Gsdmd inhibitor and use thereof

Abstract

Provided are a compound of formula (I) or a tautomer, enantiomer, diastereomer, isotope-labeled compound, solvate, or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and use thereof in the preparation of a drug for preventing and treating pyroptosis-related autoimmune diseases, infections, and non-infectious diseases.

Description

GSDMD inhibitors and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese patent application No. 202311841377.5 filed with the State Intellectual Property Office of China on December 28, 2023, and the contents disclosed in the above application are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of biomedicine and relates to GSDMD inhibitors and their uses, in particular, their use in preventing or treating autoimmune diseases, infections and non-infectious diseases associated with pyroptosis. Background Art

[0004] The gasdermin family includes six homologous genes in humans: gasdermin A (GSDMA), gasdermin B (GSDMB), gasdermin C (GSDMC), gasdermin D (GSDMD), gasdermin E (GSDME) (also known as DFNA5), and PJVK (also known as DFNB59). These proteins are associated with many inflammatory diseases and are promising therapeutic targets.

[0005] Gasdermin D (GSDMD), a cytoplasmic protein encoded by the GSDMD gene of the gasdermin family, is the final executioner of pyroptosis. It is widely expressed in various cells and tissues. It consists of 242 amino acids, a total length of 53 kDa, and contains a characteristic gasdermin domain. GSDMD has two domains: an N-terminal effector domain and a C-terminal inhibitory domain. The N-terminus is the primary functional domain involved in pyroptosis, while the C-terminus has an inhibitory function. In the resting state, the N-terminal and C-terminal domains are connected by a long loop, inhibiting the activity of the N-terminus. Upon external stimulation, caspase-1 / 4 / 5 / 11 is activated to cleave the GSDMD protein, separating it into two separate domains: the N-terminal and C-terminal fragments. The GSDMD N-terminal domain can target the cell membrane, bind to phospholipids on the cell membrane, and oligomerize to form transmembrane pores of 10-20 nm in size, damaging the cell membrane and inducing pyroptosis. At the same time, activated Caspase-1 cleaves IL-1β and IL-18 precursors to form mature IL-1β and IL-18 proinflammatory cytokines. IL-1β and IL-18 are released outside the cell through the GSDMD pores. The release of a large number of inflammatory factors outside the cell leads to the occurrence of an inflammatory response. Moreover, since the GSDMD pores are permeable to ions, small molecules and water, the formation of pores will destroy the local osmotic gradient, causing cell swelling and rupture, and releasing cell contents.

[0006] Pyroptosis is a type of inflammation-associated death that protects against microbial infection and induces excessive inflammatory responses. Growing evidence suggests that pyroptosis is highly correlated with autoimmune diseases, infectious and non-infectious inflammatory diseases. GSDMD is a key mediator of pyroptosis, and therefore, GSDMD may become a key target for the treatment or prevention of these diseases. Therefore, we are seeking to identify compounds that target GSDMD, inhibiting the release of its N-terminus and the formation of oligomers, thereby inhibiting pyroptosis and potentially treating or preventing these diseases. Summary of the Invention

[0007] In one aspect, the present application provides a compound of formula (I), or a tautomer, enantiomer, diastereomer, isotope-labeled compound, solvate, or pharmaceutically acceptable salt thereof:

[0008] in,

[0009] is a single bond or a double bond;

[0010] R1 and R2 are each independently selected from -H, -COOH, -COOR a 、-COR b , heterocyclic or heteroaryl, said R a and R b Each independently selected from alkyl, the heterocyclyl and heteroaryl are each optionally substituted by one or more independently selected from oxo, halogen and C 1-6 Substitution of alkyl groups;

[0011] X is NR3 or CR4R5, wherein R3, R4 and R5 are each independently selected from H or C 1-6 alkyl;

[0012] L1 is -(Ar) m -(CH2) p -L2-, wherein Ar is an aryl group, which is optionally substituted by one or more independently selected from halogen, -CN, C 1-6 Alkyl and -CON(R c R d ) is substituted by a substituent; m is 0 or 1; p is 0, 1, 2, 3 or 4; L2 is selected from a direct bond, -N(R e )-、-O-、-N=C(R f )-、-C(R g )=C(R h )-、-OC(R i R j )-、-N(R k )C(Rl R m )-、-N(R n )CO-、-N(R o )C(R p )=、-CON(R q )-or-CO-; R c to R q Each independently selected from H and C 1-6 alkyl;

[0013] Ring A is selected from aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl are each optionally substituted by one or more independently selected from -OH, -NO2, oxo, halogen, C 1-6 Alkyl and C 1-6 The substituents of the haloalkyl group are substituted.

[0014] In some embodiments, the compound of formula (I) is not:

[0015] In some embodiments, R1 and R2 are each independently selected from -H, -COOH, -COOR a 、-COR b , 3-12 membered heterocyclic group or 5-14 membered heteroaryl group, wherein R a and R b Each independently selected from C 1-6 The 3-12 membered heterocyclic group and the 5-14 membered heteroaryl are each optionally substituted by one or more independently selected from oxo, halogen and C 1-6 The alkyl group is substituted with a substituent.

[0016] In some embodiments, R1 and R2 are each independently selected from -H, -COOH, -COOR a 、-COR b , 5-10 membered heterocyclic group or 5-10 membered heteroaryl group, said R a and R b Each independently selected from C 1-3 The 5-10 membered heterocyclic group and the 5-10 membered heteroaryl are each optionally substituted by 1, 2 or 3 independently selected from oxo, halogen and C 1-3 The alkyl group is substituted with a substituent.

[0017] In some embodiments, R1 and R2 are each independently selected from -H, -COOH, -COOCH3, -COCH3,

[0018] In some embodiments, one of R1 and R2 is -COOR a, the other one is selected from -H, -COOH, -COOR a 、-COR b , 5-10 membered heterocyclic group or 5-10 membered heteroaryl group, said R a and R b Each independently selected from C 1-6 The 5-10 membered heterocyclic group and the 5-10 membered heteroaryl are each optionally substituted by 1, 2 or 3 independently selected from oxo, halogen and C 1-6 The alkyl group is substituted with a substituent.

[0019] In some embodiments, one of R1 and R2 is -COOCH3 and the other is -H, -COOH, -COOCH3, -COCH3,

[0020] In some embodiments, R1 and R2 are both -COOCH3. In some embodiments, R1 and R2 are both -COOH.

[0021] In some embodiments, R3, R4 and R5 are each independently selected from H or C 1-3 alkyl;

[0022] In some embodiments, R3 is H.

[0023] In some embodiments, R4 and R5 are both H.

[0024] In some embodiments, X is NR3, R3 is selected from H or C 1-3 alkyl.

[0025] In some embodiments, X is NH or CH2.

[0026] In some embodiments, X is NH.

[0027] In some embodiments, L1 is selected from -(Ar) m -(CH2) p -L2-, wherein Ar is a 6-10 membered aryl group, which is optionally substituted by 1, 2 or 3 independently selected from halogen, -CN, C 1-6 Alkyl and -CON(R c R d ) is substituted by a substituent; m is 0 or 1; p is 0, 1, 2, 3 or 4; L2 is selected from a direct bond, -N(R e )-、-O-、-N=C(R f )-、-C(R g )=C(R h )-、-OC(R i R j )-、-N(R k)C(R l R m )-、-N(R n )CO-、-N(R o )C(R p )=、-CON(R q )-or-CO-; R c to R q Each independently selected from H and C 1-3 alkyl.

[0028] In some embodiments, L1 is -Ar-L2-, wherein Ar is a 6-10 membered aryl group, which is optionally substituted by 1, 2 or 3 independently selected from halogen, -CN, C 1-6 Alkyl and -CON(R c R d ) is substituted by a substituent; L2 is selected from a direct bond, -N(R e )-、-O-、-N=C(R f )-、-C(R g )=C(R h )-、-OC(R i R j )-、-N(R k )C(R l R m )-、-N(R n )CO-、-N(R o )C(R p )=、-CON(R q )-or-CO-; R c to R q Each independently selected from H and C 1-3 alkyl.

[0029] In some embodiments, L1 is -Ar-L2-, wherein Ar is phenyl, which is optionally substituted by 1, 2 or 3 independently selected from halogen, -CN, C 1-6 Alkyl and -CON(R c R d ) is substituted by a substituent; L2 is selected from a direct bond, -N(R e )-、-O-、-N=C(R f )-、-C(R g )=C(R h )-、-OC(R i R j )-、-N(R k )C(R l R m )-、-N(R n )CO-、-N(R o )C(Rp )=、-CON(R q )-or-CO-; R c to R q Each independently selected from H and C 1-3 alkyl.

[0030] In some embodiments, L1 is -Ar-L2-, wherein Ar is phenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from -F, -Cl, -Br, -CN, -CH3 and -CONH2; and L2 is selected from a direct bond, -NH-, -O-, -N=CH-, -CH=CH-, -OCH2-, -NHCH2-, -NHCO- or -NHCH=.

[0031] In some embodiments, L1 is -Ar-L2-, wherein Ar is * represents the connection site with L2; L2 is selected from a direct bond, -NH-, -O-, -N=CH-, -CH=CH-, -OCH2-, -NHCH2-, -NHCO- or -NHCH=.

[0032] In some embodiments, L1 is -Ar-L2-, wherein Ar is * represents the connection site with L2; L2 is selected from a direct bond, -NH-, -N=CH-, -CH=CH-, -NHCH2-, -NHCO- or -NHCH=.

[0033] In some embodiments, L1 is Wherein * indicates the connection site with ring A.

[0034] In some embodiments, L1 is Wherein * indicates the connection site with ring A.

[0035] In some embodiments, L1 is -(CH2) p -, p is 1, 2, 3 or 4. In some embodiments, L1 is -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0036] In some embodiments, Ring A is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered cycloalkyl or 5-14 membered heterocyclyl, wherein each of the 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered cycloalkyl and 5-14 membered heterocyclyl is optionally substituted by one or more independently selected from -OH, -NO2, oxo, halogen, C 1-6 Alkyl and C 1-6The substituents of the haloalkyl group are substituted.

[0037] In some embodiments, ring A is selected from 6-14 membered aryl, 5-10 membered heteroaryl, 5-10 membered cycloalkyl or 5-10 membered heterocyclyl, wherein the 6-14 membered aryl, 5-10 membered heteroaryl, 5-10 membered cycloalkyl and 5-10 membered heterocyclyl are each optionally substituted by 1, 2 or 3 groups independently selected from -OH, -NO2, oxo, halogen, C 1-6 Alkyl and C 1-6 The substituents of the haloalkyl group are substituted.

[0038] In some embodiments, Ring A is selected from phenyl, naphthyl, phenanthrenyl, benzothiophenyl, benzothiazolyl, dihydronaphthyl, isoquinolinyl, tetrahydroisoquinolinyl, and isoindolinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from -OH, -NO2, oxo, -F, -Cl, and -CF3.

[0039] In some embodiments, Ring A is selected from

[0040] In some embodiments, Ring A is

[0041] In some embodiments, L1 is -(CH2) p -, p is 1, 2 or 3, and ring A is phenyl or naphthyl.

[0042] In the above embodiments, the definitions of the various groups or structural fragments in formula (I) can be combined with each other.

[0043] In some embodiments, the compound of formula (I) is selected from:

[0044] In some embodiments, the isotopically labeled compound is a deuterated compound.

[0045] On the other hand, the present application provides a pharmaceutical composition comprising a compound of formula (I) described herein, or its tautomers, enantiomers, diastereomers, isotope-labeled compounds, solvates or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients.

[0046] In some embodiments, the excipients include one or more of a diluent, a filler, a binder, a wetting agent, an absorption enhancer, a surfactant, a lubricant, and a stabilizer.

[0047] In some embodiments, the pharmaceutical composition is a pharmaceutical preparation selected from tablets, capsules, pills, granules, pellets, aerosols, sprays, nasal drops, inhalants, suppositories, enemas, intramuscular injection preparations, intravenous injection preparations, intra-articular injections, ointments or patches.

[0048] On the other hand, the present application provides the use of the compound of formula (I) described herein, or its tautomers, enantiomers, diastereomers, isotope-labeled compounds, solvates or pharmaceutically acceptable salts, or the pharmaceutical composition described herein in the preparation of a drug for preventing or treating diseases associated with pyroptosis.

[0049] On the other hand, the present application provides the use of the compound of formula (I) described herein, or its tautomers, enantiomers, diastereomers, isotope-labeled compounds, solvates or pharmaceutically acceptable salts, or the pharmaceutical composition described herein in preventing or treating diseases related to pyroptosis.

[0050] On the other hand, the present application provides a method for treating diseases associated with pyroptosis, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of formula (I) described herein, or its tautomers, enantiomers, diastereomers, isotope-labeled compounds, solvates or pharmaceutically acceptable salts, or the pharmaceutical composition described herein.

[0051] On the other hand, the present application provides a compound of formula (I) described herein, or its tautomer, enantiomer, diastereomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt, or a pharmaceutical composition described herein for preventing or treating diseases associated with pyroptosis.

[0052] In some embodiments, the disease associated with pyroptosis is an autoimmune disease, infectious disease, or non-infectious inflammatory disease caused by or associated with pyroptosis.

[0053] In some embodiments, the autoimmune disease comprises rheumatoid arthritis, dyskeratosis, chronic proliferative dermatitis, neutrophilic dermatosis, Sjögren's syndrome, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, Guillain-Barré syndrome, colitis, ulcerative colitis, and Crohn's disease.

[0054] In some embodiments, the infectious and non-infectious inflammatory diseases include sepsis, Gram-negative bacterial infections, viral infections, HIV, influenza A virus, Zika virus, hand, foot and mouth disease caused by enterovirus 71, fungal infections, Candida albicans infection, Aspergillus fumigatus infection, atherosclerosis, neuromyelitis optica, infectious encephalitis, ischemic brain injury, ischemic stroke, epilepsy, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, type 2 diabetes, non-alcoholic fatty liver disease, alcoholic or non-alcoholic hepatitis, liver fibrosis, cirrhosis, acute kidney injury, traumatic brain injury, acute lung injury, chronic obstructive pulmonary disease, trachea or bronchitis, asthma, pulmonary fibrosis, lung cancer, preeclampsia, gestational diabetes, other adverse pregnancy complications, familial Mediterranean fever, cryoprotein-associated periodic syndrome (CAPS), age-related macular degeneration, gout, Muckle-Wells syndrome and neonatal multisystem inflammatory disease.

[0055] The compounds of the present application have one or more of the following effects:

[0056] (1) The compounds of the present application have a good inhibitory effect on cell pyroptosis.

[0057] (2) The compounds of the present application can inhibit the release of the GSDMD N-terminus and the formation of oligomers, thereby inhibiting the occurrence of pyroptosis.

[0058] (3) The compounds of the present application can significantly prolong the survival of sepsis model mice.

[0059] Definitions and Explanations of Terms

[0060] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0061] In this article Indicates the attachment site.

[0062] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0063] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0064] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0065] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0066] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0067] When any variable (such as n, R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0068] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0069] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C6 alkyl" refers to a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl. The term "C1-C4 alkyl" is understood to mean a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms.

[0070] The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group substituted by one or more (e.g., 1, 2, or 3) halogens such as F, Cl, Br, or I, including mono-, poly-, or fully substituted. Specific examples of "C1-C6 haloalkyl" include, but are not limited to, CF3.

[0071] The term "alkoxy" refers to a group resulting from the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-." The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-." The "C1-C6 alkoxy" group may further include a "C1-C4 alkoxy group." The term "C1-C4 haloalkoxy" refers to a C1-C4 haloalkyl-O- group.

[0072] The term "cycloalkyl" refers to a saturated or partially unsaturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5- to 14-membered ring, a 5- to 10-membered ring, or a 3- to 8-membered ring. The term "5- to 14-membered cycloalkyl" may be understood to mean a saturated or partially unsaturated monocyclic, cyclic, spirocyclic, or bridged ring having 5 to 14 (e.g., 5, 6, 10, or 14) carbon atoms. "Cycloalkyl" includes "cycloalkyl." The term "3- to 8-membered cycloalkyl" may be understood to mean a saturated monocyclic, cyclic, spirocyclic, or bridged ring having 3-8 (e.g., 5, 6, or 7) carbon atoms. Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "3- to 6-membered cycloalkyl" is understood to mean a saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0073] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring, a ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically 5 to 14 yuan, 5 to 10 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 12 yuan, 6 to 8 yuan containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen or nitrogen. In some embodiments, the heterocyclic radical contains 1 or 2 heteroatoms independently selected from N and O. Non-limiting examples of heterocyclic radicals include but are not limited to pyrrolidine, dihydropyrrole, oxazolidine, oxazolidinone, isoindoline, tetrahydroisoindoline, dihydronaphthalene, isoquinoline, tetrahydroisoquinoline etc.

