Amide derivatives, their preparation methods, and their applications in medicine

Abstract

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

Description

Technical Field

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

[0002] NOD-like receptors (NLRs), which are nucleotide-binding oligomerization domains (NOD), are a class of cytoplasmic pattern recognition receptors (PRRs) in mammalian cells, playing a crucial role in innate immune responses. NLRs are a group of cytoplasmic proteins with signal transduction functions, widely involved in the body's inflammatory responses. The NLR family includes NOD, NALP (NLRP), CII TA (NLRA), and IPAF (NLRC), with the NLRP and NLRC subfamilies being the two main types of NOD-like receptors (NLRs). NLRP can be further divided into inflammasome members such as NLRP1, NLRP3, NLRP6, NLRP7, and NLRP12. The NLRP3 inflammasome is a multi-protein complex composed of the NLRP3 protein itself, caspase-1, and apoptosis-associated speck-like protein containing CARD (ASC). It can recognize various pathogenic microorganisms and stress-related endogenous signaling molecules. Classical NLRP3 inflammasome activation is triggered by two signals: the first activates the TLR4 (Toll-like receptor 4) signaling pathway, promoting nuclear transcription factor κB translocation into the nucleus and inducing the production of precursors such as IL-1β and IL-18. The second signal promotes the formation of the NLRP3 / ASC / pro-caspase-1 complex. When activated, it polymerizes with apoptosis-associated specklike protein (ASC) containing caspase activation and recruitment domains. ASC then interacts with cysteine ​​proteasecaspase-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 the activation and release of Gasdermin D, thereby mediating cell death (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 treatments for NLRP3-related diseases include the recombinant IL-1 receptor antagonist anakinra, the IL-1β neutralizing antibody canakinu mab, and the soluble IL-1 receptor trap rilonacept, all of which are biologics. In recent years, some small-molecule NLRP3 inhibitors have been reported, such as glibenclamide, parthenolide, and 3,4-methylenedioxy-β-nitrostyrene. However, these drugs or small molecules still suffer from low specificity or poor activity. Therefore, it is necessary to develop a new generation of small-molecule NLRP3 inhibitors with high specificity and activity for the treatment of autoimmune diseases caused by NLRP3 mutations. Summary of the Invention

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

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

[0007]

[0008] in:

[0009] W is selected from =O or -N(R8). m ;

[0010] R6 is selected from

[0011] X5 and X6 are each independently selected from CR9 and N;

[0012] X7 and X8 are each independently selected from -(C(R9)2) q -、-O-、-NR9-;

[0013] R9 is independently selected from H, halogen, OH, cyano, hydroxyl, -NR a1 R a2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy;

[0014] q is selected from 0, 1, 2, or 3;

[0015] R7 is selected from

[0016] L is selected from -(CR) L1 R L2 )p-;R L1 R L2 Each is independently selected from H and C 1-6 Alkyl or 3 to 10-membered carbocyclic group, wherein the C 1-6 Alkyl groups, 3 to 10-membered carbon cyclo groups optionally further surrounded by 1 to 4 groups selected from halogens, C 1-6 Alkyl, C 1-6 The substituted group is replaced by an alkoxy group, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O, or S;

[0017] A is a 3- to 10-membered cycloalkyl group;

[0018] X1 is selected from CR2;

[0019] X2 is selected from CR3;

[0020] X3 is selected from CR4;

[0021] X4 is selected from CR5;

[0022] R2, R3, R4, and R5 are each independently selected from deuterium, H, halogens, CN, NH2, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6alkynyl group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -O(C=O)-3 to 10-membered carbon cycloyl, -O(C=O)-3 to 10-membered heterocyclic, -(C=O)O-3 to 10-membered carbon cycloyl, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 4- to 10-membered heterocyclic, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2 or (C=O)NR a1 R a2 The heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S, wherein the alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, Cl, Br, I, CN, NR. a1 R a2 =O,C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -(C=O)O-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered heterocyclic, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, -NHCOC 1-6 Alkyl groups, -NH(C=O)-3 to 10-membered carbocyclic groups, -NH(C=O)-3 to 10-membered heterocyclic groups, or -(C=O)NR a1 R a2 The substituents are replaced;

[0023] Alternatively, R2 and R3 can form a 4- to 8-membered ring, the 4- to 8-membered ring containing 0 to 4 heteroatoms selected from N, O, or S, the 4- to 8-membered ring optionally further surrounded by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, -NR. a1 R a2 =O,C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)OC 1-6 Substituents of alkyl, 3- to 10-membered carbocyclic or 5- to 10-membered heterocyclic groups;

[0024] R1 and R8 are each independently selected from H, halogen, OH, cyano, hydroxyl, and -NR. a1 R a2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy;

[0025] R a1 R a2 Each is independently selected from H, cyano, hydroxy, C1-6 alkyl, or C1-6 alkoxy;

[0026] m is selected from 1 or 2;

[0027] n is selected from 0, 1, 2, or 3.

[0028] P is selected from 1, 2, or 3.

[0029] In one or more embodiments of this application, the compound or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals, wherein:

[0030] R6 is selected from

[0031] X8 is selected from -(C(R9)2) q -、-O-、-NR9-;

[0032] R9 is independently selected from H, halogen, OH, cyano, hydroxyl, -NR a1 R a2 C 1-6 alkyl;

[0033] q can be selected from 0, 1, 2 or 3.

