Compounds as nlrp3 inhibitors

Abstract

The present application provides compounds as NLRP3 inhibitors, in particular, the present application provides a compound of the following formula (I), or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates thereof. The compound can be used for treating or preventing diseases or disorders associated with the activity or expression amount of NLRP3.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry; specifically, it relates to a novel class of derivatives containing tricyclic heteroaryl groups, their synthesis methods, and their application as an NLRP3 inhibitor in the preparation of drugs for the treatment of tumors and other related diseases. Background Technology

[0002] The NLRP3 (nod-like receptor family, pyrin domain-containing protein 3) inflammasome is a complex composed of multiple proteins, including the core member nucleotide-binding oligomerized domain-like receptor (NLRP3), the adaptor protein apoptosis-associated speck-like protein (ASC, containing a caspase activation and recruitment domain), and a caspase-1 precursor. It primarily participates in the body's inflammatory response. As an intracellular receptor protein, NLRP3 can sense specific inflammatory signals. Upon stimulation, NLRP3 binds to the adaptor protein ASC, forming the NLRP3-ASC complex. The polymerized NLRP3-ASC and the caspase-1 precursor form a larger complex, which is the inflammasome. The generation of inflammasomes leads to the activation of caspase-1, which in turn cleaves the inflammatory cytokines IL-1β and IL-18 precursors, processing and secreting active IL-1β and IL-18, promoting inflammatory responses and even causing inflammatory cell death, i.e., pyroptosis. ASCs can also recruit and activate caspase-8, cleaving IL-1β and IL-18 precursors and inducing apoptosis.

[0003] Caspase-1 cleaves IL-1β and IL-18 precursors to generate active IL-1β and IL-18, which are then secreted extracellularly. Activated caspase-1 can also cleave GSDMD (gasdermin-D), inducing pyroptosis. By regulating this cell death pathway, caspase-1 can also mediate the release of alarm factors such as IL-33 and HMGB1 (high mobility groupbox 1). Caspase-1 can also cleave the intracellular IL-1R2 receptor, leading to its degradation and the release of IL-1α. In addition, other substrates of caspase-1, such as cytoskeletal proteins and proteins involved in glycolysis signaling pathways, may also be involved in caspase-1-dependent inflammatory responses.

[0004] Cytokines activated by the NLRP3 inflammasome can promote inflammatory responses and, together with other cytokine signaling pathways, shape the body's immune response to infection and injury. For example, the IL-1β signaling pathway induces the release of pro-inflammatory cytokines IL-6 and tumor necrosis factor. In the absence of T cell receptors, IL-1β, IL-18, and IL-23 synergistically induce memory CD4Th17 cells and γδT cells to produce IL-17. IL-18 and IL-12 can also synergistically induce memory T cells and natural killer cells to secrete IFN-γ, promoting Th1 immune responses.

[0005] Other intracellular pattern recognition receptors can also form inflammasomes, such as NLR (nod-like receptor) family members NLRP1 and NLRP4, as well as non-NLR family members such as double-stranded DNA sensors AIM2 (absent in melanoma 2) and IFI16 (interferon, gamma-inducible protein 16). Indirect, non-canonical signaling pathways downstream of Caspase-11 can also activate NLRP3-dependent IL-1β.

[0006] Abnormal activation of NLRP3 can lead to a variety of diseases, such as Cryopyrin-associated periodic syndrome (CAPS) caused by acquired mutations in NLRP3, including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease. In addition, NLRP3 is involved in mediating the development of various complex diseases, such as multiple sclerosis, type 2 diabetes, obesity, Alzheimer's disease, gout, and atherosclerosis. The role of NLRP3 in central nervous system, lung, liver, and kidney diseases is also receiving increasing attention. Therefore, NLRP3 inhibitors have broad clinical application prospects. Summary of the Invention

[0007] The purpose of this invention is to provide a novel class of NLRP3 inhibitors.

[0008] In a first aspect, the present invention provides a compound, or an optical isomer thereof, of the structure shown in formula (I), a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate:

[0009]

[0010] In formula (I):

[0011] Ring A is selected from the group consisting of substituted or unsubstituted 8-15 membered bicyclic or tricyclic fused ring systems; wherein the substitution refers to the hydrogen atom on the substituent group being substituted by one or more R groups. e The bicyclic or tricyclic fused ring system includes at least one aromatic ring structure and one or two saturated or unsaturated rings fused with the aromatic ring structure, wherein the A ring and the X linker are located on the aromatic ring.

[0012] Ring B is selected from the group consisting of: unsubstituted or unsubstituted aryl groups, substituted or unsubstituted 5-12 membered heterocycles (including partially unsaturated or saturated heterocycles), or substituted or unsubstituted heteroaryl groups; wherein, the substitution refers to the hydrogen atom on the group being substituted by one or more R groups. f Replace; and when B is non-existent, E and G do not exist;

[0013] X is selected from -NR 5 -、-CR 6 R 7 -;

[0014] Y is selected from O, -NR 5 -;

[0015] T is selected from chemical bonds, -NR 5 -、-(CR a R b ) 1-2 -、C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl;

[0016] R is selected from the following group: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, or NR 8 R 9 ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups, NR 8 R 9 CN, NO2, SR h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t ; or the cycloalkyl or heterocyclic group is substituted with =M, wherein M is selected from O or CR. 10 R 11 ;

[0017] E is selected from the following group: chemical bonds, -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, -C=C-, -C≡C-, C 3-6 cycloalkyl;

[0018] G is selected from the following group: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkyne group, saturated C 3-8 cycloalkyl, unsaturated C 3-8 Cycloalkyl, saturated 3- to 12-membered heterocyclic, unsaturated 3- to 12-membered heterocyclic, aryl, or heteroaryl, NR 8 R 9 ; wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4Haloalkyl, C 2-4 Haloalkenyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 8 R 9 CN, NO2, SR h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t ;

[0019] R 5 Selected from the following group: hydrogen, C 1-4 Alkyl, or C 3-6 cycloalkyl;

[0020] R 6 and R 7 Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, or C 3-6 cycloalkyl; or R 6 and R 7 Together with the carbon atoms it is attached to, they form C 3-6 Cycloalkyl, or a 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains one or two heteroatoms selected from N, O, and S;

[0021] R 8 and R 9 Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4- to 8-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted with "=M", wherein M is selected from O or CR. 10 R 11 ; or R 8 and R 9 Together with the nitrogen atom attached thereto, they form a 4- to 8-membered heterocyclic group, which contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O or S;

[0022] R 10 and R 11 Each is independently selected from the following group: hydrogen, deuterium, halogen, or C. 1-4 Alkyl; wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups, NR 8 R 9 C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl; or R 10 and R 11 Together with the carbon atom to which it is attached, it forms 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;

[0023] R a and R b Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, or C 3-6 cycloalkyl;

[0024] R e and R f Each is independently selected from the following groups: deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR h SR h NR h R h C(O)R t C(O)NR h R h ;

[0025] R t C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, or heteroaryl;

[0026] Each R h Each can be independently hydrogen or C 1-4 Alkyl; or two R h Together with the nitrogen atom attached thereto, they form a 3- to 8-membered heterocyclic group, which contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O or S;

[0027] In this embodiment, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally and independently substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR h SR h NR h R h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t The prerequisite is that the resulting chemical structure is stable and meaningful; among them, R h and R t The definition is as described above;

[0028] Unless otherwise specified, the aryl group mentioned above is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaryl group.

[0029] In another preferred embodiment, ring A is a tricyclic fused ring system, and R is an unsaturated C 3-8 Cycloalkyl (non-aromatic) or unsaturated 3- to 8-membered heterocyclic groups (non-aromatic).

[0030] In another preferred embodiment, ring A is a tricyclic fused ring system, and R is C 3-8 The R is a cycloalkyl or 3- to 8-membered heterocyclic group, and the R is substituted with at least one =M.

[0031] In another preferred embodiment, R is C. 3-8 Cycloalkyl or 3- to 8-membered heterocyclic groups, and T is -NR 5 - and the R is substituted by at least one substituent selected from the group consisting of: fluorine, C 1-4 Fluoroalkyl, C 2-4 Fluoroalkenyl.

[0032] 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.

[0033] In another preferred embodiment, R is C. 3-8 The R is a cycloalkyl or 3- to 8-membered heterocyclic group, and the R is substituted with at least one =M.

[0034] In another preferred embodiment, R is C. 3-8Cycloalkyl or 3- to 8-membered heterocyclic groups, and T is -NR 5 - and the R is substituted by at least one substituent selected from the group consisting of: fluorine, C 1-4 Fluoroalkyl, C 2-4 Fluoroalkenyl.

[0035] In another preferred embodiment, R is selected from C. 3-8 Cycloalkyl or 3- to 8-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 8 R 9 , or = M, where M is selected from O or CR 10 R 11 ;

[0036] A, B, E, G, X, Y, T, R 8 R 9 R 10 R 11 The definition is as described above.

[0037] In another preferred embodiment, R is selected from C. 3-8 Cycloalkyl or 3- to 8-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted with =M, wherein M is selected from CR 10 R 11 Among them, R 10 and R 11 The definition is as described above;

[0038] In another preferred embodiment, Selected from

[0039] This indicates the connection point between the above structural fragment (IIa) or (IIb) and other structures in (I);

[0040] R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0041] Each R 3 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 alkyl;

[0042] m can be 0, 1, 2, or 3;

[0043] It is pyridinyl, pyrimidinyl, or pyridazinyl;

[0044] E is selected from the following group: chemical bonds, -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 ) 1-2 NR 5 -、-NR 5 (CR a R b ) 1-2 -、C 1-2 Alkylene, -C=C-, -C≡C-; where R a and R b Each is independently selected from hydrogen or C 1-4 alkyl;

[0045] G is selected from unsaturated C. 3-8 Cycloalkyl or unsaturated 3- to 12-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 8 R 9 CN, NO2, SR h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t ;

[0046] R 5 R 8R 9 R h R t The definition is as described above.

