RU2795512C2 - Sulphonylureas and related compounds and their use - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, a method for treatment, a method for inhibiting the activity of a biological target, and the use of a compound of formula (I). In formula (1): W is selected from O, S and Se; J is selected from S and Se; R₁ is selected from the group consisting of 5-membered and 6-membered heterocyclyl, each of which contains 1 to 4 heteroatoms selected from N, O and S, and each of which may be optionally substituted, where any optional substituent is independently selected from the group consisting of C_1-10 alkyl; C_3-6 cycloalkyl; C_1-9 hydroxyalkyl; C_1-10 alkoxy; C_2-10 alkenyl; C_2-10 alkynyl; C₆-C₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C_1-9 alkyl; amino; C_1-9 alkylamino; acyl; amido; CN; NO₂; N₃; CH₂OH; CONH₂; CONR₂R₂₅; CO₂R₂₄; CH₂OR₂₄; NHCOR₂₄; NHCO₂R₂₄; C_1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R₂₄SO; R₂₄SO₂; CF₃S; CF₃SO₂; and trialkylsilyl; where R₂₄ and R₂₅ are each independently selected from H or C_1-10 alkyl; R₂ is selected from 2,6-dialkylphenyl, 2,6-dialkyl-4-halophenyl, 2,6-dicycloalkylphenyl, 2,6-dicycloalkyl-4-halophenyl and

, where each occurrence of Y is independently selected from C, N, S and O, which may be optionally substituted, where any optional substituent is independently selected from the group consisting of C_1-10 alkyl; C_3-6 cycloalkyl; C_1-9 hydroxyalkyl; C_1-10 alkoxy; C_2-10 alkenyl; C_2-10 alkynyl; C₆-C₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C_1-9 alkyl; amino; C_1-9 alkylamino; acyl; amido; CN; NO₂; N₃; CH₂OH; CONH₂; CONR₂₄R₂₅; CO₂R₂₄; CH₂OR₂₄; NHCOR₂₄; NHCO₂R₂₄; C_1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R₂₄SO; R₂₄SO₂; CF₃S; CF₃SO₂; and trialkylsilyl; where R₂₄ and R₂₅ are each independently selected from H or C_1-10 alkyl; R₅ is selected from the group consisting of hydrogen, halo, cyano, amide, sulfonamide, acyl, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₅ cycloalkyl and C₁-C₆ alkoxy, all of which may be optionally substituted with halo, cyano or C₁-C₆ alkoxy; and as R₁ is directly bonded to J, so is R₂ directly bonded to the adjoining nitrogen atom via a carbon atom; provided that when W is O, J is S, and R₁ is a 5-membered heterocyclyl, then this 5-membered heterocyclyl does not contain any ring nitrogen atoms.

EFFECT: compound of formula (I) having the properties of an inhibitor of NLRP3 inflammasome activation, used for the treatment of diseases that respond to inhibition of NLRP3 inflammasome activation.

29 cl, 6 dwg, 10 tbl

Description

FIELD OF TECHNOLOGY

[0001] The present invention relates to the field of medical treatment and diagnosis of a disease. More specifically, the present invention relates to a novel sulfonylurea and related compounds and their use in the treatment or identification of a disease or condition responsible for modulating NLRP3 or inhibiting the activation of NLRP3 or related components of the inflammatory process.

BACKGROUND OF THE INVENTION

[0002] Any reference to prior art herein should not be construed as an admission that such prior art constitutes common knowledge in Australia or elsewhere.

[0003] The inflammasome with pyrine domain-containing protein 3 (NLRP3) of the NOD-like receptor (NLR) family is a component of the inflammatory process, and its abnormal activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.

[0004] NLRP3 is an intracellular signaling molecule that senses many pathogenic, environmental, and host-derived factors. Upon activation, NLRP3 binds to a speckled apoptosis-associated protein containing a caspase activation and recruitment domain (ASC). The ASC then polymerizes to form a large aggregate known as the ASC complex. The polymerized ASC in turn interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1β and IL-18 to their active forms and is involved in a type of inflammatory cell death known as pyroptosis. The ASC complex can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death.

[0005] Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are released from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic pathway of cell death, caspase-1 is also involved in the release of alarmin molecules such as IL-33 and the high mobility group protein box 1 (HMGB1). Caspase-1 also cleaves intracellular IL-III2, leading to its degradation and release of IL-1α. In human cells, caspase-1 can also direct the processing and secretion of IL-37. A number of other caspase-1 substrates, such as components of the cytoskeleton and the glycolytic pathway, may contribute to caspase-1 dependent inflammation.

[0006] NLRP3-dependent ASC complexes are released into the extracellular environment, where they can activate caspase-1, induce processing of caspase-1 substrates, and propagate inflammation.

[0007] Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to generate an immune response to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 act synergistically with IL-23 to induce IL-17 production by Th17 CD4 memory cells and γδ T cells in the absence of T cell receptor action. IL-18 and IL-12 also act synergistically to induce the production of IFN-γ from memory T cells and natural killer cells, driving the Th1 response.

[0008] Other intracellular pattern recognition receptors (ORRs) are also capable of forming inflammasomes. These include other members of the NLR family, such as NLRP1 and NLRC4, as well as non-NLR-type ORRs, such as double-stranded DNA sensors (dsDNA), melanoma-deficient protein 2 (AIM2), and interferon gamma-inducible protein 16 (IFI16). NLRP3-dependent IL-1β processing can also be activated in an indirect, non-canonical way after caspase-11.

[0009] Inherited CAPS diseases Mackle-Wales syndrome (MWS), familial cold autoinflammatory syndrome, and neonatal multisystem inflammatory disease are caused by gain-of-function mutations in NLRP3, which define NLRP3 as a critical component of the inflammatory process. NLRP3 is also implicated in the pathogenesis of a number of complex diseases, particularly those involving metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0010] The role of NLRP3 in diseases of the central nervous system is revealed, and it is shown that NLRP3 also influences lung diseases. In addition, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations have been made using Nlrp3 ^-/- mice, but there is also an emerging understanding of specific NLRP3 activation in these diseases. In type 2 diabetes, islet amyloid polypeptide deposition in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0011] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits the formation of IL-1β at micromolar concentrations in response to the activation of NLRP3, but not NLRC4 or NLRP1. Other previously characterized NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), although these agents have limited activity and are non-specific.

[0012] Current treatments for NLRP3-associated diseases include biological agents that act on IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the IL-1β neutralizing antibody canakinumab, and the soluble IL-1 decoy receptor rilonacept. These approaches have proven effective in the treatment of CAPS and these biological agents are being used in clinical trials for other IL-1β associated diseases.

[0013] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits the formation of IL-1β at micromolar concentrations in response to the activation of NLRP3, but not NLRC4 or NLRP1. Other previously characterized NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), although these agents have limited activity and are non-specific.

[0014] Several diarylsulfonylurea compounds have been identified as cytokine release inhibitory drugs (CRID) (Perregaux et al.; J. Pharmacol. Exp. Ther. 299, 187-197, 2001). IVCPs (CRID) are a class of diarylsulfonylurea compounds that inhibit post-translational processing of IL-1β. Posttranslational processing of IL-1β is accompanied by caspase-1 activation and cell death. IMCPs (CRID) block activated monocytes so that caspase-1 remains inactive and cell membrane-bound delay is maintained.

[0015] There is a need to provide compounds with improved pharmacological and/or physiological and/or physicochemical properties and/or those that provide a useful alternative to known compounds.

BRIEF DESCRIPTION OF THE INVENTION

[0016] According to a first aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where W is selected from O, S and Se;

J is selected from S and Se;

R ₁ is selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, all of which may be optionally substituted;

R ₂ is selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl, all of which may be optionally substituted; And

just as R ₁ is directly bonded to J, so R ₂ is directly bonded to the adjoining nitrogen atom via a carbon atom.

[0017] According to a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient.

[0018] A third aspect of the invention is a method of treating or preventing a disease, disorder or condition, comprising the step of administering an effective amount of a compound of the first aspect, or a pharmaceutically effective salt, solvate or prodrug thereof, or a pharmaceutical composition of the second aspect, to treat or prevent the disease, disorders or conditions.

[0019] A fourth aspect of the invention provides a compound of the first aspect, or a pharmaceutically effective salt, solvate, or prodrug thereof, or a pharmaceutical composition of the second aspect, for use in the treatment or prevention of a disease, disorder, or condition.

[0020] A fifth aspect of the invention provides for the use of a compound of the first aspect, or a pharmaceutically effective salt, solvate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease, disorder, or condition.

[0021] In one embodiment of the disease, the disorder or condition is responsive to inhibition of NLRP3 inflammasome activation.

