Compounds as NLRP3 inhibitors

Abstract

The present invention provides a compound as an NLRP3 inhibitor, specifically, a compound represented by the following formula (I), or an optical isomer, pharma- ceutically acceptable salt, prodrug, deuterium-substituted derivative, hydrate, or solvate thereof, which is useful for treating or preventing a disease or condition associated with the activity or expression level of NLRP3. [Formula 1] JPEG2024508728000078.jpg3568

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, specifically to novel tricyclic heteroaryl group-containing derivatives, their synthesis methods and use as NLRP3 inhibitors in the manufacture of drugs for treating multiple related diseases, such as tumors. [Background technology]

[0002] NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammatory bodies are multiprotein complexes containing the core member nucleotide-binding oligomerization domain-like receptor (NLRP3), the linker protein apoptosis-associated speck-like protein (ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain), and the aspartate-specific cysteine ​​protease (caspase-1) precursor, which are primarily involved in the inflammatory response process in the body. As an intracellular receptor protein, NLRP3 recognizes specific inflammatory signals. Upon stimulation, NLRP3 binds to the linker protein ASC to form the NLRP3-ASC complex. The multimerized NLRP3-ASC complex then forms a larger complex with the caspase-1 precursor, which is called the inflammatory body. The generation of inflammatory bodies leads to the activation of caspase-1, which further cleaves and processes the inflammatory factors IL-1β and IL-18 precursors to secrete active IL-1β and IL-18, promoting the development of inflammatory responses and leading to inflammatory cell death, i.e., pyroptosis. ASC can also recruit and activate caspase-8, which cleaves IL-1β and IL-18 precursors and induces apoptosis.

[0003] Caspase-1 cleaves IL-1β and IL-18 precursors to generate active IL-1β and IL-18, which are secreted extracellularly. Activated caspase-1 can also cleave GSDMD (gasdermin D) and induce cell pyroptosis. By regulating the pyroptotic cell death pathway, caspase-1 can also mediate the release of alarmins, such as IL-33 and HMGB1 (high mobility group box 1). Caspase-1 can also cleave the intracellular IL-1R2 receptor, leading to its degradation and the release of IL-1α. Other caspase-1 substrates, such as cytoskeletal proteins and proteins involved in the glycolytic signaling pathway, may also be involved in caspase-1-dependent inflammatory responses.

[0004] Cytokines activated by NLRP3 inflammatory bodies promote the development of inflammatory responses and, together with other cytokine signaling pathways, establish immune responses to infection and injury. For example, the IL-1β signaling pathway induces the release of the pro-inflammatory factors IL-6 and tumor necrosis factor (TNF). In the absence of T cell receptor (TCR) engagement, IL-1β and IL-18 cooperate with IL-23 to induce memory CD4+ Th17 cells and γδ T cells to produce IL-17. IL-18 and IL-12 also cooperate to induce memory T cells and natural killer cells to secrete IFN-γ, promoting Th1 immune responses.

[0005] Other intracellular pattern recognition receptors, such as the NLR (nod-like receptor) family members NLRP1 and NLRP4, as well as non-NLR family members such as the double-stranded DNA sensor AIM2 (absent in melanoma 2) and IFI16 (interferon gamma inducible protein 16), can also form inflammatory bodies. An indirect, atypical signaling pathway downstream of caspase-11 can also activate IL-1β, which is dependent on NLRP3.

[0006] Abnormal activation of NLRP3 leads to the development of many diseases, including comprehensive Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NEID). NLRP3 is also involved in mediating the development of many complex diseases, including multiple sclerosis, type 2 diabetes, obesity, Alzheimer's disease, gout, and atherosclerosis. Its role in diseases of the central nervous system, lungs, liver, and kidneys has also garnered significant attention. Therefore, the development of NLRP3 inhibitors holds great promise for broad clinical applications. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a novel NLRP3 inhibitor. [Means for solving the problem]

[0008] In a first aspect, the present invention provides a compound represented by the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterium-substituted derivative, hydrate, or solvate thereof: [ka]

[0009] (In formula (I), Ring A is selected from the group consisting of substituted or unsubstituted 8-15 membered bicyclic or tricyclic fused ring systems, where substitution means that a hydrogen atom in a group is replaced by one or more R e The bicyclic or tricyclic fused ring system includes at least one aromatic ring structure and one or two saturated or unsaturated rings fused to the aromatic ring structure, and the linking site between ring A and X is located on the aromatic ring.

[0010] Ring B is selected from the group consisting of an unsubstituted, substituted or unsubstituted aryl group, a substituted or unsubstituted 5- to 12-membered heterocycle (including partially unsaturated or saturated heterocycle), or a substituted or unsubstituted heteroaryl group, where the substitution means that a hydrogen atom in the group is replaced by one or more R f And if B is absent, E and G do not exist.

[0011] X is -NR 5 -, -CR 6 R 7 -Selected from. Y is O, -NR 5 -Selected from. T is a chemical bond, -NR 5 -,-(CR a R b ) 1-2 -, C 3-6 It is selected from a cycloalkyl group, a 3- to 8-membered heterocyclic group, an aryl group, or a heteroaryl group.

[0012] R is hydrogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C2-4 Alkynyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclic group, an aryl group, a heteroaryl group, or NR 8 R 9 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from the group consisting of halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Haloalkenyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 , CN, NO2, SR h , C(O)R t , C(O)OR h , C(O)NR h R h , N.R. h C(O)R t , N.R. h S(O)2R t , or S(O)2R t Alternatively, the cycloalkyl or heterocyclic group is substituted with ═M, where M is O or CR 10 R 11 Selected from.

[0013] E is a chemical bond, -O-, -O(CR a R b ) 1-2 -,-(CR a R b ) 1-2 O-, -S-, -S(CR a R b ) 1-2 -,-(CR a R b ) 1-2 S-, -NR 5 -,-(CR a R b ) 1-2 NR 5 -, -NR 5 (CR a R b ) 1-2-, C 1-2 Alkylene group, -C=C-, -C≡C-, C 3-6 It is selected from the group consisting of cycloalkyl groups.

[0014] G is hydrogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, saturated C 3-8 Cycloalkyl groups, unsaturated C 3-8 Cycloalkyl groups, saturated 3-12 membered heterocyclic groups, unsaturated 3-12 membered heterocyclic groups, aryl groups, or heteroaryl groups, NR 8 R 9 wherein said cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from the group consisting of halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Haloalkenyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 , CN, NO2, SR h , C(O)R t , C(O)OR h , C(O)NR h R h , N.R. h C(O)R t , N.R. h S(O)2R t , or S(O)2R t and is substituted with one or more groups selected from the group consisting of:

[0015] R 5 is hydrogen, a C1-C4 alkyl group, or C 3-6 It is selected from the group consisting of cycloalkyl groups. R 6 and R 7 are each independently hydrogen, halogen, or C 1-4 Alkyl group, or C 3-6 cycloalkyl groups, or R 6 and R 7C together with the carbon atoms connected to them 3-6 It forms a cycloalkyl group or a 4- to 6-membered heterocyclic group, and the heterocyclic group contains 1 or 2 heteroatoms selected from N, O, and S.

[0016] R 8 and R 9 are each independently hydrogen, C 1-4 Alkyl group, C 3-6 The cycloalkyl group or heterocyclic group is optionally substituted with "=M", where M is O or CR 10 R 11 Alternatively, R 8 and R 9 form a 4-8 membered heterocyclic group together with the nitrogen atom linked thereto, and the heterocyclic group contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O and S.

[0017] R 10 and R 11 are each independently hydrogen, deuterium, halogen, or C 1-4 alkyl groups, wherein the alkyl groups are optionally selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 , C 3-8 Alternatively, R is substituted with one or more groups selected from the group consisting of a cycloalkyl group, a 3- to 8-membered heterocyclic group, an aryl group, or a heteroaryl group. 10 and R 11 together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, the heterocyclic group containing one or two heteroatoms selected from N, O and S.

[0018] R a and R b are each independently hydrogen, halogen, or C1-4 Alkyl group, or C 3-6 It is selected from the group consisting of cycloalkyl groups. R e and R f are independently deuterium, halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 4-8 membered heterocyclic groups, aryl groups, heteroaryl groups, CN, NO2, OR h , S.R. h , N.R. h R h , C(O)R t , C(O)NR h R h is selected from the group consisting of:

[0019] R t is C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 It is a cycloalkyl group, a 4-8 membered heterocyclic group, an aryl group, or a heteroaryl group. Each R h are each independently hydrogen or C 1-4 alkyl group or two R h form a 3-8 membered heterocyclic group together with the nitrogen atom linked thereto, and the heterocyclic group contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O and S.

[0020] wherein each of the above alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups optionally and independently contain 1 to 3, each independently, halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, aryl groups, heteroaryl groups, CN, NO2, ORh , S.R. h , N.R. h R h , C(O)R t , C(O)OR h , C(O)NR h R h , N.R. h C(O)R t , N.R. h S(O)2R t , or S(O)2R t The prerequisite is that the resulting chemical structure is stable and meaningful. h and R t The definition is as above.

[0021] Unless otherwise specified, the aryl groups are aromatic groups containing 6-12 carbon atoms, and the heteroaryl groups are 5-15 membered (preferably 5-12 membered) heteroaromatic groups.

[0022] In another preferred embodiment, ring A is a tricyclic fused ring system and R is an unsaturated C 3-8 It is a cycloalkyl group (non-aromatic) or an unsaturated 3-8 membered heterocyclic group (non-aromatic). In another preferred embodiment, ring A is a tricyclic fused ring system and R is C 3-8 A cycloalkyl group or a 3-8 membered heterocyclic group, and said R is substituted with at least one =M.

[0023] In another preferred embodiment, R is C 3-8 a cycloalkyl group or a 3- to 8-membered heterocyclic group, and T is -NR 5 - and the R is fluorine, C 1-4 Fluoroalkyl group, C 2-4 It is substituted with at least one substituent selected from the group consisting of fluoroalkenyl groups.

[0024] In another preferred embodiment, ring A is a bicyclic fused ring system, and G is an unsaturated 3- to 12-membered heterocyclic group (non-aromatic), a spirocyclic saturated 3- to 12-membered heterocyclic group, a fused-ring saturated 3- to 12-membered heterocyclic group, or a bridged-ring saturated 3- to 12-membered heterocyclic group. In another preferred embodiment, R is C 3-8 A cycloalkyl group or a 3-8 membered heterocyclic group, and said R is substituted with at least one =M.

[0025] In another preferred embodiment, R is C 3-8 a cycloalkyl group or a 3- to 8-membered heterocyclic group, and T is -NR 5 - and the R is fluorine, C 1-4 Fluoroalkyl group, C 2-4 It is substituted with at least one substituent selected from the group consisting of fluoroalkenyl groups.

[0026] In another preferred embodiment, R is C 3-8 cycloalkyl groups or 3-8 membered heterocyclic groups, wherein said cycloalkyl groups or heterocyclic groups are optionally selected from halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Haloalkenyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 or ═M, where M is O or CR 10 R 11 Selected from A, B, E, G, X, Y, T, R 8 , R 9 , R 10 , R 11 The definition of is as above.

[0027] In another preferred embodiment, R is C 3-8 a cycloalkyl group or a 3-8 membered heterocyclic group, wherein said cycloalkyl group or heterocyclic group is optionally substituted with ═M, where M is CR 10 R 11where R 10 and R 11 The definition is as above.

[0028] In another preferred embodiment, [ka] teeth, [ka] Selected from [ka] represents a linking site between the structural fragment of formula (IIa) or formula (IIb) and another structure in formula (I), R 1 and R 2 are independently hydrogen, deuterium, halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, C 1-4 haloalkoxy groups, Each R 3 are independently hydrogen, deuterium, halogen, C 1-4 alkyl groups, m is 0, 1, 2, or 3, [ka] is a pyridyl, pyrimidyl, or pyridazyl group, E is a chemical bond, -O-, -O(CR a R b ) 1-2 -,-(CR a R b ) 1-2 O-, -S-, -S(CR a R b ) 1-2 -,-(CR a R b ) 1-2 -, -NR 5 -,-(CR a R b ) 1-2NR 5 -, -NR 5 (CR a R b ) 1-2 -, C 1-2 alkylene group, -C=C-, -C≡C-, where R a and R b are each independently hydrogen or C 1-4 alkyl groups, G is an unsaturated C 3-8 cycloalkyl groups or unsaturated 3- to 12-membered heterocyclic groups, wherein said cycloalkyl groups or heterocyclic groups are optionally selected from halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Haloalkenyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 , CN, NO2, SR h , C(O)R t , C(O)OR h , C(O)NR h R h , N.R. h C(O)R t , N.R. h S(O)2R t , or S(O)2R t and is substituted with one or more groups selected from the group consisting of R 5 , R 8 , R 9 , R h , R t The definition is as above.