[0047] In another preferred embodiment, equation (I) is equation (III):

[0048]

[0049] R 1 and R 2 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0050] Each R 3 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 alkyl;

[0051] m is 0, 1, or 2;

[0052] E is selected from the following group: chemical bonds, -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, -C=C-, -C≡C-; where R a and R b Each is independently selected from hydrogen or C 1-4 alkyl;

[0053] G is selected from unsaturated C. 3-8 Cycloalkyl or unsaturated 3- to 12-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C2-4 Haloalkenyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 8 R 9 CN, NO2, SR h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t ;

[0054] X, Y, T, R, R 5 R 8 R 9 R h R t The definition is as described above.

[0055] In another preferred embodiment, G is selected from the group consisting of: Furthermore, the G may optionally be substituted by one or more groups selected from the group consisting of halogens, C, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 8 R 9 CN, NO2, SR h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t .

[0056] In another preferred embodiment, E is selected from the group consisting of: chemical bonds, -O-, -O(CR). a R b ) 1-2 -、-(CR a R b ) 1-2 O-、-NR 5 -、-(CR a R b ) 1-2 NR5 -、-NR 5 (CR a R b ) 1-2 -、-C≡C-;where R a and R b Each is independently selected from hydrogen or C 1-4 alkyl.

[0057] In another preferred embodiment, equation (I) is equation (IV):

[0058]

[0059] M is selected from CR 10 R 11 Among them, R 10 and R 11 The definition is as described above;

[0060] U is selected from N or CR 12 Among them, R 12 Selected from hydrogen, halogen, or C 1-4 alkyl;

[0061] W is selected from chemical bonds, -NR 13 (CR c R d ) 1-2 -、-O(CR c R d ) 1-2 -; where R 13 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, C(O)R t , or S(O)2R t ;R c and R d Each is independently selected from hydrogen or C 1-4 alkyl;

[0062] p and q are each independently selected from 0, 1, 2, 3, 4, 5, or 6; the prerequisite is that p and q cannot be 0 at the same time.

[0063] A, B, E, G, X, Y, T, R t The definition is as described above.

[0064] In another preferred embodiment, the formula (I) is formula (Va) or formula (Vb):

[0065]

[0066] T is selected from chemical bonds, -NR 5- aryl, or heteroaryl;

[0067] The definitions of M, U, W, p, and q are as described above;

[0068] R 1 R 2 R 3 The definitions of m are as described above;

[0069] E, G, R 5 The definition is as described above.

[0070] In another preferred embodiment, equation (I) is equation (VIa) or equation (VIb):

[0071]

[0072] R 5 Selected from hydrogen or C 1-4 alkyl;

[0073] U is selected from CR 12 Among them, R 12 Selected from hydrogen or C 1-4 alkyl;

[0074] The definitions of M, W, p, and q are as described above;

[0075] R 1 R 2 R 3 The definitions of m are as described above;

[0076] The definitions of E and G are as described above.

[0077] In another preferred embodiment, equation (I) is equation (VIIa) or equation (VIIb):

[0078]

[0079] U is selected from CR 12 Among them, R 12 Selected from hydrogen or C 1-4 alkyl;

[0080] The definitions of M, W, p, and q are as described above;

[0081] R 1 R 2 R 3 The definitions of m are as described above;

[0082] The definitions of E and G are as described above.

[0083] In another preferred embodiment, formula (I) is formula (VIIIa) or formula (VIIIb):

[0084]

[0085] M, U, W, R 1 R 2 R 3 The definitions of E, G, m, p, and q are as described above.

[0086] In another preferred embodiment, formula (I) is formula (IXa) or formula (IXb):

[0087]

[0088] k and j are each independently selected from 0, 1, or 2;

[0089] R 14 and R 15 Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, or C 3-6 cycloalkyl;

[0090] T, U, W, R 1 R 2 R 3 The definitions of E, G, m, and p are as described above.

[0091] In another preferred embodiment, equation (I) is equation (X):

[0092]

[0093] Z is selected from N or CR. 16 Among them, R 16 Selected from hydrogen, halogen, or C 1-4 alkyl;

[0094] p and q are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0095] U is selected from CR 12 Among them, R 12 Selected from hydrogen or C 1-4 alkyl;

[0096] M is selected from CR 10 R 11 Among them, R 10 and R 11 The definition is as described above;

[0097] The definitions of A, B, E, and G are as described above.

[0098] In another preferred embodiment, formula (I) is formula (XIa) or formula (XIb):

[0099]

[0100] Selected from pyridinyl, pyrimidinyl, or pyridazinyl;

[0101] The definitions of Z, U, M, p, and q are as described above;

[0102] R 1 R 2 R 3 The definitions of m are as described above;

[0103] The definitions of E and G are as described above.

[0104] In another preferred embodiment, equation (I) is equation (XII):

[0105]

[0106] p and q are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0107] M is selected from CR 10 R 11 Among them, R 10 and R 11 Each is independently selected from the following group: hydrogen, fluorine, or C. 1-2 Alkyl; wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 8 R 9 C 3-8 cycloalkyl, 3- to 8-membered heterocyclic groups;

[0108] R 1 and R 2 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0109] Each R 3 Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl;

[0110] m is 0, 1, or 2;

[0111] E is selected from the following group: chemical bonds, -O-, -O(CR) a R b ) 1-2-、-(CR a R b ) 1-2 O-, -S-, -NR 5 -、-(CR a R b ) 1- 2NR 5 -、-NR 5 (CR a R b ) 1-2 -、C 1-2 Alkylene, -C≡C-, C 3-6 cycloalkyl; wherein, R a and R b Each is independently selected from the following group: hydrogen, or C. 1-4 Alkyl; R 5 Selected from the following group: hydrogen, C 1-4 Alkyl, or C 3-6 cycloalkyl;

[0112] G is selected from the following group: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkyne group, saturated C 3-8 cycloalkyl, unsaturated C 3-8 Cycloalkyl, saturated 3- to 12-membered heterocyclic, unsaturated 3- to 12-membered heterocyclic, aryl, or heteroaryl, NR 8 R 9 ; wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, NR 8 R 9 CN, C(O)R t , or S(O)2R t Among them, R t C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, or heteroaryl;

[0113] R 8 and R 9 Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4- to 8-membered heterocyclic groups.

[0114] In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0115]

[0116]

[0117]

[0118]

[0119] "*" indicates a chiral center.

[0120] In another preferred embodiment, the pharmaceutically acceptable salt is an alkali metal salt, preferably a salt selected from the group consisting of sodium salts, potassium salts, and lithium salts.

[0121] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

[0122] A third aspect of the invention provides the use of a compound, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, as described in the first aspect of the invention, for the preparation of a pharmaceutical composition for treating diseases, conditions, or symptoms associated with NLRP3 activity or expression levels.

[0123] In another preferred embodiment, the disease, symptom, or condition is selected from the group consisting of: inflammation, autoimmune diseases, knee osteoarthritis, cancer, infection, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic conditions, psychological disorders, graft-versus-host disease, abnormal pain, cryotherapy-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), and familial... Mediterranean fever (FMF), septic arthritis, pyoderma gangrenosa and acne syndrome (PAPA), hyperimmunoglobulinemia type D and periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Schnitzler syndrome, Sweet's syndrome, Behçet's disease, antisynthetic enzyme syndrome, interleukin-1 receptor antagonist deficiency (DIRA), and haploinsufficiency of A2o (HA2o). Detailed Implementation

[0124] Through long-term and in-depth research, the inventors unexpectedly discovered a novel class of NLRP3 inhibitors containing tricyclic aryl compounds, along with their preparation methods and applications. The compounds of this invention can be used to treat various diseases related to the activity of the kinase. Based on the above findings, the inventors completed this invention.

[0125] the term

[0126] Unless otherwise specified, the word “or” as used in this article has the same meaning as “and / or” (referring to both “or” and “and”).

[0127] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0128] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, either alone or as part of other substituents, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number definiteness (e.g., C...), it is used to indicate a carbon atom number. 1-10 When ), it refers to the alkyl group containing 1-10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0129] As used herein, the term "alkenyl," whether alone or as part of other substituents, refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number definiteness (e.g., C...), it signifies a carbon chain group. 2-8 When ), it refers to the alkenyl group containing 2-8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0130] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of other substituents. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number limit (e.g., C...), it is considered a alkynyl group. 2-8 When alkynyl is used, it means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C 2-8 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0131] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number determination (e.g., C...), it is used to indicate the presence of a carbon number limit (e.g., C...). 3-10 When ), it refers to the cycloalkyl group containing 3-10 carbon atoms. In some preferred embodiments, the term "C" is used. 3-8 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to a fully carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. All atoms in the cycloalkyl group are carbon atoms. The following are some examples of cycloalkyl groups; the present invention is not limited to the cycloalkyl groups described below.

[0132]

[0133] Unless otherwise stated, the terms used in the specification and claims have the following meanings. "Aryl" refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent group must be on a carbon atom of a ring having a conjugated π-electron system. Aryl groups can be substituted or unsubstituted. Some examples of aryl groups are given below; the invention is not limited to the aryl groups described below.

[0134]

[0135] "Heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms (optionally nitrogen, oxygen, and sulfur), or a polycyclic group consisting of a heterocyclic group (containing one or more heteroatoms, optional nitrogen, oxygen, and sulfur) fused with an aryl group, with the linking site located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below; however, this invention is not limited to the heteroaryl groups described below.