[0022] In specific non-limiting embodiments of the above aspects, the disease, disorder or condition is a disease, disorder or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, respiratory system, central nervous system, is cancer or other malignant tumor and / or caused by a pathogenic factor or associated with it.

[0023] In a sixth aspect of the invention, there is provided a method for diagnosing a disease, disorder or condition in a mammal, comprising the step of administering a labeled compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically effective salt, solvate thereof or a prodrug, to a mammal, or into a biological sample derived from a mammal, to aid in the diagnosis of a disease, disorder, or condition in the mammal.

[0024] A seventh aspect of the invention is a method for modulating the activity of a biological target, comprising the step of exposing the biological target to a compound of the first aspect, or a pharmaceutically acceptable salt thereof.

[0025] The biological target may be selected from the group consisting of NLRP3 inflammasome, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33, and Th17 cells.

[0026] The various features and embodiments of the present invention referred to in the individual sections above refer, as appropriate, to other sections, mutatis mutandis. Therefore, the characteristics specified in one section may be combined with the characteristics specified in other sections, if possible.

[0027] Additional features and advantages of the present invention will be apparent from the following detailed description.

BRIEF DESCRIPTION OF GRAPHICS

[0028] In order that the invention may be easily understood and practiced, the preferred embodiments will be described by means of examples with reference to the attached drawings, in which:

[0029] FIG. 1A-1C are a series of graphical representations of plasma concentrations of a known sulfonylurea (MCC950) showing various dosage levels in mice; And

[0030] FIG. 2A-2C are a series of graphical representations of the plasma concentrations of the sulfonylurea of the present invention (MCC7840) depicting various dosage levels in mice.

DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention is based at least in part on the discovery that certain sulfonylureas and related compounds have advantageous properties and exhibit beneficial activity in inhibiting NLRP3 inflammasome activation and/or inhibition of IL-1β and/or IL-17 and/or IL -18 and/or IL-1α and/or IL-37 and/or IL-33, and interfere with or modulate the activity of T-helper cells such as Th17. In particular, the compounds of the present invention are useful in the treatment of a wide range of disorders in which the inflammatory process plays a role, or the NLRP3 inflammasome and/or IL-1β and/or IL-17 and/or IL-18 and/or IL-1α, and/or IL-37 and/or IL-33 and/or Th17 cells.

[0032] Data obtained from human CAPS patients and CAPS mouse models led the present inventors to believe that NLRP3 inhibition would be a better treatment compared to IL-1 targeting biologics, since inhibition of all NLRP3 dependent processes would be more effective than inhibition of a single NLRP3-dependent process, such as IL-1 signaling.

[0033] Individuals with CAPS (CAPS) exhibit deregulated release of both IL-1β and IL-18, and patients with CAPS (CAPS) treated with biologics that antagonize IL-1 have residual disease effects. Symptoms such as hyperostosis and joint deformity are not prevented by biologics that act on IL-1. In addition, symptoms involving the central nervous system, such as hearing loss, are difficult to control with biologics that act on IL-1, apparently not penetrating the central nervous system sufficiently. Studies in murine models of CAPS (CAPS) show that disruption in signaling involving either IL-1 or IL-18 alone is insufficient to block systemic inflammation, especially in older animals. In the severe CAPS model, only complete loss of caspase-1 signaling completely eliminated the disease.

[0034] Specific inhibition of NLRP3 by sulfonylurea compounds, such as those from the first aspect, can block all post-NLRP3 processes, including ASC complex formation and activation of caspase-8 and caspase-1. Therefore, NLRP3 inhibition will block all caspase-1 dependent processes such as IL-1β, IL-18 and IL-37 processing and secretion, gasdermin D cleavage, pyroptosis and release of IL-1α, IL-33 and HMGB. In addition, NLRP3 dependent extracellular release of the ASC complex will be blocked and caspase-8 dependent cleavage of pro-IL-1β and pro-IL-18 and apoptotic cell death will be prevented. Thus, specific inhibition of NLRP3 by the compounds from the first aspect will prevent a number of subsequent inflammatory signals and therefore should show a more effective anti-inflammatory therapy than IL-1 blockade alone.

[0035] Biologics that antagonize IL-1 block IL-1 derived from sources independent of NLRP3, such IL-1 produced by other inflammasomes (e.g., NLRC4, NLRP1, NLRP6, AIM2) and IL-1 formed by subsequent pathways, may be important for immune defense against pathogenic factors. For example, patients taking IL-1/IL-1 R antagonists exhibit an increased incidence of upper respiratory tract infections. Specific inhibition of NLRP3 by the present compounds may therefore exhibit less generalized immunosuppression compared to biologics that antagonize IL-1.

[0036] IL-1β and IL-18, derived from the Nlrp3/caspase-1 lineage, play critical roles in controlling the production of IL-17 by Th17 CD4 cells and γδ T cells. IL-1β and IL-18 act synergistically with IL-23 to induce IL-17 production by Th17 CD4 memory cells and γδ T cells in the absence of T cell receptor activation. IL-17, driven by IL-1, is also implicated in psoriasis, type I diabetes, rheumatoid arthritis, type 2 diabetes, atherosclerosis, obesity, gout, and, more recently, asthma.

[0037] As such, each of these diseases has been shown to involve activation of tissue macrophages, dendritic cells, or brain microglia driven by either soluble alarmins or incomplete phagocytosis of metabolites that accumulate extracellularly. NLRP3 responds to these events by releasing IL-1, triggering inflammation to clear harmful material. The result will be disease if this process becomes chronic or overactivated, which explains why so many diseases have shown NLRP3 incorporation. Therefore, inhibitors that act to prevent NLRP3 activation may be of benefit in IL-17-driven as well as IL-1-driven diseases.

[0038] As used herein, the terms "comprises", "comprising", "comprises", "comprising", or similar terms are intended to have the meaning of non-exclusive inclusion, such that a method or composition comprising a plurality of elements includes not only those elements, but may well include other items not listed.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as will generally be understood by those skilled in the art to which this invention pertains.

[0040] The term "pharmaceutically acceptable salt" in this context refers to salts that are toxicologically safe for systemic or localized administration, such as salts derived from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. The pharmaceutically acceptable salts may be selected from the group consisting of alkali and alkaline earth metal, ammonium, aluminum, iron, amine, glucosamine, chloride, sulfate, sulfonate, bisulfate, nitrate, citrate, tartrate, bitartrate, phosphate, carbonate, bicarbonate, malate, maleate, napsilate, fumarate, succinate, acetate, benzoate, terephthalate, palmoate, piperazine, pectinate and S-methylmethionine and the like.

[0041] The term "alkyl" refers to a straight chain or branched alkyl substituent containing, for example, from 1 to about 12 carbon atoms, preferably from 1 to about 9 carbon atoms, more preferably from 1 to about 6 carbon atoms, even more preferably from 1 to about 4 carbon atoms, even more preferably 1 to 2 carbon atoms. Examples of such substituents may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, isoamyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, 2 -methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The indicated number of carbons refers to the carbon skeleton and carbon branches, but does not include carbon atoms belonging to any substituents, for example, carbon atoms of an alkoxy substituent branched from the main carbon chain. Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo (eg, Cl, F, Br, and I); halogenated alkyl (eg CF ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ or CF ₂ CF ₃ ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate and phosphonate, as well as described by the definition of "optionally substituted".

[0042] The term "alkenyl" refers to optionally substituted unsaturated linear or branched hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 9 carbon atoms, more preferably 2 to 6 carbon atoms, and having at least one carbon -carbon double bond. Where appropriate, the alkenyl group may have a certain number of carbon atoms, for example, C ₂ -C ₆ alkenyl, including alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms in linear or branched arrangements. The indicated number of carbons refers to the carbon skeleton and carbon branches, but does not include carbon atoms belonging to any substituents. Examples of such substituents may be selected from the group consisting of ethenyl, propenyl, isopropenyl, butenyl, sec- and tert-butenyl, pentenyl, hexenyl, hept-l,3-diene, hex-l,3-diene, non-l, 3,5-triene and the like. Substituted alkenyl includes alkenyl substituted with one or more moieties selected from the group consisting of halo (eg, Cl, F, Br, and I); halogenated alkyl (eg CF ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ or CF ₂ CF ₃ ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate and phosphonate, as well as described by the definition of "optionally substituted".

[0043] The term "alkoxy" as used herein means straight or branched chain alkyl groups linked by an oxygen atom (ie, -O-alkyl), where alkyl is as described above. In particular embodiments, alkoxy refers to oxygen-linked groups containing from 1 to 10 carbon atoms ("C1-10 alkoxy"). In additional embodiments, alkoxy refers to oxygen-linked groups containing 1 to 8 carbon atoms ("C1-8 alkoxy"), 1 to 6 carbon atoms ("C1-6 alkoxy"), 1 to 4 carbon atoms ( "C1-4 alkoxy") or from 1 to 3 carbon atoms ("C1-3 alkoxy").