[0029] In another preferred embodiment, the formula (I) is formula (III): [ka] R 1 and R 2 are independently hydrogen, deuterium, halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, C1-4 haloalkoxy groups, Each R 3 are independently hydrogen, deuterium, halogen, C 1-4 alkyl groups, m is 0, 1, or 2, E is a chemical bond, -O-, -O(CR a R b ) 1-2 -,-(CR a R b ) 1-2 O-, -S-, -S(CR a R b ) 1-2 -,-(CR a R b ) 1-2 S-, -NR 5 -,-(CR a R b ) 1-2 NR 5 -, -NR 5 (CR a R b ) 1-2 -, C 1-2 alkylene group, -C=C-, -C≡C-, where R a and R b are each independently hydrogen or C 1-4 alkyl groups, G is an unsaturated C 3-8 cycloalkyl groups or unsaturated 3- to 12-membered heterocyclic groups, wherein said cycloalkyl groups or heterocyclic groups are optionally selected from halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Haloalkenyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 , CN, NO2, SR h , C(O)R t , C(O)OR h , C(O)NR h R h , N.R. h C(O)R t , N.R. h S(O)2Rt , or S(O)2R t and is substituted with one or more groups selected from the group consisting of X, Y, T, R, R 5 , R 8 , R 9 , R h , R t The definition is as above.

[0030] In another preferred embodiment, G is [ka] and wherein G is optionally selected from the group consisting of halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Haloalkenyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 , CN, NO2, SR h , C(O)R t , C(O)OR h , C(O)NR h R h , N.R. h C(O)R t , N.R. h S(O)2R t , or S(O)2R t and is substituted with one or more groups selected from the group consisting of:

[0031] In another preferred embodiment, E is a chemical bond, —O—, —O(CR a R b ) 1-2 -,-(CR a R b ) 1-2 O-, -NR 5 -,-(CRaR b ) 1-2 NR 5 -, -NR 5 (CR a R b ) 1-2 -, -C≡C-, where Ra and R b are each independently hydrogen or C 1-4 It is selected from alkyl groups.

[0032] In another preferred embodiment, the formula (I) is formula (IV): [ka] M is for CR 10 R 11 where R 10 and R 11 The definition of is as above, U is N or CR 12 where R 12 is hydrogen, halogen, or C 1-4 alkyl groups, W is a chemical bond, -NR 13 (CR c R d ) 1-2 -, -O(CR c R d ) 1-2 -, where R 13 is hydrogen, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, aryl groups, heteroaryl groups, C(O)R t , or S(O)2R t Selected from R c and R d are each independently hydrogen or C 1-4 alkyl groups, p and q are each independently selected from 0, 1, 2, 3, 4, 5, or 6, with the proviso that p and q are not simultaneously 0; A, B, E, G, X, Y, T, R t The definition is as above.

[0033] In another preferred embodiment, the formula (I) is formula (Va) or formula (Vb), [ka] T is a chemical bond, -NR 5 -, an aryl group, or a heteroaryl group; The definitions of M, U, W, p, and q are as above. R 1 , R 2 , R 3 , m is defined as above, E, G, R 5 The definition is as above.

[0034] In another preferred embodiment, formula (I) is formula (VIa) or formula (VIb): [ka] R 5 is hydrogen or C 1-4 alkyl groups, U is for CR 12 where R 12 is hydrogen or C 1-4 alkyl groups, The definitions of M, W, p, and q are as above. R 1 , R 2 , R 3 , m is defined as above, The definitions of E and G are as described above.

[0035] In another preferred embodiment, formula (I) is formula (VIIa) or formula (VIIb): [ka] U is for CR 12 where R 12 is hydrogen or C 1-4 alkyl groups, The definitions of M, W, p, and q are as above. R 1 , R 2 , R 3 , m is defined as above, The definitions of E and G are as described above.

[0036] In another preferred embodiment, the formula (I) is formula (VIIIa) or formula (VIIIb), [ka] M, U, W, R 1 , R 2 , R 3 , E, G, m, p, and q are defined as above.

[0037] In another preferred embodiment, the formula (I) is formula (IXa) or formula (IXb), [ka] k and j are each independently selected from 0, 1, or 2; R 14 and R 15 are each independently hydrogen, halogen, or C 1-4 Alkyl group, or C 3-6 cycloalkyl groups, T, U, W, R 1 , R 2 , R 3 , E, G, m, and p are defined as above.

[0038] In another preferred embodiment, the formula (I) is formula (X): [ka] Z is N or CR 16 where R 16 is hydrogen, halogen, or C 1-4 alkyl groups, p and q are each independently 0, 1, 2, 3, 4, 5, or 6; U is for CR 12 where R 12 is hydrogen or C 1-4 alkyl groups, M is for CR 10 R 11 where R 10 and R 11The definition of is as above, The definitions of A, B, E, and G are as above.

[0039] In another preferred embodiment, the formula (I) is formula (XIa) or formula (XIb), [ka] [ka] is a pyridyl, pyrimidyl, or pyridazyl group, The definitions of Z, U, M, p, and q are as above. R 1 , R 2 , R 3 , m is defined as above, The definitions of E and G are as described above.

[0040] In another preferred embodiment, the formula (I) is formula (XII): [ka] p and q are each independently 0, 1, 2, 3, 4, 5, or 6; M is for CR 10 R 11 where R 10 and R 11 are each independently hydrogen, fluorine, or C 1-4 alkyl groups, wherein said alkyl groups are optionally selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, NR 8 R 9 , C 3-8 substituted with one or more groups selected from the group consisting of a cycloalkyl group and a 3- to 8-membered heterocyclic group; R 1 and R 2 are each independently hydrogen, halogen, or C 1-4 Alkyl group, C1-4 Haloalkyl group, C 1-4 Alkoxy group, C 1-4 haloalkoxy groups, Each R 3 are each independently hydrogen, halogen, or C 1-4 alkyl groups, m is 0, 1, or 2, E is a chemical bond, -O-, -O(CR a R b ) 1-2 -,-(CR a R b ) 1-2 O-, -S-, -NR 5 -,-(CR a R b ) 1-2 NR 5 -, -NR 5 (CR a R b ) 1-2 -, C 1-2 Alkylene group, -C≡C-, C 3-6 cycloalkyl groups, where R a and R b are each independently hydrogen or C 1-4 alkyl groups, R 5 is hydrogen, C 1-4 Alkyl groups, or from C 3-6 cycloalkyl groups, G is hydrogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, saturated C 3-8 Cycloalkyl groups, unsaturated C 3-8 Cycloalkyl groups, saturated 3-12 membered heterocyclic groups, unsaturated 3-12 membered heterocyclic groups, aryl groups, or heteroaryl groups, NR 8 R 9 wherein said cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from the group consisting of halogen, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, C1-4 Haloalkoxy group, NR 8 R 9 ,CN,C(O)R t , or S(O)2R t and is substituted with one or more groups selected from the group consisting of: t is C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 a cycloalkyl group, a 4-8 membered heterocyclic group, an aryl group, or a heteroaryl group; R 8 and R 9 are each independently hydrogen, C 1-4 Alkyl group, C 3-6 It is selected from the group consisting of a cycloalkyl group, and a 4- to 8-membered heterocyclic group.

[0041] In another preferred embodiment, the compound of formula (I) is selected from the group consisting of: [ka] [ka] [ka] [ka] "*" denotes a chiral center.

[0042] In another preferred embodiment, the pharmaceutically acceptable salt is an alkali metal salt, preferably a sodium salt, a potassium salt, or a lithium salt.

[0043] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterium-substituted derivative, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

[0044] In a third aspect of the present invention, there is provided the use of a compound according to the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterium-substituted derivative, hydrate or solvate thereof, in the manufacture of a pharmaceutical composition for treating a disease, disorder or condition associated with the activity or expression level of NLRP3.

[0045] In another preferred embodiment, the disease, disorder, or condition is inflammation, autoimmune disease, knee arthritis, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory system disease, liver disease, kidney disease, eye disease, skin disease, lymphatic disorder, psychological disorder, graft-versus-host disease, abnormal pain, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF). , septic arthritis, suppurative sterile arthritis-pyoderma gangrenosum-acne syndrome (PAPA), hyper-IgD periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic-onset juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Schnitzler syndrome, Down syndrome, Behcet's disease, antisynthetase syndrome, interleukin-1 receptor antagonist deficiency (DIRA), and A2o (HA2o) haploinsufficiency. DETAILED DESCRIPTION OF THE INVENTION

[0046] After extensive and in-depth research, the present inventors have unexpectedly discovered novel tricyclic heteroaryl group-containing NLRP3 inhibitors, as well as their preparation and use. The compounds of the present invention are useful for treating various diseases associated with the activity of the kinase. Based on the above findings, the present inventors have completed the present invention.

[0047] term Unless otherwise stated, "or" as used herein has the same meaning as "and / or" (referring to both "or" and "and"). Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R or S configuration, or may be a mixture of the R and S configurations.

[0048] As used herein, alone or as part of another substituent, the term "alkyl group" refers to a saturated hydrocarbon group having carbon atoms, either straight (i.e., unbranched) or branched, or a combination of straight and branched chain groups. The alkyl group may be preceded by a limit on the number of carbon atoms (e.g., C 1-10 ) means that the alkyl group has 1 to 10 carbon atoms. For example, C 1-8 Alkyl groups are those having from 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, or similar groups.

[0049] As used herein, alone or as part of another substituent, the term "alkenyl group" refers to a carbon chain group, straight or branched, containing at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. The alkenyl group may be preceded by a limit on the number of carbon atoms (e.g., C 2-8 ) means that the alkenyl group has 2 to 8 carbon atoms. For example, C 2-8 The alkenyl group is an alkenyl group having 2 to 8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0050] As used herein, alone or as part of another substituent, the term "alkynyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be linear or branched, or a combination thereof. The alkynyl group may be preceded by a restriction on the number of carbon atoms (e.g., C 2-8 When the term "alkynyl group" is used, it means that the alkynyl group has 2 to 8 carbon atoms. For example, the term "C 2-8An "alkynyl group" is a straight or branched chain alkynyl group having from 2 to 8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, t-butynyl, or similar groups.

[0051] As used herein, alone or as part of another substituent, the term "cycloalkyl group" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic (including fused, bridged, or spiro) ring system radical. A cycloalkyl group may be preceded by a limitation on the number of carbon atoms (e.g., C 3-10 ) refers to the cycloalkyl group having 3 to 10 carbon atoms. 3-8 "Cycloalkyl group" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl group" refers to a bicyclic or polycyclic group in which the monocyclic rings share one carbon atom (called a spiro atom). These groups may contain one or more double bonds, but no ring has a completely conjugated π-electron system. "Fused cycloalkyl group" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system. One or more of the rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. "Bridged cycloalkyl group" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These groups may contain one or more double bonds, but no ring has a completely conjugated π-electron system. All atoms in the cycloalkyl group are carbon atoms. The following are some examples of cycloalkyl groups, but the present invention is not limited to these cycloalkyl groups. [ka]

[0052] Unless stated to the contrary, the terms used in the following specification and claims have the following meanings: "Aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π-electron system, such as a phenyl group or a naphthyl group. The ring of the aryl group may be fused to other cyclic groups (including saturated and unsaturated rings), but does not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be a carbon atom in the ring that has a conjugated π-electron system. Aryl groups may be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to these aryl groups: [ka]

[0053] A "heteroaryl group" refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms (optionally selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by condensing a heterocyclic group (optionally containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur) with an aryl group, with the linking site being located on the aryl group. The heteroaryl group may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to these heteroaryl groups. [ka]

[0054] A "heterocyclic group" refers to a saturated or partially saturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, and homopiperazyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with the other rings in the system, in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. A "fused-ring heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, and one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon. A "bridged-ring heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly connected carbon atoms, and these rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon. When a heterocyclic group contains both saturated and aromatic rings (e.g., a saturated ring and an aromatic ring are fused together), the bond to the parent ring is always located on the saturated ring. Note: When the bond to the parent ring is located on the aromatic ring, the group is referred to as a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to these heterocyclic groups. [ka]

[0055] As used herein, the term "halogen" alone or as part of another substituent refers to F, Cl, Br, and I.

[0056] As used herein, the term "substituted" (with or without the "optionally" modification) refers to the replacement of one or more hydrogen atoms in a specified group with a specified substituent. Specific substituents are those listed above as corresponding substituents or in the individual examples. Unless otherwise specified, an optionally substituted group may have one substituent selected from a specified group at any substitutable position of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be linked to another ring, such as a cycloalkyl group, to form a spiro-bicyclic ring system, i.e., the two rings share one carbon atom. As will be appreciated by those skilled in the art, combinations of substituents envisioned by the present invention are those that are stable or chemically feasible. The substituents may be, for example, C 1-8 Alkyl group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups, aryl groups, heteroaryl groups, halogens, hydroxy groups, carboxy groups (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl group, C 2-10 Examples of the hydroxyl group include, but are not limited to, an ester group and an amino group.

[0057] For convenience, and in keeping with common understanding, the term "optionally substituted" applies only to moieties that are capable of being substituted with a substituent, and does not include substitutions that are not chemically feasible.