[0136]

[0137] "Heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein 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 pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups. "Spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system; one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic groups" refer to polycyclic heterocyclic groups in which any two rings share two non-directly connected atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, while the remaining ring atoms are carbon. If a saturated ring and an aromatic ring are present simultaneously in the heterocyclic group (for example, a saturated ring and an aromatic ring fused together), the point of attachment to the parent ring must be on the saturated ring. Note: When the point of attachment to the parent ring is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. Below are some examples of heterocyclic groups; this invention is not limited to the heterocyclic groups described below.

[0138]

[0139] As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0140] As used herein, the term "substitution" (with or without the "arbitrarily" modified) refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, i.e., two rings sharing a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents include, for example (but are not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group.

[0141] For convenience and to conform to common understanding, the terms "arbitrary substitution" or "optional substitution" apply only to sites that can be substituted by substituents, and do not include chemically impossible substitutions.

[0142] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" means a salt suitable for contact with the tissues of an object (e.g., a human) without producing undesirable side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes salts of the compounds of the present invention having acidic groups (e.g., potassium, sodium, magnesium, calcium salts) or salts of the compounds of the present invention having basic groups (e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates).

[0143] use:

[0144] The present invention provides the use of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients for the inhibition of NLRP3.

[0145] The compound of this invention can be used as an NLRP3 inhibitor.

[0146] This invention is a single inhibitor of NLRP3, which aims to prevent, alleviate, or cure diseases by regulating the enzymatic activity of NLRP3. The diseases referred to include Cryopyrin-associated periodic syndrome (CAPS), which is mainly caused by acquired mutations in NLRP3 and includes types such as Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal multisystem inflammatory diseases.

[0147] In addition, the diseases referred to also include the following categories:

[0148] Hereditary diseases, such as sickle cell anemia and valine-containing protein diseases.

[0149] Autoimmune diseases, including but not limited to rheumatoid arthritis, knee arthritis, suppurative arthritis, pyoderma gangrenosa, acute febrile neutrophilic dermatosis, chronic non-infectious myelitis, systemic lupus erythematosus, inflammatory bowel disease (ulcerative colitis and Crohn's disease), Behçet's syndrome, Schnitzler's syndrome, familial Mediterranean fever, tumor necrosis factor receptor-related periodic fever, high IgD syndrome, and macrophage activation syndrome, etc.

[0150] Central nervous system diseases, including but not limited to Alzheimer's disease, Parkinson's disease, multiple sclerosis, dementia, etc.

[0151] Metabolic-related diseases, including but not limited to type 1 diabetes, type 2 diabetes, obesity, gout, pseudogout, atherosclerosis, and metabolic syndrome;

[0152] Lung diseases, including but not limited to asthma, pulmonary fibrosis, idiopathic pulmonary fibrosis, pulmonary ischemia-reperfusion injury, chronic obstructive disease, asbestosis and silicosis;

[0153] Eye diseases, including but not limited to age-related macular degeneration, diabetic retinopathy, and optic nerve damage;

[0154] Liver diseases, including but not limited to non-alcoholic fatty liver disease, hepatic ischemia-reperfusion injury, fulminant hepatitis, liver fibrosis, and liver failure;

[0155] Kidney diseases, including but not limited to renal calcification and renal fibrosis;

[0156] Heart diseases, including but not limited to cardiac hypertrophy and fibrosis, heart failure, aortic aneurysm and dissection, cardiac damage caused by metabolic disorders, atrial fibrillation and hypertension, etc.

[0157] Skin diseases, including but not limited to psoriasis, atopic dermatitis, contact allergy, hidradenitis suppurativa, acne vulgaris, and sarcoidosis;

[0158] In addition, the types of diseases that can be relieved or cured by inhibiting NLRP3 enzyme activity include inflammatory hyperalgesia, neuralgia, and controlling infections of various bacteria, viruses, fungi and worms.

[0159] NLRP3 is also involved in the development and progression of various cancers, including myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly with polycythemia, eosinophilic leukemia syndrome, primary thrombocytopenic purpura, 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 cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, and many other solid tumors and hematologic malignancies.

[0160] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates thereof and / or compositions thereof, can be formulated together with pharmaceutically acceptable excipients or carriers to obtain compositions that can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections, sterile powders, etc. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (added), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular weight polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic), and lubricants (such as magnesium stearate, glycerin and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form 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 the patient is not fixed and is usually given at a pharmaceutically effective dose. Simultaneously, the actual amount of compound administered can be determined by the physician based on the actual situation, including the condition being treated, the chosen route of administration, the actual compound administered, and the patient's individual condition. The dosage of the compound of the present invention depends on the specific purpose of treatment, the route of administration, the patient's condition, and the physician's judgment. The proportion or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, and route of administration.

[0161] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions.

[0162] General synthetic methods for compounds

[0163] The compound of formula III-A of the present invention can be prepared by the following method:

[0164]

[0165] The expressions for m, E, G, R1, R2, and R3 in the above reaction formula are the same as those in Formula III above. The expressions for T and R are the same as those in Formula I in claim 1.

[0166] Starting with III-A-1 in an inert solvent, a substitution reaction occurs to give intermediate III-A-2, which then reacts with active compound III-A-3 to reach target compound III-A.

[0167] The compound of formula IA of the present invention can be prepared by the following method:

[0168]

[0169] R in the above reaction formula 1 The expression is the same as R in formula IIa above. 1 The expressions are the same; T and R are the same as those in Formula I above.

[0170] Starting with IA-1 in an inert solvent, a substitution reaction was carried out with III-A-3 to obtain the target compound IA.

[0171] The compound of formula XII-A of the present invention can be prepared by the following method:

[0172]

[0173] The expressions for p, q, m, E, G, R1, R2, and R3 in the above reaction formula are the same as those in formula XII above.

[0174] Starting with XII-A-1 in an inert solvent, a substitution reaction occurs with XII-A-2 to give compound XII-A-3, which then reacts with reagent XII-A-4 to give difluorinated compound XII-A-5. Following this, the protecting group is removed under acidic conditions to give intermediate XII-A-6. Starting with III-A-1 in an inert solvent, a substitution reaction occurs to give intermediate III-A-2, which then reacts with triphosgene to give isocyanate compound XII-A-7. Finally, an addition reaction occurs with XII-A-6 to give the target compound XII-A.

[0175] The compound of formula XII-B of the present invention can also be prepared by the following method:

[0176]

[0177] The expressions for p, q, m, E, G, R1, R2, and R3 in the above reaction formula are the same as those in formula XII above.

[0178] In an inert solvent, starting with XII-A-1, a substitution reaction occurs with XII-A-2 to give compound XII-A-3, followed by a witting reaction to give XII-B-1. Reduction of the ester group yields the hydroxyl compound XII-B-2, which is then sulfonated to give the active ester compound XII-B-3. A substitution reaction occurs with an amine to give compound XII-B-4, and deprotection of the protecting group yields intermediate XII-B-5. In an inert solvent, starting with III-A-1, a substitution reaction occurs to give intermediate III-A-2, which then reacts with triphosgene to give the isocyanate compound XII-A-7. This is followed by an addition reaction with XII-B-5 to give the target compound XII-B.

[0179] Pharmaceutical Compositions and Administration

[0180] Because the compounds of the present invention have excellent inhibitory activity against a range of protein kinases, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent, and alleviate diseases related to NLRP3 activity or expression levels.

[0181] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0182] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0183] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0184] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl 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. Buffers may also be included in capsules, tablets, and pills.

[0185] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0186] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0187] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0188] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0189] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0190] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0191] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0192] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0193] The main advantages of this invention include:

[0194] 1. A compound as shown in Formula I is provided.

[0195] 2. A novel NLRP3 inhibitor is provided, as well as its preparation and application, wherein the inhibitor can inhibit the activity of NLRP3 at extremely low concentrations.

[0196] 3. A class of pharmaceutical compositions for treating diseases related to NLRP3 activity is provided.

[0197] 4. A well-absorbed NLRP3 inhibitor is provided.

[0198] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0199] Example 1: Preparation of Compound 1

[0200]

[0201] Compounds 1a and 1d were prepared using the method described in patent WO2020035465.

[0202] 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. The reaction mixture was stirred for 1 hour under nitrogen protection, followed by the addition of a DMF solution of compound 1a (14 mg, 0.06 mmol) (0.8 mL). The reaction mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate (3 × 5 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product 1c was used directly in the next reaction step. LCMS: m / z 350.5 [M+H] + .

[0203] 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 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-plate chromatography (dichloromethane:methanol = 8:1, 2% ammonia) to give a grayish-white solid compound 1 (9 mg, yield 33%). 1 H NMR(500MHz,CD3OD)δ8.16(d,J=5.0Hz,1H),7.06(s,1H),6.86(d,J=5.0Hz,1H), 6.68(s,1H),5.78(s,1H),4.94(d,J=13.5Hz,1H),4.71(d,J=13.5Hz,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,3 H),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] + .

[0204] Example 2: Preparation of Compound 2

[0205]

[0206] (1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)methanol 2a (20 mg, 0.16 mmol) was dissolved in DMF (2 mL), and 60% sodium hydride (7 mg, 0.17 mmol) was added under ice bath conditions, with stirring continued for 0.5 hours. Then, a DMF (1 mL) solution of compound 1a (20 mg, 0.08 mmol) was added. The reaction mixture was stirred at 60 °C for 4 hours under nitrogen protection. The reaction was monitored by TLC until completion. The reaction mixture was distilled under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain a white solid compound 2b (13 mg, 45%). LCMS: m / z 350.5 [M+H] + .

[0207] 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 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.1) to obtain a white solid compound 2 (3 mg, 17%). 1 H NMR (500MHz, CD3OD) δ8.14(d,J=5.0Hz,1H),7.08(s,1H),6.84(d,J=5.0Hz,1H),6.70(s,1H),6.05(s,1H),5.00(d,J=12.0Hz,1H) ,4.70(d,J=12.0Hz,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] + .