[0044] The terms "cycloalkyl" and "cycloalkenyl" refer to optionally substituted saturated and unsaturated monocyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyl or cycloalkenyl group may have a specified number of carbon atoms, for example C ₃ -C ₆ cycloalkyl or cycloalkenyl includes within its scope a carbocyclic group having 3, 4, 5 or 6 carbon atoms. Examples of such substituents may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Substituted cycloalkyl or cycloalkenyl includes substitutions with one or more moieties selected from the group consisting of halo (eg, Cl, F, Br, and I); halogenated alkyl (eg CF ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ or CF ₂ CF ₃ ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate and phosphonate, as well as described by the definition of "optionally substituted".

[0045] The term "alkylthio" in this context means a thio group with one or more alkyl substituents, where the definition of alkyl is given above.

[0046] the Term "amino" in this context means a fragment, which is represented by the structure NR ₂₃ and includes primary amines and secondary and tertiary amines, substituted by alkyl (ie, alkylamino). Thus, R ₂₃ may represent, for example, two hydrogen atoms, two alkyl moieties, or one hydrogen atom and one alkyl moiety.

[0047] The term "aryl" refers to a stable monocyclic, bicyclic, or tricyclic carbon ring with up to 8 members in each ring, where at least one ring is aromatic as defined by Hückel's 4n+2 rule. The term includes polycyclic systems containing saturated carbon rings or heteroaryl or heterocyclic groups in case at least one ring is aryl, as described.

[0048] The terms "aralkyl" and "arylalkyl" in this context means an aryl group, as defined above, connected to the molecule through an alkyl group, as defined above.

[0049] The term "heteroaryl" refers to an aryl group containing from one or more (in particular, from one to four) non-carbon(s) atom(s) (in particular, N, O or S) or a combination thereof, while the heteroaryl group is optionally substituted on one or more carbon or nitrogen atom(s). Heteroaryl rings may also be fused to one or more cyclic hydrocarbon, heterocyclic, aryl or heteroaryl rings. Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one heteroatom (eg, thiophenes, pyrroles, furans); 5-membered heteroaryls having two heteroatoms in the 1,2- or 1,3- positions (eg oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (eg triazoles, thiadiazoles); 5-membered heteroaryls having four heteroatoms (eg tetrazoles); 6-membered heteroaryls with one heteroatom (for example, pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (eg pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heteroaryls with three heteroatoms (for example, 1,3,5-triazine) and 6-membered heteroaryls with four heteroatoms. "Substituted heteroaryl" means a heteroaryl having one or more unrelated groups as substituents, and including those defined as "optionally substituted".

[0050] "Heterocyclyl" as used herein refers to a non-aromatic ring having 5 to 8 ring atoms, and of these atoms, 1 to 4 are heteroatoms. Heterocyclic rings may also be fused to one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings. Heterocyclic include partially and fully saturated heterocyclic groups. Heterocyclic systems can be linked to another moiety through any number of carbon atoms or radical heteroatoms, and can be either saturated or unsaturated. Non-limiting examples of heterocycles include C ₄ -C ₆ selenocycles, pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxynyl, oxazinyl, azepinyl, diazepinyl, triazepinyl, ox epinil and thiapinil, imidazolinil , thiomorpholinil and the like.

[0051] "Optionally substituted" in relation to a substituent group refers to substituent groups optionally substituted with one or more fragments, for example, selected from the group consisting of optionally substituted C1-10 alkyl (for example, optionally substituted C1-6 alkyl); optionally substituted C3-6 cycloalkyl (eg optionally substituted cyclopropyl); optionally substituted hydroxyalkyl; optionally substituted C1-10 alkoxy (eg, optionally substituted C1-6 alkoxy); optionally substituted C2-10 alkenyl; optionally substituted C2-10 alkynyl; optionally substituted C6-C12 aryl; aryloxy; optionally substituted heteroaryl; optionally substituted heterocyclyl; halo (eg, Cl, F, Br, and I); hydroxyl; halogenated alkyl (eg CF ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ CF ₃ , and CF ₂ CF ₃ ); amino (eg NH ₂ , NR ₁₂ H, and NR ₁₂ R ₁₃ ); alkylamino; arylamino; acyl; amido; CN; _NO2 ; N3; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C1-3 alkylthio; sulfate; sulfonic acid; esters of sulfonic acids such as alkyl or aralkylsulfonyl, including methanesulfonyl; phosphonic acid; phosphate; phosphonate; mono-, di-, or triphosphate esters; trityl or monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; and CF ₃ SO ₂ ; trialkylsilyl such as dimethyl tert-butylsilyl or diphenylmethylsilyl; and R ₂₄ and R ₂₅ are each independently selected from H or optionally substituted C1-10 alkyl, C1-6 alkyl or C1-4 alkyl.

[0052] In all cases where the range of the number of atoms in the structure is indicated (for example, C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₉ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₂ -C ₂₀ , C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₉ , C ₂ -C ₈ , C ₂ -C ₆ , C ₂ -C ₄ alkyl, alkenyl, etc.), specifically it is contemplated that any sub-range or individual number of carbon atoms falling within the specified range may also be used. So, for example, bringing the range of 1-12 carbon atoms (for example, C ₁ -C ₁₂ ), 1-9 carbon atoms (for example, C ₁ -C ₉ ), 1-6 carbon atoms (for example, C ₁ -C ₆ ) , 1-4 carbon atoms (for example, C ₁ -C ₄ ), 1-3 carbon atoms (for example, C ₁ -C ₃ ), or 2-8 carbon atoms (for example, C ₂ -C ₈ ), used in relation any chemical group (e.g. alkyl, etc.) mentioned in this context encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and/or 12 atoms carbon, if appropriate, as well as any of its subrange (for example, 1-2 carbons, 1-3 carbons, 1-4 carbons, 1-5 carbons, 1-6 carbons, 1-7 carbons, 1-8 carbons, 1-9 carbons, 1-10 carbons, 1-11 carbons, 1-12 carbons, 2-3 carbons, 2-4 carbons, 2-5 carbons, 2- 6 carbons, 2-7 carbons, 2-8 carbons, 2-9 carbons, 2-10 carbons, 2-11 carbons, 2-12 carbons, 3-4 carbons, 3-5 carbons carbon, 3-6 carbons, 3-7 carbons, 3-8 carbons, 3-9 carbons, 3-10 carbons, 3-11 carbons, 3-12 carbons, 4-5 carbons, 4-6 carbons, 4-7 carbons, 4-8 carbons, 4-9 carbons, 4-10 carbons, 4-11 carbons and/or 4-12 carbons, etc., if appropriate).

[0053] According to a first aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where W is selected from O, S and Se;

J is selected from S and Se;

R ₁ is selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl a, all of which may be optionally substituted;

R ₂ is selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocyclyl a, all of which may be optionally substituted; And

just as R ₁ is directly bonded to J, so R ₂ is directly bonded to the adjoining nitrogen atom via a carbon atom.

[0054] In one preferred embodiment, W is O.

[0055] In one preferred embodiment, J is S.

[0056] In a particularly preferred embodiment, W is O and J is S.

[0057] In one embodiment, R ₁ is selected from the group consisting of C ₅ or C ₆ cycloalkyl, 5-membered or 6-membered heteroaryl, bicyclic heteroaryl, wherein at least one ring is heteroaryl, phenyl, biphenyl, phenylheterocyclyl , 5-membered or 6-membered heterocyclyl, and heterocyclylcycloalkyl, all of which may be optionally substituted.

[0058] In certain embodiments, W is O, J is S, and R ₁ is selected from the group consisting of pyrazole, furan, tetrahydrofuran, tetrahydropyran, pyran, pyrrolidine, pyrrole, triazole, tetrazole, imidazole, pyridine, morpholine, piperazine, piperidine, substituted phenyl, phenylheteroaryl, phenylheterocyclyl, biphenyl, quinoline, isoquinoline, naphthyl, pyrazine and pyrimidine, all of which may be optionally substituted as needed.

[0059] In one embodiment, where W is O, J is S, and R ₁ is 2-furan or 2-thiophene, it is selected from unsubstituted 2-furan or 2,5-substituted furan and unsubstituted 2- thiophene or 2,5-substituted thiophene.

[0060] In one embodiment, where W is O, J is S, and R ₁ is 2,5-substituted furan or 2,5-substituted thiophene, then 2,5-substituted furan or 2,5- the substituted thiophene is not substituted with a tertiary alcohol group.