[0034] In one or more embodiments of this application, the compound or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals are selected from compounds represented by general formula (II):

[0035]

[0036] in:

[0037] L is selected from CR L1 R L2 ;

[0038] R L1 R L2Each is independently selected from H, C1-6 alkyl or 3 to 10-membered carbocyclic group, wherein the C1-6 alkyl is optionally further substituted by 1 to 4 substituents selected from F, Cl, Br, I, C1-6 alkyl, C1-6 alkoxy, 3 to 10-membered carbocyclic group or 3 to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O or S;

[0039] A is a 3- to 10-membered cycloalkyl group;

[0040] R1 is selected from H, F, Cl, Br, I, OH, -NR a1 R a2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy;

[0041] X1 is selected from CR2;

[0042] X2 is selected from CR3;

[0043] X3 is selected from CR4;

[0044] X4 is selected from CR5;

[0045] R2, R3, R4, and R5 are each independently selected from deuterium, H, F, Cl, Br, I, CN, NH2, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -O(C=O)-3 to 10-membered carbon cycloyl, -O(C=O)-3 to 10-membered heterocyclic, -(C=O)O-3 to 10-membered carbon cycloyl, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 4- to 10-membered heterocyclic, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2 or (C=O)NR a1 R a2 The heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S, wherein the alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, Cl, Br, I, CN, NR. a1 R a2 =O,C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C1-6 Alkoxy group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -(C=O)O-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered heterocyclic, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, -NHCOC 1-6 Alkyl groups, -NH(C=O)-3 to 10-membered carbocyclic groups, -NH(C=O)-3 to 10-membered heterocyclic groups, or -(C=O)NR a1 R a2 The substituents are replaced;

[0046] Alternatively, R2 and R3 can form a 4- to 8-membered ring, the 4- to 8-membered ring containing 0 to 4 heteroatoms selected from N, O, or S, the 4- to 8-membered ring optionally further surrounded by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, -NR. a1 R a2 =O,C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)OC 1-6 Substituents of alkyl, 3- to 10-membered carbocyclic or 5- to 10-membered heterocyclic groups;

[0047] R a Selected from H, cyano, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy;

[0048] n can be selected from 0, 1, 2, or 3.

[0049] In one or more embodiments of this application, the compound or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals, wherein:

[0050] R7 is selected from

[0051] L is selected from -(CR) L1 R L2 )p-;R L1 R L2 Each is independently selected from H and C 1-6 Alkyl or 3- to 10-membered cycloalkyl, wherein the C 1-6 Alkyl groups, 3 to 10-membered cycloalkyl groups optionally further comprising 1 to 4 elements selected from halogens, C 1-6 Alkyl, C1-6 The substituted group is replaced by an alkoxy group, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O, or S;

[0052] R2, R3, R4, and R5 are each independently selected from deuterium, H, halogens, CN, NH2, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl optionally further composed of 1 to 4 elements selected from OH, halogen, CN, NR a1 R a2 C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Substituents include alkoxy groups, 3- to 10-membered cycloalkyl groups, and 4- to 10-membered heterocycloalkyl groups;

[0053] r is selected from 0, 1, 2, 3, and 4;

[0054] A, R a1 R a2 The definitions of and p are the same as those in general formula (I).

[0055] In one or more embodiments of this application, the compound or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals, wherein:

[0056] R7 is selected from

[0057] L is selected from -(CR) L1 R L2 )p-;R L1 R L2 Each is independently selected from H and C 1-6 Alkyl or 3- to 10-membered cycloalkyl;

[0058] R2, R3, R4, and R5 are each independently selected from deuterium, H, halogens, CN, NH2, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, said C 1-6 Alkyl, C 1-6 The alkoxy group and the 3- to 6-membered cycloalkyl group are optionally further surrounded by 1 to 4 groups selected from OH, halogen, CN, C. 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Substituents include alkoxy groups, 3- to 6-membered cycloalkyl groups, and 4- to 6-membered heterocycloalkyl groups;

[0059] A, R a1 R a2 The definitions of , p, and r are the same as those in general formula (I).

[0060] In one or more embodiments of this application, the compound or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals, wherein:

[0061] R7 is selected from

[0062] L is selected from -CR L1 R L2 -;R L1 R L2 Each is independently selected from H or C 1-6 alkyl;

[0063] A is a 3- to 6-membered cycloalkyl group;

[0064] R2, R3, R4, and R5 are each independently selected from deuterium, H, halogens, CN, NH2, OH, and C. 1-6 Alkyl, 3- to 6-membered cycloalkyl, said C 1-6 Alkyl groups, 3 to 6-membered cycloalkyl groups optionally further surrounded by 1 to 4 elements selected from OH, halogen, CN, C 1-6 Substituted with alkyl groups or 3- to 6-membered cycloalkyl groups;

[0065] r can be selected from 0, 1, 2, or 3.

[0066] In one or more embodiments of this application, the compound, or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from one of the following structures: or

[0067] One or more embodiments of this application provide an intermediate for preparing the above-described compound, the intermediate being selected from one of the following structures:

[0068]

[0069] One or more embodiments of this application provide pharmaceutical compositions comprising:

[0070] The above-mentioned compounds, or their stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts, or cocrystals;

[0071] One or more pharmaceutically acceptable carriers and / or excipients.