[0208] Example 3: Preparation of Compound 3

[0209]

[0210] Compound 3f was prepared using the method described in patent WO2020035465.

[0211] 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 at 0 °C with stirring. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was filtered, and the solid was washed with a small amount of petroleum ether and dried to give a brown solid product 3b (1.70 g, 80% yield). 1H NMR (500MHz, D2O) δ8.59 (d, J = 6.5 Hz, 2H), 8.24 (d, J = 6.5 Hz, 2H), 4.28 (s, 3H) ppm.

[0212] 3b (0.70 g, 2.33 mmol) and 4-bromo-2-hydroxypyridine (0.40 g, 2.33 mmol) were dispersed in acetonitrile (10 mL). Cesium carbonate (1.14 g, 3.50 mmol) was added in portions at room temperature with stirring. The reaction mixture was then 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 obtain crude intermediate 3c (2.0 g). LCMS: m / z 265.2 & 267.2 [M+H] + .

[0213] The crude intermediate 3c (2.0 g) was dispersed in methanol (30 mL), and sodium borohydride (173 mg, 4.6 mmol) was added in portions at 0 °C with stirring. The reaction mixture was then stirred at 0 °C for 1 hour. The pH was carefully adjusted to 8 with a saturated sodium bicarbonate aqueous solution, and stirring was continued for 5 minutes. The mixture was diluted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give the crude product. The crude product was purified by silica gel column chromatography (0-10% methanol / dichloromethane) to give a brown solid product 3d (0.3 g, 50% yield). 1 H NMR(500MHz,CD3OD)δ7.44(d,J=7.0Hz,1H),6.80(d,J=2.0Hz,1H),6.60(dd,J=7.0,2.0Hz,1H),5.93-5.80(m, 1H), 3.19 (dd, J = 6.0Hz, J = 3.0Hz, 2H), 2.79 (t, J = 6.0Hz, 2H), 2.54 (td, J = 6.0Hz, J = 3.0Hz, 2H), 2.44 (s, 3H) ppm.

[0214] Compound 3d (120 mg, 0.445 mmol), bis(diphenylphosphine)boronic acid ester (169 mg, 0.668 mmol), potassium acetate (131 mg, 1.34 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (36 mg, 0.045 mmol) were added to 1,4-dioxane (1 mL), nitrogen was purged, and the mixture was stirred at 90 °C for 16 hours. After cooling, the resulting mixture 3e was used directly for the next step. Compound 3f (50 mg, 0.22 mmol), potassium carbonate (123 mg, 0.891 mmol), water (0.1 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (18 mg, 0.022 mmol) were added to the resulting mixture 3e, nitrogen was purged, and the mixture was stirred at 80 °C for 4 hours. 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 to dryness to give the crude product, which was purified by silica gel column chromatography (0-20% methanol / dichloromethane, containing 1% ammonia) to give 3 g (70 mg, yield 46%) of a brown solid product. 1 H NMR (500MHz, CD3OD) δ7.56(d,J=7.0Hz,1H),6.56(s,1H),6.38(d,J=1.5Hz,1H),6.27(dd,J=7.0Hz,J=1.5Hz,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 / z336.4[M+H] + .

[0215] Compound 3 g (25 mg, 0.07 mmol) and compound 1 d (18 mg, 0.07 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was heated and stirred at 60 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:2:0.1, V:V:V) to give compound 3 (5 mg, 15% yield) as a white solid. 1H NMR (500MHz, CD3OD) δ7.52(d,J=7.0Hz,1H),7.09(s,1H),6.38(s,1H),6.31(dd,J=7.0Hz,J=1.0Hz,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] + .

[0216] Compound 3 (1.72 mg, 0.0038 mmol / L) was dissolved in acetonitrile (1 mL), and 0.01 mol / L NaOH aqueous solution (0.38 mL) was added at room temperature. The reaction mixture was stirred for 5 minutes and then freeze-dried to obtain a white solid sodium salt of compound 3 (1.8 mg, 100% yield). MS m / z 457.5 [M+H] + .

[0217] Example 4: Preparation of Compound 4

[0218]

[0219] Compound 4a (1.00 g, 4.22 mmol), compound 4b (1.31 g, 4.22 mmol), sodium carbonate (894 mg, 8.44 mmol), and tetraphenylphosphine palladium (487 mg, 0.42 mmol) were dissolved in a toluene / ethanol / water mixture (8:4:2, v:v:v) (14 mL). The reaction mixture was heated and stirred at 100 °C for 2 hours under nitrogen protection. The reaction was monitored by TLC until completion. 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 gel column chromatography (ethyl acetate:petroleum ether = 10:1, v:v) to give a white solid compound 4c (815 mg, yield 57%). LCMS: m / z 340.2 [M+H] + .

[0220] Compound 4c (180 mg, 0.53 mmol), bis(diphenylphosphine)boronic acid ester (139 mg, 0.55 mmol), potassium acetate (208 mg, 2.12 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (41 mg, 0.05 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was heated and stirred at 100 °C for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature, and then a solution of 1,4-dioxane (2 mL) of compound 3f (80 mg, 0.35 mmol) and an aqueous solution of potassium carbonate (219 mg, 1.59 mmol) (1 mL) were added sequentially. The reaction mixture was heated and stirred at 100 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS until completion. 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 preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a white solid compound 4e (27 mg, yield 19%). LCMS: m / z 406.5 [M+H] + .

[0221] 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 and stirred at 60 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 15:1:0.1, v:v:v) to obtain a white solid compound 4f (22 mg, yield 63%). LCMS: m / z 527.6 [M+H] + .

[0222] Compound 4f (22 mg, 0.04 mmol) was dissolved in methanol (5 mL), and then 0.5 mL of 4 M hydrogen chloride methanol solution was added. The reaction mixture was heated and stirred at 50 °C for 2 hours. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 4 g (15 mg, yield 83%) of white solid compound. LCMS: m / z 427.5 [M+H] + .

[0223] 4 g (15 mg, 0.04 mmol) of compound was dissolved in methanol (5 mL), and paraformaldehyde (2 mg, 0.07 mmol), anhydrous zinc chloride (14 mg, 0.11 mmol), and sodium cyanoborohydride (7 mg, 0.11 mmol) were added sequentially. The reaction mixture was heated and stirred at 60 °C for 2 hours. The reaction was monitored by TLC until completion. 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 chromatography (dichloromethane:methanol:ammonia = 15:1:0.1, v:v:v) to give a gray solid compound 4 (3 mg, yield 19%). 1 H NMR (500MHz, CD3OD) δ8.57(d,J=5.0Hz,1H),7.43(s,1H),7.20(dd,J=5.0,1.5Hz,1H),7.15(s,1H),6.68-6.63(m,1H),3.92(s ,2H),3.47(t,J=6.0Hz,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] + .

[0224] Example 5: Preparation of Compound 5

[0225]

[0226] Compound 5b (15 mg, 26% yield) was obtained as a yellow solid from compound 1a (30 mg, 0.12 mmol) and compound 5a (28 mg, 0.24 mmol) using the method described in Example 2. LCMS: m / z 337.4 [M+H] + .

[0227] Compound 5 (12 mg, yield 59%) was obtained as a white solid from compound 5b (15 mg, 0.04 mmol) and compound 1d (11 mg, 0.04 mmol) using the method described in Example 2. 1H NMR (500MHz, CD3OD) δ8.14(d,J=5.0Hz,1H),7.10(s,1H),6.81(dd,J=5.0,1.0Hz,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=7.5Hz,2H),2.86 (t,J=7.5Hz,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] + .

[0228] Example 6: Preparation of Compound 6

[0229]

[0230] 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 minutes. Then, diphenyl carbonate (3.89 g, 18.16 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction solution containing 6b was used directly in the next reaction step.

[0231] Compound 2b (40 mg, 0.11 mmol) and compound 6b (0.5 mL of the above reaction solution) were dissolved in acetonitrile (5 mL). The reaction mixture was heated and stirred at 60 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.1) to obtain a white solid compound 6 (17 mg, yield 30%). 1H NMR(500MHz,CD3OD)δ8.14(d,J=5.2Hz,1H),7.07(s,1H),6.83(d,J=5.2Hz,1H),6.69(s,1H ),6.01(s,1H),4.94(d,J=12.5Hz,1H),4.69(d,J=12.5Hz,1H),3.53(s,2H),3.03(dd,J=10 .9,5.6Hz,2H),2.94(t,J=7.4Hz,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] + .

[0232] Compound 6 (14.36 mg, 0.0289 mmol / L) was dissolved in acetonitrile (2 mL), and 0.01 mol / L NaOH aqueous solution (2.89 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 6 (15 mg, 100% yield). MS m / z 497.5 [M+H] + .

[0233] Example 7: Preparation of Compound 7

[0234]

[0235] 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. Then, diphenyl carbonate (3.80 g, 17.72 mmol) was added, and the reaction mixture was stirred overnight at room temperature, resulting in the precipitation of a white solid. The reaction mixture was filtered, the filter cake was washed with methyl tert-butyl ether, and the solid was dried under reduced pressure to give compound 7b (1.20 g, 27% yield). 1 H NMR (500MHz, DMSO-d6) δ8.80 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 3.25 (s, 6H), 2.66 (s, 6H) ppm.

[0236] The method described in Example 2 was used to prepare a white solid compound 7 (15 mg, yield 26%) from compound 2b (40 mg, 0.11 mmol) and compound 7b (63 mg, 0.23 mmol). 1H NMR (500MHz, CD3OD) δ8.16(d,J=5.2Hz,1H),7.09(s,1H),6.81(d,J=5.2Hz,1H),6.67(s,1H),6.00(s,1H),4.89(d,J=12.6Hz,1H),4.72(d,J=1 2.3Hz,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 / z500.5[M+H] + .