[0061] In certain embodiments, it has been found that when Ri is an unsubstituted furan, it has the ability to cross the blood-brain barrier at concentrations about 10 times greater than CRID3, a prior art sulfonylurea.

[0062] In the above embodiments, reference to a 2,5-substitution does not preclude the presence of additional ring substitutions, but merely indicates that the listed substitutions must be present. For example, 2,4,5-substitutions are considered to be within such terms.

[0063] Reference to 2-furan and 2-thiophene means that the ring is connected to the sulfur of the sulfonyl at position 2 of the ring, as shown below:

[0064] In one embodiment, R ₁ is a 5-membered heterocyclyl or heteroaryl, each of which may be optionally substituted, containing at least one, preferably at least two, ring heteroatoms selected from N, O, and S.

[0065] In certain embodiments, R ₁ is nitrogen-containing heterocyclyl or nitrogen-containing heteroaryl, each of which may be optionally substituted.

[0066] In one embodiment, R ₁ is a 5-membered nitrogen-containing heterocyclyl or a 5-membered nitrogen-containing heteroaryl, each of which may be optionally substituted.

[0067] In an embodiment, R ₁ is a 5-membered heterocyclyl or a 5-membered heteroaryl, each of which contains at least two ring nitrogen atoms and each of the rings of which may be optionally substituted.

[0068] In one embodiment, W is O, J is S, and R ₁ is selected from the group consisting of quinoline, isoquinoline, naphthyl, pyrazine, tetrazole, imidazole, pyrrolidine, pyrrole, tetrahydropyran, pyran, piperidine, piperazine, pyrazole, pyridine, pyrimidine and triazole, each of which may be optionally substituted.

[0069] In one embodiment, R ₁ and/or R ₂ may contain a selenocycle.

[0070] In one embodiment, R ₂ may be selected from bicyclic and tricyclic hydrocarbons, 5-, 6-, and 7-membered heterocycle or heteroaryl, each of whose rings may be optionally substituted, and substituted phenyl.

[0071] Suitably, the tricyclic hydrocarbon may be indacene.

[0072] In one embodiment, R ₂ can be selected from 5-, 6-, or 7-membered nitrogen-containing heterocycles, 6-membered nitrogen-containing heteroaryl, and fused cycloalkyl ring aryl.

[0073] In one embodiment of a compound of formula (I), W is O, J is S, and R ₁ may be selected from the group consisting of:

and for each of these groups R ₁ , R ₂ may be independently selected from the group consisting of:

[0074] In any embodiment of the first aspect, if J is S and W is O, and in combination with any of the above R ₁ groups, R ₂ may be selected from:

where each occurrence of Y is independently selected from C, N, S, and O, and which may be optionally substituted as needed;

R ₅ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from the group consisting of hydrogen, halo, cyano, amide, sulfonamide, acyl, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₆ alkoxy, all of which may optionally be substituted, as appropriate, with C ₁ -C ₆ halo, cyano or alkoxy; And

where R ₁₁ and R ₁₂ can be combined to form phenyl, a 5- or 6-membered oxygen-containing heterocycle, or a 5- or 6-membered nitrogen-containing heteroaryl, each of which may be optionally substituted;

R ₁₂ and R ₁₃ may be combined to form a 5- or 6-membered nitrogen-containing heteroaryl which may be optionally substituted; And

R ₁₄ and R ₁₅ may be combined to form a 5- or 6-membered cycloalkyl ring, phenyl, a 5- or 6-membered oxygen-containing heterocycle, or a 5- or 6-membered nitrogen-containing heteroaryl, each of which may be optionally substituted.

[0075] Suitably, each occurrence of Y is carbon and R ₅ is hydrogen or halo.

[0076] In one embodiment, R ₁₂ and R ₁₄ are hydrogen, R ₁₁ and R ₁₅ are C ₁ C ₆ alkyl, and R ₁₃ is hydrogen or halo.

[0077] Preferably R ₂ is selected from substituted or hydrogenated indacene, 2,6-dialkylphenyl, 2,6-dialkyl-4-halophenyl, 2,6-dicycloalkylphenyl, and 2,6-dicycloalkyl-4-halophenyl.

[0078] In certain preferred embodiments, and in combination with any R ₁ group described for any of the formulas of the first aspect, R ₂ is selected from hexahydroindacene, 2,6-diisopropylphenyl, 2,6-diisopropyl-4-chlorophenyl, 2, 6-dicyclopropylphenyl and 2,6-dicyclopropyl-4-chlorophenyl.

[0079] In one embodiment, W is O and J is S, R ₁ is heteroaryl, and R ₂ is

where each Y is CH and R ₅ is H or halogen, preferably R ₅ is H.

[0080] In one embodiment, W is O and J is S, R ₁ is heteroaryl, and R ₂ is

Where

R ₁₁ and R ₁₅ are C _1-6 alkyl, preferably isopropyl;

R ₁₂ and R ₁₄ are H,

R ₁₃ is H or halogen, preferably H or Cl.

[0081] In one embodiment, W is O and J is S, R ₁ is heteroaryl, and R ₂ is

where R ₁₁ and R ₁₅ are isopropyl, R ₁₂ and R ₁₄ are H, and R ₁₃ is H or Cl.

[0082] In specific embodiments, a compound of formula (I) may be selected from a compound of formula (Ia), (Ib), and (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where R ₁ is as described previously for any embodiment of formula (I).

[0083] In one embodiment of a compound of formula (Ia), (Ib), and (Ic), R ₁ is selected from the group consisting of pyrazole, furan, tetrahydrofuran, tetrahydropyran, pyran, pyrrolidine, pyrrole, triazole, tetrazole, imidazole, pyridine, morpholine, piperazine, piperidine, substituted phenyl, phenylheteroaryl, phenylheterocyclyl, biphenyl, quinoline, isoquinoline, naphthyl, pyrazine and pyrimidine, all of which may be optionally substituted as needed.

[0084] In one embodiment of a compound of formula (Ia), (Ib), and (Ic), R ₁ is selected from the group consisting of:

[0085] In one embodiment, a compound of formula (I) may be selected from a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where A, B, D and E are independently selected from C, N, O, S and Se, but at least one of them is C;

each dotted line may represent a link;

R ₂ is as previously defined for any embodiment of formula (I), (Ia), (Ib) or (Ic), or may be a fluorescent group;

each occurrence of R ₆ is independently selected from the group consisting of hydrogen, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylhydroxy, C ₃ -C ₆ cycloalkyl, alkylphenyl, phenyl, benzyl , C ₁ -C ₆ ester, C ₂ -C ₆ alkenyl, C ₁ -C ₆ trifluoroalkyl, and C ₁ -C ₆ alkoxy, each of which may be optionally substituted, or R ₆ may be a fluorescent group.

[0086] In one preferred embodiment of a compound of formula (II), at least one of A, B, D, and E is N (i.e., nitrogen).

[0087] In a further preferred embodiment of the compounds of formula (II), at least two of A, B, D, and E are N.

[0088] In one embodiment, compounds of formula (II) A, B, D and E are selected from N and C.

[0089] In an additional embodiment of the compound of formula (II), A is C and at least two of B, D and E are N.

[0090] In one embodiment, A, B, D, and E form a ring selected from pyrazole, imidazole, triazole, and tetrazole.

[0091] Preferably, A, B, D, and E form a ring selected from a pyrazole or imidazole ring, most preferably a pyrazole ring.

[0092] In one embodiment, A, B, D, and E and/or R ₂ may constitute a selenocycle.

[0093] In one embodiment, a compound of formula (I) may be selected from a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where R ₁₁ R ₁₂ R ₁₃ R ₁₄ and R ₁₅ are as defined above;

A, B, D and E are selected from N and C and at least two of A, B, D, and E are N;

each occurrence of R ₆ is independently selected from the group consisting of hydrogen, halide, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylhydroxy, C ₃ -C ₆ cycloalkyl, alkylphenyl, phenyl, benzyl , C ₁ -C ₆ ester, C ₂ -C ₆

alkenyl, C ₁ -C ₆ trifluoroalkyl and C ₁ -C ₆ alkoxy, each of which may be optionally substituted.

[0094] In one embodiment, a compound of formula (I) may be selected from a compound of formula (IIb), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where Y and R ₅ correspond to those defined above;

A, B, D and E are selected from N and C and at least two of A, B, D, and E are N;

each occurrence of R ₆ is independently selected from the group consisting of hydrogen, halide, cyano, C ₁ -C ₆ alkyl, C _{1 -C 6 alkylamino, C 1 -C 6 alkylhydroxy} , C ₃ -C ₆ cycloalkyl, alkylphenyl, phenyl, benzyl , C ₁ -C ₆ ester, C ₂ -C ₆ alkenyl, C ₁ -C ₆ trifluoroalkyl and C ₁ C ₆ alkoxy, each of which may be optionally substituted.