[0074] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. An aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 or 6-10 carbon atoms. In particular, an aryl group may have a ring of 6 carbon atoms ("6-membered aryl"), such as phenyl; or a ring of 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring of 10 carbon atoms ("C 10 aryl), such as naphthyl; or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 aryl”), such as phenanthrenyl, anthracenyl. The term “C6-C 14 "Aryl" is understood to be an aromatic radical having 6 to 14 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl), such as naphthyl; or a ring having 14 carbon atoms ("C 14 "aryl"), for example, phenanthrenyl, anthracenyl.

[0075] The term "heteroaryl" or "heteroaromatic ring" refers to an aromatic monocyclic or fused polycyclic ring system containing at least one (1, 2, or 3) ring atom selected from N, O, and S, with the remaining ring atoms being C. "Heteroaryl" typically contains 5-14 or 5-10 ring atoms. The term "5-14 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5 to 14 ring atoms and containing 1-3 heteroatoms independently selected from N, O, and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "6-membered heteroaryl" refers to an aromatic ring system having 6 ring atoms and containing 1-3, preferably 1-2, heteroatoms independently selected from N, O and S (eg, containing 1 or 2 N atoms).

[0076] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0077] The term "cyano" refers to a -CN group.

[0078] The term "hydroxy" refers to an -OH group.

[0079] The term "oxo" refers to a =0 group.

[0080] The term "heteroatom" includes atoms of any element other than carbon or hydrogen. In some embodiments, the heteroatom is selected from boron, nitrogen, oxygen, sulfur, silicon, and phosphorus. In some embodiments, the heteroatom is selected from N, O, and S. The number of heteroatoms contained in the group can be 1, 2, or 3.

[0081] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0082] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0083] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0084] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0085] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that: (i) treats a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a specific disease, condition, or disorder as described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and this disclosure.

[0086] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0087] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0088] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0089] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0090] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0091] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0092] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0093] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into tablets, capsules, pills, granules, pellets, aerosols, sprays, nasal drops, inhalants, suppositories, enemas, intramuscular injection preparations, intravenous injection preparations, intra-articular injection preparations, ointments or patches, etc.

[0094] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0095] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0096] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, capsules, pills, granules, pellets, etc. for oral administration to a patient.

[0097] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, one or more of a diluent, a filler, a binder, a wetting agent, an absorption enhancer, a surfactant, a lubricant, and a stabilizer.

[0098] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0099] In all administration methods described herein, the compound of formula (I) is administered at a daily dosage of 0.01 mg / kg to 200 mg / kg body weight, preferably 0.05 mg / kg to 50 mg / kg body weight, in the form of single or divided doses. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] Figure 1: Inhibitory effect of RGW-1 on LDH release at the cellular level.

[0101] FIG2A : WB results of the inhibitory effect of compounds on GSDMD activation.

[0102] Figure 2B: Quantification of tetramer bands in WB results.

[0103] Figure 2C: Quantification of monomeric bands in the WB results.

[0104] Figure 3: Effects of compounds in sepsis models. DETAILED DESCRIPTION

[0105] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, various modifications thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure were commercially available and used without further purification.

[0106] The following examples illustrate the present invention in detail: This example is implemented based on the technical solution of the present invention, and provides detailed implementation plans and processes, but the scope of the present invention is not limited to the following examples. The conditions and methods not specified in the following examples are all carried out according to conventional methods.

[0107] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0108] Unless otherwise stated, % refers to wt%.

[0109] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0110] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0111] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0112] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0113] Example 1 Synthesis of Compounds

[0114] Synthesis of RGW-1

[0115] Step 1: Preparation of RGW-1-A1

[0116] 1,3-Dimethyl-5-aminobenzene-1,3-dicarboxylate (20.0 g, 95.6 mmol, 1.00 eq) was dissolved in 200 mL of dichloromethane. Pyridine (22.7 g, 287 mmol, 3.00 eq) and 4-chloro-3-nitrobenzenesulfonyl chloride (29.4 g, 115 mmol, 1.20 eq) were added at 0°C. The reaction solution was stirred at 20°C for 2 hours. LCMS monitoring showed that 1,3-dimethyl-5-aminobenzene-1,3-dicarboxylate completely disappeared, and a new major peak was formed. The reaction solution was adjusted to pH 1 with 1N hydrochloric acid, then filtered. The filter cake was rinsed with 200 mL of dichloromethane, collected, and slurried with 200 mL of dichloromethane at 20°C for 30 minutes. After beating, the filter cake was collected by filtration and dried to obtain an off-white solid RGW-1-A1 (38.0 g, 85.4 mmol, yield 89.4%, purity 96.4%).

[0117] Step 2: Preparation of RGW-1-A2

[0118] RGW-1-A1 (25.0 g, 58.3 mmol, 1.00 eq) was dissolved in 250 mL of tetrahydrofuran and 50 mL of water, and ammonium chloride (6.24 g, 117 mmol, 2.00 eq) was added. The reaction solution was heated to 60 degrees Celsius and iron powder (16.3 g, 292 mmol, 5.00 eq) was added. The reaction solution was heated and stirred at 60 degrees Celsius for 24 hours. LCMS monitoring showed that 93.0% of the product was formed. The reaction solution was filtered, and the mother liquor was collected and dried to obtain the crude product. The crude product was slurried with 200 mL of dichloromethane at 20 degrees Celsius for 30 minutes. After slurrying, the filter cake was collected by filtration and dried to obtain an off-white solid RGW-1-A2 (21.0 g, 49.4 mmol, yield 84.8%, purity 93.9%).

[0119] Step 3: Synthesis of RGW-1

[0120] RGW-1-A2 (1.00 g, 2.51 mmol, 1.00 eq) and 2-hydroxynaphthalene-1-carboxaldehyde (518 mg, 3.01 mmol, 1.20 eq) were dissolved in 20 mL of methanol. Triethylamine (761 mg, 7.52 mmol, 1.05 mL, 3.00 eq) was added, and the reaction was stirred at 70°C for 16 hours. LCMS analysis indicated 79.8% product formation. The reaction mixture was cooled to 20°C and filtered to obtain a filter cake. The filter cake was rinsed with 20 mL of methanol and dried to afford RGW-1 as a yellow solid (0.90 g, 1.60 mmol, 63.7% yield, 98.18% purity).

[0121] MS (ESI) m / z = 553.1 [M+H] +

[0122] 1H NMR (400MHz, DMSO-d6): δ15.13-15.01(m,1H),11.13-10.84(m,1H),9.73-9.56(m,1H),8.61-8.49(m,1H),8.28-8.24(m,1H),8.1 6-8.12(m,1H),8.07-7.99(m,3H),7.90-7.81(m,2H),7.70-7.60(m,2H),7.48-7.40(m,1H),7.16-7.10(m,1H),3.85-3.76(m,6H)

[0123] Synthesis of RGW-2

[0124] Step 1: Synthesis of RGW-2-A1

[0125] To a 20 mL vial at room temperature, dimethyl 5-((3-amino-4-chlorophenyl)sulfonamido)isophthalate (300 mg, 0.752 mmol, 1 eq), lithium hydroxide (36.03 mg, 1.504 mmol, 2 eq), water (3 mL), and methanol (3 mL) were added. After the addition was complete, the system was stirred at room temperature for 2 hours. The resulting residue was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: C18 column; mobile phase: water and acetonitrile, gradient from 0% to 50% over 15 minutes; UV detection at 254 nm. This yielded RGW-2-A1 (80 mg, 25.70%) as a white solid.

[0126] Step 2: Synthesis of RGW-2

[0127] A solution of RGW-2-A1 (40 mg, 0.104 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (26.85 mg, 0.156 mmol, 1.5 eq), and glacial acetic acid (0.62 mg, 0.010 mmol, 0.1 eq) in methanol (1 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature. The resulting residue was slurried with methanol (3 mL). This afforded RGW-2 (25.0 mg, 44.40%) as a yellow solid.

[0128] MS (ESI) m / z = 538.70 [M+H] +

[0129] 1 H NMR (400MHz, DMSO-d6): δ15.08(d,J=2.0Hz,1H),13.39(br,1H),10.90(s,1H),9.68( d,J=2.0Hz,1H),8.54(d,J=8.4Hz,1H),8.24(d,J=2.0Hz,1H),8.18(t,J=1.6Hz,1H),8 .07(d,J=9.0Hz,1H),7.99(q,J=2.2,1.8Hz,2H),7.93–7.87(m,1H),7.85–7.81(m,1H ),7.70–7.61(m,2H),7.45(td,J=7.2,1.0Hz,1H),7.16(d,J=9.0Hz,1H),3.82(s,3H).

[0130] Synthesis of RGW-3

[0131] Step 1: Synthesis of RGW-3-A1

[0132] To a 100 mL round-bottom flask at room temperature, methyl 3-amino-5-bromobenzoate (2 g, 8.693 mmol, 1 eq), 4-dimethylaminopyridine (1.06 g, 8.693 mmol, 1 eq), and dichloromethane (20 mL) were added. Di-tert-butyl dicarbonate (2.28 g, 10.432 mmol, 1.2 eq) was added dropwise at 0°C over approximately 10 minutes. After the addition was complete, the system was stirred at room temperature overnight. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with dichloromethane (3 x 100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with petroleum ether / ethyl acetate (6:01) to afford RGW-3-A1 (1.1 g, 34.49%) as a white solid.

[0133] Step 2: Synthesis of RGW-3-A2

[0134] Under argon, a solution of RGW-3-A1 (700 mg, 2.120 mmol, 1 eq), tributyl-(1-ethoxyvinyl)tin (859.51 μL, 2.544 mmol, 1.2 eq), and bistriphenylphosphine palladium dichloride (297.62 mg, 0.424 mmol, 0.2 eq) in 1,4-dioxane (10 mL) was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature. The reaction mixture was stirred with 2M HCl at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, backwashed with water (4 x 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with petroleum ether / ethyl acetate (6:01) to obtain RGW-3-A2 (387 mg, 52.90%) as a pale yellow solid.

[0135] Step 3: Synthesis of RGW-3-A3

[0136] A solution of RGW-3-A2 (387 mg, 1.319 mmol, 1 eq) and 4 M hydrogen chloride in 1,4-dioxane (5 mL) was stirred at room temperature for 1 hour. The resulting residue was concentrated under reduced pressure to afford RGW-3-A3 (317 mg, 124.36%) as a pale yellow solid. The crude product was used in the next step without further purification.

[0137] Step 4: Synthesis of RGW-3-A4

[0138] To an 8 mL vial at 0°C, add RGW-3-A3 (257 mg, 1.330 mmol, 1 eq), potassium hydroxide (223.89 mg, 3.990 mmol, 3 eq), and N-methylpyrrolidone (3 mL). After the addition is complete, the system is stirred at room temperature for 30 minutes. 4-Chloro-3-nitrobenzenesulfonyl chloride (408.72 mg, 1.596 mmol, 1.2 eq) is added portionwise at room temperature over approximately 5 minutes. After the addition is complete, the system is stirred at room temperature overnight. The reaction mixture is quenched with water at room temperature. The reaction mixture is extracted with ethyl acetate (3 x 30 mL) and dried over anhydrous sodium sulfate. The resulting mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse-phase column chromatography using the following conditions: column size: C18; mobile phase: water and acetonitrile, gradient from 10% to 60% over 10 minutes; detection wavelength: UV 254 nm. RGW-3-A4 (267 mg, 44.73%) was obtained as an off-white solid.

[0139] Step 5: Synthesis of RGW-3-A5

[0140] Under argon, a solution of RGW-3-A4 (100 mg, 0.242 mmol, 1 eq), reduced iron powder (94.7 mg, 1.694 mmol, 7 eq), ammonium chloride (129.58 mg, 2.420 mmol, 10 eq), and water (0.5 mL) in ethanol (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and quenched with water at room temperature. The resulting residue was concentrated under reduced pressure. The residue was filtered, the filter cake was washed with ethyl acetate (3 x 20 mL), and the filtrate was concentrated under reduced pressure to afford RGW-3-A5 (96 mg, 82.81%) as an off-white solid. The crude product was used in the next step without further purification.

[0141] Step 6: Synthesis of RGW-3

[0142] A solution of RGW-3-A5 (30 mg, 0.078 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (26.99 mg, 0.156 mmol, 2 eq), and glacial acetic acid (0.45 uL, 0.008 mmol, 0.1 eq) in methanol (1.5 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature. The resulting residue was slurried with methanol (3 mL). This afforded RGW-3 (12.9 mg, 29.89%) as a yellow solid.

[0143] MS (ESI) m / z = 536.75 [M+H] +

[0144] 1 H NMR (400MHz, DMSO-d6, ppm): δ15.11–15.06(m,1H),10.92(s,1H),9.69(s,1H),8.56(d,J =8.4Hz,1H),8.26(d,J=2.2Hz,1H),8.13(t,J=1.4Hz,1H),8.06(d,J=9.2Hz,1H),7.97(d t,J=11.8,2.0Hz,2H),7.89(dd,J=8.2,1.4Hz,1H),7.83(d,J=8.4Hz,1H),7.71–7.61(m, 2H), 7.45 (ddd, J=8.0, 6.8, 1.0Hz, 1H), 7.16 (d, J=9.0Hz, 1H), 3.83 (s, 3H), 2.56 (s, 3H).

[0145] Synthesis of RGW-4

[0146] Step 1: Synthesis of RGW-4-A1

[0147] Under nitrogen protection, a solution of methyl 3-bromo-5-nitrobenzoate (1 g, 3.846 mmol, 1 eq), α-pyrrolidone (490.91 mg, 5.769 mmol, 1.5 eq), tris(dibenzylideneacetone)dipalladium (352.15 mg, 0.385 mmol, 0.1 eq), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (445.03 mg, 0.769 mmol, 0.2 eq), and cesium carbonate (3.7 g, 11.538 mmol, 3 eq) in 1,4-dioxane (10 mL) was stirred and reacted overnight at 100°C. The reaction mixture was quenched with water (50 mL). The reaction mixture was extracted with ethyl acetate (3 x 60 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product RGW-4-A1 (1.4 g, 124.00%) was obtained as a pale yellow solid and used directly in the next reaction without purification.

[0148] Step 2: Synthesis of RGW-4-A2

[0149] A solution of RGW-4-A1 (1.3 g, 4.924 mmol, 1 eq), iron powder (1.92 g, 34.383 mmol, 7 eq), and ammonium chloride (2.63 g, 49.168 mmol, 10 eq) in ethanol (13 mL) and water (4 mL) was stirred at 80°C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 20 mL). The reaction mixture was diluted with water (50 mL). The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford RGW-4-A2 (880 mg, 76.38%) as a pale yellow solid.

[0150] Step 3: Synthesis of RGW-4-A3

[0151] To a solution of RGW-4-A2 (400 mg, 1.708 mmol, 1 eq) in N-methylpyrrolidone (4 mL) was added potassium hydroxide (191.6 mg, 3.416 mmol, 2 eq) at room temperature. The reaction was stirred for 5 minutes, and then 4-chloro-3-nitrobenzenesulfonyl chloride (568.38 mg, 2.220 mmol, 1.3 eq) was added portionwise at 0°C. Stirring was continued at room temperature for 1 hour. The reaction mixture was quenched by the addition of ice water (20 mL) at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, backwashed with water (3 x 20 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: column size: C18; mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes; detection wavelength: UV 254 nm. RGW-4-A3 (400 mg, 49.03%) was obtained as a light yellow solid.