[0237] Compound 7 (13.41 mg, 0.0268 mmol / L) was dissolved in acetonitrile (2 mL), and 0.01 mol / L NaOH aqueous solution (2.68 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain the sodium salt of compound 7. MS m / z 500.7 [M+H] + .

[0238] Example 8: Preparation of Compound 8

[0239]

[0240] 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 and stirred at 60 °C for 4 hours. The reaction was monitored by TLC until completion. Saturated brine (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow oily product 8b (670 mg, 69%). 1 H NMR (500MHz, CDCl3) δ4.15-4.06(m,1H),2.49-2.38(m,2H),2.27(s,3H),2.11-1.93(m,4H)ppm.

[0241] NCS (824 mg, 6.17 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of concentrated hydrochloric acid (1.5 mL), and stirred at room temperature for 10 minutes. An acetonitrile solution (5 mL) of compound 8b (670 mg, 5.15 mmol) was added under ice bath conditions, and the reaction mixture was stirred under ice bath conditions for 10 minutes. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with methyl tert-butyl ether (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product, 8c (548 mg, 69%), which was used directly in the next reaction.

[0242] Compound 8c (548 mg, 3.56 mmol) was dissolved in dichloromethane (5 mL), and then concentrated ammonia (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure. The 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 (500MHz, DMSO-d6) δ6.72(s,2H),3.75-3.70(m,1H),2.34-2.16(m,4H),1.97-1.82(m,2H)ppm.

[0243] 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. Then, diphenyl carbonate (408 mg, 1.90 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction solution containing 8e was used directly in the next reaction step.

[0244] 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 and stirred at 60 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.1) to obtain a white solid compound 8 (11 mg, yield 19%). 1H NMR(500MHz,CD3OD)δ8.15(d,J=5.2Hz,1H),7.06(s,1H),6.82(d,J=5.1Hz,1H),6.66(s,1H) ,6.02(s,1H),4.93(d,J=12.5Hz,1H),4.71(d,J=12.1Hz,1H),3.98-3.91(m,1H),3.55(s,2H ),3.12-3.00(m,2H),2.93(t,J=7.4Hz,2H),2.88-2.82(m,2H),2.74(s,3H),2.48-2.40(m,2 H),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] + .

[0245] Compound 8 (9.59 mg, 0.0188 mmol / L) was dissolved in acetonitrile (2 mL), and 0.01 mol / L NaOH aqueous solution (1.88 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to give a white solid sodium salt of compound 8 (10 mg, 100% yield). MS m / z 511.5 [M+H] + .

[0246] Example 9: Preparation of Compound 9

[0247]

[0248] The method described in Example 6 was used to prepare a white solid compound 9 (11 mg, 19% yield) from compound 3 g (40 mg, 0.12 mmol) and compound 6b (0.5 mL reaction solution). 1 H NMR (500MHz, CDCl3) δ7.74 (brs, 1H), 7.29 (d, J = 6.8Hz, 1H), 7.02 (s, 1H), 6. 32(s,1H),6.13(d,J=6.7Hz,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] + .

[0249] Compound 9 (10.52 mg, 0.0218 mmol / L) was dissolved in acetonitrile (2 mL), and 0.01 mol / L NaOH aqueous solution (2.18 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 9 (11.0 mg, 100% yield). MS m / z 483.6 [M+H] + .

[0250] Example 10: Preparation of Compound 10

[0251]

[0252] The crude product of compound 10b (97 mg, purity approximately 55%) was obtained from compounds 1a (30 mg, 0.12 mmol) and 10a (66 mg, 0.31 mmol) using the method described in Example 1. MS m / z 436.5 [M+H] + .

[0253] Compound 10c (20 mg, yield 29%) was obtained as a white solid from compound 10b (97 mg, purity about 55%) and 1d (30 mg, 0.12 mmol) using the method described in Example 1. MS m / z 557.7 [M+H] + .

[0254] Compound 10c (20 mg, 0.04 mmol) was dissolved in methanol (3 mL) and 4 M hydrochloric acid methanol solution (4 M, 0.5 mL) was added. The reaction mixture was heated to 40 °C and reacted for 1 hour. After cooling, ammonia was added to adjust the pH to neutral. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 2:1:0.02) to obtain a white solid compound 10 (7 mg, yield 43%). 1 H NMR (500MHz, CD3OD) δ8.15(d,J=5.2Hz,1H),7.12(s,1H),6.83(d,J=4.2Hz,1H),6.60(s,1H),5.07-5.01(m,1H),4.16(s,2H) ,4.10(s,2H),3.05(s,3H),2.95(t,J=7.4Hz,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] + .

[0255] Compound 10 (3.82 mg, 0.0084 mmol / L) was dissolved in acetonitrile (1 mL), and 0.01 mol / L NaOH aqueous solution (0.84 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 10 (4.0 mg, 100% yield). MS m / z 457.6 [M+H] + .

[0256] Example 11: Preparation of Compound 11

[0257]

[0258] Compound 11a (4.00 g, 29.39 mmol) and iodophenyldiacetic acid (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 under 365 nm fluorescent light. The reaction mixture was filtered, and the filtrate was distilled at 70 °C under normal pressure until no fraction remained, followed by distillation under reduced pressure at 60 °C. The fraction was the pale yellow liquid compound 11b (2.07 g, 41% yield). 1 H NMR (500MHz, CDCl3) δ4.28-4.13(m,1H),3.38-3.19(m,2H),3.06-2.89(m,2H)ppm.

[0259] The yellow oily compound 11c (150 mg, yield 15%) was obtained from compound 11b (1.00 g, 5.85 mmol) and potassium thioacetate (1.27 g, 7.41 mmol) using the method described in Example 8. 1 H NMR (500MHz, CDCl3) δ3.87-3.75(m,1H), 3.18-3.05(m,2H), 2.64-2.50(m,2H), 2.33(s,3H)ppm.

[0260] Compound 11e (20 mg, 17% yield) was obtained from compound 11c (100 mg, 0.60 mmol) using the method of Example 8. 1 H NMR (500MHz, CDCl3) δ7.11 (s, 2H), 3.76-3.66 (m, 1H), 3.02-2.83 (m, 4H).ppm.

[0261] 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. Then, diphenyl carbonate (28 mg, 0.13 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction solution containing 11f was used directly in the next step of the reaction.

[0262] Compound 11 (5 mg, 13% yield) was obtained as a white solid from compound 2b (20 mg, 0.06 mmol) and compound 11f (1.0 mL reaction solution) using the method described in Example 6. 1 H NMR(500MHz,CD3OD)δ8.14(d,J=5.1Hz,1H),7.05(s,1H),6.83(dd,J=5.2,1.1Hz ,1H),6.70(s,1H),6.07(s,1H),5.01(d,J=12.7Hz,1H),4.69(d,J=11.2Hz,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,3 H),2.80-2.70(m,2H),2.52-2.46(m,2H),2.12-2.02(m,2H),2.05(s,3H).MSm / z 547.6 [M+H] + .

[0263] Compound 11 (4.58 mg, 0.0084 mmol / L) was dissolved in acetonitrile (1 mL), and 0.01 mol / L NaOH aqueous solution (0.84 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 11 (4.76 mg, 100% yield). MS m / z 547.8 [M+H] + .

[0264] Example 12: Preparation of Compound 12

[0265]

[0266] Compound 12a was prepared using the method described in patent WO2020104657.

[0267] The method described in Example 6 was used to prepare a white solid compound 12 (30 mg, 90% yield) from compound 2b (21 mg, 0.06 mmol) and compound 12a (40 mg, 0.12 mmol). 1H NMR(500MHz,CD3OD)δ8.15(d,J=4.5Hz,1H),7.81(d,J=2.4Hz,1H),7.11(s,1H),6.79(d,J=4.5 Hz,1H),6.68(d,J=2.4Hz,1H),6.66(s,1H),6.14(s,1H),5.04(d,J=12.8Hz,1H),4.76(d,J=12 .3Hz,1H),4.61(dt,J=13.4,6.7Hz,1H),3.88(s,2H),3.41-3.35(m,2H),2.98(s,3H),2.92(t, J=7.4Hz,2H),2.64-2.51(m,4H),2.06(s,3H),2.04-1.97(m,2H),1.51(d,J=6.7Hz,6H)ppm.MS m / z565.8[M+H] + .

[0268] Compound 12 (24 mg, 0.0426 mmol / L) was dissolved in acetonitrile (2 mL), and 0.01 mol / L NaOH aqueous solution (4.26 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 12 (25 mg, 100% yield). MS m / z 565.7 [M+H] + .

[0269] Example 13: Preparation of Compound 13

[0270]

[0271] Compound 13a (100 mg, 0.59 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of ammonia (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a white solid compound 13b (71 mg, 80% yield). 1 H NMR (500MHz, DMSO-d6) δ6.70 (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.

[0272] 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. Then, diphenyl carbonate (120 mg, 0.56 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction solution containing 13c was used directly in the next reaction step.

[0273] Compound 13 (2.8 mg, 32% yield) was obtained as a white solid from compound 2b (6 mg, 0.02 mmol) and compound 13c (0.4 mL reaction solution) using the method described in Example 6. 1 H NMR(500MHz,DMSO-d6)δ8.16(d,J=5.2Hz,1H),7.41(s,1H),7.07(s,1H),6.74(d,J=5.1Hz,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=7.3H z,2H),2.65-2.62(m,1H),2.44(t,J=5.6Hz,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] + .

[0274] Compound 13 (1.27 mg, 0.0024 mmol / L) was dissolved in acetonitrile (0.2 mL), and 0.01 mol / L NaOH aqueous solution (0.24 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 13 (1.32 mg, 100% yield). MS m / z 525.5 [M+H] + .