[0058] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) and does not produce undue side effects. In some embodiments, pharmaceutically acceptable salts of certain compounds of the present invention include salts of compounds of the present invention with an acidic group (e.g., potassium salts, sodium salts, magnesium salts, calcium salts) or salts of compounds of the present invention with a basic group (e.g., sulfate salts, hydrochloride salts, phosphate salts, nitrate salts, carbonate salts).

[0059] Usage: The present invention provides the use of a compound of formula (I), or a deuterium-substituted derivative thereof, a salt, an isomer (enantiomer or diastereomer, if any), a hydrate, a pharmaceutically acceptable carrier or excipient thereof, for inhibiting NLRP3. The compounds of the present invention are useful as NLRP3 inhibitors.

[0060] The present invention provides a single inhibitor of NLRP3, which modulates the enzymatic activity of NLRP3 to prevent, alleviate, or cure diseases, including cryopyrin-associated periodic fever syndromes (CAPS), which are mainly caused by NLRP3 acquired mutations and include Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID).

[0061] The diseases referred to herein further include the following: genetic disorders, such as sickle cell anemia and valosin-containing protein diseases; Autoimmune diseases, including but not limited to rheumatoid arthritis, knee arthritis, septic arthritis, pyoderma gangrenosum, acute febrile neutrophilic dermatosis, chronic non-infectious osteomyelitis, systemic lupus erythematosus, inflammatory bowel disease (ulcerative colitis and Crohn's disease), Behcet's disease, Schnitzler syndrome, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome, hyper-IgD syndrome, and macrophage activation syndrome; Central nervous system diseases, including but not limited to Alzheimer's disease, Parkinson's disease, multiple sclerosis, and dementia; Metabolic-related diseases, including but not limited to type 1 diabetes, type 2 diabetes, obesity, gout, pseudogout, atherosclerosis and metabolic syndrome; Pulmonary diseases, including but not limited to asthma, pulmonary fibrosis, idiopathic pulmonary fibrosis, pulmonary ischemia-reperfusion injury, chronic obstructive pulmonary disease, asbestosis, and silicosis; Eye diseases, including but not limited to age-related macular degeneration, diabetic retinopathy and optic nerve damage; Liver disease, including but not limited to nonalcoholic fatty liver disease, hepatic ischemia-reperfusion injury, acute stroke hepatitis, liver fibrosis, and liver failure; kidney disease, including but not limited to nephrocalcinosis and renal fibrosis; Heart disease, including but not limited to cardiac hypertrophy and fibrosis, heart failure, aortic aneurysms and aortic dissections, cardiac damage due to metabolic disorders, atrial fibrillation and hypertension; Skin diseases, including but not limited to psoriasis, atopic dermatitis, contact allergic reactions, hidradenitis suppurativa, acne vulgaris and sarcoidosis; Further, types of diseases that can be alleviated or cured by inhibiting NLRP3 enzyme activity include inflammatory hyperalgesia, neuralgia, and suppression of many bacterial, viral, fungal, and helminthic infections.

[0062] NLRP3 is also involved in the development and progression of many cancers, including myelofibrosis, rheumatoid arthritis, B-cell lymphoma, monocytic leukemia, polycythemia vera, hypereosinophilic syndrome, essential thrombocytopenia, systemic giant cell disease, liver cancer, rectal cancer, bladder cancer, laryngeal cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic adenocarcinoma, colon cancer, skin cancer, lymphoma, gastric cancer, and multiple myeloma, among many other solid and hematological tumors.

[0063] The compounds of the present invention, their deuterium-substituted derivatives, and pharmaceutically acceptable salts or isomers thereof (if present), hydrates thereof, and / or compositions thereof can be used to treat illnesses, symptoms, and diseases by combining them with a pharmaceutically acceptable excipient or carrier and administering the resulting compositions to a mammal, e.g., a man, a woman, or an animal. The compositions may be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, sprays, sterile injectable solutions, sterile powders, and the like. In some embodiments, the pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (e.g., starch, croscarmellose, complex silicates, and high molecular weight polyethylene glycol), granulating binders (e.g., polyvinylpyrrolidone, sucrose, gelatin, and gum arabic), and lubricants (e.g., magnesium stearate, glycerin, and talc powder). In a preferred embodiment, the pharmaceutical composition is suitable for oral administration, including, but not limited to, tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound or pharmaceutical composition of the present invention administered to a patient is not fixed and is generally administered in a pharmaceutically effective amount. The actual amount of compound administered will be determined by a physician based on the actual circumstances, including the disease being treated, the selected administration route, the actual compound administered, and the individual condition of the patient. The dosage of the compound of the present invention will be determined by the specific therapeutic application, the administration form, the patient's condition, and the physician's judgment. The proportion or concentration of the compound of the present invention in a pharmaceutical composition will depend on many factors, including the dosage, physical and chemical properties, and the administration route.

[0064] Of course, it is understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (for example, in the Examples) can be combined with each other to form new or preferred technical solutions.

[0065] Common synthesis methods for compounds The compounds of formula III-A of the present invention can be prepared by the following method. [ka] The symbols m, E, G, R1, R2 and R3 in the above reaction scheme are the same as those in formula III. The symbols T and R are the same as those in formula I in claim 1. In an inert solvent, III-A-1 is used as starting material to undergo a substitution reaction to give intermediate III-A-2, which is then reacted with activated compound III-A-3 to give the desired compound III-A.

[0066] The compounds of formula IA of the present invention can be prepared by the following methods. [ka] R in the above reaction formula 1 The notation is R in the above formula IIa 1 and T and R are the same as the notations of T and R in formula I above. In an inert solvent, IA-1 is used as the starting material and is subjected to a substitution reaction with III-A-3 to give the target compound IA.

[0067] The compounds of formula XII-A of the present invention can be prepared by the following method. [ka] The symbols p, q, m, E, G, R1, R2 and R3 in the above reaction scheme are the same as those in formula XII above.

[0068] In an inert solvent, XII-A-1 is reacted with XII-A-2 to give compound XII-A-3, which is then reacted with reagent XII-A-4 to give difluoro compound XII-A-5, and the protecting group is removed under acidic conditions to give intermediate XII-A-6. In an inert solvent, III-A-1 is reacted with triphosgene to give intermediate III-A-2, which is then reacted with XII-A-6 to give isocyanate compound XII-A-7, which is then added to XII-A-6 to give the target compound XII-A.

[0069] The compounds of formula XII-B of the present invention can be prepared by the following method. [ka] The symbols p, q, m, E, G, R1, R2 and R3 in the above reaction scheme are the same as those in formula XII above.

[0070] In an inert solvent, XII-A-1 is substituted with XII-A-2 to give compound XII-A-3, which is then subjected to a Wittig reaction to give XII-B-1, followed by reduction of the ester group to give compound XII-B-2, which is then subjected to a sulfonylation reaction to give the activated ester compound XII-B-3, which is then subjected to a substitution reaction with an amine to give compound XII-B-4, and the protecting group is removed to give intermediate XII-B-5. In an inert solvent, III-A-1 is substituted with III-A-2 to give intermediate III-A-2, which is then reacted with triphosgene to give isocyanate compound XII-A-7, which is then subjected to an addition reaction with XII-B-5 to give the desired compound XII-B.

[0071] Drug Compositions and Methods of Application The compound of the present invention has excellent inhibitory activity against a series of protein kinases, and therefore the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, as well as pharmaceutical compositions containing the compound of the present invention as a major active ingredient, are useful for the treatment, prevention, and alleviation of diseases associated with the activity or expression level of NLRP3.

[0072] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof in a safe and effective amount, and a pharmaceutically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains the compound of the present invention in an amount of 1-2000 mg / preparation, preferably 5-200 mg / preparation. Preferably, the "preparation" is a capsule or tablet.

[0073] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity for human application. "Compatible" means that each component in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the effectiveness of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tinctures, etc.), and the like. R ), humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free distilled water.

[0074] The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, but typical modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral administration (intravenous, intramuscular, or subcutaneous administration), and topical administration.

[0075] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is usually mixed with at least one inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or may contain (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant, such as agar, calcium carbonate, or the like. The pharmaceutical composition may be mixed with ingredients such as calcium, potato starch, tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retardants such as paraffin, (f) absorption promoters such as ammonium compounds, (g) wetting agents such as cetanol and glycerin monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0076] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings or shells, such as enteric coatings and other materials known in the art. Opacifying agents may be included, and in such compositions, the release of the active substance or compound may be delayed in a certain part of the digestive tract. Examples of encapsulating materials that can be used include polymeric and wax-based materials. If necessary, the active compound may also be formed into a microcapsule with one or more of the above-mentioned excipients.

[0077] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, compatibilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0078] Besides these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes. In addition to the active compound, suspensions may contain a suspending agent such as, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, aluminum methoxy or agar, or mixtures of these substances.

[0079] Compositions for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions and emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0080] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants, as required. The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0081] When using pharmaceutical compositions, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., human) in need of treatment, and the dosage is a pharmacologically effective dosage, for example, for a human weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 5-500 mg. Of course, the specific dosage should further take into account factors such as the mode of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0082] The main advantages of the present invention are as follows: 1. A compound of formula I is provided. 2. Provided are NLRP3 inhibitors with novel structures, and their production and use, which can suppress NLRP3 activity even at very low concentrations. 3. To provide a pharmaceutical composition for treating diseases associated with the activity of NLRP3. 4. Provide an NLRP3 inhibitor that is well absorbed when administered orally.

[0083] The present invention will be further described below with reference to specific examples. It is understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which no specific conditions are described were generally carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0084] Example 1: Preparation of Compound 1 [ka] Compounds 1a and 1d were prepared according to the method in patent WO2020035465.

[0085] Compound 1b (18 mg, 0.14 mmol) was dissolved in DMF (1.5 mL) and 60% sodium hydride (6 mg, 0.14 mmol) was added under ice bath conditions. After stirring the reaction mixture under nitrogen gas protection for 1 hour, a solution of compound 1a (14 mg, 0.06 mmol) in DMF (0.8 mL) was added. The reaction mixture was stirred under nitrogen gas protection at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product 1c obtained was used directly in the next step. LCMS: m / z 350.5 [M+H] + .

[0086] Crude product 1c (20 mg, 0.06 mmol) and compound 1d (14 mg, 0.06 mmol) were dissolved in acetonitrile (2.5 mL). The reaction mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 8:1, 2% aqueous ammonia) to give compound 1 (9 mg, 33% yield) as an off-white solid. 1 H NMR (500 MHz, CD3OD) δ 8.16 (d, J = 5.0 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J = 5.0 Hz, 1H), 6.68 (s, 1H), 5.78 (s, 1H), 4.94 (d, J = 13.5 Hz, 1H), 4.71 (d, J = 13.5 Hz, 1H), 3.67-3.52 (m, 2H), 3.28-3.13 (m, 2H), 2.98-2.89 (m, 3H), 2.88-2.84 (m, 1H), 2.83 (s, 3H), 2.79 (s, 3H), 2.53-2.38 (m, 2H), 2.14-2.07 (m, 2H), 2.06 (s, 3H) ppm. LCMS: m / z 471.5 [M+H] + .

[0087] Example 2: Preparation of Compound 2 [ka] (1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)methanol 2a (20 mg, 0.16 mmol) was dissolved in DMF (2 mL) and added with 60% sodium hydride (7 mg, 0.17 mmol) in an ice bath, followed by stirring for 0.5 h. A solution of compound 1a (20 mg, 0.08 mmol) in DMF (1 mL) was then added. The reaction mixture was stirred at 60 °C for 4 h under nitrogen gas protection. TLC monitoring indicated the completion of the reaction. The reaction mixture was distilled under reduced pressure, and the resulting crude product was separated and purified using a preparative thin-layer plate (dichloromethane:methanol = 15:1) to give compound 2b (13 mg, 45%) as an off-white solid. LCMS: m / z 350.5 [M+H] + .

[0088] Compound 2b (13 mg, 0.04 mmol) and 1d (10 mg, 0.04 mmol) were dissolved in acetonitrile (5 mL), and the mixture was stirred at 60°C for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer plate separation (dichloromethane:methanol:ammonia water = 10:1:0.1) to give compound 2 (3 mg, 17%) as an off-white solid. 1 H NMR (500 MHz, CD3OD) δ 8.14 (d, J = 5.0 Hz, 1H), 7.08 (s, 1H), 6.84 (d, J = 5.0 Hz, 1H), 6.70 (s, 1H), 6.05 (s, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 3.66 (s, 2H), 3.22-3.08 (m, 2H), 2.99-2.74 (m, 10H), 2.51-2.41 (m, 2H), 2.12-2.00 (m, 5H) ppm. LCMS: m / z 471.4 [M+H] + .