[0152] Step 4: Synthesis of RGW-4-A4

[0153] A solution of RGW-4-A3 (100 mg, 0.220 mmol, 1 eq), iron powder (86.13 mg, 1.540 mmol, 7 eq), and ammonium chloride (117.86 mg, 2.200 mmol, 10 eq) in ethanol (1 mL) and water (0.3 mL) was stirred at 80°C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 10 mL). The reaction mixture was diluted with water (30 mL). The reaction mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. This afforded crude RGW-4-A4 (130 mg, 125.28%) as a pale yellow solid. The crude product was used in the next step without further purification.

[0154] Step 5: Synthesis of RGW-4.

[0155] A solution of RGW-4-A4 (28 mg, 0.066 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (17.06 mg, 0.099 mmol, 1.5 eq), and glacial acetic acid (11.36 uL, 0.198 mmol, 3 eq) in methanol (1 mL) was stirred at 80°C for 3 hours. The resulting residue was slurried with methanol (3 mL). This afforded RGW-4 (23.7 mg, 61.20%) as a yellow solid.

[0156] MS (ESI) m / z = 577.8 [M+H] +

[0157] 1H NMR (400MHz, DMSO-d6, ppm): δ15.19(s,1H),10.78(s,1H),9.78(s,1H),8.61(d,J=8.6Hz,1H),8.33(s,1H),8.11–8.03(m,2H),7.89(d,J=8.0Hz,2 H),7.67(d,J=8.4Hz,3H),7.46(dt,J=13.0,5.4Hz,2H),7.16(d,J=9.2Hz ,1H),3.78(d,J=9.8Hz,5H),2.38(t,J=8.2Hz,2H),1.98(t,J=7.6Hz,2H).

[0158] Synthesis of RGW-5

[0159] Step 1: Synthesis of RGW-5-A1

[0160] A solution of methyl 3-amino-5-nitrobenzoate (800 mg, 4.078 mmol, 1 equiv) and 2,5-dimethoxy-2,5-dihydrofuran (530.76 mg, 4.078 mmol, 1 equiv) in 1 M hydrochloric acid (8 mL) was stirred at 40°C for 40 minutes. The reaction mixture was neutralized with sodium hydroxide to a pH of ~6. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (5:01) to afford RGW-5-A1 (220 mg, 18.51%) as a pale yellow solid.

[0161] Step 2: Synthesis of RGW-5-A2

[0162] A solution of RGW-5-A1 (210 mg, 0.801 mmol, 1 equiv), reduced iron powder (313.06 mg, 5.607 mmol, 7 equiv), and ammonium chloride (428.38 mg, 8.01 mmol, 10 equiv) in ethanol (2.1 mL) and water (0.7 mL) was stirred at 80°C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 15 mL). The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford RGW-5-A2 (120 mg, 64.52%) as a pale yellow solid.

[0163] Step 3: Synthesis of RGW-5-A3

[0164] To a solution of RGW-5-A2 (110 mg, 0.474 mmol, 1 equiv) in N-methylpyrrolidone (1.1 mL) was added potassium hydroxide (53.15 mg, 0.948 mmol, 2 equiv) at room temperature. After stirring for 5 minutes, 4-chloro-3-nitrobenzenesulfonyl chloride (157.66 mg, 0.616 mmol, 1.3 equiv) was added portionwise at 0°C. Stirring was continued at room temperature for 4 hours. The reaction mixture was quenched by the addition of ice water (25 mL) at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: column size: C18; mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes; detection wavelength: UV 254 nm. RGW-5-A3 (95 mg, 43.12%) was obtained as a light yellow solid.

[0165] Step 4: Synthesis of RGW-5-A4

[0166] A solution of RGW-5-A3 (85 mg, 0.188 mmol, 1 equiv), reduced iron powder (73.54 mg, 1.316 mmol, 7 equiv), and ammonium chloride (100.63 mg, 1.880 mmol, 10 equiv) in ethanol (1 mL) and water (0.3 mL) was stirred at 80°C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 10 mL). The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford RGW-5-A4 (115 mg, crude) as a pale yellow solid.

[0167] Step 5: Synthesis of RGW-5.

[0168] A solution of RGW-5-A4 (35 mg, 0.083 mmol, 1 equiv), 2-hydroxy-1-naphthaldehyde (21.43 mg, 0.124 mmol, 1.5 equiv), and glacial acetic acid (14.26 uL, 0.249 mmol, 3 equiv) in methanol (1 mL) was stirred at 80°C for 4 hours. The resulting residue was slurried with methanol (5 mL). This afforded RGW-5 (14.6 mg, 26.67%) as a yellow solid.

[0169] MS (ESI) m / z = 575.7 [M+H] +

[0170] 1H NMR (400MHz, DMSO-d6, ppm): δ15.20(s,1H),10.81(s,1H),9.78(s,1H),8.61(d, J=8.6Hz,1H),8.34(d,J=2.2Hz,1H),8.21(s,1H),8.07(d,J=9.2Hz,1H),7.88(d ,J=7.8Hz,1H),7.88–7.82(m,2H),7.68–7.65(m,2H),7.47–7.41(m,3H),7.16(d ,J=6.0Hz,1H),6.08(dt,J=6.0,1.8Hz,1H),4.57(d,J=2.0Hz,2H),3.79(s,3H).

[0171] Synthesis of RGW-6

[0172] Step 1: Synthesis of RGW-6-A1

[0173] Under argon protection, at 100°C, a solution of methyl 3-bromo-5-nitrobenzoate (1g, 3.846mmol, 1eq), 2-oxazolidinone (0.5g, 5.769mmol, 1.5eq), cuprous iodide (0.75g, 0.385mmol, 0.1eq), N,N-dimethylglycine (0.08g, 0.769mmol, 0.2eq) and potassium carbonate (1.59g, 11.538mmol, 3eq) in 1,4-dioxane (20.0mL) was stirred and reacted overnight. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (3x15mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was slurried with petroleum ether and ethyl acetate (10 / 1). Filtered, the filter cake was collected and washed with petroleum ether (1X7mL). RGW-6-A1 (500 mg, 48.84%) was obtained as a yellow solid.

[0174] Step 2: Synthesis of RGW-6-A2

[0175] Under argon, a solution of RGW-6-A1 (600 mg, 2.254 mmol, 1 eq), iron powder (883.56 mg, 15.778 mmol, 7 eq), and ammonium chloride (1.19 g, 22.541 mmol, 10 eq) in ethanol (12.0 mL) and water (4 mL) was stirred at 80°C for 2 hours. The mixture was filtered, the filter cake was washed with ethyl acetate (2 x 5 mL), and the filtrate was concentrated under reduced pressure. 200 mg of the resulting mixture was used in the next step without further purification.

[0176] Step 3: Synthesis of RGW-6-A3

[0177] To a solution of RGW-6-A2 (230 mg, 0.974 mmol, 1 eq) in N-methylpyrrolidone (7.67 mL) at 0°C was added potassium hydroxide (109.25 mg, 1.948 mmol, 2 eq). The mixture was stirred for 20 minutes, followed by the addition of 4-chloro-3-nitrobenzenesulfonyl chloride (299.15 mg, 1.168 mmol, 1.2 eq) in portions at 0°C. Stirring was continued at room temperature for 4 hours. The resulting residue was purified by reverse-phase column chromatography using the following conditions: C18 column; mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes; UV detection at 254 nm to afford RGW-6-A3 (100 mg, 22.53%) as an off-white solid.

[0178] Step 4: Synthesis of RGW-6-A4

[0179] Under argon, a solution of RGW-6-A3 (100 mg, 0.219 mmol, 1 eq), iron powder (85.76 mg, 1.533 mmol, 7 eq), and ammonium chloride (117.34 mg, 2.191 mmol, 10 eq) in ethanol (2 mL) and water (0.7 mL) was stirred at 80°C for 2 hours. The product signal was detected by mass spectrometry. The product was filtered, the filter cake was washed with ethyl acetate (2 x 5 mL), and the filtrate was concentrated under reduced pressure. The resulting 100 mg crude product was used in the next step without further purification.

[0180] Step 5: Synthesis of RGW-6.

[0181] A solution of RGW-6-A4 (15 mg, 0.035 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (15.16 mg, 0.088 mmol, 2.5 eq), and acetic acid (0.2 uL, 0.003 mmol, 0.1 eq) in ethanol (0.5 mL) was stirred at 90°C for 4 hours. Upon cooling, a solid precipitated, which was filtered and washed with methanol (2 x 4 mL) to afford RGW-6 (2.7 mg, 12.74%) as a yellow solid.

[0182] MS (ESI) m / z = 579.7 [M+H] +

[0183] 1H NMR (400MHz, DMSO-d6, ppm): δ15.14(d,J=2.2Hz,1H),10.81(s,1H),9.74(d,J=2.0Hz,1H),8.60(d, J=8.4Hz,1H),8.29(d,J=2.2Hz,1H),8.07(d,J=9.2Hz,1H),7.93–7.87(m,2H),7.84(d,J=8.4Hz,1H) ,7.72–7.67(m,2H),7.65–7.59(m,1H),7.51(t,J=1.6Hz,1H),7.45(td,J=7.4,6.8,1.2Hz,1H),7.1 6(d,J=9.2Hz,1H), 4.38(dd,J=9.2,6.8Hz,2H), 4.03(dd,J=9.0,6.8Hz,2H), 3.82(d,J=14.4Hz,3H).

[0184] Synthesis of RGW-7

[0185] Step 1: Synthesis of RGW-7-A1

[0186] To a 20 mL vial at room temperature, add methyl 3-amino-5-nitrobenzoate (200 mg, 1.020 mmol, 1 eq), trimethylsilyl azide (160.91 uL, 1.224 mmol, 1.2 eq), 2-methyltetrahydrofuran (3 mL), and acetonitrile (0.8 mL). Add tert-butyl nitrite (145.52 uL, 1.224 mmol, 1.2 eq) dropwise at -20°C over approximately 5 minutes. After the addition, stir at -10°C for 2 hours. The resulting mixture was used in the next step without further purification.

[0187] Step 2: Synthesis of RGW-7-A2

[0188] The mixture from the previous step was used directly in the next step without further purification. Trimethylethynylsilane (119.9 mg, 1.220 mmol, 1.2 eq), cuprous iodide (19.37 mg, 0.102 mmol, 0.1 eq), triethylamine (311.09 uL, 2.237 mmol, 2.2 eq), and 2-methyltetrahydrofuran (3 mL) were added to a 20 mL vial at 0°C. Stirring was continued at 5°C for 4 hours. The reaction mixture was quenched with saturated aqueous sodium sulfate at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (5:01) to afford RGW-7-A2 (120 mg, 33.14%) as an off-white solid.

[0189] Step 3: Synthesis of RGW-7-A3

[0190] A solution of RGW-7-A2 (105 mg, 0.328 mmol, 1 eq) and 4 mol hydrogen chloride in 1,4-dioxane (2 mL) was stirred overnight at 50°C. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. This afforded RGW-7-A3 (95 mg, 93.43%) as an off-white crude solid. The crude product was used in the next step without further purification.

[0191] Step 4: Synthesis of RGW-7-A4

[0192] Under argon, a solution of RGW-7-A3 (85 mg, 0.342 mmol, 1 eq), reduced iron powder (133.88 mg, 2.394 mmol, 7 eq), ammonium chloride (183.19 mg, 3.420 mmol, 10 eq), and water (0.3 mL) in ethanol (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 x 30 mL). The filtrate was concentrated under reduced pressure to obtain RGW-7-A4 (59 mg, 63.16%) as an off-white crude solid. The crude product was used in the next step without further purification.

[0193] Step 5: Synthesis of RGW-7-A5

[0194] A solution of RGW-7-A4 (51 mg, 0.234 mmol, 1 eq), 4-chloro-3-nitrobenzenesulfonyl chloride (71.81 mg, 0.281 mmol, 1.2 eq), and potassium hydroxide (39.34 mg, 0.702 mmol, 3 eq) in N-methylpyrrolidone (1 mL, 10.370 mmol, 44.37 eq) was stirred at room temperature for 2 hours. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: 20 g column, mobile phase: water and acetonitrile, gradient from 10% to 60% over 10 minutes, UV detection at 254 nm. This afforded RGW-7-A5 (38 mg, 33.42%) as an off-white solid.

[0195] Step 6: Synthesis of RGW-7-A6

[0196] Under argon, a solution of RGW-7-A5 (34 mg, 0.078 mmol, 1 eq), reduced iron powder (30.36 mg, 0.546 mmol, 7 eq), ammonium chloride (41.54 mg, 0.780 mmol, 10 eq), and water (0.3 mL) in ethanol (1 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure. The residue was filtered, the filter cake was washed with ethyl acetate (3 x 20 mL), and the filtrate was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. RGW-7-A6 (32 mg, 80.83%) was obtained as a white solid. The crude product was used in the next step without further purification.

[0197] Step 7: Synthesis of RGW-7

[0198] A solution of RGW-7-A6 (27 mg, 0.066 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (22.8 mg, 0.132 mmol, 2 eq), and glacial acetic acid (0.4 mg, 0.007 mmol, 0.1 eq) in methanol (2 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature. The resulting residue was slurried with methanol (5 mL). This afforded RGW-7 (24 mg, 62.44%) as a yellow solid.

[0199] MS (ESI) m / z = 561.70 [M+H] +

[0200] 1H NMR (400MHz, DMSO-d6, ppm): δ15.15(d,J=2.2Hz,1H),11.09(s,1H),9.71(d,J=2.0Hz,1 H),8.96(d,J=1.4Hz,1H),8.53(d,J=8.4Hz,1H),8.33(d,J=2.2Hz,1H),8.11–8.03(m,3H ),7.97(d,J=1.2Hz,1H),7.89–7.80(m,3H),7.71(dd,J=8.4,2.2Hz,1H),7.63(ddd,J=8. 4,7.0,1.4Hz,1H),7.45(ddd,J=7.8,6.8,1.0Hz,1H),7.15(d,J=9.2Hz,1H),3.83(s,3H)

[0201] Synthesis of RGW-8

[0202] Step 1: Synthesis of RGW-8-A1

[0203] A solution of methyl 3-fluoro-5-nitrobenzoate (2 g, 10.043 mmol, 1 equiv), potassium carbonate (4.16 g, 30.129 mmol, 3 equiv), and 1,2,3-triazole (0.87 mL, 15.064 mmol, 1.5 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature and quenched by the addition of water (20 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were backwashed with water (3 x 100 mL) and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: column size (40 g), mobile phase: water and acetonitrile, gradient from 10% to 100% over 20 minutes, UV detection at 254 nm. RGW-8-A1 (1.1 g, 42.09%) was obtained as an off-white solid.

[0204] Step 2: Synthesis of RGW-8-A2

[0205] A solution of RGW-8-A1 (235 mg, 1.004 mmol, 1 eq) and concentrated sulfuric acid (9.84 mg, 0.100 mmol, 0.1 eq) in methanol (3 mL) was stirred at 80°C overnight. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with water at room temperature. The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (6:01) to afford RGW-8-A2 (186 mg, 67.21%) as an off-white solid.

[0206] Step 3: Synthesis of RGW-8-A3

[0207] Under argon, a solution of RGW-8-A2 (176 mg, 0.709 mmol, 1 eq), reduced iron powder (277.2 mg, 4.963 mmol, 7 eq), ammonium chloride (379.3 mg, 7.090 mmol, 10 eq), and water (0.9 mL) in ethanol (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure. The filtrate was filtered, collected, and washed with ethyl acetate (3 x 15 mL). The filtrate was then concentrated under reduced pressure to afford RGW-8-A3 (154 mg, 99.52%) as a white solid. The crude product was used in the next step without further purification.

[0208] Step 4: Synthesis of RGW-8-A4

[0209] To an 8 mL vial at 0°C, add RGW-8-A3 (144 mg, 0.660 mmol, 1 eq), potassium hydroxide (111.07 mg, 1.980 mmol, 3 eq), and N-methylpyrrolidone (3 mL). Add 4-chloro-3-nitrobenzenesulfonyl chloride (202.76 mg, 0.792 mmol, 1.2 eq) portionwise at room temperature. Stir overnight at room temperature after the addition is complete. The reaction mixture is cooled to room temperature and extracted with ethyl acetate (3 x 30 mL). The organic phases are combined and dried over sodium sulfate. The resulting mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse-phase column chromatography using the following conditions: 20 g column, mobile phase: water and acetonitrile, gradient from 10% to 60% over 10 minutes, UV detection at 254 nm. This affords RGW-8-A4 (173 mg, 54.49%) as a pale yellow solid.