[0095] In one embodiment, the compound of formula (II) is selected from:

where R ₄₀ is selected from H, alkyl and halo;

R ₄₁ is selected from H and alkyl;

each occurrence of P is independently selected from C, O, or S; And

where each occurrence of R ₆ , if present, is independently selected from the groups defined for formula (II).

[0096] It will be appreciated that the R ₆ moiety emerging from the center of each ring may represent a group bonded to ring carbons or ring heteroatoms, as appropriate based on valence, or may not be present.

[0097] In one embodiment of formula (II), R ₆ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylhydroxy.

[0098] In certain embodiments of a compound of formula (II), for example, if R ₂ is hexahydroindacene and R ₁ is furan, R ₆ cannot be a tertiary alcohol substituent.

[0099] In one embodiment, the compound of the first aspect may be selected from a compound of formula (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where R ₂₁ is selected from H, alkyl, perhaloalkyl or hydroxyalkyl;

R ₂₂ is selected from H, alkyl, perhaloalkyl, C ₃ -C ₆ cycloalkyl, phenyl or benzyl;

R ₁₈ is H or halogen;

R ₁₆ and R ₁₇ are H or alkyl; or R ₁₆ and R ₁₇ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

R ₁₉ and R ₂₀ are H or alkyl; or R ₁₉ and R ₂₀ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

with the proviso that R ₂₁ and R ₂₂ are not both H; and provided that R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ do not simultaneously represent H.

[00100] In a preferred embodiment of the compounds of formulas (IIIa), (IIIb) and (IIIc):

R ₂₁ is selected from H, alkyl, perhaloalkyl or hydroxyalkyl; preferably C _1-6 -perhaloalkyl or hydroxylalkyl;

R ₂₂ is selected from H, alkyl, perhaloalkyl, C ₃ -C ₆ cycloalkyl, phenyl or benzyl;

R ₁₆ and R ₁₇ , together with the atoms to which they are attached, form a cyclopentyl ring;

R ₁₉ and R ₂₀ together with the atoms to which they are attached form a cyclopentyl ring;

R ₁₈ is H or halogen, preferably R ₁₈ is H; And

provided that R ₂₁ and R ₂₂ are not both H.

[00101] In another preferred embodiment of the compounds of formulas (IIIa), (IIIb) and (IIIc):

R ₂₁ is selected from H, alkyl, perhaloalkyl or hydroxyalkyl; preferably C _1-6 -perhaloalkyl or hydroxylalkyl;

R ₂₂ is selected from H, alkyl, perhaloalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl;

R ₁₆ and R ₂₀ are C _1-6 alkyl, preferably isopropyl;

R ₁₇ and R ₁₉ are H,

R ₁₈ is H or halogen; preferably R ₁₈ is H or Cl; And

provided that R ₂₁ and R ₂₂ are not both H.

[00102] In one embodiment, the compound of the first aspect may be selected from a compound of formula (IVa), (IVb) or (IVc) or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where R ₂₁ and R ₂₂ are selected from H, alkyl, perhaloalkyl, hydroxylalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl, or R ₂₁ and R ₂₂ , together with the carbon atoms to which they are attached, may form a cyclopentyl or cyclohexyl ring;

R ₁₈ is H or halogen;

R ₁₆ and R ₁₇ are H or alkyl; or R ₁₆ and R ₁₇ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

R ₁₉ and R ₂₀ are H or alkyl; or R ₁₉ and R ₂₀ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

with the proviso that R ₂₁ and R ₂₂ are not both H; And

provided that R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ do not simultaneously represent H.

[00103] In a preferred embodiment of the compounds of formulas (IVa), (IVb) and (IVc):

R ₂₁ and R ₂₂ are selected from H, alkyl, perhaloalkyl, hydroxyalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl; preferably perhaloalkyl and hydroxylalkyl are C _1-6 perhaloalkyl and hydroxylalkyl;

R ₁₆ and R ₁₇ , together with the atoms to which they are attached, form a cyclopentyl ring;

R ₁₉ and R ₂₀ together with the atoms to which they are attached form a cyclopentyl ring;

R ₁₈ is H or halogen; preferably R ₁₈ is H; And

provided that R ₂₁ and R ₂₂ are not both H.

[00104] In another preferred embodiment of the compounds of formulas (IVa), (IVb) and (IVc):

R ₂₁ and R ₂₂ are selected from H, alkyl, perhaloalkyl, hydroxyalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl; preferably perhaloalkyl and hydroxylalkyl are C _1-6 perhaloalkyl and hydroxylalkyl;

R ₁₆ and R ₂₀ are C _1-6 alkyl, preferably isopropyl;

R ₁₇ and R ₁₉ are H,

R ₁₈ is H or halogen; preferably R ₁₈ is H or Cl;

provided that R ₂₁ and R ₂₂ are not both H.

[00105] In one embodiment, the compound of the first aspect may be selected from a compound of formula (Va), (Vb) or (Vc) or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where R ₂₁ and R ₂₂ are selected from H, alkyl, perhaloalkyl, hydroxyalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl;

R ₁₈ is H or halogen;

R ₁₆ and R ₁₇ are H or alkyl; or R ₁₆ and R ₁₇ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

R ₁₉ and R ₂₀ are H or alkyl; or R ₁₉ and R ₂₀ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

with the proviso that R ₂₁ and R ₂₂ are not both H; And

provided that R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ do not simultaneously represent H.

[00106] In a preferred embodiment of the compounds of formulas (Va), (Vb) and (Vc):

R ₂₁ and R ₂₂ are selected from H, alkyl, perhaloalkyl, hydroxyalkyl, C ₃ -C ₆ -cycloalkyl, phenyl and benzyl; preferably perhaloalkyl and hydroxylalkyl are C _1-6 perhaloalkyl and hydroxylalkyl;

R ₁₆ and R ₁₇ , together with the atoms to which they are attached, form a cyclopentyl ring;

R ₁₉ and R ₂₀ together with the atoms to which they are attached form a cyclopentyl ring;

R ₁₈ is H or halogen; preferably R ₁₈ is H; And

provided that R ₂₁ and R ₂₂ are not both H.

[00107] In another preferred embodiment of the compounds of formulas (Va), (Vb) and (Vc):

R ₂₁ and R ₂₂ are selected from H, alkyl, perhaloalkyl, hydroxyalkyl, C ₃ -C ₆ -cycloalkyl, phenyl and benzyl; preferably perhaloalkyl and hydroxylalkyl are Q.6 perhaloalkyl and hydroxylalkyl;

R ₁₆ and R ₂₀ are C _1-6 alkyl, preferably isopropyl;

R ₁₇ and R ₁₉ are H;

R ₁₈ is H or halogen; preferably R ₁₈ is H or Cl; And

provided that R ₂₁ and R ₂₂ are not both H.

[00108] In one embodiment, the compound of the first aspect may be selected from a compound of formula (VIa) or (VIb) or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where R ₂₂ is selected from alkyl, perhaloalkyl, hydroxylalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl;

R ₁₈ is H or halogen;

R ₁₆ and R ₁₇ are H or alkyl; or R ₁₆ and R ₁₇ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

R ₁₉ and R ₂₀ are H or alkyl; or R ₁₉ and R ₂₀ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S; And

provided that R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ do not simultaneously represent H.

[00109] In a preferred embodiment of the compounds of formulas (VIa) and (VIb):

R ₂₂ is selected from alkyl, perhaloalkyl, hydroxylalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl; preferably perhaloalkyl and hydroxylalkyl are C _1-6 perhaloalkyl and hydroxylalkyl;

R ₁₆ and R ₁₇ , together with the atoms to which they are attached, form a cyclopentyl ring;

R ₁₉ and R ₂₀ together with the atoms to which they are attached form a cyclopentyl ring; And

R ₁₈ is H or halogen; preferably R ₁₈ is H.

[00110] In another preferred embodiment of the compounds of formulas (VIa) and (VIb):

R ₂₂ is selected from alkyl, perhaloalkyl, hydroxylalkyl, C ₃ -C ₆ cycloalkyl, phenyl and benzyl; preferably perhaloalkyl and hydroxylalkyl are C _1-6 -perhaloalkyl and hydroxylalkyl;

R ₁₆ and R ₂₀ are C _1-6 alkyl, preferably isopropyl;

R ₁₇ and R ₁₉ are H; And

R ₁₈ is H or halogen; preferably R ₁₈ is H or Cl.