[0072] One or more embodiments of this application provide the use of the above-described pharmaceutical composition or the above-described compound or its stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or cocrystals in the preparation of NLRP3 inhibitors or in the preparation of medicaments for treating NLRP3-related diseases.

[0073] In one or more embodiments of this application, the diseases treated by the NLRP3 inhibitor or NLRP3-related diseases include: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

[0074] In one or more embodiments of this application, the diseases 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, or chronic kidney disease. Amide derivatives, their preparation methods, and their pharmaceutical applications are also included.

[0075] One or more embodiments of this application provide pharmaceutical compositions comprising a compound of general formula (I) or the specific structure described above or its stereoisomers, a solvate, a metabolite, a deuterated product, a pharmaceutically acceptable salt, a cocrystal or prodrug, and one or more pharmaceutically acceptable carriers and / or excipients.

[0076] One or more embodiments of this application provide the use of the pharmaceutical composition of this application, a compound of general formula (I) or the specific structure described above or its stereoisomers, solvates, metabolites, deuterated products, pharmaceutically acceptable salts, cocrystals or prodrugs in the preparation of NLRP3 inhibitors.

[0077] In one or more embodiments of this application, the diseases treated by the NLRP3 inhibitor are selected from: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

[0078] In one or more embodiments of this application, the diseases treated by the NLRP3 inhibitor are selected from: cryptothermal protein-associated cycle syndrome (CAPS), Muker-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, and chronic kidney disease.

[0079] One or more embodiments of this application provide a method for inhibiting NLRP3, which includes contacting a compound of general formula (I) of this application or the specific structure described above or its stereoisomers, solvates, metabolites, deuterated products, pharmaceutically acceptable salts, eutectics, or prodrugs or compositions of this application with a target in need.

[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 involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 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 various branched isomers thereof; 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 embodiments include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyne-1-yl, pentyne-2-yl, hexyn-1-yl, 1-heptyne-1-yl, heptyne-3-yl, heptyne-4-yl, octyne-3-yl, nonyne-3-yl, decanyne-4-yl, undecanyne-3-yl, and dodecanyne-4-yl. The ethynyl group may optionally be further substituted with one or more substituents.

[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 groups. 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, thiophenyl, pyranyl, pyrrolidinyl, 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, furfural, etc. nylonyl, thiophenyl, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylalkyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentanecycloyl, tetrahydrofuranyl, tetrahydrothiophenyl, 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, whose ring can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic system, preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cyclohepttrienyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[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 epoxyethyl, aziridine, oxacyclobutyl, aziridine, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine, 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 C1-6 alkyl; wherein, R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 The alkyl group may optionally be further 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] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0094] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0095] "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.

[0096] "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.

[0097] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0098] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0099] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0100] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0101] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[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 determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18100×4.6mm, 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 of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0108] 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] Example

[0125] intermediate Int-1

[0126]

[0127] first step:

[0128] 2-(2,6-Dibromophenyl)ethane-1-ol (Int-1B)

[0129] 2-(2,6-dibromophenyl)ethan-1-ol

[0130] In a 1L three-necked flask, Int-1A (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 under ice-water bath cooling, and the reaction was quenched with dilute hydrochloric acid (20 mL, 2 N). Part of the reaction solution was concentrated under reduced pressure, and then extracted with ethyl acetate (100 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give Int-1B, a white solid (50.0 g, yield 88%).

[0131] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.94 (t, 1H), 3.88 (t, 2H), 3.33 (t, 2H).

[0132] Step Two:

[0133] 1,3-Dibromo-2-(2-bromoethyl)benzene (Int-1C)

[0134] 1,3-dibromo-2-(2-bromoethyl)benzene

[0135] In a 1L round-bottom flask, Int-1B (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-1C, a white solid (60.0 g, yield 98%).

[0136] 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, 2H), 6.97 (t, 1H), 3.63-3.43 (m, 4H).

[0137] Step 3:

[0138] 2-Bromobicyclo[4.2.0]oct-1(6),2,4-triene(Int-1D)

[0139] 2-bromobicyclo[4.2.0]octa-1(6),2,4-triene

[0140] In a 250 mL three-necked flask, Int-1C (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-1D, a pale yellow oil (2.5 g, 90% yield).

[0141] Step 4:

[0142] tert-Butylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamate (Int-1E)

[0143] tert-butyl bicyclo[4.2.0]octa-1(6),2,4-trien-2-ylcarbamate

[0144] In a 250 mL round-bottom flask, Int-1D (2.3 g, 0.013 mol), dioxane (50 mL), tert-butyl carbamate (2.2 g, 0.019 mol), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (476 mg, 1 mmol), and cesium carbonate (8.0 g, 0.025 mol) were added sequentially. Palladium acetate (132 mg, 6 mmol) was added under nitrogen protection. The mixture was 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-1E (2.3 g, brown oil, yield 83%).

[0145] 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).

[0146] Step 5:

[0147] Bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (Int-1F)

[0148] bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0149] In a 100 mL round-bottom flask, Int-1E (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-1F, a brown oily substance (1.0 g, yield 80%).

[0150] 1 H NMR (400MHz, CDCl3) δ = 7.02 (dd, 1H), 6.51 (dd, 2H), 3.11 (dd, 2H), 3.04 (dd, 2H).