[0210] Step 5: Synthesis of RGW-8-A5.

[0211] Under argon, a solution of RGW-8-A4 (163 mg, 0.372 mmol, 1 eq), reduced iron powder (145.54 mg, 2.604 mmol, 7 eq), ammonium chloride (199.15 mg, 3.720 mmol, 10 eq), and water (0.9 mL) in ethanol (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure. Filtered, the filter cake was washed with ethyl acetate (3 x 15 mL), and the filtrate was concentrated under reduced pressure. This afforded RGW-8-A5 (120 mg, 79.03%) as an off-white crude solid. The crude product was used in the next step without further purification.

[0212] Step 6: Synthesis of RGW-8

[0213] A solution of RGW-8-A5 (30 mg, 0.074 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (15.2 mg, 0.089 mmol, 1.2 eq), and acetic acid (0.42 mg, 0.007 mmol, 0.11 eq) in ethanol (0.8 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting residue was slurried with methanol (5 mL). This afforded RGW-8 (28.8 mg, 68.41%) as a yellow solid.

[0214] MS (ESI) m / z = 561.70 [M+H] +

[0215] 1 H NMR (400MHz, DMSO-d6, ppm): δ15.08(d,J=2.0Hz,1H),11.06(s,1H),9.71(d,J=2.0Hz,1H),8.54 (d,J=8.6Hz,1H),8.31(d,J=2.2Hz,1H),8.24(t,J=1.6Hz,1H),8.17(t,J=2.2Hz,1H),8.12(s,2 H),8.06(d,J=9.2Hz,1H),7.93–7.89(m,1H),7.87–7.84(m,1H),7.82–7.77(m,1H),7.73–7.68( m,1H),7.66–7.59(m,1H),7.45(ddd,J=8.0,6.8,1.0Hz,1H),7.16(d,J=9.2Hz,1H),3.84(s,3H).

[0216] Synthesis of RGW-9

[0217] Step 1: Synthesis of RGW-9-A1

[0218] To a solution of dimethyl 5-aminoisophthalate (1 g, 4.780 mmol, 1 eq), triethylamine (1.03 g, 14.34 mmol, 3 eq), and 4-dimethylaminopyridine (116.8 mg, 0.956 mmol, 0.2 eq) in acetonitrile (20.0 mL) at 0°C was added 4-methyl-3-nitrobenzenesulfonyl chloride (1.35 g, 5.736 mmol, 1.2 eq) portionwise. After the addition was complete, the mixture was allowed to warm to room temperature overnight. The reaction mixture was extracted with dichloromethane (2 x 20 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: Column specifications: Mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes, detection wavelength: UV 254 nm. RGW-9-A1 (500 mg, 25.61%) was obtained as a light yellow solid.

[0219] Step 2: Synthesis of RGW-9-A2

[0220] A solution of RGW-9-A1 (500 mg, 0.823 mmol, 1 eq) and potassium carbonate (1.13 g, 8.230 mmol, 10 eq) in methanol (10.0 mL) and water (3.0 mL) was stirred overnight at room temperature. The desired product was detected in the liquid phase. The methanol was removed under reduced pressure, and the resulting reaction mixture was extracted with dichloromethane (2 x 20 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using a C18 column, a mobile phase of water and methanol, with a gradient from 10% to 50% over 10 minutes, and UV detection at 254 nm. This afforded RGW-9-A2 (300 mg, 89.26%) as a pale yellow solid.

[0221] Step 3: Synthesis of RGW-9-A3

[0222] Under argon, a solution of RGW-9-A2 (150 mg, 0.367 mmol, 1 eq), iron powder (143.59 mg, 2.569 mmol, 7 eq), and ammonium chloride (196.47 mg, 3.670 mmol, 10 eq) in ethanol (1.5 mL) and water (0.45 mL) was stirred at 80°C for 2 hours. The desired product was found in the liquid, which was filtered, and the filter cake was washed with ethyl acetate (3 x 20 mL). The reaction mixture was then extracted with ethyl acetate (2 x 10 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford RGW-9-A3 (120 mg, 86.34%) as a pale yellow solid.

[0223] Step 4: Synthesis of RGW-9

[0224] At 80°C, a solution of RGW-9-A3 (60 mg, 0.159 mmol, 1 eq), acetic acid (0.88 uL, 0.016 mmol, 0.1 eq) and 2-hydroxy-1-naphthaldehyde (40.95 mg, 0.238 mmol, 1.5 eq) in methanol (3.0 mL) was stirred for 4 h. Liquid chromatography-mass spectrometry showed product signal, and the crude product was recrystallized from methanol to give RGW-9 (51.5 mg, 59.95%) as a yellow solid.

[0225] MS (ESI) m / z = 533.0 [M+H] +

[0226] 1 H NMR (400MHz, DMSO-d6, ppm): δ15.33 (d, J = 3.2Hz, 1H), 10.85 (s, 1H), 9.57 (d, J=3.2Hz,1H),8.51(d,J=8.4Hz,1H),8.14(t,J=1.4Hz,1H),8.05–7.99(m,4H) ,7.87(dd,J=8.0,1.4Hz,1H),7.67–7.57(m,2H),7.54(d,J=8.2Hz,1H),7.43( ddd,J=8.0,6.8,1.0Hz,1H),7.12(d,J=9.2Hz,1H),3.82(s,6H),2.40(s,3H).

[0227] Synthesis of RGW-10

[0228] Step 1: Synthesis of RGW-10-A1

[0229] Under nitrogen protection, a solution of dimethyl 5-(4-bromo-3-nitrobenzenesulfonamido)phthalate (250 mg, 0.528 mmol, 1 eq) and cuprous cyanide (236.57 mg, 2.640 mmol, 5 eq) in N-methylpyrrolidone (4 mL) was stirred and reacted for 4 hours at 160°C in a microwave oven. The filtrate was collected by filtration. The resulting residue was purified by reverse-phase column chromatography using a C18 column, a mobile phase of water and methanol, with a gradient from 10% to 50% over 10 minutes, and UV detection at 254 nm. RGW-10-A1 (150 mg, 67.71%) was obtained as a brown solid.

[0230] Step 2: Synthesis of RGW-10-A2

[0231] A solution of RGW-10-A1 (119.4 mg, 0.285 mmol, 1 eq) and palladium on carbon (6.09 mg, 0.057 mmol, 0.2 eq) in methanol (4.0 mL) was stirred at room temperature under 1 MPa of hydrogen for 2 hours. The mixture was filtered, the filter cake washed with ethyl acetate (2 x 2 mL), and the filtrate concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography using a C18 column, a mobile phase of water and methanol, with a gradient from 10% to 50% over 10 minutes, and UV detection at 254 nm. This afforded RGW-10-A2 (40 mg, 35.9%) as a black solid.

[0232] Step 3: Synthesis of RGW-10

[0233] A solution of RGW-10-A2 (35 mg, 0.090 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (23.22 mg, 0.135 mmol, 1.5 eq), and acetic acid (0.5 uL, 0.009 mmol, 0.1 eq) in methanol (2 mL) was stirred at 80°C for 4 hours. Liquid chromatography-mass spectrometry (LC-MS / MS) indicated product signal, which precipitated upon cooling. The filter cake was collected by filtration and washed with methanol (2 x 3 mL) to afford RGW-10 (9.0 mg, 17.02%) as a yellow solid.

[0234] MS (ESI) m / z = 544.0 [M+H] +

[0235] 1 H NMR (400MHz, DMSO-d6, ppm): δ14.27(s,1H),11.12(s,1H),9.79(s,1H),8.65(d,J=8. 4Hz,1H),8.32(d,J=1.6Hz,1H),8.20-8.13(m,1H),8.10–8.09(m,2H),8.00(d,J=1.4 Hz,2H),7.94(dd,J=8.2,1.4Hz,1H),7.77(dd,J=8.2,1.8Hz,1H),7.67(ddd,J=8.4,6 .8,1.4Hz,1H),7.48(ddd,J=8.2,6.8,1.0Hz,1H),7.25(d,J=9.0Hz,1H),3.83(s,6H).

[0236] Synthesis of RGW-11

[0237] Step 1: Synthesis of RGW-11-A1

[0238] A solution of dimethyl 5-aminoisophthalate (1 g, 4.780 mmol, 1 eq), 3-nitrobenzenesulfonyl chloride (1.27 g, 5.736 mmol, 1.2 eq), and potassium tert-butoxide (1.07 g, 9.560 mmol, 2 eq) in 1,2-dichloroethane (20 mL) was stirred overnight at 80°C. The reaction mixture was quenched by adding ice water (10 mL) at room temperature. The aqueous phase was extracted with dichloromethane (2 x 20 mL). The resulting residue was concentrated in vacuo. The residue was purified by reverse-phase column chromatography using a C18 column, mobile phase: water and methanol, gradient from 10% to 50% over 10 minutes, detection at UV wavelength of 254 nm. RGW-11-A1 (400 mg, 21.22%) was obtained as an off-white solid.

[0239] Step 2: Synthesis of RGW-11-A2

[0240] Under argon, a solution of RGW-11-A1 (180 mg, 0.456 mmol, 1 eq), iron powder (178.75 mg, 3.192 mmol, 7 eq), and ammonium chloride (244.15 mg, 4.560 mmol, 10 eq) in ethanol (2 mL) and water (0.6 mL) was stirred at 80°C for 2 hours. The mixture was filtered, the filter cake washed with ethyl acetate (2 x 10 mL), and the filtrate extracted with ethyl acetate (2 x 10 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. 150 mg of the resulting mixture was used in the next step without further purification.

[0241] Step 3: Synthesis of RGW-11

[0242] A solution of RGW-11-A2 (50 mg, 0.137 mmol, 1 eq) and acetic acid (0.78 uL, 0.013 mmol, 0.1 eq) in methanol (2.5 mL) was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature. The filter cake was collected by filtration and washed with methanol (2 x 2 mL). This afforded RGW-11 (45.6 mg, 59.53%) as a yellow solid.

[0243] MS (ESI) m / z = 518.7 [M+H] +

[0244] 1H NMR (400MHz, DMSO-d6, ppm): δ15.20(d,J=3.2Hz,1H),10.90(s,1H),9.66(d,J=3.2H z,1H),8.51(d,J=8.2Hz,1H),8.14(t,J=1.4Hz,1H),8.04–7.97(m,3H),7.91(tq,J=4 .2,2.2Hz,2H),7.85(dd,J=8.0,1.4Hz,1H),7.73–7.63(m,2H),7.59(ddd,J=8.4,6. 8,1.4Hz,1H),7.40(ddd,J=8.0,7.0,1.0Hz,1H),7.10(d,J=9.2Hz,1H),3.84(s,6H).

[0245] Synthesis of RGW-12

[0246] Step 1: Synthesis of RGW-12-A1

[0247] Under nitrogen, a solution of 3-chloro-5-nitroaniline (3 g, 17.384 mmol, 1 equiv) in concentrated hydrochloric acid (30 mL) was stirred at 0°C for 10 minutes. A solution of sodium nitrite (1.4 g, 20.861 mmol, 1.2 equiv) in water (15 mL) was then added dropwise at 0°C. The reaction system was allowed to react for 1 hour. A solution of copper chloride dihydrate (592.73 mg, 3.477 mmol, 0.2 equiv) in water (2 mL) was then added dropwise. After the addition was complete, sulfur dioxide gas was introduced and stirring continued for 1 hour. The reaction mixture was extracted with dichloromethane (2 x 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to yield RGW-12-A1 (3 g, 67.40%) as a yellow solid. This product was used in the next step without further purification.

[0248] Step 2: Synthesis of RGW-12-A2

[0249] To a solution of RGW-12-A1 (571.92 mg, 2.734 mmol, 1 equiv) in N-methylpyrrolidone (7 mL) at 0°C was added potassium hydroxide (306.76 mg, 5.468 mmol, 2 equiv). After stirring for 5 minutes, 3-chloro-5-nitrobenzenesulfonyl chloride (700 mg, 2.734 mmol, 1 equiv) was added portionwise at 0°C. After the addition was complete, the system was stirred at room temperature overnight. The reaction mixture was acidified to pH ~5 with hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: column size: C18; mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes; detection wavelength: UV 254 nm. RGW-12-A2 (190 mg, 15.40%) was obtained as a yellow solid.

[0250] Step 3: Synthesis of RGW-12-A3

[0251] Under argon, a solution of RGW-12-A2 (50 mg, 0.117 mmol, 1 equiv), reduced iron powder (45.58 mg, 0.819 mmol, 7 equiv), and ammonium chloride (62.37 mg, 1.170 mmol, 10 equiv) in ethyl acetate (1 mL) and water (0.3 mL) was stirred at 80°C for 2 hours. The mixture was filtered, the filter cake was washed with ethanol (3 x 2 mL), and the filtrate was concentrated under reduced pressure to afford RGW-12-A3 (60 mg, 129.02%) as a yellow solid.

[0252] Step 4: Synthesis of RGW-12

[0253] A solution of RGW-12-A3 (28 mg, 0.070 mmol, 1 equiv), 2-hydroxy-1-naphthaldehyde (28.05 mg, 0.162 mmol, 2.32 equiv), and acetic acid (8.05 uL, 0.140 mmol, 2 equiv) in methanol (1 mL) was stirred at 80°C for 4 hours. The resulting residue was slurried with methanol (3 mL). This afforded RGW-12 (25.9 mg, 61.11%) as a yellow solid.

[0254] MS (ESI) m / z = 552.7 [M+H] +

[0255] 1H NMR (400MHz, DMSO-d6, ppm): δ14.92(d,J=2.6Hz,1H),11.00(s,1H),9.68(d,J=2 .6Hz,1H),8.55(d,J=8.4Hz,1H),8.14(d,J=2.8Hz,2H),8.03(d,J=9.2Hz,1H),7. 98(d,J=1.4Hz,2H),7.86(dd,J=8.2,1.4Hz,1H),7.80(s,1H),7.66(d,J=2.2Hz,1 H),7.66–7.59(m,1H),7.43(t,J=7.4Hz,1H),7.13(d,J=9.2Hz,1H),3.84(s,6H).

[0256] Synthesis of RGW-13

[0257] Step 1: Synthesis of RGW-13-A1

[0258] To a solution of dimethyl 5-aminoisophthalate (1 g, 4.780 mmol, 1 equiv) in N,N-dimethylformamide (10 mL) was added sodium hydroxide (382.38 mg, 9.560 mmol, 2 equiv) at room temperature. The reaction was stirred for 5 minutes, followed by the addition of 4-fluoro-3-nitrobenzenesulfonyl chloride (1.4 g, 6.214 mmol, 1.3 equiv) at 0°C. Stirring was continued at room temperature for 2 hours. The reaction mixture was quenched by the addition of ice water (20 mL) at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic phases were backwashed with brine (3 x 25 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using a C18 column, mobile phase: water and acetonitrile, gradient from 0% to 50% over 10 minutes, detection at UV wavelength of 254 nm. RGW-13-A1 (720 mg, 34.70%) was obtained as a light yellow solid.

[0259] Step 2: Synthesis of RGW-13-A2

[0260] Under argon, a solution of RGW-13-A1 (200 mg, 0.485 mmol, 1 equiv), reduced iron powder (189.61 mg, 3.395 mmol, 7 equiv), and ammonium chloride (259.45 mg, 4.850 mmol, 10 equiv) in ethanol (2 mL) and water (0.7 mL) was stirred at 80°C for 2 hours. The mixture was filtered, the filter cake washed with ethyl acetate (3 x 5 mL), and the filtrate concentrated under reduced pressure. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to yield RGW-13-A2 (172 mg, 92.74%) as a pale yellow solid.

[0261] Step 3: Synthesis of RGW-13

[0262] A solution of RGW-13-A2 (65 mg, 0.170 mmol, 1 equiv), 2-hydroxy-1-naphthaldehyde (43.91 mg, 0.255 mmol, 1.5 equiv), and acetic acid (19.48 uL, 0.340 mmol, 2 equiv) in ethanol (1 mL) was stirred at 80°C for 3 hours. The resulting residue was slurried with ethanol (3 mL). This afforded RGW-13 (28.3 mg, 26.75%) as a yellow solid.