[00111] In one embodiment, the compound of the first aspect may be selected from a compound of formula (VII) or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

where Q is O or S;

each occurrence of R ₃₀ is independently selected from alkyl, perhaloalkyl, hydroxylalkyl, C ₃ -C ₆ cycloalkyl, and alkylamino;

R ₁₈ is H or halogen;

R ₁₆ and R ₁₇ are H or alkyl; or R ₁₆ and R ₁₇ together with the carbon atoms to which they are attached form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N, O and S;

R ₁₉ and R ₂₀ are H or alkyl; or R ₁₉ and R ₂₀ , together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, said ring being saturated, partially unsaturated or unsaturated, said ring optionally containing one or two heteroatoms selected from N , O and S;

provided that R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ do not simultaneously represent H; And

provided that if Q is O, and R ₁₆ and R ₁₇ , and R ₁₉ and R ₂₀ separately, together with the corresponding carbon atoms to which they are attached, form a cyclopentyl ring, then R ₃₀ is not C _-3 hydroxylalkyl.

[00112] In a preferred embodiment of the compounds of formulas (VII):

Q is O or S;

each occurrence of R ₃₀ is independently selected from alkyl, perhaloalkyl, hydroxylalkyl, C ₃ -C ₆ cycloalkyl, and alkylamino; preferably C _1-6 alkyl, perhaloalkyl, hydroxylalkyl and alkylamino;

R ₁₆ and R ₁₇ , together with the atoms to which they are attached, form a cyclopentyl ring;

R ₁₉ and R ₂₀ together with the atoms to which they are attached form a cyclopentyl ring; And

R ₁₈ is H or halogen; preferably R ₁₈ is H and

with the proviso that if Q is O, then R ₃₀ is not C _-3 -hydroxyalkyl.

[00113] In another preferred embodiment of the compounds of formulas (VII):

Q is O or S;

each occurrence of R ₃₀ is independently selected from alkyl, perhaloalkyl, hydroxylalkyl, C ₃ -C ₆ cycloalkyl, and alkylamino; preferably C _1-6 alkyl, perhaloalkyl, hydroxylalkyl and alkylamino;

R ₁₆ and R ₂₀ are C _1-6 alkyl, preferably isopropyl;

R ₁₇ and R ₁₉ are H; And

R ₁₈ is H or halogen; preferably R ₁₈ is H or Cl.

[00114] The compounds of the first aspect, and in particular formulas (II) to (VI), provide a number of unexpected advantages over prior art sulfonylureas, these advantages may be selected from: improved microsomal stability; improved absorption; reduced exposure to Pgp (P-glycoprotein); reduced binding to plasma proteins; increased half-life; improved oral bioavailability; improved AUC; improved Cmax; reduced inhibition of Syr; improved inhibition of NLRP3 inflammasome activation and improved solubility. Solubility and certain other improvements may be particularly noticeable in an aquatic environment.

[00115] In one embodiment, the compounds of the first aspect provide improved pharmacokinetic characteristics. CRID3, a known sulfonylurea, has a half-life of 3.2 hours (mouse), which can result in significant residual levels from once or twice daily dosing if the half-life is extrapolated to humans. The compounds from the first aspect may differ, for example, in their protein binding, metabolism and oral availability.

[00116] In particular, it has been found that the compounds of the first aspect, especially those in which A, B, D and E form a 5-membered nitrogen-containing heteroaryl, e.g. a pyrazole ring, are less metabolically labile and/or have improved pharmacokinetic properties compared to the otherwise structurally similar furans and thiophenes known in the prior art.

[00117] In one embodiment, the compounds of the first aspect have a tPSA of less than 90 A ² .

[00118] One advantage of the present compounds from the first aspect is that they can exhibit a significantly reduced polar surface area compared to prior art sulfonylureas such as CRID3.

[00119] In one additional embodiment, the compounds from the first aspect have a tPSA of less than 90 A ² and a molecular weight of less than 405.

[00120] The absence of a tertiary alcohol group in some embodiments leads to an increase in plasma concentration and contributes to a decrease in both MW and polar surface area, thereby giving an overall improvement in penetration through the blood-brain barrier.

[00121] In any of the embodiments described for the compounds of the first aspect, including compounds of formula (I) - (VII), one or more substituent or optional substitution hydrogens may be deuterated.

[00122] Deuterated analogs of the compounds of the present invention may exhibit increased metabolic stability due to the kinetic isotope effect.

[00123] In one embodiment, the compound from the first aspect is selected from the group consisting of:

[00124] In certain embodiments, the compounds of the first aspect may exhibit improved properties over known antidiabetic drugs. Examples of such compounds may include the following:

[00125] These four compounds of formula (I) can be considered as very potent versions of currently existing antidiabetic drugs based on sulfonylurea. The IC50 data presented in the experimental part reflect this point of view. It is believed that known drugs do not affect NLRP3 to any therapeutically significant extent, and therefore very high doses must be used to obtain any significant effect on the NLRP3 inflammasome. The four compounds presented above and others from the first aspect exhibit advantageously improved properties in significantly lowering the IC ₅₀ compared to the NLRP3 inflammasome and additionally have advantages not realized by existing antidiabetic and other drugs associated with NLRP3 inhibition, such as improved wound healing and other benefits described in this document.

[00126] In any one or more embodiments of the first aspect, and with respect to any one or more of the compounds of formula (I)-(VII), the compound is an inhibitor of NLRP3 inflammasome activation.

[00127] Therefore, it should be understood that the present invention provides sulfonylurea and related drugs exhibiting significantly lower NLRP3 IC ₅₀ values in a cell assay using MMCH (HMDM, human monocyte-derived macrophage) (see experimental section for protocols) than the aforementioned comparison compounds. Currently known anti-diabetic drugs are not potent NLRP3 inflammasome inhibitors at therapeutic doses and would require dosages outside the recommended levels to achieve any such inhibition. The presented compounds allow the use of lower doses and therefore limit the risk of toxic effects.

[00128] In an additional embodiment, one or more of the compounds from the first aspect may be useful as photoswitchable compounds that can be used in a number of applications, including, but not limited to, insulin secretion. Such compounds, in one embodiment, may be selected from the group consisting of:

where R ₂ is as defined in any one or more embodiments of the compounds of formula (I)-(VII) described previously.

[00129] In certain embodiments of the invention, one or more compounds from the first aspect may be suitable for use as probes, such as photoaffinity probes, or as reaction intermediates that can be modified either directly or through a linking moiety to obtain biotinylated, fluorescent or photoaffinity probes, including but not limited to those shown below:

where R ₂ corresponds to defined in any one or more embodiments described for formula (I)-(VII).

[00130] In particular, compounds such as probes or reaction intermediates may be selected from the following:

[00131] It should be understood that the compounds of the first aspect may be modified or derivatized by means well known in the art to allow binding to a molecule, such as biotin, or a fluorescent group or photoaffinity tag, as shown with some of the compounds above.

[00132] In one embodiment, the compound of formula (I) or (II) does not contain a structure selected from the groups shown below, connected to a sulfonyl moiety (i.e., as an R ₁ group):

[00133] In one embodiment, if the compound of the first aspect, including any compound of formula (I)-(VII), has J as S, W as O, and R ₂ is selected from hexahydroindacene, 2,6-diisopropylphenyl, and 2,6-diisopropyl-4-chlorophenyl, then R ₁ is not one of 2,4-disubstituted furan, 2,4-disubstituted thiophene, 2,5-disubstituted furan and 2,5-disubstituted thiophene.

[00134] In one embodiment, if the compound of the first aspect, including any compound of formula (I)-(VII), has J as S, W as O, and R ₁ is selected from substituted triazole, thiadiazole, 4-substituted pyridine and 1,2-disubstituted imidazole, then R ₂ is not unsubstituted phenyl, 2- or 4-chlorophenyl or 3,4-substituted phenyl substituted with one or more of halo, trifluoromethyl, nitro or thiomethyl.

[00135] In one embodiment, if the compound of the first aspect, including any compound of formula (I)-(VII), has J as S, W as O, and R ₁ is selected from substituted triazole, thiadiazole, benzothiazole, and substituted pyrimidine, then R ₂ is not thiophene, 3-chlorophenyl, 4-ethoxyphenyl, substituted benzimidazole or substituted benzothiazole.

[00136] In one embodiment, if a compound of the first aspect, including any compound of formula (I)-(VII), has J as S, W as O, and R ₁ is an ethoxy-substituted benzothiazole, then R ₂ is not 2,6-diisopropylphenyl.

[00137] In one embodiment, if a compound of the first aspect, including any compound of formula (I)-(VII), has J as S, W as O, and R ₁ is selected from benzofuran, benzothiophene, and indole, then R ₂ is not 3- or 3,4-halo-, methyl-, ethyl-, or trifluoromethyl-substituted phenyl.