[0089] Example 3: Preparation of Compound 3 [ka]

[0090] Compound 3f was prepared by the method in patent WO2020035465. 4-Bromopyridine (1.12 g, 7.09 mmol) was dissolved in dichloromethane (5 mL), and iodomethane (2.01 g, 14.18 mmol) was added dropwise under stirring at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the solid was washed with a small amount of petroleum ether and dried to give product 3b (1.70 g, 80% yield) as a brown solid. 1 H NMR (500 MHz, D2O) δ 8.59 (d, J = 6.5 Hz, 2H), 8.24 (d, J = 6.5 Hz, 2H), 4.28 (s, 3H) ppm.

[0091] 3b (0.70 g, 2.33 mmol) and 4-bromo-2-hydroxypyridine (0.40 g, 2.33 mmol) were dissolved in acetonitrile (10 mL). Cesium carbonate (1.14 g, 3.50 mmol) was added in portions at room temperature under stirring. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the solid was washed with a small amount of acetonitrile and dried to give crude intermediate 3c (2.0 g). LCMS: m / z 265.2 & 267.2 [M+H] + .

[0092] Crude intermediate 3c (2.0 g) was dissolved in methanol (30 mL) and sodium borohydride (173 mg, 4.6 mmol) was added in portions at 0°C under stirring. The reaction mixture was stirred at 0°C for 1 hour. The pH was carefully adjusted to 8 with saturated aqueous sodium bicarbonate, followed by stirring for 5 minutes. The mixture was diluted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (0-10% methanol / dichloromethane) to obtain product 3d (0.3 g, 50% yield) as a brown solid. 1 H NMR (500 MHz, CD3OD) δ 7.44 (d, J = 7.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 7.0, 2.0 Hz, 1H), 5.93-5.80 (m, 1H), 3.19 (dd, J = 6.0 Hz, J = 3.0 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.54 (td, J = 6.0 Hz, J = 3.0 Hz, 2H), 2.44 (s, 3H) ppm.

[0093] 3d (120 mg, 0.445 mmol), bis(pinacolato)diboron (169 mg, 0.668 mmol), potassium acetate (131 mg, 1.34 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (36 mg, 0.045 mmol) were added to 1,4-dioxane (1 mL), purged with nitrogen gas, and stirred at 90 °C for 16 h. After cooling, the resulting mixture 3e was used directly in the next step. The resulting mixture of 3e was charged with compound 3f (50 mg, 0.22 mmol), potassium carbonate (123 mg, 0.891 mmol), water (0.1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (18 mg, 0.022 mmol). The mixture was purged with nitrogen and stirred at 60 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated, and the resulting crude product was purified by silica gel column chromatography (0-20% methanol / dichloromethane, containing 1% aqueous ammonia) to give product 3g as a brown solid (70 mg, 46% yield). 1 H NMR (500 MHz, CD3OD) δ 7.56 (d, J = 7.0 Hz, 1H), 6.56 (s, 1H), 6.38 (d, J = 1.5 Hz, 1H), 6.27 (dd, J = 7.0 Hz, J = 1.5 Hz, 1H), 5.98-5.87 (m, 1H), 3.25-3.23 (m, 2H), 2.86-2.82 (m, 4H), 2.76-2.68 (m, 2H), 2.66-2.60 (m, 2H), 2.47 (s, 3H), 2.11-2.04 (m, 2H), 2.04 (s, 3H) ppm. LCMS: m / z 336.4 [M+H] + .

[0094] Compound 3g (25 mg, 0.07 mmol) and compound 1d (18 mg, 0.07 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was heated to 60 °C and stirred for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified using a preparative thin-layer plate (dichloromethane:methanol:ammonia water = 10:2:0.1, V:V:V) to give compound 3 (5 mg, 15% yield) as a white solid. 1 H NMR (500 MHz, CD3OD) δ 7.52 (d, J = 7.0 Hz, 1H), 7.09 (s, 1H), 6.38 (s, 1H), 6.31 (dd, J = 7.0 Hz, J = 1.0 Hz, 1H), 5.95-5.91 (m, 1H), 3.39-3.34 (m, 2H), 3.03 (s, 3H), 3.01-2.93 (m, 4H), 2.90-2.84 (m, 2H), 2.69-2.62 (m, 2H), 2.57 (s, 3H), 2.16 (s, 3H), 2.12-2.06 (m, 2H) ppm. LCMS: m / z 457.6 [M+H] + .

[0095] Compound 3 (1.72 mg, 0.0038 mmoL) was dissolved in acetonitrile (1 mL) and 0.01 mol / L aqueous NaOH (0.38 mL) was added at room temperature. The reaction mixture was stirred for 5 minutes and then lyophilized to give the sodium salt of compound 3 as a white solid (1.8 mg, 100% yield). MS m / z 457.5 [M+H] + .

[0096] Example 4: Preparation of Compound 4 [ka]

[0097] Compound 4a (1.00 g, 4.22 mmol), compound 4b (1.31 g, 4.22 mmol), sodium carbonate (894 mg, 8.44 mmol), and tetrakis(triphenylphosphine)palladium (487 mg, 0.42 mmol) were dissolved in a toluene / ethanol / water (8:4:2, v:v:v) mixture (14 mL). The reaction mixture was heated to 100 °C under nitrogen gas protection and stirred for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (ethyl acetate:petroleum ether = 10:1, v / v) to give compound 4c (815 mg, 57% yield) as a white solid. LCMS: m / z 340.2 [M+H] + .

[0098] Compound 4c (180 mg, 0.53 mmol), bis(pinacolato)diboron (139 mg, 0.55 mmol), potassium acetate (208 mg, 2.12 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (41 mg, 0.05 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was heated to 100 °C under a nitrogen atmosphere and stirred for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, and then a solution of compound 3f (80 mg, 0.35 mmol) in 1,4-dioxane (2 mL) and a solution of potassium carbonate (219 mg, 1.59 mmol) in water (1 mL) were added. The reaction mixture was heated to 100 °C under a nitrogen atmosphere and stirred overnight. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer plate (dichloromethane:methanol=20:1) to give compound 4e (27 mg, 19% yield) as a white solid. LCMS: m / z 406.5 [M+H] + .

[0099] Compound 4e (27 mg, 0.07 mmol) and compound 1d (16 mg, 0.07 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was heated at 60 °C and stirred for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer plate (dichloromethane:methanol:ammonia water = 15:1:0.1, v:v:v) to give compound 4f (22 mg, 63% yield) as an off-white solid. LCMS: m / z 527.6 [M+H] + .

[0100] Compound 4f (22 mg, 0.04 mmol) was dissolved in methanol (5 mL) and then 4 M hydrogen chloride in methanol (0.5 mL) was added. The reaction mixture was heated to 50 °C and stirred for 2 h. When TLC monitoring showed the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified using a preparative thin-layer plate (dichloromethane:methanol = 10:1) to give compound 4g as a white solid (15 mg, 83% yield). LCMS: m / z 427.5 [M+H] + .

[0101] Compound 4g (15 mg, 0.04 mmol) was dissolved in methanol (5 mL) and sequentially charged with paraformaldehyde (2 mg, 0.07 mmol), anhydrous zinc chloride (14 mg, 0.11 mmol), and sodium cyanoborohydride (7 mg, 0.11 mmol). The reaction mixture was heated to 60 °C and stirred for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (5 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate chromatography (dichloromethane:methanol:ammonia water = 15:1:0.1, v:v:v) to give compound 4 (3 mg, 19% yield) as a gray solid. 1H NMR (500 MHz, CD3OD) δ 8.57 (d, J = 5.0 Hz, 1H), 7.43 (s, 1H), 7.20 (dd, J = 5.0, 1.5 Hz, 1H), 7.15 (s, 1H), 6.68-6.63 (m, 1H), 3.92 (s, 2H), 3.47 (t, J = 6.0 Hz, 2H), 3.03 (s, 3H), 3.01-2.95 (m, 6H), 2.93-2.84 (m, 3H), 2.15-2.08 (m, 2H), 2.04 (s, 3H) ppm. LCMS: m / z 441.4 [M+H] + .

[0102] Example 5: Preparation of Compound 5 [ka] Compound 5b was obtained as a yellow solid (15 mg, 26% yield) from compound 1a (30 mg, 0.12 mmol) and compound 5a (28 mg, 0.24 mmol) by the method described in Example 2. LCMS: m / z 337.4 [M+H] + .

[0103] Compound 5 was obtained as a white solid (12 mg, 59% yield) from compound 5b (15 mg, 0.04 mmol) and compound 1d (11 mg, 0.04 mmol) by the method in Example 2. 1H NMR (500 MHz, CD3OD) δ 8.14 (d, J = 5.0 Hz, 1H), 7.10 (s, 1H), 6.81 (dd, J = 5.0, 1.0 Hz, 1H), 6.68 (s, 1H), 5.87-5.83 (m, 1H), 4.79-4.69 (m, 2H), 4.16-4.12 (m, 2H), 3.84-3.80 (m, 2H), 2.98 (s, 3H), 2.94 (t, J = 7.5 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.24 -2.18 (m, 2H), 2.12-2.04 (m, 2H), 2.06 (s, 3H) ppm. LCMS: m / z 458.4 [M+H] + .

[0104] Example 6: Preparation of Compound 6 [ka] Cyclopropylsulfonamide 6a (2.00 g, 16.51 mmol) and 4-dimethylaminopyridine (4.03 g, 33.02 mmol) were dissolved in acetonitrile (28 mL) and stirred at room temperature for 10 min. Diphenyl carbonate (3.89 g, 18.16 mmol) was added, and the reaction mixture was stirred at room temperature for 48 h. The resulting reaction mixture containing 6b was used directly in the next step.

[0105] Compound 2b (40 mg, 0.11 mmol) and compound 6b (0.5 mL of the above reaction mixture) were dissolved in acetonitrile (5 mL). The reaction mixture was heated to 60 °C and stirred for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified using a preparative thin-layer plate (dichloromethane:methanol:ammonia water = 10:1:0.1) to give compound 6 (17 mg, 30% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.14 (d, J = 5.2 Hz, 1H), 7.07 (s, 1H), 6.83 (d, J = 5.2 Hz, 1H), 6.69 (s, 1H), 6.01 (s, 1H), 4.94 (d, J = 12.5 Hz, 1H), 4.69 (d, J = 12.5 Hz, 1H), 3.53 (s, 2H), 3.03 (dd, J = 10.9, 5.6 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 2.90-2.84 (m, 2H), 2.73 (s, 3H), 2.65-2.59 (m, 1H), 2.48-2.39 (m, 2H), 2.13-2.06 (m, 2H), 2.05 (s, 3H), 1.04-0.97 (m, 2H), 0.91-0.84 (m, 2H) ppm. MS m / z 497.5 [M+H] + .

[0106] Compound 6 (14.36 mg, 0.0289 mmoL) was dissolved in acetonitrile (2 mL), 0.01 mol / L aqueous NaOH (2.89 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 6 as a white solid (15 mg, 100% yield). MS m / z 497.5 [M+H] + .

[0107] Example 7: Preparation of Compound 7 [ka]

[0108] N,N-Dimethylaminosulfonamide (2.00 g, 16.11 mmol) and 4-dimethylaminopyridine (3.94 g, 32.22 mmol) were dissolved in acetonitrile (28 mL) and stirred at room temperature for 10 minutes. Diphenyl carbonate (3.80 g, 17.72 mmol) was added and the reaction mixture was stirred at room temperature overnight, resulting in the precipitation of a white solid. The reaction mixture was filtered, washed with methyl t-butyl ether, and the solid was dried under reduced pressure to give compound 7b (1.20 g, 27% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 3.25 (s, 6H), 2.66 (s, 6H) ppm.

[0109] Compound 7 was obtained as a white solid (15 mg, 26% yield) from compound 2b (40 mg, 0.11 mmol) and compound 7b (63 mg, 0.23 mmol) by the method described in Example 2. 1 H NMR (500 MHz, CD3OD) δ 8.16 (d, J = 5.2 Hz, 1H), 7.09 (s, 1H), 6.81 (d, J = 5.2 Hz, 1H), 6.67 (s, 1H), 6.00 (s, 1H), 4.89 (d, J = 12.6 Hz, 1H), 4.72 (d, J = 12.3 Hz, 1H), 3.49-3.39 (m, 2H), 2.98-2.90 (m, 4H), 2.87-2.82 (m, 2H), 2.70-2.63 (m, 9H), 2.46-2.34 (m, 2H), 2.12-2.06 (m, 2H), 2.05 (s, 3H)ppm. MS m / z 500.5 [M+H] + .

[0110] Compound 7 (13.41 mg, 0.0268 mmoL) was dissolved in acetonitrile (2 mL), and 0.01 mol / L aqueous NaOH solution (2.68 mL) was added at room temperature. The mixture was stirred for 5 minutes and then lyophilized to obtain the sodium salt of compound 7. MS m / z 500.7 [M+H] + .

[0111] Example 8: Preparation of Compound 8 [ka]

[0112] Compound 8a (1.00 g, 7.41 mmol) and potassium thioacetate (1.69 g, 14.81 mmol) were dissolved in DMF (10 mL). The reaction mixture was heated to 60 °C and stirred for 4 h. TLC monitoring indicated the reaction was complete. The reaction mixture was added with saturated brine (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was further purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give product 8b (670 mg, 69%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 4.15-4.06 (m, 1H), 2.49-2.38 (m, 2H), 2.27 (s, 3H), 2.11-1.93 (m, 4H) ppm.