[0263] MS (ESI) m / z = 536.7 [M+H] +

[0264] 1 H NMR (400MHz, DMSO-d6, ppm): δ15.08(d,J=2.2Hz,1H),10.87(s,1H),9.72(d,J=2.2Hz,1 H),8.56(d,J=8.6Hz,1H),8.30(dd,J=7.6,2.4Hz,1H),8.16(t,J=1.6Hz,1H),8.05(d,J =9.2Hz,1H),8.00(d,J=1.6Hz,2H),7.87(d,J=8.0Hz,1H),7.71(dd,J=8.6,4.4Hz,1H), 7.65(td,J=6.2,5.4,2.6Hz,2H),7.63–7.57(m,1H),7.44(t,J=7.4Hz,1H),3.82(s,6H).

[0265] Synthesis of RGW-14

[0266] Step 1: Synthesis of RGW-14-A1

[0267] A solution of dimethyl 5-aminoisophthalate (1.5 g, 7.170 mmol, 1 eq), 4-bromo-3-nitrobenzenesulfonyl chloride (2.58 g, 8.6 mmol, 1.2 eq), triethylamine (2.989 mL, 21.510 mmol, 3 eq), and 4-dimethylaminopyridine (175.2 mg, 1.434 mmol, 0.2 eq) in 1,2-dichloroethane (20 mL) was stirred overnight at 80°C. The desired product was found in the liquid, which was filtered, and the filter cake was collected and washed with petroleum ether (2 x 12 mL). The resulting mixture (2.8 g) was used in the next step without further purification.

[0268] Step 2: Synthesis of RGW-14-A2

[0269] A mixture of RGW-14-A1 (2.8 g, 3.798 mmol, 1 eq) and potassium carbonate (3.67 g, 26.586 mmol, 7 eq) in methanol (56.0 mL) and N,N-dimethylformamide (56 mL) was stirred overnight at room temperature. The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic phases were dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (10:01) to afford RGW-14-A2 as a yellow solid.

[0270] Step 3: Synthesis of RGW-14-A3

[0271] Under hydrogen protection, a solution of RGW-14-A2 (150 mg, 0.317 mmol, 1 eq), iron powder (124.26 mg, 2.219 mmol, 7 eq), ammonium chloride (169.54 mg, 3.170 mmol, 10 eq), and water (0.5 mL) in ethanol (1.5 mL) was stirred at 80°C for 2 hours. The mixture was filtered, and the filtrate was collected and washed with ethyl acetate (2 x 5 mL). The reaction mixture was extracted with ethyl acetate (2 x 5 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. 110 mg of the crude product was used in the next step without further purification.

[0272] Step 4: Synthesis of RGW-14

[0273] A solution of RGW-14-A3 (50 mg, 0.113 mmol, 1 eq), acetic acid (0.66 mg, 0.011 mmol, 0.1 eq), and 2-hydroxy-1-naphthaldehyde (29.13 mg, 0.170 mmol, 1.5 eq) in methanol (5.0 mL) was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was collected and washed with methanol (2 x 12 mL). This afforded RGW-14 (37.6 mg, 53.45%) as a yellow solid.

[0274] MS (ESI) m / z = 596.6 [M+H] +

[0275] 1 H NMR (400MHz, DMSO-d6, ppm): δ14.88(d,J=1.6Hz,1H),10.96(s,1H),9.65(d,J=1.6Hz ,1H),8.56(d,J=8.4Hz,1H),8.17(q,J=1.2Hz,2H),8.08(d,J=9.2Hz,1H),8.04–7.97 (m,3H),7.91(dd,J=8.0,1.4Hz,1H),7.65(ddd,J=8.4,6.8,1.4Hz,1H),7.58(dd,J=8 .4, 2.2Hz, 1H), 7.46 (ddd, J=8.0, 6.8, 1.0Hz, 1H), 7.19 (d, J=9.0Hz, 1H), 3.82 (s, 6H).

[0276] Synthesis of RGW-15

[0277] A solution of methyl 5-(3-amino-4-carbamoylphenylsulfonamido)benzene-1,3-dicarboxylate (30 mg, 0.074 mmol, 1 equiv), 2-hydroxy-1-naphthaldehyde (19.02 mg, 0.111 mmol, 1.5 equiv), and acetic acid (12.66 uL, 0.222 mmol, 3 equiv) in methanol (1 mL) was stirred at 80°C for 3 hours. The resulting residue was slurried with methanol (3 mL). This afforded RGW-15 (7.8 mg, 18.18%) as a yellow solid.

[0278] MS (ESI) m / z = 561.7 [M+H] +

[0279] 1H NMR (400MHz, DMSO-d6, ppm): δ14.54(d,J=2.8Hz,1H),10.99(s,1H),9.46(d,J=2.8Hz,1H),8.45(d,J=8.6Hz,1H),8.15(s,1H),8.06–7.98(m,5H ),7.86(d,J=8.0Hz,1H),7.72(d,J=12.4Hz,1H),7.64(t,J=7.8Hz,2H),7.42(t,J=7.4Hz,1H),7.40(s,1H),7.06(d,J=9.2Hz,1H),3.82(s,6H).

[0280] Synthesis of RGW-16

[0281] Step 1: Synthesis of RGW-16-A1

[0282] To a solution of dimethyl 5-aminoisophthalate (300 mg, 1.434 mmol, 1 eq) in acetonitrile (4.96 mL) was added triethylamine (598.00 μL, 4.302 mmol, 3 eq) at 0°C. After stirring for 1 hour, 4-chloro-3-bromobenzenesulfonyl chloride (498.96 mg, 1.721 mmol, 1.2 eq) was added dropwise at 0°C. After the addition was complete, the system was stirred at room temperature overnight. The product signal was detected by mass spectrometry, and the reaction mixture was extracted with dichloromethane (2 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The 600 mg resulting mixture was used in the next step without further purification.

[0283] Step 2: Synthesis of RGW-16-A2

[0284] A solution of RGW-16-A1 (560 mg, 0.782 mmol, 1 eq) and potassium carbonate (540.32 mg, 3.910 mmol, 5 eq) in methanol (5 mL) and water (1.5 mL) was stirred at room temperature for 4 hours. The resulting residue was concentrated in vacuo. The reaction mixture was extracted with dichloromethane (2 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography using a C18 column, mobile phase: water and methanol, gradient from 10% to 50% over 10 minutes, detection at UV wavelength of 254 nm. This afforded RGW-16-A2 (150 mg, 41.46%) as an off-white solid.

[0285] Step 3: Synthesis of RGW-16

[0286] Under argon protection, a solution of RGW-16-A2 (50 mg, 0.108 mmol, 1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17.61 mg, 0.022 mmol, 0.2 eq), (E)-(2-(naphthalen-1-yl)vinyl)boronic acid (27.82 mg, 0.140 mmol, 1.3 eq), and sodium carbonate (34.36 mg, 0.324 mmol, 3 eq) in 1,4-dioxane (1 mL) and water (0.2 mL) was stirred at 80°C for 5 hours. The aqueous phase was extracted with ethyl acetate (2 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to afford RGW-16 (6.1 mg, 10.51%) as an off-white solid using the following conditions (column specifications: XBridge BEH C18 OBD Prep Column 130, 5 m, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 54% B to 84% B in 10 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 7.6).

[0287] MS (ESI) m / z = 533.6 [MH] +

[0288] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.96(s,1H),8.38-8.30(m,1H),8.29–8.28(m,1H),8.14(s,1H),8.08–7.94(m,5H),7. 90(d,J=7.2Hz,1H),7.73(d,J=8.4Hz,1H),7.71–7.60(m,3H),7.59–7.54(m,1H),7.46(d,J=15.8Hz,1H),3.81(s,6H).

[0289] Synthesis of RGW-17

[0290] Step 1: Synthesis of RGW-17-A1

[0291] To a solution of dimethyl 5-((3-amino-4-chlorophenyl)sulfonamido)isophthalate (200 mg, 0.501 mmol, 1 equiv) in dichloromethane (2 mL) was added triethylamine (253.74 mg, 2.505 mmol, 5 equiv) at room temperature. After stirring for 5 minutes, 1-naphthoyl chloride (382.4 mg, 2.004 mmol, 4 equiv) was added portionwise at 0°C. After the addition, the system was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water at 0°C. The reaction mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using a C18 column, mobile phase: water and acetonitrile, gradient from 20% to 50% over 10 minutes, detection: UV 254 nm. RGW-17-A1 (190 mg, 50.90%) was obtained as a light yellow solid.

[0292] Step 2: Synthesis of RGW-17

[0293] A solution of RGW-17-A1 (90 mg, 0.127 mmol, 1 equiv) and potassium carbonate (52.77 mg, 0.381 mmol, 3 equiv) in methanol (1 mL) and water (0.5 mL) was stirred at room temperature for 3 hours. The mixture was filtered, and the filter cake was washed with methanol (3 x 0.1 mL). The crude product was purified by preparative HPLC to afford RGW-17 (13.7 mg, 19.37%) as a white solid using the following conditions (column dimensions: Sunfire C18 5 m, 30 mm x 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 25% B to 90% B over 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 8.53).

[0294] MS (ESI) m / z = 550.6 [MH] +

[0295] 1 H NMR (400MHz, DMSO-d6, ppm): δ11.03(s,1H),10.44(s,1H),8.26(dd,J=6.4,2.2Hz,2H),8.25(q,J=1.2Hz,1H),8 .16(d,J=8.2Hz,1H),8.02–8.00(m,3H),7.83(dd,J=12.0,7.6Hz,2H),7.64–7.61(m,4H),3.85(d,J=0.8Hz,6H).

[0296] Synthesis of RGW-18

[0297] Step 1: Synthesis of RGW-18-A1

[0298] Under argon, a solution of 3-bromophenanthrene (500 mg, 1.945 mmol, 1 eq), pinacol diboron (592.55 mg, 2.334 mmol, 1.2 eq), potassium acetate (667.94 mg, 6.808 mmol, 3.5 eq), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (47.52 mg, 0.058 mmol, 0.03 eq) in dimethyl sulfoxide (10 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were backwashed with water (3 x 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:01) to afford RGW-18-A1 (409 mg, 62.23%) as an off-white solid.

[0299] Step 2: Synthesis of RGW-18

[0300] Under argon, a solution of RGW-18-A1 (40 mg, 0.131 mmol, 1 eq), dimethyl 5-(4-chloro-3-bromobenzenesulfonamido)-isophthalate (48.67 mg, 0.105 mmol, 0.8 eq), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (19.24 mg, 0.026 mmol, 0.2 eq), sodium carbonate (41.81 mg, 0.393 mmol, 3 eq), and water (0.5 mL) in 1,4-dioxane (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (2 mL). The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to afford RGW-18 (10.5 mg, 14.24%) as a white solid using the following conditions (column specifications: XBridge BEH C18 OBD Prep Column 130, 5 m, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 50% B to 72% B over 10 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 9.62).

[0301] MS (ESI) m / z = 557.65 [MH] +

[0302] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.98 (s, 1H), 8.84 (dd, J = 7.2, 2.4Hz, 1H), 8.7 9(d,J=1.8Hz,1H),8.17(s,1H),8.11(d,J=8.2Hz,1H),8.08–8.01(m,1H),8.0 0(d,J=1.6Hz,2H),7.94(s,3H),7.86(d,J=8.6Hz,1H),7.80(dd,J=8.6,2.2H z,1H),7.71(tt,J=7.0,5.4Hz,2H),7.66(dd,J=8.2,1.8Hz,1H),3.84(s,6H).

[0303] Synthesis of RGW-19

[0304] Step 1: Synthesis of RGW-19-A1

[0305] A solution of 1,3-dimethyl 5-(3-amino-4-chlorobenzenesulfonamido)benzene-1,3-dicarboxylate (30 mg, 0.075 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (25.9 mg, 0.150 mmol, 2 eq), and glacial acetic acid (0.48 mg, 0.008 mmol, 0.1 eq) in methanol (1 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature. The resulting residue was slurried with methanol (3 mL). This afforded RGW-19-A1 (44 mg, 84.62%) as a crude yellow solid.

[0306] Step 2: Synthesis of RGW-19

[0307] At room temperature, RGW-19-A1 (29 mg, 0.073 mmol, 1 eq), sodium borohydride (27.51 mg, 0.730 mmol, 10 eq), and dimethyl sulfoxide (0.5 mL, 7.040 mmol) were added to an 8 mL vial. Stirring was continued at 50°C overnight. The reaction mixture was cooled to room temperature. The crude product was purified by HPLC to yield RGW-19 (6.0 mg, 13.60%) as a white solid using the following conditions: Kinetex 5m EVO C18 column, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 30% B to 44% B over 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 5.83.

[0308] MS (ESI) m / z = 552.65 [MH] +

[0309] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.74(s,1H),10.10(s,1H),8.10(s,1H),8.0 0(d,J=8.1Hz,3H),7.78(d,J=8.0Hz,1H),7.72(d,J=8.8Hz,1H),7.54(d,J=2 .2Hz,1H),7.46–7.36(m,2H),7.32–7.27(m,1H),7.25–7.16(m,1H),6.93(d d,J=8.2,2.2Hz,1H),5.62–5.57(m,1H),4.67(d,J=5.0Hz,2H),3.84(s,6H).

[0310] Synthesis of RGW-20

[0311] A solution of dimethyl 5-((3-amino-4-chlorophenyl)sulfonamido)isophthalate (60 mg, 0.150 mmol, 1 equiv), salicylaldehyde (55.12 mg, 0.450 mmol, 3 equiv), and acetic acid (25.86 uL, 0.450 mmol, 3 equiv) in methanol (1 mL) was stirred at 80°C for 3 hours. The resulting residue was slurried with methanol (3 mL). This afforded RGW-20 (50.9 mg, 65.46%) as a white solid.

[0312] MS (ESI) m / z = 502.7 [M+H] +

[0313] 1 H NMR (400MHz, DMSO-d6, ppm): δ12.43(s,1H),10.93(s,1H),8.93(s,1H),8.15(t,J=1.4Hz,1H),7.98(d,J=1.4Hz,2H),7.91(d,J=2.2Hz,1H),7.8 0(d,J=8.4Hz,1H),7.75(dd,J=7.8,1.6Hz,1H),7.64(dd,J=8.4,2.2Hz,1H),7.48(ddd,J=8.6,7.2,1.8Hz,1H),7.04–6.99(m,2H),3.85(s,6H).

[0314] Synthesis of RGW-21

[0315] Step 1: Synthesis of RGW-21-A1

[0316] To a 20 mL vial at 0°C, add 5-hydroxybenzothiophene (300 mg, 1.997 mmol, 1 eq) and dichloromethane (6.0 mL). Add 1,1-dichlorodimethyl ether (0.45 mL, 4.971 mmol, 2.49 eq) and titanium tetrachloride (0.55 mL, 3.958 mmol, 1.98 eq) dropwise at 0°C over approximately 5 minutes. Stir at room temperature for 1 hour. Quench the reaction mixture with ice water at room temperature. Extract the reaction mixture with ethyl acetate (3 x 30 mL). Combine the organic phases, backwash with saturated sodium chloride solution (3 x 30 mL), and dry over anhydrous sodium sulfate. Filter the resulting mixture, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography with petroleum ether / ethyl acetate (6:01) to afford RGW-21-A1 (118 mg, 29.84%) as a white solid.

[0317] Step 2: Synthesis of RGW-21

[0318] A solution of RGW-21-A1 (35 mg, 0.196 mmol, 1 eq), dimethyl 5-((3-amino-4-chlorophenyl)sulfonamido)isophthalate (86.16 mg, 0.216 mmol, 1.1 eq), and glacial acetic acid (1.13 uL, 0.020 mmol, 0.1 eq) in methanol (1 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting residue was slurried with methanol (3 mL). This afforded RGW-21 (73.2 mg, 65.67%) as a yellow solid.

[0319] MS (ESI) m / z = 558.85 [M+H] +

[0320] 1 H NMR (400MHz, DMSO-d6, ppm): δ13.07(s,1H),10.91(s,1H),9.40(s,1H),8.19–8.17(m,1H),8.16–8.10(m,1H),8.07(d,J=8.8Hz,1H ),8.02(d,J=2.2Hz,1H),7.99–7.93(m,3H),7.79(d,J=8.4Hz,1H),7.61(dd,J=8.4,2.2Hz,1H),7.03(d,J=8.8Hz,1H),3.80(s,6H).