[00138] In one embodiment, if a compound of the first aspect, including any compound of formula (I)-(VII), has J as S, W as O, and R ₂ is a substituted pyrimidine, then Ri is not pyrazole , substituted with an ester or carboxy.

[00139] In one embodiment, if a compound of the first aspect, including any compound of formula (I)-(VII), has J as S and W as O, then the carbon atom from R ₂ that is directly bonded to the urea nitrogen , is not a carbonyl carbon.

[00140] In one embodiment, if a compound of the first aspect, including any compound of formula (I)-(VII), has J as S and W as O, then the carbon atom from R ₂ that is directly bonded to the urea nitrogen , is a carbon of an aryl, heteroaryl, or heterocyclic ring.

[00141] In one embodiment, if the compound of the first aspect, including any compound of formula (I)-(VII), has J as S and W as O, R ₂ is substituted phenyl and Ri is pyrazole, then pyrazole R ₁ is not substituted with an aryl or heteroaryl group.

[00142] In one embodiment, if the compound of the first aspect, including any compound of formula (I)-(VII), has J as S, W as O, and R ₁ is pyrazole and the sulfonylurea linker is branched at the 4 position , the pyrazole is not fused at positions 1 and 5 by a 6-membered heterocycle to form a pyrazolopyrimidine derivative.

[00143] In one embodiment, the compound of the first aspect, including any compound of formula (I)-(VII), is not a compound selected from the group consisting of:

1. 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonyl]-urea;

2. 1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl ]-urea;

3. 1-(1,2,3,5,6,7-Hexahydro-4-aza-e-indacen-8-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan -2-sulfonyl]-ureas;

4. 1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl ]-urea;

5. 1-(4-[1,3]Dioxolan-2-yl-furan-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-e-indacen-4-yl) - urea;

6. 1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-ureas;

7. 1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea;

8. 1-(4-Acetyl-thiophene-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-ureas;

9. 1-(1H-Benzimidazole-5-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-ureas;

10. 1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl ]-urea;

11. 1-(8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan -2-sulfonyl]-ureas;

12. 1-(4-Acetyl-furan-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-ureas;

13. 1-(8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan -2-sulfonylureas;

14. 1-(4-Fluoro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonyl]-ureas; And

15. 1-(6-Fluoro-1H-benzimidazole-5-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indcen-4-yl)-ureas;

16. 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(1H-indole-6-sulfonyl)-ureas;

17. 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(5-fluoro-1H-indole-6-sulfonyl)-ureas;

18. 1-[1,2,3,5,6,7-Hexahydro-s-indacen-4u-yl)-3-(1H-indole-6-sulfonyl)-ureas;

19. 1-(5-Fluoro-1H-indole-6-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-5-indacen-4-yl)-ureas;

20. 1-[4-Chloro-2,6-diisopropyl-phenyl]-3-[2-fluoro-5-(2-methyl-(1,3)dioxolan-2-yl)-benzenesulfonyl]-urea;

21. 3-[3-[4-Chloro-2,6-diisopropyl-phenyl]-ureidosulfonyl]-N-methyl-benzenesulfonamide;

22. 1-[2-Fluoro-5-(2-methyl-(1,3)dioxolan-2-yl)benzenesulfonyl]-3-1,2,3,5,6,7-hexahydro-indacen-4- silt)-urea;

23. 3-[3-(1,2,3,5,6,7-Hexahydro-5-indacen-4-yl)-ureidosulfonyl]-N-methyl-benzenesulfonamide;

24. 4-(1-Hydroxy-1-methyl-ethyl)-furan-2-sulfonamide.

[00144] In some embodiments of the present invention, therapeutically inactive prodrugs of the compounds of the first aspect are provided. Prodrugs are compounds which, when administered to a mammal, are converted in whole or in part to a compound of the present invention. In most embodiments, prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to active drug molecules to exert a therapeutic effect. Any of the compounds described herein may be administered as a prodrug to increase the potency, bioavailability, or stability of the compound, or to otherwise alter the properties of the compound. Representative examples of prodrugs include compounds having biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated and/or dephosphorylated to give the active compound.

[00145] A number of prodrug ligands are known. In general, alkylation, acylation, or other lipophilic modification of one or more heteroatoms of a compound, such as a free amine or carboxylic acid residue, can reduce polarity and allow compounds to pass into cells. Examples of substituent groups that may replace one or more hydrogen atoms on the free amine and/or carboxylic acid moiety include, but are not limited to, the following: aryl; steroids; carbohydrates (including sugars); 1,2-diacylglycerol; alcohols; acyl (including lower acyl); alkyl (including lower alkyl); a sulfonic acid ester (including alkyl or arylalkylsulfonyl such as methanesulfonyl and benzyl, where the phenyl group is optionally substituted with one or more substituents provided in the definition of aryl provided herein); optionally substituted arylsulfonyl; lipids (including phospholipids); phosphatidylcholine; phosphocholine; amino acid residues or derivatives; acyl residues or derivatives of amino acids; peptides; cholesterols or other pharmaceutically acceptable leaving groups which, when administered in vivo, provide a free amine. Any of these fragments can be used in combination with the present active agents to achieve the desired effect.

[00146] In some embodiments, compounds with one or more chiral centers are contemplated. Although racemic mixtures of the compounds of the present invention may be active, selective and bioavailable, isolated isomers may also be of interest.

[00147] The compounds of the first aspect may contain chiral centers, which may have either the (R) or (S) configuration, or which may contain a mixture of both. Accordingly, the present invention also includes stereoisomers of the compounds described herein, where applicable, either singly or mixed in any ratio.

Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and resolved using conventional techniques, either by reacting enantiomeric starting materials or by isomer separation of the compounds and prodrugs of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers at the double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either alone or in admixture with other isomers of the compounds described herein.

[00148] Various methods are known in the art for obtaining optically active forms and determining activity. Such methods include the standard tests described herein and other similar tests well known in the art. Examples of methods that can be used to obtain optical isomers of the compounds of the present invention include the following:

i) physical separation of crystals, in which macroscopic crystals of the individual enantiomers are manually separated. This technique can be applied in particular if crystals of the individual enantiomers exist (ie the material is a conglomerate) and the crystals are visually distinguishable;

ii) simultaneous crystallization, in which the individual enantiomers crystallize separately from the solution of the racemate, which is possible only if the latter is a conglomerate in the solid state;

iii) enzymatic separations, in which the racemate is separated partially or completely due to different rates of reaction of enantiomers with the enzyme;

iv) enzymatic asymmetric synthesis, a synthetic methodology in which at least one synthetic step uses an enzymatic reaction to produce an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

v) chemical asymmetric synthesis, in which the desired enantiomer is synthesized from an achiral precursor under conditions that create an asymmetry (ie, chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomeric separations in which a racemic compound is reacted with an enantiomerically pure reagent (chiral excipient) that converts individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now more pronounced structural differences, and the chiral auxiliary is then removed to obtain the desired enantiomer;

vii) asymmetric first and second order transformations, in which the diastereomers from the racemate are brought into equilibrium so that the diastereomer from the desired enantiomer dominates in solution, or in which the preferential crystallization of the diastereomer from the desired enantiomer shifts the equilibrium such that essentially all of the material is eventually converted to a crystalline diastereomer from the desired enantiomer. The desired enantiomer is then isolated from the diastereomers;

viii) kinetic separations involving partial or complete resolution of the racemate (or additional resolution of a partially resolved compound) based on unequal reaction rates of enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors in which the desired enantiomer is obtained from non-chiral starting materials and in which the stereochemical purity is not or only minimally altered during the synthesis;

x) chiral liquid chromatography, in which the enantiomers of the racemate are separated in the liquid mobile phase due to their different interactions with the stationary phase. The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral material to induce different interactions;

xi) chiral gas chromatography, in which the racemate is evaporated and the enantiomers are separated due to their different interactions in the gaseous mobile phase with a column containing a stationary phase of a non-racemic chiral adsorbent;

xii) extraction with chiral solvents, in which enantiomers are separated due to the preferential dissolution of one enantiomer in a particular chiral solvent; And

xiii) transport across chiral membranes, in which the racemate is brought into contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains a racemate, and a driving force, such as a concentration or pressure difference, causes preferential transport across the membrane barrier. The separation occurs as a result of the non-racemic chiral nature of the membrane, allowing only one enantiomer of the racemate to pass through.

[00149] The compound may optionally be provided in a composition that is enantiomerically enriched, such as a mixture of enantiomers in which one enantiomer is present in excess, in particular up to 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, including 100%.