[0151] Step 6:

[0152] (2-Aminobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(cyclopropyl)methyl ketone (Int-1G)

[0153] (2-aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclopropyl)methanone

[0154] In a 25 mL three-necked flask, Int-1F (100 mg, 0.84 mmol) and dichloroethane (5 mL) were added sequentially. After dissolving, the flask was placed in an ice-water bath. Under nitrogen protection, boron trichloride toluene solution (900 μL, 1 M) was slowly added dropwise. After 10 min, anhydrous aluminum trichloride (123 mg, 0.9 mmol) was added, followed by slow dropwise addition of cyclobutyronitrile (74 μL, 1 mmol). After the addition was complete, the mixture was reacted at 90 °C for 3 h. After cooling to room temperature, dilute hydrochloric acid solution (1 mL, 2 N) and water (5 mL) were added, and the mixture was refluxed for 30 min. The organic phase was separated, washed with saturated sodium bicarbonate (10 mL) until weakly acidic, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain Int-1G, a brown oily substance (60 mg, yield 38%).

[0155] 1 H NMR (400MHz, CDCl3) δ=7.91(d,1H),6.51(d,1H),3.12-3.05(m,2H),3.04-2.95(m,2H),2.67-2.54(m,1H),1.19-1.10(m,2H),1.00-0.87(m,2H).

[0156] Step 7:

[0157] 3-(1-Cyclopropylvinyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (Int-1H)

[0158] 3-(1-cyclopropylvinyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0159] 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-1G (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 give Int-1H (1.2 g, brown oil, yield 85%).

[0160] 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).

[0161] Step 8:

[0162] (R)-3-(1-Cyclopropylethyl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (intermediate Int-1)

[0163] (R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0164] In a 500 mL autoclave, Int-1H (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 three times with hydrogen gas. 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-1, a pale yellow oil (470 mg, yield 94%).

[0165] 1H 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).

[0166] intermediate Int-2

[0167]

[0168] first step:

[0169] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl) ketone (Int-2B)

[0170] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanone

[0171] Under nitrogen protection, Int-2A (5.0 g, 37.54 mmol) was dissolved in 1,2-dichloroethane (50 mL) in a 500 mL three-necked flask. The mixture was cooled to 0 °C in an ice-salt bath, and a dichloromethane solution of boron trichloride (37.5 mL, 1 M, 37.54 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 10 min. Then, aluminum trichloride (5.5 g, 41.3 mmol) and cyclobutyronitrile (4.55 g, 56.3 mmol) were added. The reaction system was heated to 80 °C and reacted for 4 h. After cooling to room temperature, 40 mL of 2 M HCl was added in an ice bath. After the addition was complete, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (75 mL × 3). The organic phase was washed with 40 mL of 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to give Int-2B, a white solid (2.6 g, yield 32.2%).

[0172] 1 H NMR(400MHz, CDCl3)δ=7.45(d,1H),6.56(d,1H),2.91(t,2H),2.70(t,2H),2.44-2.3 (m,3H),2.25(m,2H),2.14-2.08(m,2H),2.07-2.00(m,1H),1.90-1.81(m,1H); LC-MS m / z(ESI)=216.1[M+1].

[0173] Step Two:

[0174] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol (Int-2C)

[0175] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol

[0176] In a 50 mL round-bottom flask under nitrogen protection, ethanol (20 mL) and Int-2B (2.0 g, 9.30 mmol) were added. The mixture was cooled to 0 °C in an ice bath, and sodium borohydride (703 mg, 18.60 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. After the reaction was completed, the system was cooled to 0 °C, and the reaction was quenched dropwise with 20 mL of water. The mixture was extracted with DCM (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain Int-2C, a colorless oil (1.8 g, yield 89%).

[0177] LCMS m / z(ESI)=200.1[M-17].

[0178] Step 3:

[0179] 5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine (Int-2)

[0180] 5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine

[0181] Under nitrogen protection, Int-2C (1.3 g, 5.98 mmol) and triethylsilane (2.1 g, 17.94 mmol) were dissolved in DCM (20 mL), cooled to 0 °C in an ice bath, and trifluoroacetic acid (3.5 g, 29.90 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate water, extracted with DCM (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to give Int-2, a colorless oil (1.0 g, yield 83.1%).

[0182] 1H NMR(400MHz, CDCl3)δ=6.83(d,1H),6.66(d,1H),2.89(t,2H),2.74(t,2H),2.66-2.6 2(m,1H),2.59(d,2H),2.13-2.07(m,4H),1.88-1.83(m,2H),1.77-1.70(m,2H); LC-MS m / z(ESI)=201.1[M+1].

[0183] intermediate Int-3

[0184]

[0185] first step:

[0186] (4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methyl ketone (Int-3A)

[0187] (4-amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone

[0188] Under nitrogen protection, Int-2A (20.0 g, 150.16 mmol) was dissolved in 1,2-dichloroethane (200 mL) in a 500 mL three-necked flask. The mixture was cooled to 0 °C in an ice-salt bath, and a dichloromethane solution of boron trichloride (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, 165.2 mmol) and cyclopropyl nitrile (15.1 g, 225.24 mmol) were added. The reaction system was heated to 80 °C and reacted for 4 h. After cooling to room temperature, 160 mL (2 M HCl) was added in an ice bath. After the addition was complete, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (200 mL × 3). The organic phase was washed with 160 mL of 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to give Int-3A, a white solid (17.1 g, yield 57.2%).