[0321] Synthesis of RGW-22

[0322] Under argon protection, at 80°C, dimethyl 5-((3-amino-4-chlorophenyl)sulfonamido)isophthalate (100 mg, 0.251 mmol, 1 eq) was added. A solution of 500 molecular sieves (50 mg), 3-fluorobenzaldehyde (93.36 mg, 0.753 mmol, 3 eq), and p-toluenesulfonic acid (4.31 mg, 0.0251 mmol, 0.1 eq) in toluene (1 mL) was stirred overnight. The resulting residue was filtered, the filtrate collected, and concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane (1 mL). The resulting residue was purified by TLC using petroleum ether / ethyl acetate (2:01). The crude product was then slurried with ethanol (3 mL). RGW-22 (4.7 mg, 3.42%) was obtained as a white solid.

[0323] MS (ESI) m / z = 504.7 [M+H] +

[0324] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.93(s,1H),8.57(s,1H),8.18–8.11(m,1H),8.00–7.93(m,2H),7.82(d, J=7.8Hz,1H),7.80–7.69(m,2H),7.69–7.54(m,3H),7.47(td,J=8.6,2.6Hz,1H),3.86(d,J=0.8Hz,6H).

[0325] Synthesis of RGW-23

[0326] Step 1: Synthesis of RGW-23-A1

[0327] A solution of 6-hydroxyisoquinoline (300 mg, 2.067 mmol, 1 eq) and hexamethylenetetramine (579.44 mg, 4.134 mmol, 2 eq) in trifluoroacetic acid (3 mL) was stirred at 120°C for 3 hours. The reaction mixture was diluted with water (20 mL). The reaction mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to afford RGW-23-A1 (90 mg, 23.89%) as a pale yellow solid using the following conditions (column specifications: Sunfire C18 5m, 30mm x 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 2-2% B to 16% B over 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (min): 6.7).

[0328] Step 2: Synthesis of RGW-23

[0329] A solution of RGW-23-A1 (20 mg, 0.115 mmol, 1 eq), methyl 5-(3-amino-4-chlorophenylsulfonylamino)phenyl-1,3-dicarboxylate (69.09 mg, 0.173 mmol, 1.5 eq), and glacial acetic acid (6.62 uL, 0.115 mmol, 1 eq) in methanol (1 mL) was stirred at 80°C for 3 hours. The resulting residue was slurried with methanol (5 mL). This afforded RGW-23 (7.5 mg, 10.55%) as a yellow solid.

[0330] MS (ESI) m / z = 553.7 [M+H] +

[0331] 1 H NMR (400MHz, DMSO-d6, ppm): δ15.44(s,1H),10.99(s,1H),9.66(s,1H),9.11(s,1H),8.57(s,1H),8.46(s,1H),8.35(s,1H),8. 22–8.13(m,2H),8.01(d,J=1.6Hz,2H),7.86(d,J=8.4Hz,1H),7.67(dd,J=8.4,2.2Hz,1H),7.22(d,J=9.2Hz,1H),3.83(s,6H).

[0332] Synthesis of RGW-24

[0333] Step 1: Synthesis of RGW-24-A1

[0334] A solution of 5-hydroxybenzothiazole (250 mg, 1.654 mmol, 1 equiv), magnesium chloride (236.17 mg, 2.481 mmol, 1.5 equiv), paraformaldehyde (509.94 mg, 11.578 mmol, 7 equiv), and triethylamine (0.92 mL, 6.616 mmol, 4 equiv) in acetonitrile (2.5 mL) was stirred at 80°C for 2 hours. The reaction mixture was quenched with water (15 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: column size: C18; mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes; detection: UV 254 nm. RGW-24-A1 (185 mg, 59.31%) was obtained as a light yellow solid.

[0335] Step 2: Synthesis of RGW-24

[0336] A solution of RGW-24-A1 (34 mg, 0.190 mmol, 1.5 equiv), dimethyl 5-((3-amino-4-chlorophenyl)sulfonamido)isophthalate (50.45 mg, 0.127 mmol, 1 equiv), and glacial acetic acid (21.75 uL, 0.380 mmol, 3 equiv) in methanol (1 mL) was stirred at 80°C for 3 hours. The resulting residue was slurried with methanol (5 mL). This afforded RGW-24 (44.9 mg, 60.85%) as a yellow solid.

[0337] MS (ESI) m / z = 559.6 [M+H] +

[0338] 1 H NMR (400MHz, DMSO-d6, ppm): δ13.58(s,1H),10.97(s,1H),9.65(dd,J=3.6,1.6Hz,2H),8.31(d,J=8.8Hz,1H),8.18(t,J=1.4 Hz,1H),7.99(dd,J=3.8,1.8Hz,3H),7.86(d,J=8.4Hz,1H),7.67(dd,J=8.4,2.2Hz,1H),7.21(d,J=8.6Hz,1H),3.84(s,6H).

[0339] Synthesis of RGW-25

[0340] Step 1: Synthesis of RGW-25-A1

[0341] To a solution of dimethyl 5-aminoisophthalate (400 mg, 1.912 mmol, 1 equiv) in dichloromethane (4 mL) was added triethylamine (580.45 mg, 5.736 mmol, 3 equiv) at room temperature. The mixture was stirred for 2 minutes, and then 2-phenylethanesulfonyl chloride (469.6 mg, 2.294 mmol, 1.2 equiv) was added dropwise at 0°C. Stirring was continued at room temperature for 2 hours. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with dichloromethane (3 x 40 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. This afforded RGW-25-A1 (1 g, 99.78%) as a light brown solid. The crude product was used directly in the next step without further purification.

[0342] Step 2: Synthesis of RGW-25

[0343] A solution of RGW-25-A1 (200 mg, 0.530 mmol, 1 equiv) and lithium hydroxide (63.46 mg, 2.650 mmol, 5 equiv) in methanol (2 mL) and water (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was neutralized to pH ~7 with 2M hydrochloric acid. The crude product was purified by HPLC to afford RGW-25 (1.9 mg, 0.98%) as a white solid using the following conditions (column specifications: Xselect CSH™ Prep C18 5μm 30x150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 30% B to 70% B over 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 6.85).

[0344] MS (ESI) m / z = 364.0 [M+H] +

[0345] 1 H NMR (400MHz, DMSO-d6, ppm): δ13.33(br,1H),10.33(s,1H),8.17(t,J=1.4Hz,1H),8.04(dt,J=9.0,2.2Hz ,2H),7.25–7.23(m,2H),7.16(dt,J=9.4,3.2Hz,3H),3.88(s,3H),3.45–3.41(m,2H),3.01–2.97(m,2H).

[0346] Synthesis of RGW-26

[0347] Step 1: Synthesis of RGW-26-A1

[0348] To a solution of dimethyl 5-aminoisophthalate (400 mg, 1.912 mmol, 1 equiv) in dichloromethane (4 mL) was added triethylamine (580.45 mg, 5.736 mmol, 3 equiv) at room temperature. After stirring for 2 minutes, 2-phenylethanesulfonyl chloride (469.6 mg, 2.294 mmol, 1.2 equiv) was added dropwise at 0°C. Stirring was continued at room temperature for 2 hours. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with dichloromethane (3 x 40 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. This afforded RGW-26-A1 (1 g, 99.78%) as a light brown solid. The crude product was used directly in the next step without further purification.

[0349] Step 2: Synthesis of RGW-26

[0350] A solution of RGW-26-A1 (200 mg, 0.530 mmol, 1 equiv) and lithium hydroxide (63.46 mg, 2.650 mmol, 5 equiv) in methanol (2 mL) and water (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was neutralized to pH 7 with 2 M hydrochloric acid. The crude product was purified by HPLC to afford RGW-26 (48.7 mg, 25.75%) as a white solid using the following conditions (column specifications: Ultimate μAQ-C18; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 5% B to 27% B over 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 8.75).

[0351] MS (ESI) m / z = 371.9 [M + Na] +

[0352] 1 H NMR (400MHz, DMSO-d6, ppm): δ13.33(s,2H),10.31(s,1H),8.17(t,J=1.4Hz,1H),8.02(d,J=1. 4Hz,2H),7.26–7.22(m,2H),7.18(dt,J=6.4,1.6Hz,3H),3.44–3.32(m,2H),3.01–2.97(m,2H).

[0353] Synthesis of RGW-27

[0354] To a solution of dimethyl 5-aminoisophthalate (0.77 g, 3.672 mmol, 1 eq) in 1,2-dichloroethane (14.0 mL) at 0°C was added triethylamine (1.02 mL, 7.344 mmol, 2 eq). The mixture was stirred for 10 minutes, and then benzylsulfonyl chloride (700 mg, 3.672 mmol, 1 eq) was added portionwise at 0°C. After the addition was complete, the mixture was stirred at 80°C overnight. The reaction mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (10:01) to afford dimethyl 5-(phenylmethyl)sulfonamidoisophthalate (400 mg, 29.98%) as a white solid. 100 mg of the column chromatography product was purified by HPLC to obtain RGW-27 (24.1 mg, 24.1%) as a white solid using the following conditions (column specifications: Sunfire C18 5m, 30 mm x 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 31% B to 65% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 6.88).

[0355] MS (ESI) m / z = 361.65 [MH] +

[0356] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.35 (s, 1H), 8.12 (t, J = 1.4Hz, 1H), 7.92 (d, J =1.6Hz,2H),7.34–7.27(m,3H),7.31–7.21(m,2H),4.56(s,2H),3.89(s,6H).

[0357] Synthesis of RGW-28

[0358] Step 1: Synthesis of RGW-28-A1

[0359] A solution of 1-bromo-3-phenylpropane (1 g, 5.023 mmol, 1 eq) and sodium sulfite (696.39 mg, 5.525 mmol, 1.1 eq) in water (20 mL) and ethanol (10 mL) was stirred at 100°C overnight. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with dichloromethane (20 mL) and water (20 mL). Tetrabutylammonium hydrogensulfate (1.79 g, 5.274 mmol, 1.05 eq) and sodium hydroxide (200.9 mg, 5.023 mmol, 1 eq) were added to the above system at room temperature. After the addition was complete, the system was stirred at room temperature for 30 minutes. The reaction mixture was extracted with dichloromethane (3 x 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was not further purified and was directly used in the next step.

[0360] Step 2: Synthesis of RGW-28-A2

[0361] The mixture from the previous step was not further purified. Bis(trichloromethyl)carbonate (solid phosgene) (738.98 mg, 2.490 mmol, 0.5 eq), N,N-dimethylformamide (0.04 mL, 0.498 mmol, 0.10 eq), and dichloromethane (20.0 mL) were added portionwise to the above system at 0°C. After the addition was complete, the system was stirred at room temperature for 1 hour. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (6:01) to obtain RGW-28-A2 (664 mg, 54.86%) as an off-white solid.

[0362] Step 3: Synthesis of RGW-28

[0363] To an 8 mL vial at 0°C, add 1,3-dimethyl 5-aminobenzene-1,3-dicarboxylate (260.88 mg, 1.247 mmol, 1 eq), triethylamine (520.02 μL, 3.742 mmol, 3 eq), 4-dimethylaminopyridine (30.47 mg, 0.249 mmol, 0.2 eq), and 1,2-dichloroethane (3 mL). Add RGW-28-A2 (300 mg, 1.372 mmol, 1.1 eq) dropwise to the mixture at room temperature. After the addition is complete, stir the mixture at room temperature for 2 hours. The reaction mixture is quenched with water at room temperature. The reaction mixture is extracted with ethyl acetate (3 x 30 mL) and dried over anhydrous sodium sulfate. The resulting mixture is filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography using the following conditions: 20 g column, mobile phase: water and acetonitrile, gradient from 10% to 60% over 10 minutes, detection at UV wavelength 254 nm. This yielded RGW-28 as an off-white solid (258 mg, 47.56%). The crude product (61 mg) from the above column chromatography was purified by HPLC to yield RGW-28 as a white solid (30.5 mg, 50%) using the following conditions: Xselect CSH™ Prep C18 5μm 30x150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 36% B to 64% B over 8 minutes; detection at UV wavelength 254 nm / 220 nm; retention time (min): 7.8.

[0364] MS (ESI) m / z = 389.70 [M+H] +

[0365] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.34(s,1H),8.16(t,J=1.4Hz,1H),8.01(d,J=1.4Hz,2H),7.25–7.17 (m,2H),7.17–7.07(m,3H),3.90(s,6H),3.16–3.08(m,2H),2.64(t,J=7.4Hz,2H),2.01–1.89(m,2H).

[0366] Synthesis of RGW-29, RGW-30 and RGW-31

[0367] Step 1: Synthesis of RGW-29

[0368] To a 20 mL vial, add 1,3-dimethyl 5-aminobenzene-1,3-dicarboxylate (223.98 mg, 1.071 mmol, 1 eq), 4-dimethylaminopyridine (26.16 mg, 0.214 mmol, 0.2 eq), 1,2-dichloroethane (3 mL), and triethylamine (446.47 uL, 3.213 mmol, 3 eq). At 0°C, add 2-(naphthalen-1-yl)ethanesulfonyl chloride (300 mg, 1.178 mmol, 1.1 eq). After the addition is complete, stir at room temperature for 2 hours. The reaction mixture is diluted with water (10 mL). The reaction mixture is extracted with ethyl acetate (3 x 30 mL). The organic phases are combined and dried over anhydrous sodium sulfate. The resulting mixture is filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography using the following conditions: 20 g column, mobile phase: water and acetonitrile, gradient from 10% to 60% over 10 minutes, detection at UV wavelength 254 nm. This yielded RGW-29 (100 mg, 19.66%) as a pale yellow solid. 42 mg of the column chromatography product was purified by HPLC to yield RGW-29 (14.3 mg, 33.34%) as a white solid using the following conditions: Sunfire C18 5m, 30 mm x 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 37% B to 72% B over 7 minutes; detection at UV wavelengths 254 nm / 220 nm; retention time (min): 7.52.

[0369] MS (ESI) m / z = 425.65 [MH] +

[0370] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.54(s,1H),8.18(t,J=1.4Hz,1H),8.10(d,J=1.4Hz,2H),7.93–7.87(m,1H),7.79(dd,J=7.0,2.6Hz, 1H),7.73(d,J=8.4Hz,1H),7.49(ddd,J=8.2,6.8,1.2Hz,1H),7.45–7.34(m,3H),3.89(s,6H),3.56–3.49(m,2H),3.48–3.43(m,2H).

[0371] Step 2: Synthesis of RGW-30 and RGW-31

[0372] A solution of RGW-29 (58 mg, 0.136 mmol, 1 eq), lithium hydroxide (4.87 mg, 0.204 mmol, 1.5 eq), and water (1.0 mL) in methanol (1.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH ~6 with hydrochloric acid. The resulting residue was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 30 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give RGW-30 (7.5 mg, 12.85%) and RGW-31 (16.7 mg, 30.72%) as a white solid under the following conditions (chromatographic column specifications: Xselect CSH™ Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 36% B to 64% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 5.42 / 7.42).

[0373] RGW-30:MS(ESI)m / z=411.65[MH] +

[0374] 1 H NMR (400MHz, DMSO-d6, ppm): δ14.12(s,br),10.52(s,1H),8.19(d,J=1.6Hz,1H),8.10(d,J=15.2Hz,1H),8.10(t,J=2.0Hz,1H),7.91(d,J =8.2Hz,1H),7.79(dd,J=7.2,2.2Hz,1H),7.71(d,J=8.1Hz,1H),7.49(t,J=7.4Hz,1H),7.45–7.33(m,3H),3.88(s,3H),3.52–3.44(m,4H).

[0375] RGW-31:MS(ESI)m / z=397.60[MH] +

[0376] 1H NMR (400MHz, DMSO-d6, ppm): δ13.37(s,2H),10.49(s,1H),8.20(d,J=1.8Hz,1H),8.10(d,J=1.4Hz,2H),7.91(d,J=8.2Hz ,1H),7.79(dd,J=7.3,2.0Hz,1H),7.69(d,J=8.4Hz,1H),7.49(t,J=7.4Hz,1H),7.45–7.33(m,3H),3.47(d,J=2.8Hz,4H).

