1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.05(s,1H),7.86(s,2H),7.27(s,1H),6.27(s,1H),2.94(s,4H),2.40-2.27(m,1H), 1.50(s,6H),1.12(d,3H),0.99-0.86(m,1H),0.49-0.40(m,1H),0.29-0.18(m,1H),0.14-0.06(m,1H),0.04--0.09(m,1H).

[0687] Compound 15-2: 1 H NMR(400MHz,DMSO)δ8.39(s,1H),8.04(s,1H),7.8(s,2H),7.27(s,1H),6.28(s,1H),3.04-2.84(m,4H),2.39-2.25(m,2H), 1.50(s,6H),1.09(d,3H),1.01-0.87(m,2H),0.53-0.42(m,1H),0.31-0.22(m,1H),0.17-0.08(m,1H),0.06--0.04(m,1H).

[0688] Example 16

[0689] (R)-N-((3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amides and (S)-N-((3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amides (compounds 16-1 and 16-2)

[0690] (R)-N-((3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide and

[0691] (S)-N-((3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0692]

[0693] It was prepared using intermediate int-5,14G as the main raw material, following the synthesis method described in Example 14.

[0694] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.78(s,1H),7.56(s,1H),7.02(d,1H),6.64(d,1H),2.89(dd,2H),2.82(t,2H),2.29-2.1 9(m,1H),1.34(s,6H),1.01(d,3H),0.90-0.79(m,1H),0.40-0.29(m,1H),0.20-0.09(m,1H),0.00(t,1H),-0.04-0.11(m,1H).

[0695] LCMS m / z = 435.1 [M+1].

[0696] Example 17

[0697] N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-2-(2-hydroxypropyl-2-yl)thiazolyl-5-sulfonylimide (compound 17)

[0698] N-((2-(cyclobutylmethyl)-6-cyclopropyl-4-fluorophenyl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0699]

[0700] It was prepared using 12A and 14G as the main raw materials, following the synthesis method described in Example 14.

[0701] LCMS m / z = 467.2 [M+l].

[0702] Example 18

[0703] (R)-N-((5-bromo-3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide and (S)-N-((5-bromo-3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide (compounds 18-1 and 18-2)

[0704] (R)-N-((5-bromo-3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide and(S)-N-((5-bromo-3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0705]

[0706] first step

[0707] (S)-5-bromo-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine(18A)

[0708] (S)-5-bromo-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0709] Under nitrogen protection, intermediate int-5 (300 mg, 1.60 mmol) and dichloromethane (10 mL) were added sequentially to a 100 mL round-bottom flask. Pyridinium tribromide (513 mg, 1.60 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature for 1 h. Upon completion of the reaction, an aqueous sodium sulfite solution was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (PE:EA = 50:1–20:1) to give 18A, a pale yellow oil (313 mg, yield 73.3%).

[0710] LCMS m / z = 266.0 [M+l].

[0711] Step Two:

[0712] N-((5-bromo-3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazolyl-5-sulfonylimide (compound 18)

[0713] N-((5-bromo-3-((S)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0714] Under nitrogen protection, in a 50 mL round-bottom flask, 18A (300 mg, 1.13 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (218 mg, 1.69 mmol), and 2,2,2-trichloroethyl chloroformate (288 mg, 1.36 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 (20 mL), and 14G (381 mg, 1.13 mmol) and sodium hydride (92 mg, 2.26 mmol) were added. The reaction was carried out at room temperature for 2 h. Tetrabutylammonium fluoride tetrahydrofuran solution (2.3 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), and the organic phase was dried over anhydrous sodium sulfate and filtered to remove the organic solvent. The crude product was purified by column chromatography (PE:EA = 2:1) to give compound 18 as a white solid (315 mg, yield 40.8%).

[0715] LCMS m / z = 513.1 [M+l].

[0716] Step 3

[0717] (R)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide and (S)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropane-2-yl)thiazole-5-sulfonylimide amide (compounds 18-1 and 18-2)

[0718] (R)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide and(S)-N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

[0719] Racemic compound 18 was resolved by SFC to obtain compound 18-1 (116 mg, ee%: 99.99%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 5.423 min) and compound 18-2 (108 mg, ee%: 99.99%, chiral HPLC (OX-3); mobile phase: methanol; column temperature: 35°C; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 215 nm @ 4.8 nm; diode array detector start wavelength: 200 nm; diode array detector stop wavelength: 400 nm): RT = 8.213 min).