[0189] 1 H NMR (400MHz, DMSO-d6) δ = 7.87 (s, 1H), 6.90 (br, 2H), 6.54 (s, 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); LC-MS m / z(ESI)=202.1[M+1].

[0190] Step Two:

[0191] 5-(1-Cyclopropylvinyl)-2,3-Dihydro-1H-indene-4-amine (Int-3B)

[0192] 5-(1-cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine

[0193] Under nitrogen protection, methyltriphenylphosphine bromide (24.8 g, 69.6 mmol) was dissolved in THF (300 mL) in a 500 mL three-necked flask. 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 Int-3A (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 Int-3B, a pale yellow oil (6.4 g, yield 92.3%).

[0194] 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(d,2H),2.02-1.96(m,2H),1.62-1.57(m,1H),0.69-0.64(m,2H),0.40-0.36(m,2H); LC-MS m / z(ESI)=200.1[M+1].

[0195] Step 3:

[0196] (S)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-Indene-4-amine (Int-3)

[0197] (S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0198] The intermediate Int-3 was prepared according to patent WO2016119758. In a 500 mL autoclave, Int-3B (7.3 g, 36.7 mmol) and dichloromethane (80 mL) were added, followed by the catalyst [(S)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl]ruthenium diacetate (1.54 g, 1.83 mmol). After the addition was complete, the autoclave was tightly sealed, purged with hydrogen three times, and then filled with hydrogen. The pressure gauge on the autoclave showed a pressure of 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-3, a pale yellow oil (7.1 g, yield 96.3%, ee%: 98.18%). Chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35°C; mobile phase (%): 15; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: ...). 215nm@4.8nm (Diode array detector start wavelength: 200nm; Diode array detector end wavelength: 400nm): RT = 2.802min).

[0199] 1 H NMR(400MHz, DMSO-d6)δ=6.92(d,1H),6.46(d,1H),4.43(s,2H),2.75(t,2H),2.63(t,2H),2.26-2.20(m,1H),2.00-1.93 LCMS m / z(ESI)=202.1[M+l].

[0200] intermediate Int-4

[0201]

[0202] first step:

[0203] (R)-5-(1-Cyclopropylethyl)-2,3-Dihydro-1H-Indene-4-amine (Int-4)

[0204] (R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine

[0205] The intermediate Int-4 was prepared according to patent WO2016119758. Int-3B (8.3 g, 41.7 mmol) and dichloromethane (90 mL) were added to a 500 mL autoclave, 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-4, a pale yellow oil (8.2 g, yield 97.8%, ee%: 97.74%). Chiral HPLC (CHIRALPAK AY-3 (4.6 × 100 mm); mobile phase: methanol; column temperature: 35°C; mobile phase (%): 15; column pressure: 2000 psi; flow rate: 2 mL / min; detector signal channel: ...). 215nm@4.8nm (Diode array detector start wavelength: 200nm; Diode array detector end wavelength: 400nm): RT = 3.295min).

[0206] 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 LCMS m / z(ESI)=202.1[M+1].

[0207] Example 1

[0208] RN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazole[5,1-b]oxazole-7-sulfonylimide and SN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazole[5,1-b]oxazole-7-sulfonylimide (compounds 1-1 and 1-2)

[0209] RN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamideand SN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimi damide

[0210]

[0211]

[0212] first step:

[0213] 3-Hydroxy-1H-pyrazole-1-carboxylic acid tert-butyl ester (1b)

[0214] tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate

[0215] In a 1000 mL three-necked flask, 1a (50 g, 594.68 mmol) and triethylamine (90.1 g, 892.02 mmol) were dissolved in dichloromethane (500 mL). The mixture was cooled to 0 °C in an ice bath, and a dichloromethane solution (50 mL) of di-tert-butyl carbonate (142.6 g, 654.15 mmol) was slowly added dropwise. After the addition was complete, the temperature was slowly restored, and the reaction was allowed to proceed for 16 h. The reaction was monitored by TLC until it ended, and then quenched with water. The mixture was extracted with dichloromethane (300 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 100:1 to 95:1) to give 1b, a white solid (85 g, yield: 77.6%).

[0216] LCMS m / z(ESI) = 185.1 [M+1].

[0217] Step Two:

[0218] 3-tert-butyl ester (1-ethoxy-2-methyl-1-oxopropane-2-yl)-1H-pyrazole-1-carboxylic acid ester (1c)

[0219] tert-butyl-3-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-1-carboxylate

[0220] Under nitrogen protection, in a 1000 mL three-necked flask, 1b (48 g, 260.87 mmol), potassium carbonate (72.0 g, 521.74 mmol), and acetonitrile (400 mL) were added sequentially, and the mixture was heated to 80 °C and reacted for 1 h. After 1 h, ethyl 2-bromo-2-methylpropionate (56.0 g, 286.96 mmol) was added, and the reaction was continued at this temperature for 16 h. The reaction was monitored by TLC until it ended. The mixture was filtered, and the filtrate was removed under reduced pressure. The residue was purified by column chromatography (PE:EA = 100:1 to 5:1) to give 1c, a pale yellow oil (44 g, yield: 56.6%).