[0377] Synthesis of RGW-33

[0378] Step 1: Synthesis of RGW-33-A1

[0379] To a solution of methyl 3-aminobenzoate (1 g, 6.619 mmol, 1 equiv) in N-methylpyrrolidone (10 mL) was added potassium hydroxide (0.74 g, 13.214 mmol, 2 equiv) at room temperature. The reaction was stirred for 5 minutes, and then 4-chloro-3-nitrobenzenesulfonyl chloride (2.2 g, 8.630 mmol, 1.3 equiv) was added portionwise at 0°C. Stirring was continued at room temperature for 1 hour. The reaction mixture was quenched by the addition of ice water (50 mL) at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 60 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: column size: C18; mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes; detection: UV 254 nm. RGW-33-A1 (2.3 g, 94.87%) was obtained as a light yellow solid.

[0380] Step 2: Synthesis of RGW-33-A2

[0381] Under argon, a solution of RGW-33-A1 (300 mg, 0.809 mmol, 1 equiv), reduced iron powder (316.31 mg, 5.663 mmol, 7 equiv), and ammonium chloride (432.81 mg, 8.090 mmol, 10 equiv) in ethanol (3 mL) and water (1 mL) was stirred at 80°C for 3 hours. The mixture was filtered, the filter cake washed with ethyl acetate (3 x 10 mL), and the filtrate concentrated under reduced pressure. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to yield RGW-33-A2 (220 mg, 71.81%) as a pale yellow solid.

[0382] Step 3: Synthesis of RGW-33

[0383] A solution of RGW-33-A2 (50 mg, 0.147 mmol, 1 equiv), 2-hydroxy-1-naphthaldehyde (37.89 mg, 0.220 mmol, 1.5 equiv), and acetic acid (21.02 uL, 0.367 mmol, 2.5 equiv) in methanol (1 mL) was stirred at 80°C for 3 hours. The resulting residue was slurried with methanol (3 mL). RGW-33 (42.9 mg, 58.54%) was obtained as a yellow solid.

[0384] MS (ESI) m / z = 494.7 [M + H] +

[0385] 1H NMR (400MHz, DMSO-d6, ppm): δ15.11(s,1H),10.68(s,1H),9.69(s,1H),8.57(d,J=8.4Hz,1H),8.24(d,J=2.2Hz,1H),8.05(d,J=9.2Hz,1H),7.9 0(dd,J=8.2,1.4Hz,1H),7.83(d,J=8.4Hz,1H),7.77(q,J=1.4Hz,1H),7 .68–7.62(m,3H),7.46–7.41(m,3H),7.17(d,J=9.2Hz,1H),3.79(s,3H).

[0386] Synthesis of RGW-34

[0387] Step 1: Synthesis of RGW-34-A1

[0388] Under nitrogen, 4-chloro-3-nitrobenzenesulfonyl chloride (2 g, 7.811 mmol, 1.00 eq), triphenylphosphine (6.15 g, 23.433 mmol, 3 eq), and toluene (47 mL) were added to a 250 mL three-necked flask at 0°C. The reaction system was allowed to return to room temperature and stirred for 2 hours. The reaction mixture was quenched with water at 0°C. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were backwashed with water (3 x 100 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (5:01) to afford RGW-34-A1 (1.25 g, 67.52%) as a light brown solid.

[0389] Step 2: Synthesis of RGW-34-A2

[0390] A solution of RGW-34-A1 (600 mg, 3.164 mmol, 1 eq), dimethyl 5-bromomethylisophthalate (1.36 g, 4.746 mmol, 1.5 eq), and potassium carbonate (1.31 g, 9.492 mmol, 3 eq) in N-methylpyrrolidone (10 mL) was stirred overnight at room temperature. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were backwashed with water (3 x 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (6:01) to afford RGW-34-A2 (469 mg, 33.70%) as a white solid.

[0391] Step 3: Synthesis of RGW-34-A3

[0392] At room temperature, RGW-34-A2 (200 mg, 0.505 mmol, 1 eq), H₂O₂ (30%) (5 mL), and glacial acetic acid (10 mL) were added to a 40 mL vial. The resulting mixture was heated to 50°C and stirred overnight. The reaction mixture was cooled to room temperature. Water (10 mL) was added to the reaction mixture at room temperature to quench the reaction mixture. The reaction mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, backwashed with water (3 x 15 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: 20 g column, mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes, detection at UV wavelength of 254 nm. RGW-34-A3 (80 mg, 33.31%) was obtained as a white solid.

[0393] Step 4: Synthesis of RGW-34-A4

[0394] Under argon, a solution of RGW-34-A3 (75 mg, 0.175 mmol, 1 eq), reduced iron powder (68.53 mg, 1.225 mmol, 7 eq), ammonium chloride (93.77 mg, 1.750 mmol, 10 eq), and water (0.9 mL) in ethanol (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure. Filtered, the filter cake was washed with ethyl acetate (3 x 10 mL), and the filtrate was concentrated under reduced pressure to afford RGW-34-A4 (83 mg, 95.21%) as a crude white solid.

[0395] Step 5: Synthesis of RGW-34.

[0396] A solution of RGW-34-A4 (40 mg, 0.101 mmol, 1 eq), 2-hydroxy-1-naphthaldehyde (34.62 mg, 0.202 mmol, 2 eq), and glacial acetic acid (6 mg, 0.01 mmol, 0.1 eq) in methanol (1 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature. The resulting residue was slurried with methanol (3 mL). This afforded RGW-34 (46.4 mg, 80.68%) as a yellow solid.

[0397] MS (ESI) m / z = 551.75 [M+H] +

[0398] 1 H NMR (400MHz, DMSO-d6, ppm): δ15.31 (s, 1H), 9.71 (s, 1H), 8.55 (d, J = 8.6Hz, 1H),8.43(t,J=1.6Hz,1H),8.28(d,J=2.0Hz,1H),8.11–8.03(m,3H),7.93– 7.89(m,1H),7.88–7.85(m,1H),7.70–7.61(m,1H),7.57(dd,J=8.4,2.2Hz, 1H),7.46(t,J=7.6Hz,1H),7.17(d,J=9.0Hz,1H),5.06(s,2H),3.84(s,6H).

[0399] Synthesis of RGW-35

[0400] Under argon, a solution of dimethyl 5-(4-chloro-3-bromobenzenesulfonamido)-isophthalate (100 mg, 0.216 mmol, 1 equiv), 8-aminoquinoline (93.48 mg, 0.648 mmol, 3 equiv), (±)-trans-1,2-diaminocyclohexane (4.94 mg, 0.043 mmol, 0.2 equiv), cuprous iodide (4.12 mg, 0.022 mmol, 0.1 equiv), and potassium carbonate (59.74 mg, 0.432 mmol, 2 equiv) in dimethyl sulfoxide (1 mL) was stirred and reacted overnight at 100°C. The resulting residue was purified by reverse-phase column chromatography using the following conditions: C18 column; mobile phase: water and acetonitrile, gradient from 10% to 50% over 10 minutes; detection: UV 254 nm. The crude product was purified by HPLC to afford RGW-35 (1.6 mg, 1.39%) as a pale yellow solid using the following conditions (column specifications: Xselect CSH™ Prep C18 5μm 30x150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 52% B to 76% B over 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 9.13).

[0401] MS (ESI) m / z = 525.7 [M+H] +

[0402] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.93 (s, 1H), 8.88 (dd, J = 4.2, 1.6Hz, 1H), 8.76 (s, 1H), 8 .42(dd,J=8.4,1.6Hz,1H),8.15(t,J=1.4Hz,1H),7.99(d,J=1.6Hz,2H),7.84(d,J=2.2 Hz,1H),7.77(d,J=8.4Hz,1H),7.65(dd,J=8.4,4.2Hz,1H),7.60(dd,J=8.4,1.2Hz,1H) ,7.48(t,J=7.8Hz,1H),7.34(dd,J=8.4,2.2Hz,1H),7.22(d,J=7.2Hz,1H),3.84(s,6H).

[0403] Synthesis of RGW-36

[0404] Under argon, a solution of dimethyl 5-(3-bromo-4-chlorobenzenesulfonamido)isophthalate (70 mg, 0.151 mmol, 1 equiv), aniline (42.27 mg, 0.453 mmol, 3 equiv), tris(dibenzylideneacetone)dipalladium (13.85 mg, 0.015 mmol, 0.1 equiv), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (17.51 ​​mg, 0.030 mmol, 0.2 equiv), and sodium tert-butoxide (21.81 mg, 0.226 mmol, 1.5 equiv) in toluene (1 mL) was stirred overnight at 100°C. The resulting residue was concentrated under reduced pressure. The reaction mixture was diluted with N,N-dimethylformamide (1 mL). Filtered, the filter cake washed with N,N-dimethylformamide (3 x 0.2 mL), and the filtrate concentrated under reduced pressure. The crude product was purified by HPLC to afford RGW-36 (31.4 mg, 43.57%) as a pale yellow solid using the following conditions (column specifications: YMC Triart C18 ExRs 5m, 30mm x 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 40% B to 75% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 8.98).

[0405] MS (ESI) m / z = 474.7 [M+H] +

[0406] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.81(s,1H),8.16(s,1H),7.99(s,1H),7.91(d,J=1.4Hz,2H),7.60(d,J=8.4Hz,1H),7. 37(d,J=2.2Hz,1H),7.28–7.25(m,2H),7.16(dd,J=8.4,2.2Hz,1H),7.06–7.04(m,1H),6.97–6.95(m,2H),3.86(s,6H).

[0407] Synthesis of RGW-37

[0408] Under argon, a solution of 1,3-dimethyl 5-(3-bromo-4-chlorophenylsulfonamido)benzene-1,3-dicarboxylate (80 mg, 0.173 mmol, 1 eq), 1,2,3,4-tetrahydroisoquinoline (69.09 mg, 0.519 mmol, 3 eq), cesium carbonate (169.0 mg, 0.519 mmol, 3 eq), tris(dibenzylideneacetone)dipalladium (15.83 mg, 0.017 mmol, 0.1 eq), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (20.01 mg, 0.035 mmol, 0.2 eq) in 1,4-dioxane (3.0 mL) was stirred at 100°C overnight. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure. Filtered, and the filter cake was washed with N,N-dimethylformamide (2 x 2 mL). The crude product was purified by HPLC to afford RGW-37 (10.0 mg, 11.07%) as an off-white solid using the following conditions (column specifications: Sunfire C18 5m, 30 mm x 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 62% B to 80% B in 7 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 6.8).

[0409] MS (ESI) m / z = 514.75 [M+H] +

[0410] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.87(s,1H),8.15(t,J=1.4Hz,1H),7.96(d,J=1.6Hz,2H),7.66(d,J=8.2Hz,1H),7.52(d,J=2.2Hz,1H),7.40( dd,J=8.4,2.2Hz,1H),7.18(q,J=2.6,2.0Hz,3H),7.15–7.10(m,1H),4.14(s,2H),3.86(s,6H),3.29(t,J=5.8Hz,2H),2.93(t,J=5.8Hz,2H).

[0411] Synthesis of RGW-38

[0412] Under argon, a solution of 1,3-dimethyl 5-(3-bromo-4-chlorophenylsulfonamido)benzene-1,3-dicarboxylate (80 mg, 0.173 mmol, 1 eq), isoindoline (61.81 mg, 0.519 mmol, 3 eq), cesium carbonate (169.0 mg, 0.519 mmol, 3 eq), tris(dibenzylideneacetone)dipalladium (15.83 mg, 0.017 mmol, 0.1 eq), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (20.01 mg, 0.035 mmol, 0.2 eq) in 1,4-dioxane (3 mL) was stirred overnight at 100°C. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure. The reaction mixture was dissolved in N,N-dimethylformamide (2 mL), and the crude product was purified by high-performance liquid chromatography to obtain RGW-38 (11.2 mg, 12.75%) as a white solid under the following conditions (chromatographic column specifications: Sunfire C18 5m, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 60% B to 80% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.25).

[0413] MS (ESI) m / z = 500.75 [M+H] +

[0414] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.89(s,1H),8.11(t,J=1.6Hz,1H),7.99(d,J=1.6Hz,2H),7.53(d,J=8.2Hz,1H),7.43 –7.39(m,2H),7.38–7.35(m,1H),7.32(dd,J=5.6,3.2Hz,2H),7.15(dd,J=8.4,2.0Hz,1H),4.83(s,4H),3.84(s,6H).

[0415] Synthesis of RGW-39

[0416] 1,3-Dimethyl-5-(3-amino-4-chlorophenylsulfonylamino)benzene-1,3-dicarboxylate (150 mg, 376 μmol, 1.00 eq) and 6-chloro-2-hydroxynaphthalene-1-carboxaldehyde (93.3 mg, 451 μmol, 1.20 eq) were dissolved in 2 mL of methanol. Triethylamine (114 mg, 1.13 mmol, 157 μL, 3.00 eq) was added, and the reaction mixture was stirred at 70°C for 16 hours. LCMS analysis indicated 84.7% product formation. The methanol was removed by vacuum drying. After rotary evaporation, the residue was added with 10 mL of dimethylformamide and 10 mL of water. The mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with 10 mL of saturated brine and dried over magnesium sulfate. The crude product was purified by flash silica gel column to obtain yellow solid RGW-39 (35.0 mg, 56.4 μmol, yield 15.0%, purity 94.63%).

[0417] MS (ESI) m / z = 587.1 [M+H] +

[0418] 1H NMR (400MHz, DMSO-d6): δ15.16-14.98(m,1H),11.12-10.84(m,1H),9.77-9.59(m,1H),8.74-8.55(m,1H),8.31-8.25(m ,1H),8.17-8.13(m,1H),8.09-7.97(m,4H),7.87-7.81(m,1H),7.69-7.61(m,2H),7.25-7.19(m,1H),3.86-3.80(m,6H)

[0419] Synthesis of RGW-40

[0420] 1,3-Dimethyl-5-(3-amino-4-chlorophenylsulfonylamino)benzene-1,3-dicarboxylate (300 mg, 752 μmol, 1.00 eq) and 2-hydroxy-5-(trifluoromethyl)benzaldehyde were dissolved in 8 mL of methanol. Acetic acid (136 mg, 2.26 mmol, 3.00 eq) was added, and the reaction mixture was stirred at 70°C for 16 hours. LCMS analysis indicated 78.9% product formation. The reaction mixture was cooled to 20°C and filtered to obtain a filter cake, which was then rinsed with 20 mL of methanol and dried to afford RGW-40 as a yellow solid (248 mg, 426 μmol, 56.6% yield, 98.0% purity).

[0421] MS (ESI) m / z = 571.5 [M+H] +

[0422] 1H NMR (400MHz, DMSO-d6): δ13.02-12.88(m,1H),11.06-10.90(m,1H),9.09-8.96(m,1H),8.21-8.11(m,2H),8.0 0-7.96(m,2H),7.95-7.91(m,1H),7.86-7.77(m,2H),7.71-7.64(m,1H),7.22-7.15(m,1H),3.97-3.77(m,6H)

[0423] Synthesis of RGW-41

[0424] To 1,3-dimethyl-5-(3-amino-4-chlorophenylsulfonylamino)benzene-1,3-dicarboxylate (300 mg, 752 μmol, 1.00 eq) and 2-hydroxy-5-nitrobenzaldehyde (377 mg, 2.26 mmol, 3.00 eq) were added acetic acid (136 mg, 2.26 mmol, 3.00 eq). The reaction was stirred at 70°C for 16 hours. LCMS analysis indicated 93.5% product formation. The reaction mixture was cooled to 20°C and filtered to obtain a filter cake, which was then rinsed with 20 mL of methanol and dried to afford RGW-41 as a yellow solid (125 mg, 205 μmol, 27.3% yield, 90.0% purity).

[0425] MS (ESI) m / z = 548.1 [M+H] +

[0426] Synthesis of RGW-42

[0427] 1,3-Dimethyl-5-(3-amino-4-chlorophenylsulfonylamino)benzene-1,3-dicarboxylate (100 mg, 251 μmol, 1.00 eq) and 2-hydroxynaphthalene-1-carboxaldehyde (87.1 mg, 401 μmol, 1.60 eq) were dissolved in 5 mL of methanol. Acetic acid (45.2 mg, 752 μmol, 3.00 eq) was added, and the reaction mixture was stirred at 70°C for 16 hours. LCMS analysis indicated 76.6% product formation. The reaction mixture was cooled to 20°C and filtered to obtain a filter cake, which was then rinsed with 10 mL of methanol and dried to afford RGW-42 as a yellow solid (95.0 mg, 156 μmol, 62.2% yield, 98.22% purity).