[0275] Example 14: Preparation of Compound 14

[0276]

[0277] Sulfonamide (353 mg, 3.68 mmol) was dissolved in 1,4-dioxane (4 mL), and then compound 14a (200 mg, 3.50 mmol) was added. The reaction mixture was heated and stirred at 90 °C for 24 hours. The reaction was confirmed by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in chloroform. The reaction solution was then concentrated again under reduced pressure to obtain a white solid, crude compound 14b, which was directly used in the next step of the reaction. 1 H NMR (500MHz, DMSO-d6) δ6.84 (s, 2H), 3.67 (t, J = 7.7Hz, 4H), 2.11-2.03 (m, 2H) ppm.

[0278] 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. Then, diphenyl carbonate (900 mg, 4.20 mmol) was added, and the reaction mixture was stirred at room temperature for 3 days. The resulting reaction solution containing 14c was used directly in the next step of the reaction.

[0279] The method described in Example 6 was used to prepare a white solid compound 14 (6.37 mg, 35% yield) from compound 2b (12 mg, 0.03 mmol) and compound 14c (1 mL reaction solution). 1 H NMR(500MHz,CD3OD)δ8.17(d,J=5.2Hz,1H),7.08(s,1H),6.84(dd,J=5.2,1.2Hz,1 H),6.71(s,1H),6.01(s,1H),4.96(d,J=12.6Hz,1H),4.69(d,J=12.6Hz,1H),3.76- 3.65(m,4H),3.60-3.46(m,2H),3.09-3.00(m,2H),2.95(t,J=7.4Hz,2H),2.88(t,J =7.4Hz,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] + .

[0280] Compound 14 (2.34 mg, 0.0046 mmol / L) was dissolved in acetonitrile (0.5 mL), and 0.01 mol / L NaOH aqueous solution (0.46 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 14 (2.44 mg, 100% yield). MS m / z 512.6 [M+H] + .

[0281] Example 15: Preparation of Compound 15

[0282]

[0283] Compound 15a (200 mg, 1.08 mmol) was dissolved in dichloromethane (5 mL) under ice-water bath conditions, followed by the slow dropwise addition of diethylaminotrifluoride 15b (261 mg, 1.62 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic phases 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 (petroleum ether: ethyl acetate = 8:1) to give a white solid compound 15c (45 mg, yield 20%). 1 H NMR (500MHz, DMSO-d6) δ7.52 (s, 1H), 5.90 (t, J = 57.1Hz, 1H), 1.38 (s, 9H), 0.97-0.91 (m, 2H), 0.84-0.76 (m, 2H) ppm.

[0284] Compound 15c (45 mg, 0.22 mmol) was dissolved in dichloromethane (4 mL), and then a 1,4-dioxane solution of hydrogen chloride (4 M, 1 mL) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to give a brown solid product 15d (31 mg, 100% yield). 1 H NMR (500MHz, DMSO-d6) δ9.11 (brs, 3H), 5.96 (t, J = 53.8Hz, 1H), 1.21-1.14 (m, 2H), 1.04-1.00 (m, 2H) ppm.

[0285] Chlorosulfonyl isocyanate 15f (7 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL) under an ice-water bath, followed by the addition of compound 15e (8 mg, 0.05 mmol). The reaction mixture was stirred under an ice-water bath for 10 minutes. After the reaction was completed as monitored by TLC, 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 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to obtain a white solid compound 15 (4 mg, yield 22%). 1H NMR (500MHz, DMSO-d6) δ10.29(s,1H),7.89(s,1H),6.91(s,1H),6.12(t,J=57.6Hz,1H),2.80(t, J=7.3Hz,4H),2.70(t,J=7.3Hz,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] + .

[0286] Compound 15 (2.89 mg, 0.0075 mmol / L) was dissolved in acetonitrile (1 mL), and 0.01 mol / L NaOH aqueous solution (0.75 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 15 (3.05 mg, 100% yield). MS m / z 386.3 [M+H] + .

[0287] Example 16: Preparation of Compound 16

[0288]

[0289] Potassium tert-butoxide (549 mg, 4.89 mmol) was dissolved in DMF (5 mL), cooled to -50 °C, and DMF (5 mL) solutions of compound 16a (503 mg, 2.72 mmol) and compound 16b (472 mg, 2.44 mmol) were added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at -50 °C for 1 hour. Saturated ammonium chloride (10 mL) and concentrated hydrochloric acid (5 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. 30 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a white solid compound 16c (353 mg, yield 59%). 1 H NMR (500MHz, CDCl3) δ5.01 (s, 1H), 4.54 (d, J = 24.5Hz, 1H), 1.44 (s, 9H), 1.04-0.90 (m, 4H) ppm.

[0290] Compound 16c (353 mg, 1.61 mmol) was dissolved in dichloromethane (10 mL), and then a dioxane solution of hydrogen chloride (4 M, 3 mL) was added. The reaction mixture was heated and stirred overnight at 40 °C. The reaction was monitored by TLC until complete. The reaction mixture was concentrated under reduced pressure, and the crude compound 16d was used directly in the next reaction step.

[0291] Compound 16d (250 mg, 1.61 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), followed by the addition of diisopropylethylamine (5 drops) and then sulfonamide (185 mg, 1.93 mmol). The reaction mixture was heated and stirred overnight at 90 °C. After the reaction was complete as determined by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a white solid compound 16e (82 mg, yield 26%). 1 H NMR (500MHz, DMSO-d6) δ7.30 (s, 1H), 6.63 (s, 2H), 4.90 (dd, J = 25.9, 3.3Hz, 1H), 1.12 (q, J = 4.8Hz, 2H), 0.78 (q, J = 5.0Hz, 2H) ppm.

[0292] 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. Then, diphenyl carbonate (98 mg, 0.46 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction solution containing 16f was used directly in the next reaction step.

[0293] Compound 16 (3 mg, yield 13%) was obtained as a white solid from compound 15e (10 mg, 0.06 mmol) and compound 16f (1.0 mL reaction solution) using the method described in Example 6. 1 H NMR (500MHz, CD3OD) δ6.98 (s, 1H), 4.82 (dd, J = 24.8, 2.4Hz, 1H), 2.87 (t, J = 7.3Hz, 4H), 2. 79(t,J=7.3Hz,4H),2.11–2.02(m,4H),1.24(q,J=5.0Hz,2H),0.94(q,J=5.0Hz,2H)ppm.MS m / z 398.4[M+H] + .

[0294] Compound 16 (2.41 mg, 0.0061 mmol / L) was dissolved in acetonitrile (1 mL), and 0.01 mol / L NaOH aqueous solution (0.61 mL) was added at room temperature. After stirring for 5 minutes, the mixture was freeze-dried to obtain a white solid sodium salt of compound 16 (2.54 mg, 100% yield). MS m / z 398.3 [M+H] + .

[0295] Example 17: Preparation of Compound 17

[0296]

[0297] The method described in Example 16 was used to prepare a white solid compound 17b (384 mg, 32% yield) from compound 17a (1.00 g, 5.40 mmol), compound 16b (939 mg, 4.86 mmol), and potassium tert-butoxide (1.09 g, 9.72 mmol). 1 H NMR (500MHz, CDCl3) δ4.79(brs,1H),4.23(brs,1H),3.13-2.99(m,2H),2.60-2.48(m,2H),1.44(s,9H)ppm.

[0298] The crude product of compound 17c was obtained from compound 17b (148 mg, 0.68 mmol) using the method in Example 16 and was directly used in the next reaction.

[0299] The method described in Example 16 was used to prepare a white solid compound 17d (50 mg, 37% yield) from compound 17c (105 mg, 0.67 mmol) and sulfonamide (78 mg, 0.81 mmol). 1 H NMR (500MHz, DMSO-d6) δ7.16 (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.

[0300] 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. Then, diphenyl carbonate (59 mg, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction solution containing 17e was used directly in the next reaction step.

[0301] 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) using the method described in Example 6. 1 H NMR(500MHz,CD3OD)δ6.98(s,1H),4.10-4.02(m,1H),3.11-3.03(m,2H),2.87(t ,J=7.4Hz,4H),2.79(t,J=7.4Hz,4H),2.77-2.72(m,2H),2.09-2.03(m,4H)ppm. MS m / z 398.4[M+H] + .

[0302] Compound 17 (6.4 mg, 0.0161 mmol) was dissolved in acetonitrile (1 mL), and 0.01 mol / L NaOH aqueous solution (1.61 mL) was added at room temperature. After stirring the compound for 5 minutes, it was freeze-dried to obtain a white solid sodium salt of compound 17 (6.74 mg, 100% yield). 1 H NMR (500MHz, CD3OD) δ6.88(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] + .

[0303] Example 18: Preparation of Compound 18

[0304]

[0305] Compound 18a (90 mg, 0.53 mmol) was dissolved in 1,4-dioxane (1.5 mL), and 2 drops of diisopropylethylamine were added to adjust the pH of the mixture to alkaline. Then, sulfonamide (62 mg, 0.64 mmol) was added. The reaction mixture was stirred overnight at 95 °C. After cooling to room temperature, the reaction solution was filtered and washed. The resulting filtrate was concentrated under reduced pressure to obtain a white crude solid, 18b, which was directly added to the next reaction step.

[0306] 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 minutes. Then, diphenyl carbonate (123 mg, 0.58 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The resulting reaction solution containing 18c was used directly in the next step of the reaction.

[0307] 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) using the method described in Example 6. 1 H NMR (500MHz, CDCl3) δ7.00(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. MSm / z 412.4[M+H] + .

[0308] Compound 18 (6.93 mg, 0.0168 mmol) was dissolved in acetonitrile (1 mL), and 0.01 mol / L NaOH aqueous solution (1.68 mL) was added at room temperature. After stirring the compound for 5 minutes, it was freeze-dried to obtain a white solid sodium salt of compound 18 (7.30 mg, 100% yield). 1 H NMR (500MHz, CD3OD) δ6.87 (s, 1H), 3.22 (t, J = 5.5Hz, 4H), 2.87-2.77 (m, 8H), 2.27 (t, J = 5.5Hz, 4H), 2.08-1.98 (m, 4H). MS m / z 412.4[M+H] + .