[0221] LCMS m / z(ESI) = 299.2 [M+1].

[0222] Step 3:

[0223] Ethyl 2-(1H-pyrazol-3-yl)oxy-2-methylpropionate (1d)

[0224] ethyl 2-((1H-pyrazol-3-yl)oxy)-2-methylpropanoate

[0225] In a 500 mL single-necked flask, 1c (44.0 g, 147.48 mmol) was dissolved in 200 mL of dichloromethane. The mixture was cooled to 0 °C in an ice bath, and 20 mL of trifluoroacetic acid was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature for 3 h. The reaction was monitored by TLC until it ended. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography to give 1d, a colorless oil (28.5 g, yield: 97.6%).

[0226] LCMS m / z(ESI) = 199.1 [M+1].

[0227] Step 4:

[0228] 2-(1H-pyrazol-3-yl)oxy-2-methyl-1-propanol (1e)

[0229] 2-((1H-pyrazol-3-yl)oxy)-2-methylpropan-1-ol

[0230] Under nitrogen protection, 1d (28.5 g, 143.94 mmol) was dissolved in 300 mL of anhydrous tetrahydrofuran in a 1 L three-necked flask. The mixture was cooled to 0 °C in an ice bath, and lithium aluminum hydride (288 mL, 287.8 mmol, 1 M) was slowly added dropwise. After the addition was complete, the mixture was slowly brought back to room temperature, and the reaction was allowed to proceed for 0.5 h. The reaction was monitored by TLC until it was complete. The mixture was then quenched with saturated sodium sulfate. The reaction system was dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain crude product 1e, a pale yellow oil (15.3 g, yield: 68.2%). This unpurified product can be used directly in the next step.

[0231] LCMS m / z(ESI) = 157.1 [M+1].

[0232] Step 5:

[0233] 2-(1H-pyrazol-5-yl)oxy-2-methylpropyl methanesulfonate (1f)

[0234] 2-((1H-pyrazol-5-yl)oxy)-2-methylpropyl methanesulfonate

[0235] In a 500 mL three-necked flask, 1e (15.0 g, 96.15 mmol) and triethylamine (14.6 g, 144.23 mmol) were dissolved in 150 mL of anhydrous dichloromethane. The mixture was cooled to 0 °C in an ice bath, and a solution of methanesulfonic anhydride (18.4 g, 105.77 mmol) in dichloromethane (50 mL) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. The reaction was monitored by TLC until it was complete. The mixture was then quenched with water, extracted with dichloromethane (100 mL × 3 × 3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 100:1 to 95:5) to give 1f, a pale yellow oil (16.3 g, yield: 72.4%).

[0236] LCMS m / z(ESI) = 235.1 [M+1].

[0237] Step 6:

[0238] 2,2-Dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (1g)

[0239] 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole

[0240] Under nitrogen protection, 1f (16.3g, 69.66mmol) was dissolved in 200mL of anhydrous DMF in a 500mL three-necked flask. The mixture was cooled to 0℃ in an ice bath, and NaH (5.6g, 139.3mmol) was added. After the addition was complete, the mixture was slowly restored to room temperature and reacted for 12h. The reaction was monitored by TLC until it ended. The mixture was then quenched with ice water, extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (PE:EA = 100:1 to 5:1) to give 1g of a colorless oil (7.6g, yield: 79.1%).

[0241] LCMS m / z(ESI) = 139.1 [M+1].

[0242] Step 7:

[0243] 7-Bromo-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (1h)

[0244] 7-bromo-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole

[0245] In a 250 mL three-necked flask, 1 g (7.5 g, 54.35 mmol) was dissolved in 100 mL of acetonitrile, cooled to 0 °C in an ice bath, and NBS (9.7 g, 54.35 mmol) was added. The reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until it ended. The solution was quenched with sodium sulfite aqueous solution, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (PE:EA = 100:1-3:1) to give a pale yellow solid (7.75 g, yield: 65.1%).

[0246] LCMS m / z(ESI) = 216.0 [M+1].

[0247] Step 8:

[0248] 2,2-Dimethyl-N'-triphenylmethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonylimide (1i)

[0249] 2,2-dimethyl-N'-trityl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide

[0250] Under nitrogen protection, 1 h (6.5 g, 29.95 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran in a 250 mL three-necked flask. The mixture was cooled to -78 °C in a dry ice bath, and n-butyllithium (13.1 mL, 32.95 mmol, 2.5 M) was slowly added, maintaining this temperature for the reaction. After 30 min, a THF (20 mL) solution of (triphenylmethyl)thionimide (4.03 g, 13.18 mmol) was added dropwise. The reaction was carried out at -78 °C for 30 min, then heated to 0 °C and reacted for 10 min. Tert-butyl hypochlorite (1.43 g, 13.18 mmol) was added, and the reaction was maintained at 0 °C for 30 min. Ammonia gas was then bubbled through the mixture for 10 min, and the reaction was allowed to return to room temperature for 16 h. The reaction was monitored by TLC until it ended. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (PE:EA = 100:1 to 1:1) to give 1i, a pale yellow solid (4.1 g, yield: 29.9%).