[0113] NCS (824 mg, 6.17 mmol) was dissolved in acetonitrile (10 mL), and concentrated hydrochloric acid (1.5 mL) was added. The mixture was stirred at room temperature for 10 min. A solution of compound 8b (670 mg, 5.15 mmol) in acetonitrile (5 mL) was added in an ice bath, and the reaction mixture was stirred in an ice bath for 10 min. TLC monitoring indicated the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with methyl t-butyl ether (3 × 30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 8c (548 mg, 69%) as a yellow oil, which was used directly in the next step.

[0114] Compound 8c (548 mg, 3.56 mmol) was dissolved in dichloromethane (5 mL), concentrated aqueous ammonia (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. When TLC monitoring showed the reaction was complete, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 8d (234 mg, 34%). 1 H NMR (500 MHz, DMSO-d6) δ 6.72 (s, 2H), 3.75-3.70 (m, 1H), 2.34-2.16 (m, 4H), 1.97-1.82 (m, 2H) ppm.

[0115] Compound 8d (234 mg, 1.73 mmol) and 4-dimethylaminopyridine (423 mg, 3.46 mmol) were dissolved in acetonitrile (3 mL) and stirred at room temperature for 10 minutes. Diphenyl carbonate (408 mg, 1.90 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction mixture containing 8e was used directly in the next step.

[0116] Compound 2b (40 mg, 0.11 mmol) and compound 8e (0.5 mL reaction solution) were dissolved in acetonitrile (5 mL). The reaction mixture was heated to 60 °C and stirred for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified using a preparative thin-layer plate (dichloromethane:methanol:ammonia water = 10:1:0.1) to give compound 8 (11 mg, 19% yield) as a white solid. 1 H NMR (500 MHz, CD3OD) δ 8.15 (d, J = 5.2 Hz, 1H), 7.06 (s, 1H), 6.82 (d, J = 5.1 Hz, 1H), 6.66 (s, 1H), 6.02 (s, 1H), 4.93 (d, J = 12.5 Hz, 1H), 4.71 (d, J = 12.1 Hz, 1H), 3.98-3.91 (m, 1H), 3.55 (s, 2H), 3.12-3.00 (m, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.88-2.82 (m, 2H), 2.74 (s, 3H), 2.48-2.40 (m, 2H), 2.40-2.32 (m, 2H), 2.21-2.13 (m, 2H), 2.11-2.05 (m, 2H), 2.04 (s, 3H), 2.00-1.85 (m, 2H). MS m / z 511.6 [M+H] + .

[0117] Compound 8 (9.59 mg, 0.0188 mmoL) was dissolved in acetonitrile (2 mL), 0.01 mol / L aqueous NaOH (1.88 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 8 as a white solid (10 mg, 100% yield). MS m / z 511.5 [M+H] + .

[0118] Example 9: Preparation of Compound 9 [ka]

[0119] Compound 9 (11 mg, 19% yield) was obtained as a white solid from compound 3g (40 mg, 0.12 mmol) and compound 6b (0.5 mL reaction solution) by the method of Example 6. 1 H NMR (500 MHz, CDCl3) δ 7.74 (brs, 1H), 7.29 (d, J = 6.8 Hz, 1H), 7.02 (s, 1H), 6.32 (s, 1H), 6.13 (d, J = 6.7 Hz, 1H), 5.77 (s, 1H), 4.80 (brs, 1H), 3.19-3.04 (m, 2H), 2.98-2.77 (m, 6H), 2.74-2.61 (m, 2H), 2.59-2.50 (m, 1H), 2.43 (s, 3H), 2.12 (s, 3H), 2.10-2.00 (m, 2H), 1.20-1.10 (m, 2H), 0.90-0.80 (m, 2H) ppm. MS m / z 483.5 [M+H] + .

[0120] Compound 9 (10.52 mg, 0.0218 mmoL) was dissolved in acetonitrile (2 mL), 0.01 mol / L aqueous NaOH (2.18 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 9 as a white solid (11.0 mg, 100% yield). MS m / z 483.6 [M+H] + .

[0121] Example 10: Preparation of Compound 10 [ka]

[0122] The crude product of compound 10b (97 mg, 55% yield) was obtained from compound 1a (30 mg, 0.12 mmol) and compound 10a (66 mg, 0.31 mmol) by the method described in Example 1. MS m / z 436.5 [M+H] + . Compound 10c was obtained as a white solid (20 mg, 29% yield) from compound 10b (97 mg, purity: approximately 55%) and 1d (30 mg, 0.12 mmol) by the method described in Example 1. MS m / z 557.7 [M+H] + .

[0123] Compound 10c (20 mg, 0.04 mmol) was dissolved in methanol (3 mL) and a 4 M solution of hydrogen hydrochloride in methanol (4 M / 0.5 mL) was added. The reaction mixture was heated to 40 °C and reacted for 1 hour. After the reaction mixture was cooled, aqueous ammonia was added to adjust the pH to neutral, and the reaction mixture was concentrated under reduced pressure. The resulting crude product was separated and purified using a preparative thin-layer plate (dichloromethane:methanol:ammonia water = 2:1:0.02) to give compound 10 as a white solid (7 mg, 43% yield). 1 H NMR (500 MHz, CD3OD) δ 8.15 (d, J = 5.2 Hz, 1H), 7.12 (s, 1H), 6.83 (d, J = 4.2 Hz, 1H), 6.60 (s, 1H), 5.07-5.01 (m, 1H), 4.16 (s, 2 H), 4.10 (s, 2H), 3.05 (s, 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.90-2.82 (m, 4H), 2.46-2.36 (m, 2H), 2.13-2.07 (m, 2H), 2.06 (s, 3H) ppm. MS m / z 457.4 [M+H] + .

[0124] Compound 10 (3.82 mg, 0.0084 mmoL) was dissolved in acetonitrile (1 mL), 0.01 mol / L aqueous NaOH (0.84 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 10 as a white solid (4.0 mg, 100% yield). MS m / z 457.6 [M+H] + .

[0125] Example 11: Preparation of Compound 11 [ka]

[0126] Compound 11a (4.00 g, 29.39 mmol) and iodobenzene diacetate (14.20 g, 44.09 mmol) were dissolved in dichloromethane and potassium bromide (5.95 g, 49.96 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours while irradiating with a 365 nm fluorescent lamp. The reaction mixture was filtered, and the filtrate was distilled at 70 °C under atmospheric pressure until no further distillates remained. Further distillation at 60 °C under reduced pressure yielded compound 11b (2.07 g, 41% yield) as a pale yellow liquid. 1 H NMR (500 MHz, CDCl3) δ 4.28-4.13 (m, 1H), 3.38-3.19 (m, 2H), 3.06-2.89 (m, 2H) ppm.

[0127] Compound 11c (150 mg, 15% yield) was obtained as a yellow oil from compound 11b (1.00 g, 5.85 mmol) and potassium thioacetate (1.27 g, 7.41 mmol) by the method of Example 8. 1 H NMR (500 MHz, CDCl3) δ 3.87-3.75 (m, 1H), 3.18-3.05(m, 2H), 2.64-2.50 (m, 2H), 2.33 (s, 3H) ppm.

[0128] Compound 11c (100 mg, 0.60 mmol) and compound 11e (20 mg, 17% yield) were prepared by the method of Example 8. 1 H NMR (500 MHz, CDCl3) δ 7.11 (s, 2H), 3.76-3.66 (m, 1H), 3.02-2.83 (m, 4H). ppm.

[0129] Compound 11e (20 mg, 0.12 mmol) and 4-dimethylaminopyridine (29 mg, 0.23 mmol) were dissolved in acetonitrile (1 mL) and stirred at room temperature for 10 minutes. The resulting reaction solution containing 11f was used directly in the next step.

[0130] Compound 11 was obtained as a white solid (5 mg, 13% yield) from compound 2b (20 mg, 0.06 mmol) and compound 11f (1.0 mL reaction solution) by the method of Example 6. 1 H NMR (500 MHz, CD3OD) δ 8.14 (d, J = 5.1 Hz, 1H), 7.05 (s, 1H), 6.83 (dd, J = 5.2, 1.1 Hz, 1H), 6.70 (s, 1H), 6.07 (s, 1H), 5.01 (d, J = 12.7 Hz, 1H), 4.69 (d, J = 11.2 Hz, 1H), 3.88-3.79 (m, 1H), 3.72 (m, 2H), 3.27-3.18 (m, 2H), 2.96-2.84 (m, 6H), 2.87 (s, 3H), 2.80-2.70 (m, 2H), 2.52-2.46 (m, 2H), 2.12-2.02 (m, 2H), 2.05 (s, 3H).MS m / z 547.6 [M+H] + .

[0131] Compound 11 (4.58 mg, 0.0084 mmoL) was dissolved in acetonitrile (1 mL), 0.01 mol / L aqueous NaOH (0.84 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 11 as a white solid (4.76 mg, 100% yield). MS m / z 547.8 [M+H] + .

[0132] Example 12: Preparation of Compound 12 [ka] Compound 12a was prepared by the method in patent WO2020104657.

[0133] Compound 12 was obtained as a white solid (30 mg, yield 90%) from compound 2b (21 mg, 0.06 mmol) and compound 12a (40 mg, 0.12 mmol) by the method in Example 6. 1 H NMR (500 MHz, CD3OD) δ 8.15 (d, J = 4.5 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.11 (s, 1H), 6.79 (d, J = 4.5 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.66 (s, 1H), 6.14 (s, 1H), 5.04 (d, J = 12.8 Hz, 1H), 4.76 (d, J = 12.3 Hz, 1H), 4.61 (dt, J = 13.4, 6.7 Hz, 1H), 3.88 (s, 2H), 3.41-3.35 (m, 2H), 2.98 (s, MS m / z 565.8 [M+H] + .

[0134] Compound 12 (24 mg, 0.0426 mmoL) was dissolved in acetonitrile (2 mL), 0.01 mol / L aqueous NaOH (4.26 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 12 as a white solid (25 mg, 100% yield). MS m / z 565.7 [M+H] + .

[0135] Example 13: Preparation of Compound 13 [ka]

[0136] Compound 13a (100 mg, 0.59 mmol) was dissolved in dichloromethane (1 mL) and aqueous ammonia (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. Complete reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica column chromatography to give compound 13b (71 mg, 80% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 6.70 (s, 2H), 3.43-3.35 (m, 1H), 1.94-1.81 (m, 4H), 1.70-1.60 (m, 2H), 1.59- 1.50 (m, 2H) ppm.

[0137] Compound 13b (70 mg, 0.47 mmol) and 4-dimethylaminopyridine (115 mg, 0.94 mmol) were dissolved in acetonitrile (3 mL) and stirred at room temperature for 5 minutes. Diphenyl carbonate (120 mg, 0.56 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction mixture containing 13c was used directly in the next step.

[0138] Compound 13 was obtained as a white solid (2.8 mg, 32% yield) from compound 2b (6 mg, 0.02 mmol) and compound 11f (0.4 mL reaction solution) by the method of Example 6. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.41 (s, 1H), 7.07 (s, 1H), 6.74 (d, J = 5.1 Hz, 1H), 6.57 (s, 1H), 5.83 (s, 1H), 4.70 (s, 2H), 3.71-3.63 (m, 1H), 2.94-2.85 (m, 3H), 2.74 (t, J = 7.3 Hz, 2H), 2.65-2.62 (m, 1H), 2.44 (t, J = 5.6 Hz, 2H), 2.38-2.34 (m, 1H), 2.27 (s, 3H), 2.14 (s, 2H), 2.03-2.00 (m, 1H), 1.98 (s, 3H), 1.80-1.71 (m, 4H), 1.64-1.56 (m, 2H), 1.56-1.48 (m, 2H) ppm. MS m / z 525.7 [M+H] + .

[0139] Compound 13 (1.27 mg, 0.0024 mmoL) was dissolved in acetonitrile (0.2 mL), 0.01 mol / L aqueous NaOH (0.24 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 13 as a white solid (1.32 mg, 100% yield). MS m / z 525.5 [M+H] + .

[0140] Example 14: Preparation of Compound 14 [ka]

[0141] Sulfonamide (353 mg, 3.68 mmol) was dissolved in 1,4-dioxane (4 mL), and compound 14a (200 mg, 3.50 mmol) was added. The reaction mixture was heated at 90°C and stirred for 24 hours. Complete reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was dissolved in chloroform. The reaction mixture was further concentrated under reduced pressure to give crude compound 14b as a white solid, which was used directly in the next step. 1 H NMR (500 MHz, DMSO-d6) δ 6.84 (s, 2H), 3.67 (t, J = 7.7 Hz, 4H), 2.11-2.03 (m, 2H) ppm.