[0309] Example 19: Preparation of Compound 19

[0310]

[0311] Sodium hydrogen 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-(diethoxyphosphonyl)acetate (3.60 g, 16.06 mmol) was added dropwise. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred for 0.5 hours. Compound 19a (2.50 g, 14.60 mmol) was added under ice bath conditions, and the reaction mixture was heated to room temperature and stirred overnight. The reaction was monitored by TLC until completion. The reaction mixture was quenched with sodium bicarbonate aqueous solution under ice bath conditions, extracted with ethyl acetate (50 mL × 3), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound 19b (2.50 g, 71%).

[0312] Compound 19b (590 mg, 2.45 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -78 °C under a nitrogen atmosphere, and 1.0 M diisobutylaluminum hydride tetrahydrofuran solution (5.1 mL, 5.10 mmol) was added dropwise. After the addition was complete, the reaction mixture was kept at -78 °C and stirred for 1 hour. The reaction was monitored by TLC until it was complete. The reaction mixture was then heated to 0 °C, and water (0.2 mL), 15% sodium hydroxide aqueous solution (0.2 mL), and water (0.4 mL) were added dropwise in sequence. The reaction mixture was then heated to room temperature and stirred for 15 minutes. An appropriate amount of anhydrous sodium sulfate was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 19c (372 mg, 76%).

[0313] 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 under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction was monitored by TLC until completion. 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 compound 19d (208 mg, 75%) was used directly in the next step of the reaction.

[0314] Compound 19d (100 mg, 0.36 mmol), sodium iodide (5 mg, 0.04 mmol), and 1.0 M dimethylaminetetrahydrofuran solution (2 mL, 2.00 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated and stirred at 60 °C for 3 hours in a sealed tube. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 19e (51 mg, 63%). MS m / z 227.4 [M+H] + .

[0315] Compound 19e (30 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.5 mL) was added. The reaction mixture was heated and stirred at 40 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, dissolved in acetonitrile (1 mL), and concentrated hydrochloric acid (0.1 mL) was added dropwise. The solution was then lyophilized to give compound 19f (21 mg, 97%). MS m / z 127.2 [M+H] + .

[0316] Chlorosulfonyl isocyanate (6 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL), and compound 19 g (8 mg, 0.04 mmol) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 10 minutes, and then compound 19f (11 mg, 0.09 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was detected by TLC to indicate completion. The reaction mixture was quenched with water, extracted with dichloromethane (5 mL × 3), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography to obtain compound 19 (0.7 mg, 4%). MS m / z 405.4 [M+H] + .

[0317] Example 20: Preparation of Compound 20

[0318]

[0319] Potassium tert-butoxide (163 mg, 1.46 mmol) was dissolved in DMF (2 mL) and cooled to -50 °C under a nitrogen atmosphere. A mixed solution of compound 20a (150 mg, 0.81 mmol) and compound 20b (140 mg, 0.73 mmol) in DMF (2 mL) was then added. The reaction mixture was kept at -50 °C and stirred for 1 hour. The reaction was monitored by TLC until completion. The reaction mixture was quenched with concentrated hydrochloric acid (1 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, 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 obtain compound 20c (63 mg, 36%). 1 H NMR (500MHz, CDCl3) δ5.01 (s, 1H), 4.54 (d, J = 24.5Hz, 1H), 1.44 (s, 9H), 1.02-0.96 (m, 2H), 0.94-0.89 (m, 2H) ppm.

[0320] Compound 20c (45 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL), and then 4.0 M dioxane hydrochloride solution (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude compound 20d was used directly in the next reaction step. 1 H NMR (500MHz, DMSO-d6) δ 8.73 (s, 3H), 4.94 (dd, J = 1.4Hz, J = 25.1Hz, 1H), 1.22 (t, J = 6.3Hz, 2H), 0.94 (t, J = 6.3Hz, 2H) ppm.

[0321] 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 under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 0.5 hours. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography to obtain compound 20e (27 mg, 47%).

[0322] 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 minutes. Then, diphenyl carbonate (32 mg, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The resulting reaction solution containing compound 20f was used directly in the next reaction step.

[0323] 20g of compound was synthesized using the method described in patent WO20190211463.

[0324] Compound 20 g (14 mg, 0.06 mmol) and compound 20f (1 mL reaction solution) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 60 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.1) to obtain a white solid compound 20 (3 mg, 11%). 1 H NMR(500MHz,CD3OD)δ8.17(d,J=5.2Hz,1H),7.12(s,1H),6.78(dd,J=5.2,1.3Hz,1H),6.63(s,1H),4.68(dd,J=24.6,2.4Hz,1H), 3.93(s,3H),2.95(t,J=7.4Hz,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 / z479.5[M+H] + .

[0325] Example 21: Preparation of Compound 21

[0326]

[0327] Compound 21a was synthesized using the method described in patent WO2019034690.

[0328] Compound 21a (700 mg, 1.81 mmol) was dissolved in tetrahydrofuran (14 mL), followed by the addition of 3-bromocyclobutanone (404 mg, 2.71 mmol) and potassium carbonate (499 mg, 3.61 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until completion. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound 21b (505 mg, 61%). 1 H NMR (500MHz, CDCl3) δ7.54(d,J=2.0Hz,1H),7.12-7.07(m,4H),6.80-6.76(m,4H),6.72(d,J=1 .9Hz,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] + .

[0329] Potassium tert-butoxide (111 mg, 0.99 mmol) was dissolved in DMF (3 mL) and cooled to -50 °C under a nitrogen atmosphere. A mixed solution of compound 20b (95 mg, 0.49 mmol) and compound 21b (250 mg, 0.55 mmol) in DMF (2 mL) was then added. The reaction mixture was kept at -50 °C and stirred for 1 hour. The reaction was monitored by TLC until completion. The reaction mixture was quenched with concentrated hydrochloric acid (1 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was 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 obtain compound 21c (72 mg, 27%). MS m / z 490.4 [M+H] +

[0330] Compound 21c (72 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography to obtain compound 21d (10 mg, 27%).

[0331] 19 g (15 mg, 0.09 mmol) of the compound was dissolved in tetrahydrofuran (1 mL), followed by the addition of diisopropylethylamine (22 mg, 0.17 mmol) and triphosgene (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure, slurried with petroleum ether, filtered, and the filtrate was concentrated under reduced pressure. The crude product 21e was used directly in the next reaction step.

[0332] Compound 21d (5 mg, 0.02 mmol) was dissolved in tetrahydrofuran (0.5 mL), and sodium tert-butoxide (2 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, and then compound 21e (4 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain a white solid compound 21 (8 mg, 89%). 1 H NMR(500MHz,CD3OD)δ7.87(d,J=2.3Hz,1H),6.96(s,1H),6.83(d,J=2.3Hz,1H),5.16-5.0 8(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] + .

[0333] Example 22: Preparation of compound 22

[0334]

[0335] 20 g (12 mg, 0.05 mmol) of the compound was dissolved in tetrahydrofuran (1 mL), followed by the addition of diisopropylethylamine (12 mg, 0.10 mmol) and triphosgene (7 mg, 0.02 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure, slurried with petroleum ether, filtered, and the filtrate was concentrated under reduced pressure. The crude product 22a was used directly in the next reaction step.

[0336] Compound 21d (6 mg, 0.02 mmol) was dissolved in tetrahydrofuran (0.5 mL), and sodium tert-butoxide (2 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, and then compound 22a (7 mg, 0.02 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain a white solid compound 22 (6 mg, 51%). 1 H NMR (500MHz, CD3OD) δ8.09(d,J=5.1Hz,1H),7.81(d,J=1.2Hz,1H),7.08(s,1H),6.72(d,J=5.2Hz,1H),6.63(d,J=1.4Hz,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=7.4Hz,2H),2.72-2.66(m,2H),2.05-1.99(m,5H)ppm. MS m / z 530.5[M+H] + .

[0337] Compound 22 (100 mg, 0.19 mmol) was dispersed in water (5 mL), and 0.1 mol / L NaOH aqueous 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 freeze-dried to obtain a white solid sodium salt of compound 22 (104 mg, 100% yield). 1H NMR(500MHz,CD3OD)δ8.07(d,J=5.2Hz,1H),7.69(d,J=2.3Hz,1H),6.99(s,1H),6.76(d,J=5.1Hz,1H) ,6.62(s,1H),6.49(d,J=2.3Hz,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 = 7.4Hz, 2H), 2.76 (t, J = 7.1Hz, 2H), 2.04-1.95 (m, 5H). MS m / z 530.2[M+H] + .

[0338] Example 23: Preparation of compound 23

[0339]

[0340] Sodium hydrogen 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-(diethoxyphosphazene)acetate (143 mg, 0.64 mmol) was added dropwise. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred for 0.5 hours. Compound 21b (264 mg, 0.58 mmol) was added under ice bath conditions, and the reaction mixture was heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was quenched with sodium bicarbonate aqueous solution under ice bath conditions, extracted with ethyl acetate (20 mL × 3), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound 23a (179 mg, 59%). MS m / z 526.5 [M+H] + .

[0341] Compound 23a (179 mg, 0.34 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to -78 °C under a nitrogen atmosphere, and 1.0 M diisobutylaluminum hydride tetrahydrofuran solution (0.85 mL, 0.85 mmol) was added dropwise. After the addition was complete, the reaction mixture was kept at -78 °C and stirred for 1 hour. The reaction was monitored by TLC until completion. The reaction mixture was then heated to 0 °C, and water (0.05 mL), 15% sodium hydroxide aqueous solution (0.05 mL), and water (0.10 mL) were added dropwise sequentially. The reaction mixture was then heated to room temperature and stirred for 15 minutes. An appropriate amount of anhydrous sodium sulfate was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 23b (116 mg, 70%). MS m / z 484.4 [M+H] + .