[0251] 1 H NMR (400MHz, DMSO): δ7.44(d,6H),7.18(t,6H),7.10(t,3H),7.05(s,1H),6.31(s,2H),3.98(s,2H),1.58(s,3H),1.52(s,3H); LCMS m / z(ESI)=481.2[M+23].

[0252] Step 9

[0253] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazole[5,1-b]oxazol-7-sulfonylimide (compound 1)

[0254] N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide

[0255] In a 25 mL round-bottom flask, under nitrogen protection, intermediate Int-1 (300 mg, 1.493 mmol), 10 mL of dry tetrahydrofuran, diisopropylethylamine (289 mg, 2.239 mmol), and 2,2,2-trichloroethyl chloroformate (380 mg, 1.792 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 combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness. 3 mL of dry tetrahydrofuran was added to dissolve the mixture to form solution C. In another 50 mL three-necked flask, Int-1 (684 mg, 1.493 mmol) and 10 mL of dry tetrahydrofuran were added. Sodium hydride (120 mg, 60%, 2.986 mmol) was added under ice bath conditions, and the mixture was stirred for 1 h. Solution C was slowly added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 1 hour. LC-MS was used to monitor the reaction until complete. 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 dissolved in 20 mL of dichloromethane, and trifluoromethanesulfonic acid (449 mg, 2.986 mmol) was added dropwise under ice bath conditions. The reaction was carried out at room temperature for 1 hour, and TLC was used to monitor the reaction until complete. The reaction solution was poured into water, and dichloromethane (20 mL × 2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium-pressure preparation (acetonitrile / water = 40%) to give compound 1, a white solid (288 mg, yield 45%).

[0256] LCMS m / z(ESI) = 430.2[M+1].

[0257] Step 10:

[0258] RN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazole[5,1-b]oxazole-7-sulfonylimide and SN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazole[5,1-b]oxazole-7-sulfonylimide (compounds 1-1 and 1-2)

[0259] RN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamideand SN-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimi damide

[0260] Compound 1 (288 mg, 0.671 mmol) was resolved by SFC to give compound 1-1 (110 mg, yield 38.2%, RT = 9.954 min, ee%: 100%) and compound 1-2 (131 mg, yield 45.4%, RT = 13.709 min, ee%: 100%). 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.

[0261] Compound 1-1: 1 H NMR (400MHz, DMSO): δ7.98(s,1H),7.53(s,1H),7.16(d,1H),6.81(d,1H),6.35(s,2H),4.15(s,2H),2.97(dd,4H),2.35(dd,1H) ,1.59(d,6H),1.11(d,3H),1.00-0.89(m,1H),0.51-0.39(m,1H),0.30-0.19(m,1H),0.17-0.08(m,1H),0.06--0.03(m,1H); LCM S m / z(ESI)=430.2[M+1].

[0262] Compounds 1-2: 1H NMR (400MHz, DMSO): δ7.98(s,1H),7.53(s,1H),7.35(s,2H),7.16(d,1H),6.82(d,1H),4.15(s,2H),3.02-2.91(m,4H),2.34(dd,1 LCMS m / z(ESI)=430.2[M+1].

[0263] Example 2

[0264] (5-Bromo-3-(R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonylimide and ((5-Bromo-3-(R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonylimide (compounds 2-1 and 2-2)

[0265] (R)-N'-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide and(S)-N'-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide

[0266]

[0267] first step

[0268] (R)-5-bromo-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine(2a)

[0269] (R)-5-bromo-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine

[0270] Under nitrogen protection, intermediate Int-1 (200 mg, 1.07 mmol) and dichloromethane (10 mL) were added sequentially to a 100 mL round-bottom flask. Pyridinium tribromide (343 mg, 1.07 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 2a, a pale yellow oil (198 mg, yield 69.9%).

[0271] LCMS m / z = 266.0 [M+l].

[0272] Step 2

[0273] N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-7-sulfonylimide (compound 2)

[0274] N-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dim ethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide

[0275] In a 25 mL round-bottom flask, under nitrogen protection, 2a (198 mg, 0.747 mmol), 10 mL of dry tetrahydrofuran, diisopropylethylamine (145 mg, 1.12 mmol), and 2,2,2-trichloroethyl chloroformate (190 mg, 0.896 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 combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness. 3 mL of dry tetrahydrofuran was added to dissolve the mixture to form solution C. In another 50 mL three-necked flask, 1i (343 mg, 0.747 mmol) and 10 mL of dry tetrahydrofuran were added. Sodium hydride (60 mg, 60%, 1.494 mmol) was added under ice bath conditions, and the mixture was stirred for 1 h. Solution C was slowly added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 1 hour. LC-MS was used to monitor the reaction until complete. 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 dissolved in 20 mL of dichloromethane, and trifluoromethanesulfonic acid (225 mg, 1.49 mmol) was added dropwise under ice bath conditions. The reaction was carried out at room temperature for 1 hour, and TLC was used to monitor the reaction until complete. The reaction solution was poured into water, and dichloromethane (20 mL × 2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by medium-pressure preparation (acetonitrile / water = 45%) to give compound 2, a white solid (245 mg, yield 64%).

[0276] LCMS m / z(ESI) = 508.1 [M+1].