[0142] Compound 14b (477 mg) and 4-dimethylaminopyridine (855 mg, 7.00 mmol) were dissolved in acetonitrile (5 mL) and stirred at room temperature for 5 minutes. Diphenyl carbonate (900 mg, 4.20 mmol) was added, and the reaction mixture was stirred at room temperature for 3 days. The resulting reaction mixture containing 14c was used directly in the next step.

[0143] Compound 14 (6.37 mg, 35% yield) was obtained as a white solid from compound 2b (12 mg, 0.03 mmol) and compound 14c (1 mL reaction solution) by the method described in Example 6. 1 H NMR (500 MHz, CD3OD) δ 8.17 (d, J = 5.2 Hz, 1H), 7.08 (s, 1H), 6.84 (dd, J = 5.2, 1.2 Hz, 1H), 6.71 (s, 1H), 6.01 (s, 1H), 4.96 (d, J = 12.6 Hz, 1H), 4.69 (d, J = 12.6 Hz, 1H), 3.76-3.65 (m, 4H), 3.60-3.46 (m, 2H), 3.09-3.00 (m, 2H), 2.95 (t, J = 7.4 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.74 (s, 3H), 2.51-2.35 (m, 2H), 2.13-2.07 (m, 4H), 2.06 (s, 3H) ppm. MS m / z 512.6 [M+H] + .

[0144] Compound 14 (2.34 mg, 0.0046 mmoL) was dissolved in acetonitrile (0.5 mL), 0.01 mol / L aqueous NaOH (0.46 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 14 as a white solid (2.44 mg, 100% yield). MS m / z 512.6 [M+H] + .

[0145] Example 15: Preparation of Compound 15 [ka]

[0146] Compound 15a (200 mg, 1.08 mmol) was dissolved in dichloromethane (5 mL) in an ice-water bath, and diethylaminosulfur trifluoride 15b (261 mg, 1.62 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 15c (45 mg, 20% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (s, 1H), 5.90 (t, J = 57.1 Hz, 1H), 1.38 (s, 9H), 0.97-0.91 (m, 2H), 0.84-0.76 (m, 2H) ppm.

[0147] Compound 15c (45 mg, 0.22 mmol) was dissolved in dichloromethane (4 mL) and a solution of hydrogen chloride in 1,4-dioxane (4 M, 1 mL) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give product 15d (31 mg, 100% yield) as a brown solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.11 (brs, 3H), 5.96 (t, J = 53.8 Hz, 1H), 1.21-1.14 (m, 2H), 1.04-1.00 (m, 2H) ppm.

[0148] In an ice-water bath, chlorosulfonyl isocyanate 15f (7 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL) and compound 15e (8 mg, 0.05 mmol) was added. The reaction mixture was stirred in the ice-water bath for 10 min. When TLC monitoring showed the reaction was complete, a mixture of compound 15d (13 mg, 0.09 mmol) and diisopropylethylamine (2 drops) in dichloromethane (2 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The resulting crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to obtain compound 15 as a white solid (4 mg, 22% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.89 (s, 1H), 6.91 (s, 1H), 6.12 (t, J = 57.6 Hz, 1H), 2.80 (t, J = 7.3 Hz, 4H), 2.70 (t, J = 7.3 Hz, 4H), 2.02-1.92 (m, 4H), 1.10-1.05 (m, 2H), 0.96-0.91 (m, 2H) ppm. MS m / z 386.5 [M+H] + .

[0149] Compound 15 (2.89 mg, 0.0075 mmoL) was dissolved in acetonitrile (1 mL), 0.01 mol / L aqueous NaOH (0.75 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 15 as a white solid (3.05 mg, 100% yield). MS m / z 386.3 [M+H] + .

[0150] Example 16: Preparation of Compound 16 [ka]

[0151] Potassium t-butoxide (549 mg, 4.89 mmol) was dissolved in DMF (5 mL) and cooled to -50 °C. Under a nitrogen atmosphere, a solution of 16a (503 mg, 2.72 mmol) and 16b (472 mg, 2.44 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at -50 °C for 1 h. Saturated ammonium chloride (10 mL) and concentrated hydrochloric acid (5 mL) were added and stirred at room temperature for 3 h. Complete reaction was confirmed by TLC. 30 mL of water was added and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 16c (353 mg, 59% yield) as a white solid. 1 H NMR (500 MHz, CDCl3) δ 5.01 (s, 1H), 4.54 (d, J = 24.5 Hz, 1H), 1.44 (s, 9H), 1.04-0.90 (m, 4H) ppm.

[0152] Compound 16c (353 mg, 1.61 mmol) was dissolved in dichloromethane (10 mL) and a solution of hydrogen chloride in dioxane (4 M, 3 mL) was added. The reaction mixture was heated at 40°C and stirred overnight. Complete reaction was detected by TLC. The reaction mixture was concentrated under reduced pressure, and the crude product, compound 16d, was used directly in the next step.

[0153] Compound 16d (250 mg, 1.61 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), and diisopropylethylamine (5 drops) and sulfonamide (185 mg, 1.93 mmol) were added. The reaction mixture was heated to 90 °C and stirred overnight. When TLC showed the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 16e (82 mg, 26% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.30 (s, 1H), 6.63 (s, 2H), 4.90 (dd, J = 25.9, 3.3 Hz, 1H), 1.12 (q, J = 4.8 Hz, 2H), 0.78 (q, J = 5.0 Hz, 2H) ppm.

[0154] Compound 16e (82 mg, 0.41 mmol) and 4-dimethylaminopyridine (101 mg, 0.83 mmol) were dissolved in acetonitrile (2 mL) and stirred at room temperature for 5 minutes. Diphenyl carbonate (98 mg, 0.46 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction mixture containing 16f was used directly in the next step.

[0155] Compound 16 (3 mg, 13% yield) was obtained as a white solid from compound 15e (10 mg, 0.06 mmol) and compound 16f (1.0 mL reaction solution) by the method described in Example 6. 1 H NMR (500 MHz, CD3OD) δ 6.98 (s, 1H), 4.82 (dd, J = 24.8, 2.4 Hz, 1H), 2.87 (t, J = 7.3 Hz, 4H), 2.79 (t, J = 7.3 Hz, 4H), 2.11 - 2.02 (m, MS m / z 398.4 [M+H] + .

[0156] Compound 16 (2.41 mg, 0.0061 mmoL) was dissolved in acetonitrile (1 mL), 0.01 mol / L aqueous NaOH (0.61 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The resulting mixture was then lyophilized to give the sodium salt of compound 16 as a white solid (2.54 mg, 100% yield). MS m / z 398.3 [M+H] + .

[0157] Example 17: Preparation of Compound 17 [ka]

[0158] Compound 17b was obtained as a white solid (384 mg, 32% yield) from compound 17a (1.00 g, 5.40 mmol), compound 16b (939 mg, 4.86 mmol), and potassium t-butoxide (1.09 g, 9.72 mmol) by the method of Example 16. 1 H NMR (500 MHz, CDCl3) δ 4.79 (brs, 1H), 4.23 (brs, 1H), 3.13-2.99 (m, 2H), 2.60-2.48 (m, 2H), 1.44 (s, 9H) ppm.

[0159] A crude product of compound 17c was obtained from compound 17b (148 mg, 0.68 mmol) by the method in Example 16, and was used as it was in the next reaction step. Compound 17d was obtained as a white solid (50 mg, 37% yield) from compound 17c (105 mg, 0.67 mmol) and sulfamide (78 mg, 0.81 mmol) by the method of Example 16. 1 H NMR (500 MHz, DMSO-d6) δ 7.16 (d, J = 8.8 Hz, 1H), 6.62 (s, 2H), 3.92-3.76 (m, 1H), 3.03-2.91 (m, 2H), 2.74-2.62 (m, 2H) ppm.

[0160] Compound 17d (50 mg, 0.25 mmol) and 4-dimethylaminopyridine (62 mg, 0.50 mmol) were dissolved in acetonitrile (2 mL) and stirred at room temperature for 5 minutes. Diphenyl carbonate (59 mg, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction mixture containing 17e was used directly in the next step.

[0161] Compound 17 (7 mg, 20% yield) was obtained as a white solid from compound 15e (15 mg, 0.09 mmol) and compound 17e (1.0 mL reaction solution) by the method described in Example 6. 1 H NMR (500 MHz, CD3OD) δ 6.98 (s, 1H), 4.10-4.02 (m, 1H), 3.11-3.03 (m, 2H), 2.87 (t, J = 7.4 Hz, 4H), 2.79 (t, J = 7.4 Hz, 4H), 2.77-2.72 (m, 2H), 2.09-2.03 (m, 4H) ppm. MS m / z 398.4 [M+H] + .

[0162] Compound 17 (6.4 mg, 0.0161 mmoL) was dissolved in acetonitrile (1 mL), and 0.01 mol / L aqueous NaOH solution (1.61 mL) was added at room temperature. The mixture was stirred for 5 minutes and then lyophilized to give the sodium salt of compound 17 as a white solid (6.74 mg, 100% yield). 1 H NMR (500 MHz, CD3OD) δ 6.88 (s, 1H), 3.99-3.90 (m, 1H), 3.05-2.94 (m, 2H), 2.88-2.74 (m, 8H), 2.74-2.61 (m, 2H), 2.11-1.95 (m, 4H) ppm. MS m / z 398.3 [M+H] + .

[0163] Example 18: Preparation of Compound 18 [ka]

[0164] Compound 18a (90 mg, 0.53 mmol) was dissolved in 1,4-dioxane (1.5 mL), and two drops of diisopropylethylamine were added to adjust the pH of the mixture to basic. Sulfoamide (62 mg, 0.64 mmol) was then added. The reaction mixture was stirred at 95 °C overnight. After cooling to room temperature, the reaction mixture was filtered and washed. The filtrate was concentrated under reduced pressure to give crude product 18b as a white solid, which was used directly in the next step.

[0165] The white solid crude product 18b (111 mg) and 4-dimethylaminopyridine (96 mg, 0.78 mmol) were dissolved in acetonitrile (3 mL) and stirred at room temperature for 5 min. Diphenyl carbonate (123 mg, 0.58 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The resulting reaction mixture containing 18c was used directly in the next step.

[0166] Compound 17 (7.30 mg, 31% yield) was obtained as a white solid from compound 15e (10 mg, 0.06 mmol) and compound 18c (0.5 mL reaction solution) by the method described in Example 6. 1 H NMR (500 MHz, CDCl3) δ 7.00 (s, 1H), 3.41-3.22 (m, 4H), 2.93-2.81 (m, 4H), 2.81-2.68 (m, 4H), 2.39-2.19 (m, 4H), 2.13-1.96 (m, 4H)ppm. MS m / z 412.4 [M+H] + .

[0167] Compound 18 (6.93 mg, 0.0168 mmoL) was dissolved in acetonitrile (1 mL), and 0.01 mol / L aqueous NaOH solution (1.68 mL) was added at room temperature. The mixture was stirred for 5 minutes and then lyophilized to give the sodium salt of compound 18 as a white solid (7.30 mg, 100% yield). 1H NMR (500 MHz, CD3OD) δ 6.87 (s, 1H), 3.22 (t, J = 5.5 Hz, 4H), 2.87-2.77 (m, 8H), 2.27 (t, J = 5.5 Hz, 4H), 2.08-1.98 (m, 4H). MS m / z 412.4 [M+H] + .

[0168] Example 19: Preparation of Compound 19 [ka]

[0169] Sodium hydride (642 mg, 60%, 16.06 mmol) was dissolved in tetrahydrofuran (25 mL) under a nitrogen atmosphere. The reaction mixture was cooled to -78 °C, and ethyl 2-(diethoxyphosphanyl)acetate (3.60 g, 16.06 mmol) was added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 0.5 h. Compound 19a (2.50 g, 14.60 mmol) was added in an ice bath, and the reaction mixture was warmed to room temperature and stirred overnight. When TLC monitoring showed the reaction was complete, the reaction mixture was quenched with aqueous sodium bicarbonate in an ice bath and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give compound 19b (2.50 g, 71% yield).

[0170] Compound 19b (590 mg, 2.45 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to −78 °C under a nitrogen atmosphere. A 1.0 M solution of diisobutylaluminum hydride in tetrahydrofuran (5.1 mL, 5.10 mmol) was added dropwise. After the addition, the reaction mixture was stirred for 1 h at −78 °C. When TLC monitoring indicated the reaction was complete, the reaction mixture was warmed to 0 °C, and water (0.2 mL), 15% aqueous sodium hydroxide (0.2 mL), and water (0.4 mL) were added dropwise. The reaction mixture was then warmed to room temperature and stirred for 15 min. Anhydrous sodium sulfate was added, stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 19c (372 mg, 76%).

[0171] Compound 19c (200 mg, 1.00 mmol) was dissolved in dichloromethane (5 mL), and diisopropylethylamine (388 mg, 3.01 mmol) and methanesulfonyl chloride (172 mg, 1.51 mmol) were added dropwise in an ice bath. The reaction mixture was warmed to room temperature and stirred for 2 hours. TLC monitoring indicated the reaction was complete. Saturated brine was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product, compound 19d (208 mg, 75%), was used directly in the next step.