[0342] 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 under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude compound 23c (134 mg) was used directly in the next step of the reaction.

[0343] Compound 23c (134 mg, 0.24 mmol), sodium iodide (2 mg, 0.01 mmol), and 1.0 M dimethylaminetetrahydrofuran solution (2 mL, 2.00 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated and stirred at 60 °C for 2 hours in a sealed tube. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 23d (54 mg, 44%). MS m / z 511.7 [M+H] + .

[0344] Compound 23d (54 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography to obtain compound 23e (16 mg, 56%).

[0345] Compound 23e (8 mg, 0.03 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium tert-butoxide (3 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, and then compound 21e (6 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain a white solid compound 23 (8 mg, 56%). 1 H NMR (500MHz, CD3OD) δ7.84(d,J=2.4Hz,1H),6.93(s,1H),6.79(d,J=2.4Hz,1H),5.54-5.48(m,1H),5.10-5.04(m,1 H), 3.62 (d, J = 7.8Hz, 2H), 3.43-3.33 (m, 4H), 2.86-2.81 (m, 10H), 2.67 (t, J = 7.3Hz, 4H), 2.01 (p, J = 7.4Hz, 4H) ppm. MS m / z 470.5[M+H] + .

[0346] Example 24: Synthesis of Compound 24

[0347]

[0348] Compound 23e (8 mg, 0.03 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium tert-butoxide (3 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, and then compound 22a (8 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain a white solid compound 24 (8 mg, 52%). 1 H NMR(500MHz,CD3OD)δ8.08(d,J=5.0Hz,1H),7.82(d,J=2.3Hz,1H),7.09(s,1 H),6.71(d,J=5.0Hz,1H),6.61(d,J=2.3Hz,1H),6.58(s,1H),5.55-5.49(m,1 H),5.11-5.04(m,1H),3.92(s,3H),3.65(d,J=7.9Hz,2H),3.43-3.30(m,4H), 2.92(t,J=7.4Hz,2H),2.86(s,6H),2.72-2.65(m,2H),2.07-1.99(m,5H)ppm. MSm / z 551.6 [M+H] + .

[0349] Example 25: Study on the inhibitory activity of compounds against NLRP3

[0350] Step 1: IL1β induction

[0351] Add 60 μL / well of polylysine to a 96-well cell culture plate and incubate at 37°C for 30 minutes. Discard the solution and wash the cell culture plate twice with PBS. Seed THP1 (50,000 cells / well / 95 μL) into the cell culture plate, add 5 μL of PMA (final concentration 50 ng / mL) to each well, and incubate overnight at 37°C. Gently aspirate the supernatant, wash the cell culture plate twice with PBS, add 80 μL of FBS-free medium to each well, and then add 5 μL / well of LPS (final concentration 500 ng / mL), and incubate at 37°C for 3 hours. Dilute the compound (10 mM stock solution dissolved in DMSO) accordingly with 100% DMSO. Add 2 μL of the serially diluted compound to 98 μL of medium and mix well. Add 5 μL / well of the diluted compound to the cell culture plate and incubate at 37°C for 1 hour. Next, add 10 μL / well of Nigericin (final concentration 10 μg / mL) to the cell plate and incubate at 37°C for 0.5 hours. Collect the cell supernatant into a new cell plate and freeze at -80°C for later use.

[0352] Step 2: IL1β detection

[0353] Dilute the IL1β antibody 60-fold with coating buffer. Add 100 μL of the diluted antibody to each well of an ELISA plate and incubate overnight at 4°C. Discard the liquid in the ELISA plate and wash four times with elution buffer. Add 300 μL / well of reagent diluent to block the ELISA plate and incubate at room temperature for 1.5 hours. Wash four times with elution buffer. Add 100 μL / well of sample to the IL1β-coated ELISA plate and incubate at room temperature for 2 hours. Wash four times with elution buffer. Add 100 μL of detection antibody to each well and incubate at 37°C for 2 hours. Wash four times with elution buffer. Add 100 μL of HRP-labeled secondary antibody to each well. Incubate at 37°C for 1 hour. Wash four times with elution buffer. Add 100 μL of A+B substrate to each well. Incubate at 37°C for 30 minutes. Add 100 μL of STOP solution to each well. Gently vortex for a few seconds. The absorbance at 450 nm was read on an EnVision multi-function plate reader, and the inhibition rate was calculated using the following formula: Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L). Where Ave_H represents the average read value of the DMSO wells, Sample represents the average read value of the compound wells, and Ave_L represents the average read value of the 10 μM positive control group. The concentration logarithm was plotted on the X-axis, and the percentage inhibition rate on the Y-axis. A dose-response curve was fitted using the log(inhibitor) vs. response-variable slope function in GraphPad Prism 5 to obtain the IC50 for each compound. 50 Value. Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope)).

[0354] Table 1: Results of the compounds inhibiting NLRP3 activity at a concentration of 300 nM

[0355] Compound 1 >50％ <![CDATA[Compound 6 * > >50％ <![CDATA[Compound 7 * > >50％ <![CDATA[Compound 8 * > >50％ <![CDATA[Compound 13 * > >50％ <![CDATA[Compound 14 * > >50％ Compound 22 >50％ <25 <![CDATA[MCC950 * ]]> >50％ <100

[0356] * The representative compound is the sodium salt.

[0357]

[0358] Example 26: Pharmacokinetic Study in Rats

[0359] Instrumentation: Waters XEVO TQ-S LC-MS / MS. All data were acquired and processed using Masslynx V4.1 software, and calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNonLin 8.0 software using the statistical moment method. This mainly included the kinetic parameter T... max T 1 / 2 C max AUC last Column: ACQUITYUPLC BEH C18 (2.1 mm × 50 mm, 1.7 μm); column temperature: 40 °C; mobile phase A: water (0.1% formic acid); mobile phase B: acetonitrile; flow rate: 0.350 mL / min; gradient elution: 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Injection volume: 1 μL.

[0360] Animals: Three male SD rats, weighing 200-220g, were purchased and housed in the laboratory of the experimental animal center for two days before use. They were fasted for 12 hours before and 4 hours after administration, but had free access to water during the experiment. Blood samples were collected from the rats at predetermined time points after gavage.

[0361] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450). Preparation of oral administration solution: Accurately weigh the compound, add it to the solvent, and sonicate at room temperature for 5 minutes to completely dissolve the drug, preparing a solution of 0.3 mg / mL.

[0362] Drug samples: Generally, multiple structurally similar samples (with molecular weights differing by more than 2 units) are accurately weighed and administered together (cassette PK). This allows for the simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single-dose administration is also used to study the pharmacokinetics of drug samples in rats.

[0363] Blood samples were collected from the orbital cavity at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. 50 μL of plasma was collected and 200 μL of acetonitrile (containing 2 ng / mL verapamil as internal standard) was added. The mixture was vortexed for 3 min, centrifuged at 20000 rcf for 10 min at 4 °C, and the supernatant was analyzed by LC-MS / MS.

[0364] Compounds were accurately weighed and formulated into different concentrations, then quantitatively analyzed by mass spectrometry to establish a standard curve. The concentrations of the compounds in the plasma were then measured to determine the concentrations at different time points. All data were acquired and processed using relevant software, and pharmacokinetic parameters (primarily including the kinetic parameter T) were calculated using the statistical moment method. max T 1 / 2 C max AUC last (etc.). The kinetic parameters of some representative compounds are shown in Table 2.

[0365] Table 2 Pharmacokinetic parameters in rats

[0366]

[0367] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound with the structure shown in formula (XII), or a pharmaceutically acceptable salt thereof: p and q are each independently selected from 1 or 2; M is selected from CR 10 R 11 ;in, R 10 and R 11 Each is independently selected from the following group: hydrogen, fluorine, or C. 1-2 alkyl; R 1 and R 2 Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl; Each R 3 Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl; m is 0, 1, or 2; E is selected from the following group; -O-; G is selected from the following group; C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, saturated C 3-8 Cycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from the following group: "*" indicates a chiral center.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound mentioned is compound 22: 。 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts mentioned are alkali metal salts.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts are selected from the group consisting of sodium salts, potassium salts, and lithium salts.

6. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that, Used to prepare pharmaceutical compositions for treating diseases, conditions, or symptoms associated with NLRP3 activity or expression levels.

8. The use as described in claim 7, characterized in that, The diseases, symptoms, or conditions described are selected from the following group: inflammation, autoimmune diseases, cancer, infection, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic conditions, mental disorders, graft-versus-host disease, abnormal pain, cryotherapy-related periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, familial Mediterranean fever, pyoderma gangrene and acne syndrome, type D hyperimmunoglobulinemia and periodic fever syndrome, tumor necrosis factor (TNF) receptor-related periodic syndrome, adult-onset Still's disease, Schnitzler syndrome, Sweet's syndrome, Behçet's disease, antisynthetic enzyme syndrome, interleukin-1 receptor antagonist deficiency, and A2o haploinsufficiency.

9. The use as described in claim 7, characterized in that, The diseases, symptoms, or conditions described are selected from the following group: autoimmune diseases, knee osteoarthritis, cancer, infections, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic conditions, mental disorders, graft-versus-host disease, abnormal pain, cryotherapy-related periodic syndromes, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease, familial Mediterranean fever, pyogenic arthritis, pyoderma gangrenosa and acne syndrome, D-type hyperimmunoglobulinemia and periodic fever syndrome, tumor necrosis factor (TNF) receptor-related periodic syndromes, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Schnitzler syndrome, Sweet's syndrome, Behçet's disease, antisynthetic enzyme syndrome, interleukin-1 receptor antagonist deficiency, and A2o haploinsufficiency.

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