[0428] MS (ESI) m / z = 598.1 [M+H] +

[0429] 1H NMR (400MHz, DMSO-d6): δ15.81-15.48(m,1H),11.21-10.81(m,1H),9.81-9.54(m,1H),8.93-8.87(m,1H),8.80-8.71(m,1H),8.4 0-8.30(m,3H),8.20-8.13(m,1H),8.05-7.97(m,2H),7.90-7.83(m,1H),7.73-7.64(m,1H),7.32-7.25(m,1H),3.88-3.78(m,6H)

[0430] Synthesis of RGW-43

[0431] 2-Hydroxy-6-(trifluoromethyl)naphthalene-1-carboxaldehyde (45.17 mg, 188.06 μmol, 1.5 eq) was dissolved in 1 mL of methanol. Acetic acid (22.59 mg, 376.11 μmol, 21.53 μL, 3 eq) and 1,3-dimethyl 5-(3-amino-4-chlorophenylsulfonylamino)benzene-1,3-dicarboxylate (50 mg, 125.37 μmol, 1 eq) were added. The reaction was stirred at 70°C for 6 hours. LCMS analysis indicated 89% product formation. The reaction mixture was cooled to 25°C and filtered. The filter cake was rinsed with 20 mL of methanol and filtered to obtain RGW-43 as a yellow solid (54.17 mg, 86.52 μmol, 69.01% yield, 99.18% purity).

[0432] MS (ESI) m / z = 586.0 [M+H] +

[0433] 1HNMR (400MHz, DMSO-d6): δ15.38(br s,1H),10.98(br s,1H),9.71(s,1H),8.77(d,J=9.0Hz,1H),8.39-8.29(m,2H),8.23(d,J=9.3Hz,1H),8.16(s,1H),8.01 (d,J=1.1Hz,2H),7.86(d,J=8.5Hz,2H),7.67(dd,J=1.9,8.4Hz,1H),7.27(d,J=9.1Hz,1H),3.82(s,6H)

[0434] Example 2 Inhibitory effect of RGW-1 on cell pyroptosis

[0435] The main purpose of this example is to investigate the inhibitory effect of the compound in Example 1 on cell pyroptosis.

[0436] Methods: THP-1 cells were plated and allowed to stabilize for 1 day. 50 ng / ml PMA was added to each well to induce cell adhesion. After 72 h, 1 μg / ml LPS was added for 4 h. 25, 50 and 100 μM RGW-1 compounds were added and reacted for 1 h. 20 μM Nigericin was added to each group and reacted for 2 h. The supernatant was collected and the LDH content in the supernatant was detected using the CytoTox 96 Non-Radioactive Cytotoxicity Assay kit (Promega) according to the instructions. The absorbance was measured at 490 nm using a microplate reader.

[0437] Results: As shown in Figure 1, all concentrations of RGW-1 can effectively reduce the release of cellular LDH, indicating that each compound has an inhibitory effect on cell pyroptosis.

[0438] Example 3 Inhibitory effects of other compounds on cell pyroptosis

[0439] The main purpose of this example is to investigate the inhibitory effect of the compound in Example 1 on cell pyroptosis.

[0440] Methods: THP-1 cells were plated. After the cells stabilized for 1 day, 50 ng / ml PMA was added to each well to induce cell attachment. After 72 h, 1 μg / ml LPS was added for 4 h, and then 25, 50, and 100 μM RGW-1 or other compounds were added and reacted for 1 h. Then, 20 μM Nigericin was added to each group and reacted for 2 h. The supernatant was collected and the LDH content in the supernatant was detected using the CytoTox 96 Non-Radioactive Cytotoxicity Assay kit (Promega) according to the instructions. The absorbance was measured at 490 nm using a microplate reader.

[0441] Results: Taking the efficacy of RGW-1 as the standard, the inhibitory effects of other compounds on pyroptosis were evaluated, as shown in Table 1, which shows that each compound has a certain inhibitory effect on cell pyroptosis.

[0442] Table 1

[0443] Note: The LDH reduction of the compound / the LDH reduction of RGW-1 is ≥1: A; The LDH reduction of the compound / the LDH reduction of RGW-1 is <1: B

[0444] Example 4 Inhibitory Effect of Compounds on GSDMD Activation

[0445] The main purpose of this example is to investigate the inhibitory effect of the compound in Example 1 on GSDMD activation.

[0446] Methods: THP-1 cells were plated. After the cells stabilized for 1 day, 50 ng / ml PMA was added to each well to induce cell adhesion. After 72 hours, 1 ug / ml LPS was added for 4 hours, and then 25 uM RGW-1 was added for 1 hour. Then, 20 uM Nigericin was added to each group for 2 hours. The supernatant was discarded, 75 ul lysis buffer was added, and the cell proteins were collected. The expression of GSDMD was detected by western blotting (WB).

[0447] Results: As shown in the WB results in Figure 2A and the quantitative results in Figures 2B and 2C, it can be seen that the GSDMD N-terminus and oligomers in the RGW-1 compound group were significantly decreased compared with the induced group, indicating that the compound inhibits the occurrence of pyroptosis by inhibiting the release of the GSDMD N-terminus and the formation of oligomers.

[0448] Example 5 Effects of Compounds in Sepsis Model

[0449] The main purpose of this example is to investigate the effect of the compound in Example 1 on the mouse sepsis model.

[0450] Methods: Male C57BL / 6J mice, 8 weeks old, were intraperitoneally injected with LPS 50 mg / kg. RGW-1 was administered 30 minutes before LPS injection and 10 hours after model establishment. The survival of each group was then observed. The specific groups were as follows:

[0451] Model group: 15 male C57BL / 6J mice, 8 weeks old, received intraperitoneal injection of LPS 50 mg / kg, using the same solvent and volume as the treatment group, with the first administration 30 minutes before LPS injection and the second administration 10 hours after model establishment.

[0452] RGW-1 group: 15 male C57BL / 6J mice, 8 weeks old, received intraperitoneal injection of LPS 50 mg / kg and RGW-1 20 mg / kg, the first administration was 30 minutes before LPS injection and the second administration was 10 hours after model establishment.

[0453] Results: As shown in Figure 3, it can be seen that compound RGW-1 can significantly prolong the survival time of sepsis model mice.

Claims

1. A compound of formula (I), or a tautomer, enantiomer, diastereoisomer, isotopically-labelled compound, solvate or pharmaceutically acceptable salt thereof: Wherein, is a single bond or a double bond; R1 and R2 are each independently selected from -H, -COOH, -COOR a , -COR b , a heterocyclic group or a heteroaryl group, wherein said R a and R b are each independently selected from alkyl groups, and said heterocyclic group and heteroaryl group are each optionally substituted by one or more substituents independently selected from oxo, halogen, and C 1-6 alkyl groups; X is NR3 or CR4R5, where R3, R4, and R5 are each independently selected from H or C 1-6 alkyl; L1 is -(Ar) m -(CH2) p -L2-, where Ar is an aryl group, which is optionally substituted by one or more substituents independently selected from halogen, -CN, C 1-6 alkyl and -CON(R c R d ); m is 0 or 1; p is 0, 1, 2, 3 or 4; L2 is selected from a direct bond, -N(R e )-, -O-, -N=C(R f )-, -C(R g )=C(R h )-, -OC(R i R j )-, -N(R k )C(R l R m )-, -N(R n )CO-, -N(R o )C(R p )=, -CON(R q )- or -CO-; R c to R q are each independently selected from H and C 1-6 alkyl; Ring A is selected from aryl, heteroaryl, cycloalkyl or heterocyclic group, and the aryl, heteroaryl, cycloalkyl or heterocyclic group is each optionally substituted by one or more substituents independently selected from -OH, -NO2, oxo, halogen, C 1-6 alkyl and C 1-6 haloalkyl, provided that the compound of formula (I) is not 2. The compound of formula (I) according to claim 1, or its tautomer, enantiomer, diastereoisomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt, wherein: R1 and R2 are each independently selected from -H, -COOH, -COOR a , -COR b , a 3- to 12-membered heterocyclic group or a 5- to 14-membered heteroaryl group, where the R a and R b are each independently selected from C 1-6 alkyl, and the 3- to 12-membered heterocyclic group and the 5- to 14-membered heteroaryl group are each optionally substituted by one or more substituents independently selected from oxo, halogen, and C 1-6 alkyl; Alternatively, R1 and R2 are each independently selected from -H, -COOH, -COOR a , -COR b , a 5- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein said R a and R b are each independently selected from C 1-3 alkyl; the 5- to 10-membered heterocyclic group and the 5- to 10-membered heteroaryl group are each optionally substituted by one, two or three substituents independently selected from oxo, halogen and C 1-3 alkyl; Alternatively, each of R1 and R2 is independently selected from -H, -COOH, -COOCH3, -COCH3, Alternatively, one of R1 and R2 is -COOR a , and the other is selected from -H, -COOH, -COOR a , -COR b , a 5- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein each of said R a and R b is independently selected from C 1-6 alkyl; and each of said 5- to 10-membered heterocyclic group and 5- to 10-membered heteroaryl group is optionally substituted with 1, 2 or 3 substituents independently selected from oxo, halogen and C 1-6 alkyl; Alternatively, one of R1 and R2 is -COOCH3 and the other is -H, -COOH, -COOCH3, -COCH3, 3. The compound of formula (I) according to claim 1 or 2, or its tautomer, enantiomer, diastereoisomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt, wherein, R3, R4, and R5 are each independently selected from H or C 1-3 alkyl; alternatively, R3 is H; alternatively, both R4 and R5 are H; Alternatively, X is NR3, and R3 is selected from H or C 1-3 alkyl; alternatively, X is NH.

4. The compound of formula (I) according to any one of claims 1-3, or its tautomer, enantiomer, diastereoisomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt, wherein, L1 is selected from -(Ar) m -(CH2) p -L2-, where Ar is a 6- to 10-membered aryl group, which is optionally substituted with one, two or three substituents independently selected from halogen, -CN, C 1-6 alkyl and -CON(R c R d ) ; m is 0 or 1; p is 0, 1, 2, 3 or 4; L2 is selected from a direct bond, -N(R e )-, -O-, -N=C(R f )-, -C(R g )=C(R h )-, -OC(R i R j )-, -N(R k )C(R l R m )-, -N(R n )CO-, -N(R o )C(R p )=, -CON(R q )- or -CO-; R c to R q are each independently selected from H and C 1-3 alkyl; Alternatively, L1 is -Ar-L2-, where Ar is a 6-10 membered aryl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, -CN, C 1-6 alkyl and -CON(R c R d ); L2 is selected from a direct bond, -N(R e ), -O-, -N═C(R f ), -C(R g )═C(R h ), -OC(R i R j ), -N(R k )C(R l R m ), -N(R n )CO-, -N(R o )C(R p )═, -CON(R q ), or -CO-; R c to R q are each independently selected from H and C 1-3 alkyl; Alternatively, L1 is -Ar-L2-, where Ar is phenyl, which is optionally substituted by one, two or three substituents independently selected from halogen, -CN, C 1- 6-alkyl and -CON(R c R d ); L2 is selected from a direct bond, -N(R e )-, -O-, -N═C(R f )-, -C(R g )═C(R h )-, -OC(R i R j )-, -N(R k )C(R l R m )-, -N(R n )CO-, -N(R o )C(R p )═, -CON(R q )- or -CO-; R c to R q are each independently selected from H and C 1-3 alkyl; alternatively, L1 is -Ar-L2-, wherein Ar is phenyl, which is optionally substituted by one, two or three substituents independently selected from -F, -Cl, -Br, -CN, -CH3 and -CONH2; L2 is selected from a direct bond, -NH-, -O-, -N=CH-, -CH=CH-, -OCH2-, -NHCH2-, -NHCO- or -NHCH=; Alternatively, L1 is -Ar-L2-, where Ar is * represents the connection site with L2; L2 is selected from a direct bond, -NH-, -O-, -N=CH-, -CH=CH-, -OCH2-, -NHCH2-, -NHCO- or -NHCH=; Alternatively, L1 is -(CH2) p -, and p is 1, 2, 3 or 4; alternatively, L1 is -CH2-, -CH2CH2- or -CH2CH2CH2-.

5. The compound of formula (I) according to any one of claims 1-4, or its tautomer, enantiomer, diastereoisomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt, wherein, Ring A is selected from 6- to 14-membered aryl, 5- to 14-membered heteroaryl, 5- to 14-membered cycloalkyl or 5- to 14-membered heterocyclic group, and the 6- to 14-membered aryl, 5- to 14-membered heteroaryl, 5- to 14-membered cycloalkyl and 5- to 14-membered heterocyclic group are each optionally substituted by one or more substituents independently selected from -OH, -NO2, oxo, halogen, C 1-6 alkyl and C 1-6 haloalkyl; Alternatively, ring A is selected from 6- to 14-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered cycloalkyl or 5- to 10-membered heterocyclic group, and the 6- to 14-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered cycloalkyl and 5- to 10-membered heterocyclic group are each optionally substituted with 1, 2 or 3 substituents independently selected from -OH, -NO2, oxo, halogen, C 1-6 alkyl and C 1-6 haloalkyl; alternatively, ring A is selected from phenyl, naphthyl, phenanthryl, benzothienyl, benzothiazolyl, dihydronaphthyl, isoquinolyl, tetrahydroisoquinolyl and isoindolinyl, each of which is optionally substituted by one or two substituents independently selected from -OH, -NO2, oxo, -F, -Cl and -CF3; Alternatively, ring A is selected from 6. The compound of formula (I) according to claim 1, or a tautomer, enantiomer, diastereoisomer, isotopically-labelled compound, solvate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

7. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-6, or the compound shown below, or a tautomer, enantiomer, diastereoisomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, 8. The pharmaceutical composition according to claim 7, wherein the excipients include one or more of diluents, fillers, binders, wetting agents, absorption promoters, surfactants, lubricants and stabilizers.

9. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition is a pharmaceutical preparation, and the pharmaceutical preparation is selected from tablets, capsules, pills, granules, dripping pills, aerosols, sprays, nasal drops, inhalants, suppositories, enemas, intramuscular injection preparations, intravenous injection preparations, intra-articular injection preparations, ointments or patches.

10. Use of a compound of formula (I) according to any one of claims 1-6, or a compound as shown below, or a tautomer, enantiomer, diastereoisomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 7-9, in the manufacture of a medicament for the prevention or treatment of a disease associated with pyroptosis.

11. The use according to claim 10, wherein the diseases related to pyroptosis are autoimmune diseases, infectious and non-infectious inflammatory diseases caused by or related to pyroptosis.

12. The use according to claim 11, wherein the autoimmune disease includes rheumatoid arthritis, dyskeratosis, chronic proliferative dermatitis, neutrophilic dermatosis, Sjogren's syndrome, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, Guillain-Barré syndrome, colitis, ulcerative colitis, and Crohn's disease.

13. The use according to claim 11, wherein the infectious and non-infectious inflammatory diseases include sepsis, Gram-negative bacterial infectious diseases, viral infectious diseases, HIV, influenza A virus, Zika virus, hand, foot, and mouth disease caused by enterovirus 71, fungal infectious diseases, Candida albicans infection, Aspergillus fumigatus infection, atherosclerosis, neuromyelitis optica, infectious encephalitis, ischemic brain injury, ischemic stroke, epilepsy, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, type II diabetes, non-alcoholic fatty liver, alcoholic or non-alcoholic hepatitis, liver fibrosis, cirrhosis, acute kidney injury, traumatic brain injury, acute lung injury, chronic obstructive pulmonary disease, tracheitis or bronchitis, asthma, pulmonary fibrosis, lung cancer, preeclampsia, gestational diabetes, other adverse pregnancy complications, familial Mediterranean fever, cryopyrin-associated periodic syndromes (CAPS), age-related macular degeneration, gout, Muckle-Wells syndrome, and neonatal multi-system inflammatory disease.

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