[0172] Compound 19d (100 mg, 0.36 mmol), sodium iodide (5 mg, 0.04 mmol), and a 1.0 M solution of dimethylamine in tetrahydrofuran (2 mL, 2.00 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated in a sealed tube at 60 °C and stirred for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by silica column chromatography to give compound 19e (51 mg, 63% yield). MS m / z 227.4 [M+H] + .

[0173] Compound 19e (30 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction mixture was heated to 40 °C and stirred for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, dissolved in acetonitrile (1 mL), and concentrated hydrochloric acid (0.1 mL) was added dropwise. The mixture was lyophilized to give compound 19f (21 mg, 97%). MS m / z 127.2 [M+H] + .

[0174] Chlorosulfonyl isocyanate (6 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL) and compound 19g (8 mg, 0.04 mmol) was added in an ice bath. The reaction mixture was stirred in an ice bath for 10 minutes, and then compound 19f (11 mg, 0.09 mmol) was added and stirred at room temperature for 1 hour. Complete reaction was confirmed by TLC. The reaction mixture was quenched with water and extracted with dichloromethane (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reverse-phase column chromatography to give compound 19 (0.7 mg, 4%). MS m / z 405.4 [M+H] + .

[0175] Example 20: Preparation of Compound 20 [ka]

[0176] Potassium t-butoxide (163 mg, 1.46 mmol) was dissolved in DMF (2 mL) and cooled to -50 °C under a nitrogen atmosphere. A mixture of compound 20a (150 mg, 0.81 mmol) and compound 20b (140 mg, 0.73 mmol) in DMF (2 mL) was added. The reaction mixture was maintained at -50 °C and stirred for 1 h. TLC monitoring indicated the reaction was complete. The reaction was quenched with concentrated hydrochloric acid (1 mL) and stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give compound 20c (63 mg, 36%). 1 H NMR (500 MHz, CDCl3) δ 5.01 (s, 1H), 4.54 (d, J = 24.5 Hz, 1H), 1.44 (s, 9H), 1.02-0.96 (m, 2H), 0.94-0.89 (m, 2H) ppm.

[0177] Compound 20c (45 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL) and a 4.0 M solution of hydrochloric acid in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature overnight. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product, compound 20d, was used directly in the next step. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 3H), 4.94 (dd,J = 1.4 Hz, J = 25.1 Hz, 1H), 1.22 (t, J = 6.3 Hz, 2H), 0.94 (t, J = 6.3 Hz, 2H) ppm.

[0178] Compound 20d (45 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL), and diisopropylethylamine (148 mg, 1.15 mmol) and aminosulfonyl chloride (40 mg, 0.35 mmol) were added dropwise in an ice bath. The reaction mixture was stirred in an ice bath for 0.5 h. When TLC monitoring showed the reaction was complete, the mixture was concentrated under reduced pressure and purified by preparative thin-layer plate separation to give compound 20e (27 mg, 47% yield).

[0179] Compound 20e (27 mg, 0.14 mmol) and DMAP (33 mg, 0.27 mmol) were dissolved in acetonitrile (1 mL) and stirred at room temperature for 10 min. Diphenyl carbonate (32 mg, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 48 h. The resulting reaction mixture containing compound 20f was used directly in the next step. Compound 20g was prepared by the method in patent WO20190211463.

[0180] Compound 20g (14 mg, 0.06 mmol) and compound 20f (1 mL reaction solution) were dissolved in acetonitrile (1 mL). The reaction mixture was heated to 60 °C and stirred for 3 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified using a preparative thin-layer plate (dichloromethane:methanol:ammonia water = 10:1:0.1) to give compound 20 (3 mg, 11%) as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.17 (d, J = 5.2 Hz, 1H), 7.12 (s, 1H), 6.78 (dd, J = 5.2, 1.3 Hz, 1H), 6.63 (s, 1H), 4.68 (dd, J = 24.6, 2.4 Hz, 1H), 3.93 (s, 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.86-2.81 (m, 2H), 2.12-2.05 (m, 2H), 2.04 (s, 3H), 1.32-1.26 (m, 2H), 1.10-1.03 (m, 2H)ppm. MS m / z 479.5 [M+H] + .

[0181] Example 21: Preparation of Compound 21 [ka] Compound 21a was synthesized according to the method in patent WO2019034690.

[0182] Compound 21a (700 mg, 1.81 mmol) was dissolved in tetrahydrofuran (14 mL) and 3-bromocyclobutanone (404 mg, 2.71 mmol) and potassium carbonate (499 mg, 3.61 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. TLC monitoring indicated the reaction was complete. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 21b (505 mg, 61%). 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 2.0 Hz, 1H), 7.12-7.07 (m, 4H), 6.80-6.76 (m, 4H), 6.72 (d, J = 1.9 Hz, 1H), 5.08-4.99 (m, 1H), 4.33 (s, 4H), 3.79 (s, 6H), 3.74-3.65 (m, 2H), 3.61-3.52 (m, 2H). MS m / z 456.3 [M+H] + .

[0183] Potassium t-butoxide (111 mg, 0.99 mmol) was dissolved in DMF (3 mL) and cooled to -50 °C under a nitrogen atmosphere. A mixture of compound 20b (95 mg, 0.49 mmol) and compound 21b (250 mg, 0.55 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at -50 °C for 1 h. TLC monitoring indicated the reaction was complete. The reaction was quenched with concentrated hydrochloric acid (1 mL) and stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 21c (72 mg, 27%). MS m / z 490.4 [M+H] +

[0184] Compound 21c (72 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature overnight. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer plate separation to give compound 21d (10 mg, 27%).

[0185] Compound 19g (15 mg, 0.09 mmol) was dissolved in tetrahydrofuran (1 mL) and further added with diisopropylethylamine (22 mg, 0.17 mmol) and triphosgene (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, mixed with petroleum ether, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product 21e was used directly in the next step.

[0186] Compound 21d (5 mg, 0.02 mmol) was dissolved in tetrahydrofuran (0.5 mL) and sodium t-butoxide (2 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 10 min, and then compound 21e (4 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer plate separation to give compound 21 (8 mg, 89%) as a white solid. 1 H NMR (500 MHz, CD3OD) δ 7.87 (d, J = 2.3 Hz, 1H), 6.96 (s, 1H), 6.83 (d, J = 2.3 Hz, 1H), 5.16-5.08 (m, 1H), 3.29-3.24 (m, 4H), 2.89-2.80 (m, 4H), 2.74-2.63 (m, 4H), 2.07-1.97 (m, 4H) ppm. MS m / z 449.3 [M+H] + .

[0187] Example 22: Preparation of Compound 22 [ka] Compound 20g (12 mg, 0.05 mmol) was dissolved in tetrahydrofuran (1 mL) and further added with diisopropylethylamine (12 mg, 0.10 mmol) and triphosgene (7 mg, 0.02 mmol). The reaction mixture was stirred at room temperature for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, mixed with petroleum ether, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product 22a was used directly in the next step.

[0188] Compound 21d (6 mg, 0.02 mmol) was dissolved in tetrahydrofuran (0.5 mL) and sodium t-butoxide (2 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 10 min, and then compound 22a (7 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer plate separation to give compound 22 (6 mg, 51%) as a white solid. 1 H NMR (500 MHz, CD3OD) δ 8.09 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.08 (s, 1H), 6.72 (d, J = 5.2 Hz, 1H), 6.63 (d, J = 1.4 Hz, 1H), 6.59 (s, 1H), 5.13-5.06 (m, 1H), 3.92 (s, 3H), 3.28-3.24 (m, 4H), 2.92 (t, J = 7.4 Hz, 2H), 2.72-2.66 (m, 2H), 2.05-1.99 (m, 5H) ppm. MS m / z 530.5 [M+H] + .

[0189] Compound 22 (100 mg, 0.19 mmol) was dispersed in water (5 mL) and 0.1 mol / L aqueous NaOH solution (1.9 mL, 0.19 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and then lyophilized to give the sodium salt of compound 22 as a white solid (104 mg, 100% yield). 1H NMR (500 MHz, CD3OD) δ 8.07 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 6.99 (s, 1H), 6.76 (d, J = 5.1 Hz, 1H), 6.62 (s, 1H), 6.49 (d, J = 2.3 Hz, 1H), 5.07-4.97 (m, 1H), 3.91 (s, 3H), 3.29-3.26 (m, 2H), 3.24-3.15 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.1 Hz, 2H), 2.04-1.95 (m, 5H). MS m / z 530.2 [M+H] + .

[0190] Example 23: Preparation of Compound 23 [ka]

[0191] Sodium hydride (26 mg, 60%, 0.64 mmol) was dissolved in tetrahydrofuran (2 mL) under a nitrogen atmosphere. The reaction mixture was cooled to -78 °C, and ethyl 2-(diethoxyphosphanyl)acetate (143 mg, 0.64 mmol) was added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 0.5 h. Compound 21b (264 mg, 0.58 mmol) was added in an ice bath, and the reaction mixture was warmed to room temperature and stirred for 3 h. When TLC monitoring showed the reaction was complete, the reaction mixture was quenched with aqueous sodium bicarbonate solution in an ice bath and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give Compound 23a (179 mg, 59%). MS m / z 526.5 [M+H] + .

[0192] Compound 23a (179 mg, 0.34 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to −78°C under a nitrogen atmosphere. A 1.0 M solution of diisobutylaluminum hydride in tetrahydrofuran (0.85 mL, 0.85 mmol) was added dropwise. After the addition, the reaction mixture was stirred for 1 hour at −78°C. When TLC monitoring indicated the reaction was complete, the reaction mixture was warmed to 0°C and water (0.05 mL), 15% aqueous sodium hydroxide (0.05 mL), and water (0.10 mL) were added dropwise. The reaction mixture was then warmed to room temperature and stirred for 15 minutes. Active anhydrous sodium sulfate was added, stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give compound 23b (116 mg, 70%). MS m / z 484.4 [M+H] + .

[0193] Compound 23b (116 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL), and diisopropylethylamine (93 mg, 0.72 mmol) and methanesulfonyl chloride (55 mg, 0.48 mmol) were added dropwise in an ice bath. The reaction mixture was warmed to room temperature and stirred for 1 hour. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product, compound 23c (134 mg), was used directly in the next step.

[0194] Compound 23c (134 mg, 0.24 mmol), sodium iodide (2 mg, 0.01 mmol), and a 1.0 M solution of dimethylamine in tetrahydrofuran (2 mL, 2.00 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated in a sealed tube at 60°C and stirred for 2 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by silica column chromatography to give compound 23d (54 mg, 44%). MS m / z 511.7 [M+H] + .

[0195] Compound 23d (54 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred overnight at room temperature. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer plate separation to give compound 23e (16 mg, 56%).

[0196] Compound 23e (8 mg, 0.03 mmol) was dissolved in tetrahydrofuran (1 mL) and sodium t-butoxide (3 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 10 min, and then compound 21e (6 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer plate separation to give compound 23 (8 mg, 56%) as a white solid. 1 H NMR (500 MHz, CD3OD) δ 7.84 (d, J = 2.4 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.54-5.48 (m, 1H), 5.10-5.04 (m, 1H), 3.62 (d, J = 7.8 Hz, 2H), 3.43-3.33 (m, 4H), 2.86-2.81 (m, 10H), 2.67 (t, J = 7.3 Hz, 4H), 2.01 (p, J = 7.4 Hz, 4H) ppm. MS m / z 470.5 [M+H] + .

[0197] Example 24: Synthesis of Compound 24 [ka]

[0198] Compound 23e (8 mg, 0.03 mmol) was dissolved in tetrahydrofuran (1 mL) and sodium t-butoxide (3 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 10 min, and then compound 22a (8 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer plate separation to give compound 24 (8 mg, 52%) as a white solid. 1 H NMR (500 MHz, CD3OD) δ 8.08 (d, J = 5.0 Hz,1H), 7.82 (d, J = 2.3 Hz, 1H), 7.09 (s, 1H), 6.71 (d, J = 5.0 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 6.58 (s, 1H), 5.55-5.49 (m, 1H), 5.11-5.04 (m, 1H), 3.92 (s, 3H), 3.65 (d, J = 7.9 Hz, 2H), 3.43-3.30 (m, 4H), 2.92 (t, J = 7.4 Hz, 2H), 2.86 (s, 6H), 2.72-2.65 (m, 2H), 2.07-1.99 (m, 5H) ppm. MS m / z 551.6 [M+H] + .