[0720] Compound 18-1: 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.03(s,1H),7.86(s,2H),7.26(s,1H),6.27(s,1H),2.93(s,4H),2.40-2.27(m,1H), 1.50(s,6H),1.12(d,3H),0.99-0.86(m,1H),0.49-0.40(m,1H),0.29-0.18(m,1H),0.14-0.06(m,1H),0.04--0.09(m,1H).

[0721] Compound 18-2: 1H NMR(400MHz,DMSO)δ8.39(s,1H),8.03(s,1H),7.81(s,2H),7.25(s,1H),6.27(s,1H),3.03-2.83(m,4H),2.38-2.23(m,2H) ,1.50(s,6H),1.09(d,3H),1.02-0.88(m,2H),0.54-0.42(m,1H),0.31-0.23(m,1H),0.18-0.07(m,1H),0.05-0.03(m,1H).

[0722] Biological test cases

[0723] 1. THP-1 cell culture

[0724] 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.

[0725] 2. Detection of pyroptosis in THP-1 cells

[0726] 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 for a total of 10 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. Use the Inflammasome Assay Kit. Refer to the kit instructions for detailed steps. Calculate the IC50 using GraphPad Prism 7.0 software. 50 The results are shown in the table below.

[0727] compound <![CDATA[IC 50 ]]> 1 B 3-1 B 5-2 B 6-2 B

[0728] 14-1 A 15-1 A 15-2 B

[0729] Note: A≤0.1uM, 0.1uM<B≤0.5uM, 0.5uM<C≤1uM, D>1uM.

[0730] The results showed that the compound of this application can effectively inhibit pyroptosis in the human mononuclear cell line THP-1.

[0731] 3. IL-1β Release Analysis in Human PBMCs

[0732] 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 collected and 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 mixture was incubated for 3 hours at a density of 1×10⁻⁶. 5 Cells 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 .

[0733] The results showed that the compound of this application can significantly inhibit the release of human PBMC IL-1β.

[0734] 4. Analysis of TNFα release from human PBMCs

[0735] 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 collected and placed in petri dishes and incubated overnight at 37°C in a 5% CO2 incubator. The next day, cells were cultured at a rate of 1×10⁻⁶. 5Cells 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 .

[0736] The results showed that the compound in this application did not downregulate the expression level of TNFα induced by LPS in PBMCs.

[0737] 5. Detection of compound distribution in rat brain tissue

[0738] Accurately weigh an appropriate amount of drug and prepare a 1 mg / mL solution using 5% DMSO and 30% HP-β-CD. Healthy adult male SD rats were fasted overnight and then administered the test drug (compound 15-1 and control example 1) (10 mg / kg) or a blank solution by gavage. Blood was collected from the orbital venous plexus at different time points after administration (EDTA-K2 anticoagulation). The animals were then sacrificed, and brain tissue samples were collected. Blood samples were centrifuged at 2000g for 10 min at 4°C to obtain plasma. All samples were stored at -80°C for analysis. The drug concentration of the compound in brain tissue was determined using LC-MS / MS. Brain tissue samples were homogenized before analysis. The main pharmacokinetic parameters were calculated using a Winnolin 8.2 non-compartmental model. The brain tissue drug concentration results are shown below. Figure 1 As shown.

[0739] Among them, Comparative Example 1 was 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]urea, which was prepared according to the method of Compound 1 in Synthetic Communications (2003), 33(12), 2029-2043.

[0740] Figure 1 The results showed that the compounds of this application, represented by compound 15-1, had better central nervous system permeability than control example 1.

[0741] 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. Compounds of formula (I) or all their stereoisomers and tautomers, (I) in Q is or ; for , or ; W can be O or NH.

2. A compound, wherein the compound has the following structure: , , , or .

3. A compound, wherein the compound has the following structure: , or .

4. A pharmaceutical composition comprising the compound of claim 1 or all its stereoisomers, tautomers, and one or more pharmaceutically acceptable carriers and / or excipients.

5. A pharmaceutical composition comprising the compound of claim 2 or 3 and one or more pharmaceutically acceptable carriers and / or excipients.

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