[0277] Step 3:

[0278] (5-Bromo-3-(R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonylimide and ((5-Bromo-3-(R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonylimide (compounds 2-1 and 2-2)

[0279] (R)-N'-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide and(S)-N'-((5-bromo-3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidamide

[0280] Compound 2 (245 mg, 0.482 mmol) was resolved by SFC to give compound 2-1 (95 mg, yield 38.7%, RT = 10.733 min, ee%: 99.42%) and compound 2-2 (97 mg, yield 39.5%, RT = 13.613 min, ee%: 99.36%). 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 end wavelengths: 200–400 nm.

[0281] Compound 2-1: 1 H NMR (400MHz, DMSO): δ8.11(s,1H),7.53(s,1H),7.36(s,2H),7.26(s,1H),4.15(s,2H),2.96(s,2H),2.93(s,2H),2.39–2.30(m,1H LCMS m / z(ESI)=508.1[M+1].

[0282] Compound 2-2: 1H NMR (400MHz, DMSO): δ8.12(s,1H),7.53(s,1H),7.36(s,2H),7.26(s,1H),4.15(s,2H),3.02–2.94(m,2H),2.94–2.89(m,2H),2.40–2.30 LCMS m / z(ESI)=508.1[M+1].

[0283] Examples 3 to 5

[0284] The compounds in Examples 3 to 5 were obtained by the same synthesis method as in Example 1, as shown in Table 1.

[0285] Table 1. Compound structure and characterization data from Examples 3-5

[0286]

[0287]

[0288] a: Chiral HPLC (OZ); Mobile phase: n-hexane / ethanol = 90 / 10; Column temperature: 35°C; Column pressure: 80 bar; Flow rate: 1 mL / min; Detector signal channel: 215 nm @ 4.8 nm; Diode array detector start wavelength: 200 nm; Diode array detector stop wavelength: 400 nm)

[0289] Reference Example 1

[0290] Compounds RF1 and RF2 were synthesized according to patent WO2020018975.

[0291]

[0292] Biological test cases

[0293] 1. THP-1 cell culture

[0294] 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.

[0295] 2. Detection of pyroptosis in THP-1 cells

[0296] Cell counting was performed, and 50,000 THP-1 cells were seeded per well in 96-well plates. Induction was initiated at 37°C with 5% CO2 for 48 hours using 20 nM PMA. The medium was discarded, and 100 μL of serum-free RPMI-1640 medium containing 1 μg / mL LPS was added. 5 μL of the compound or solvent control was added, starting with the highest dose of 10 μM and serially diluted 3-fold to establish 10 different concentrations. Incubation was continued at 37°C with 5% CO2 for 3 hours. After incubation, the cells were centrifuged at 300g for 5 minutes, the medium was discarded, and pyroptosis analysis was performed. 1. Follow the detailed steps for the Inflammasome Assay Kit, referring to the kit instructions. Calculate the IC50 using GraphPad Prism 7.0 software. 50 The results are shown in Table 2.

[0297] Table 2. Results of pyroptosis assay for compound THP-1

[0298] Compound 1-1 46 Compound 2-1 63 Compound 4-1 99 RF2 908

[0299] Note: A≤100nM, 100nM<B≤500nM, 500nM<C≤1000nM, D>1uM.

[0300] The results showed that the compound of the present invention can effectively inhibit pyroptosis in the human mononuclear cell line THP-1.

[0301] 3. IL-1β Release Analysis in Human PBMCs

[0302] Five mL of whole blood from a healthy human venous donor was collected and placed in a Li-heparin tube. PBMCs were isolated and incubated in medium containing 10 ng / mL LPS at 37°C with 5% CO2 for 3 hours. Cells were seeded into 96-well plates at 50 μL per well. 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 The results are shown in Table 3.

[0303] The results showed that the compound of the present invention downregulated the release of mature IL-1β by inhibiting the activity of Caspase-1.

[0304] Table 3. IL-1β test results for compound PBMC

[0305] Compound 1-1 56 Compound 2-1 40 Compound 2-2 13

[0306] 4. Analysis of TNFα release from human PBMCs

[0307] Five mL of whole blood from a healthy human venous donor was collected and placed in a Li-heparin tube. PBMCs were isolated, and cells were seeded in 96-well plates at 50 μL per well. 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 .

[0308] The results showed that the compound of the present invention did not downregulate the expression level of TNFα induced by LPS in PBMCs.

[0309] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. A compound as shown below, or its stereoisomers, or pharmaceutically acceptable salts: 、 、 、 。 2. The compound according to claim 1, or its stereoisomer or pharmaceutically acceptable salt, has one of the following structures: 、 、 、 、 、 、 、 、 、 。 3. A pharmaceutical composition comprising: The compound according to any one of claims 1-2, or its stereoisomers, or pharmaceutically acceptable salts; One or more pharmaceutically acceptable carriers and / or excipients.

4. Use of the pharmaceutical composition of claim 3 or the compound of any one of claims 1-2 or its stereoisomers or pharmaceutically acceptable salts in the preparation of an NLRP3 inhibitor or a medicament for treating NLRP3-related diseases.

5. The use according to claim 4, wherein the NLRP3 inhibitor treats diseases or NLRP3-related diseases including: Inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

6. The use according to claim 5, wherein the NLRP3 inhibitor treats diseases or NLRP3-related diseases including: Cryptothermal protein-associated cycle syndrome (CAPS), Muker-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, Alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.

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