[0199] Example 25: Study of the inhibition of compounds on NLRP3 activity Step 1: Induction of IL1β 60 μL of polylysine was added to a 96-well cell culture plate at 60 μL per well and incubated at 37°C for 30 minutes. The solution in the plate was discarded, and the cell culture plate was washed twice with PBS. THP1 cells (50,000 cells / well / 95 μL) were seeded into the cell culture plate, and 5 μL of PMA (final concentration: 50 ng / mL) was added to each well. The plate was then incubated overnight in a 37°C incubator. The supernatant was carefully removed, the cell culture plate was washed with PBS, and 80 μL of FBS-free medium was added to each well. 5 μL of LPS (final concentration: 500 ng / mL) was then added and incubated in a 37°C incubator for 3 hours. Compounds (10 mM stock solutions, dissolved in DMSO) were diluted accordingly with 100% DMSO. 2 μL of the diluted compounds were added to 98 μL of medium and mixed evenly. 5 μL / well of diluted compounds were added to the cell plates and incubated in a 37°C incubator for 1 hour. Then, 10 μL / well of nigericin (final concentration 10 μg / mL) was added to the cell plates and incubated in a 37°C incubator for 0.5 hours. The cell supernatant was collected into a new cell plate and frozen at -80°C for further use.

[0200] Step 2: Detection of IL1β The IL1β antibody was diluted 60-fold in coating buffer, and 100 μL of the diluted antibody was added to an ELISA plate at each well and incubated overnight at 4°C. The liquid in the ELISA plate was discarded and washed four times with eluent. 300 μL of reagent diluent was added per well to block the ELISA plate, which was then incubated at room temperature for 1.5 hours. The plate was then washed four times with eluent. 100 μL of sample per well was added to the IL1β-coated ELISA plate and incubated at room temperature for 2 hours. The plate was then washed four times with eluent. 100 μL of detection antibody was added to each well and incubated at 37°C for 2 hours. The plate was then washed four times with eluent. 100 μL of HRP-conjugated secondary antibody was added to each well and incubated at 37°C for 1 hour. The plate was then washed four times with eluent. 100 μL of A+B substrate was added to each well and incubated at 37°C for 30 minutes. 100 μL of STOP solution was added to each well. The plate was gently shaken for a few seconds. The absorbance at 450 nm was read using an EnVision multifunction plate reader, and the inhibition rate was calculated using the following formula: Inhibition rate % = (Ave_H - Sample) / (Ave_H - Ave_L). Here, Ave_H represents the average reading of the DMSO wells, Sample represents the average reading of the compound wells, and Ave_L represents the average reading of the 10 μM positive control group. The IC value of each compound was calculated by fitting a dose-effect curve using the logarithm of the concentration on the X axis and the percentage inhibition rate on the Y axis with log(inhibitor) vs. response - variable slope in the analysis software GraphPad Prism 5. 50 The value was obtained. Calculation formula: Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)). [Table 1] [ka] MCC950

[0201] Example 26: Pharmacokinetic studies in rats Equipment: Waters XEVO TQ-S phase mass spectrometer. All measurement data were collected and processed using Masslynx V4.1 software, and data were calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNonLin 8.0 software by the statistical moment method. Pharmacokinetic parameters were mainly calculated using the T max , T 1 / 2 , C max , AUC last Chromatography column: ACQUITY UPLC BEH C18 (2.1 mm x 50 mm, 1.7 μm); column temperature: 40 °C; mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, flow rate: 0.350 mL / min; gradient elution was used, with the elution gradient being 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Load volume: 1 μL.

[0202] Animals: Three male SD rats weighing 200-220 g were purchased and housed in the laboratory of the Experimental Animal Center for two days before use. Food was withheld from 12 hours before administration until 4 hours after administration, and water was allowed ad libitum throughout the study. Blood samples were collected from the rats at designated time points after intragastric administration.

[0203] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450). Preparation of intragastric administration solution: The compound was precisely weighed, added to the solvent, and sonicated at room temperature for 5 minutes to completely dissolve the drug, resulting in a 0.3 mg / mL drug solution.

[0204] Drug samples: Generally, multiple samples with similar structures (molecular weights differing by more than 2 units) were used, precisely weighed, and administered together (cassette PK). In this way, multiple compounds were simultaneously selected and their oral absorption rates were compared. The pharmacokinetics of the drug samples in rats was studied after single administration.

[0205] After intragastric administration, blood was collected from the eye margin at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours. 50 μL of plasma samples were taken, and 200 μL of acetonitrile (containing 2 ng / mL of verapamil as an internal standard) was added. After vortex shaking for 3 minutes, the samples were centrifuged at 20,000 rcf and 4°C for 10 minutes. The supernatant was then analyzed by LC-MS / MS.

[0206] The compound was precisely weighed and prepared at different concentrations, and quantitative analysis was performed by mass spectrometry to construct a standard curve. The concentration of the compound in the plasma was then measured to obtain the compound concentration at different time points. All measurement data were collected and processed using related software, and the pharmacokinetic parameters were calculated using the statistical moment method (mainly the kinetic parameter T max , T 1 / 2 , C max , AUC last The kinetic parameters of some representative compounds are shown in Table 2. [Table 2]

[0207] All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. After reading the above content of the present invention, it should be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalents thereof are within the scope of the claims of the present invention.

Claims

1. A compound represented by the following formula (III), or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof: 【Chemistry 1】 (In formula (III), R １ and R ２ are each independently hydrogen, deuterium, halogen, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group, C １－４ haloalkoxy groups, Each R ３ are each independently hydrogen, deuterium, halogen, C １－４ selected from alkyl groups, m is 0 or 1, E is a chemical bond, -O-, -O(CR ａ R ｂ ) １－２ -, - (CR ａ R ｂ ) １－２ O-, C １－２ alkylene groups, where R ａ and R ｂ are each independently hydrogen or C １－４ selected from alkyl groups, G is unsaturated C ３－８ cycloalkyl groups or unsaturated 3- to 12-membered heterocyclic groups, wherein said cycloalkyl groups or heterocyclic groups optionally contain halogen, C １－４ substituted with one or more groups selected from the group consisting of alkyl groups; X is —NH—. Y is O. T is a chemical bond, -NR ５ - or a heteroaryl group. R is hydrogen, C １－４ Alkyl group, C １－４ Haloalkyl group, C ３－８ a cycloalkyl group, a 3- to 8-membered heterocyclic group, or NR ８ R ９ wherein the alkyl group, cycloalkyl group, and heterocyclic group are optionally selected from the group consisting of halogen, C １－４ Alkyl group, C １－４ Haloalkyl group, C ２－４ Haloalkenyl group, C １－４ Alkoxy group, C １－４ haloalkoxy groups. Alternatively, the cycloalkyl or heterocyclic group is substituted with ═M, where M is CR １０ R １１ Selected from. R ５ is hydrogen, C １ -C ４ alkyl group, or C ３－６ It is selected from the group consisting of cycloalkyl groups. R ８ and R ９ are each independently hydrogen or C １－４ Alternatively, R ８ and R ９ together with the nitrogen atom to which they are linked form a 4-8 membered heterocyclic group, which contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O and S. R １０ and R １１ are each independently hydrogen, deuterium, halogen, or C １－４ Alternatively, R １０ and R １１ together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, which contains one or two heteroatoms selected from N, O and S. wherein each of the above alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, and heteroaryl groups optionally and independently may contain 1 to 3, each independently, halogen, C １－４ Alkyl group, C １－４ Haloalkyl group, C ３－８ It is substituted with a substituent selected from the group consisting of cycloalkyl groups. Unless otherwise specified, the aryl groups are aromatic groups containing 6-12 carbon atoms, and the heteroaryl groups are 5-15 membered heteroaromatic groups.

2. E is a chemical bond, -O-, -O(CR ａ R ｂ ) １－２ -, - (CR ａ R ｂ ) １－２ O—, where R ａ and R ｂ are each independently hydrogen or C １－４ 2. The compound according to claim 1, or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof, wherein the alkyl group is selected from the group consisting of aryl, arylsulfonyl ...

3. A compound represented by formula (IV), or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof: 【Chemistry 2】 Formula (IV) has the structure of formula (Va) or (Vb): 【Transformation 3】 T is selected from a chemical bond, —NR 5 —, an aryl group, or a heteroaryl group. R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, a C 1-4 alkyl group, a C 1-4 haloalkyl group, a C 1-4 alkoxy group, and a C 1-4 haloalkoxy group. Each R 3 is independently selected from hydrogen, deuterium, halogen, and a C 1-4 alkyl group. m is 0, 1, 2, or 3. M is CR １０ R １１ Selected from. U is N or CR １２ where R １２ is hydrogen, halogen, or C １－４ It is selected from alkyl groups. W is selected from chemical bonds. p and q are each independently selected from 0, 1, 2, and 3, provided that p and q are not simultaneously 0. E is a chemical bond, -O-, -O(CR ａ R ｂ ) １－２ -, - (CR ａ R ｂ ) １－２ O-, C １－２ Alkylene group, C ３－６ cycloalkyl groups, wherein R ａ and R ｂ are each independently hydrogen or C １－４ It is selected from alkyl groups. G is hydrogen, C １－４ Alkyl group, C １－４ Haloalkyl group, or NR ８ R ９ is selected from the group consisting of: R ５ is hydrogen, C １ -C ４ alkyl group, or C ３－６ It is selected from the group consisting of cycloalkyl groups. R ８ and R ９ are each independently hydrogen or C １－４ Alternatively, R ８ and R ９ together with the nitrogen atom to which they are linked form a 4-8 membered heterocyclic group, which contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O and S. R １０ and R １１ are each independently hydrogen, deuterium, halogen, or C １－４ Alternatively, R １０ and R １１ together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, which contains one or two heteroatoms selected from N, O and S. wherein each of the above alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, and heteroaryl groups optionally and independently may contain 1 to 3, each independently, halogen, C １－４ Alkyl group, C １－４ Haloalkyl group, C ３－８ It is substituted with a substituent selected from the group consisting of cycloalkyl groups. Unless otherwise specified, the aryl groups are aromatic groups containing 6-12 carbon atoms, and the heteroaryl groups are 5-15 membered heteroaromatic groups.

4. The compound according to claim 3, wherein formula (IV) is formula (VIa) or formula (VIb), or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof: 【Chemistry 4】 R ５ is hydrogen or C １－４ selected from alkyl groups, U is CR １２ where R １２ is hydrogen or C １－４ selected from alkyl groups, M, W, p, q, E, and G are defined as in claim 3; R １ , R ２ , R ３ , m are defined as in claim 3.

5. The compound according to claim 3, wherein formula (IV) is formula (VIIa) or formula (VIb), or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof: 【Transformation 5】 U is CR １２ where R １２ is hydrogen or C １－４ selected from alkyl groups, M, W, E, G, p, and q are defined as in claim 3, R １ , R ２ , R ３ , m are defined as in claim 3.

6. The compound according to claim 3, wherein formula (IV) is formula (VIIIa) or formula (VIIb), or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof: 【Transformation 6】 M, U, W, p, q, E, and G are defined as in claim 3; R １ and R ２ are each independently hydrogen, deuterium, halogen, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group, C １－４ haloalkoxy groups, Each R ３ are each independently hydrogen, deuterium, halogen, C １－４ selected from alkyl groups, m is 0, 1, 2, or 3.

7. The compound of claim 3, wherein formula (IV) is formula (XIII), or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof: 【Transformation 7】 p and q are each independently 0, 1, 2, or 3; M is CR １０ R １１ where R １０ and R １１ are each independently hydrogen, fluorine, or C １－４ alkyl groups, R １ and R ２ are each independently hydrogen, halogen, or C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group, C １－４ haloalkoxy groups, Each R ３ are each independently hydrogen, halogen, or C １－４ selected from alkyl groups, m is 0, 1, or 2; E is a chemical bond, -O-, -O(CR ａ R ｂ ) １－２ -, where R ａ and R ｂ are each independently hydrogen or C １－４ selected from alkyl groups, G is hydrogen, C １－４ Alkyl group, C １－４ Haloalkyl group or NR ８ R ９ selected from the group consisting of R ８ and R ９ are each independently hydrogen, C １－４ The alkyl group is selected from the group consisting of alkyl groups.

8. A compound selected from the group consisting of: 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 ("*" represents a chiral center.)

9. The compound according to any one of claims 1 to 8, or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof, wherein the pharmaceutically acceptable salt is an alkali metal salt.

10. The compound of claim 9, or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of sodium salt, potassium salt, and lithium salt.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier.

12. Use of a compound according to any one of claims 1 to 8, or an optical isomer, pharmaceutically acceptable salt, deuterium-substituted derivative, hydrate, or solvate thereof, for the manufacture of a pharmaceutical composition for treating a disease, disorder, or condition associated with the activity or expression level of NLRP3.

13. The disease, disorder or condition may be inflammation, autoimmune disease, knee arthritis, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory system disease, liver disease, kidney disease, eye disease, skin disease, lymphatic disorder, psychological disorder, graft versus host disease, abnormal pain, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), septic arthritis, suppurative sterile disease, or the like.

13. The use of claim 12, characterized in that the disease is selected from the group consisting of arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), hyper-IgD periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic-onset juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Schnitzler syndrome, Down syndrome, Behcet's disease, antisynthetase syndrome, interleukin-1 receptor antagonist deficiency (DIRA), and A2o (HA2o) haploinsufficiency.

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