[00150] The terms (R), (S), (R,R), (S,S), (R,S) and (S,R) in this context mean that the composition contains a greater proportion of the specified isomer of the compound compared to with other isomers. In a preferred embodiment, these terms indicate that the composition contains at least 90% by weight of the indicated isomer and 10% by weight or less of one or more other isomers; or more preferably about 95% by weight of said isomer and 5% or less of one or more other isomers. In some embodiments, the composition may contain at least 99% by weight of the specified isomer and 1% or less by weight of one or more other isomers, or may contain 100% by weight of the specified isomer and 0% by weight of one or more other isomers. These percentages are based on the total amount of the compound of the present invention present in the composition.

[00151] The compounds of the first aspect can be used alone or as a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or isomer as needed. For example, the compound may be provided as a pharmaceutically acceptable salt. If used, the salt of the drug compound must be both pharmacologically and pharmaceutically acceptable, but pharmaceutically unacceptable salts may conveniently be used to prepare the free active compound or its pharmaceutically acceptable salts and are not excluded from the scope of the present invention. Such pharmacologically and pharmaceutically acceptable salts can be obtained by reacting the drug with an organic or inorganic acid using standard methods detailed in the literature.

[00152] Examples of pharmaceutically acceptable salts of compounds useful in accordance with the invention include acid addition salts. However, salts of pharmaceutically unacceptable acids may be useful, for example, in the preparation and purification of compounds. Suitable acid addition salts according to the present invention include organic and inorganic acids. Preferred salts include those derived from hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic and isethionic acids. Other suitable acid addition salts include propionic acid, glycolic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, and the like. Specific examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-diolates, hexine-1,6-diolates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates, phenyl acetates, phenyl propionates, phenyl butyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane sulfonates, propane sulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[00153] The acid addition salt can be converted back to the free base by exposure to a suitable base. Preparation of basic salts of acidic moieties that may be present in a compound or prodrug useful in the present invention may be carried out in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, triethylamine, or the like.

[00154] Esters of the compounds of the active substances of the present invention can be obtained through the functionalization of hydroxyl and/or carboxyl groups that may be present in the molecular structure of the compounds. Amides and prodrugs can also be prepared using methodologies known to those skilled in the art. For example, amides can be prepared from esters using suitable amine reagents, or they can be prepared from an anhydride or acid chloride by reaction with ammonia or a lower alkylamine. In addition, esters and amides of the compounds of the present invention can be prepared by reaction with a carbonylating agent (e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesulfonyl chloride) and a suitable base (e.g., 4-dimethylaminopyridine, pyridine, triethylamine, potassium carbonate) in a suitable organic solvent (for example, tetrahydrofuran, acetone, methanol, pyridine, N,N-dimethylformamide) at a temperature of from 0°C to 60°C. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by the individual's metabolic system. Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of the present invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[00155] In the case of solid compositions, it is understood that the compounds used in the methods of the present invention may exist in various forms. For example, the compounds may exist in stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.

[00156] If the compound useful as the active ingredient of the invention is a base, the desired salt may be prepared by any suitable method known in the art, including the treatment of the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid acid and galacturonic acid, alpha hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. .

[00157] If the compound described herein as an active ingredient is an acid, the desired salt may be prepared by any suitable method known in the art, including treating the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium. , magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[00158] According to a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) to (VII), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient.

[00159] Suitably, the pharmaceutically acceptable carrier, diluent, and/or excipient may be or include one or more of diluents, solvents, pH buffers, binders, fillers, emulsifiers, disintegrants, polymers, lubricants, oils, fats, waxes , coatings, viscosity modifiers, glidants and the like.

[00160] Salt forms of the compounds of the present invention may be particularly useful due to their improved solubility.

[00161] In one embodiment, the pharmaceutical composition includes a cyclodextrin.

[00162] The cyclodextrin may be selected from alpha, beta or gamma cyclodextrins.

[00163] In one embodiment, the cyclodextrin is selected from methylcyclodextrin, hydroxypropylcyclodextrin, and sulfobutyl ether cyclodextrin.

[00164] Cyclodextrins have been found to provide significant advantages in the manufacturing and delivery of the compounds of the present invention.

[00165] Cyclodextrin formulations, such as, for example, one or more of the compounds of the present invention with hydroxypropyl-beta-cyclodextrin or methyl-beta-cyclodextrin, may have applications in cholesterol sequestration/lowering cholesterol levels or through NLRP3 inhibition for non-alcoholic steatohepatitis (NASH). ), alcoholic liver disease, atherosclerosis, and Alzheimer's disease (AD).

[00166] Diluents may include one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like. The binders may include one or more of povidone, starch, stearic acid, gums, hydroxypropyl methylcellulose, and the like. The disintegrants may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like. Solvents may include one or more of ethanol, methanol, isopropanol, chloroform, acetone, methyl ethyl ketone, methylene chloride, water, and the like. Lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate, and the like. The glidant may be one or more of colloidal silica, talc or cornstarch and the like. Buffers may include, but are not limited to, phosphate buffers, borate buffers, and carbonate buffers. Fillers may include one or more gels, including, but not limited to, gelatin, starch, and synthetic polymer gels. Coatings may include one or more of film formers, solvents, plasticizers, and the like. Suitable film formers can be one or more of hydroxypropylmethylcellulose, methylhydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, povidone, sodium carboxymethylcellulose, polyethylene glycol, acrylates, and the like. Suitable solvents may be one or more of water, ethanol, methanol, isopropanol, chloroform, acetone, methyl ethyl ketone, methylene chloride, and the like. The plasticizers may be one or more of propylene glycol, castor oil, glycerin, polyethylene glycol, polysorbates, and the like.

[00167] Reference is made to Handbook of Excipients 6 ^th Edition, Eds. Rowe, Sheskey & Quinn (Pharmaceutical Press), which provides non-limiting examples of excipients that may be useful according to the invention.

[00168] It should be understood that the choice of pharmaceutically acceptable carriers, diluents and/or excipients will depend at least in part on the mode of administration of the composition. By way of example only, the composition may take the form of a tablet, capsule, caplet, powder, injection liquid, suppository, slow release formulation, osmotic pump formulation, or any other form that is effective and safe to administer.

[00169] Suitably, the pharmaceutical composition is for the treatment or prevention of a disease, disorder or condition in a mammal.

[00170] A third aspect of the invention is a method for treating or preventing a disease, disorder or condition, comprising the step of administering an effective amount of a compound of formula (I)-(VII), or a pharmaceutically effective salt, solvate or prodrug thereof, or a pharmaceutical composition of the second aspect to treating or preventing the disease, disorder or condition.

[00171] A fourth aspect of the invention provides a compound of formula (I)-(VII), or a pharmaceutically effective salt, solvate, or prodrug thereof, or a pharmaceutical composition of the second aspect, for use in the treatment or prevention of a disease, disorder, or condition.

[00172] A fifth aspect of the invention provides for the use of a compound of formula (I)-(VII), or a pharmaceutically effective salt, solvate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease, disorder, or condition.

[00173] As commonly used in this context, the terms "administration" or "administration" and the like describe the administration of a compound or composition to a mammal, for example, via a specific route or medium. Routes of administration may include topical, parenteral, and enteral, which include, but are not limited to, oral, buccal, sublingual, nasal, anal, gastrointestinal, subcutaneous, intramuscular, and intradermal routes of administration.

[00174] By "treat" or "treatment" is meant the administration of a compound or composition to a subject for the purpose of at least improving, reducing, or suppressing existing signs or symptoms of a disease, disorder, or condition experienced by the subject.

[00175] By "prevention", "prophylaxis", or "prophylactic" is meant the prophylactic administration of a composition to a subject who is not showing signs or symptoms of a disease, disorder, or condition, but who is expected or likely to exhibit such signs or symptoms in the absence of prophylaxis. Prophylactic treatment may at least reduce or partially correct the expected symptoms or signs.

[00176] As used herein, an "effective amount" refers to administering an amount of the appropriate compound or composition sufficient to prevent the onset of symptoms of the condition being treated, or to cause the symptoms to cease to worsen, or to treat and correct or at least reduce the severity of the symptoms. The effective amount will vary in a manner understood by one of ordinary skill in the art with the age, sex, weight of the patient, and so on. A suitable dosage or dosing regimen can be determined by routine examination.

[00177] In this context, the terms "subject" or "individual" or "patient" can refer to any subject, in particular, a vertebrate subject, and even more specifically, a mammalian subject for which treatment is required. Suitable vertebrate animals include, but are not limited to, primates, birds, farm animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), domestic animals (eg cats, dogs) and captured wild animals (eg foxes, deer, dingoes). A preferred subject is a human in need of treatment for the disease, disorder or condition described herein. However, it will be understood that the above terms do not mean that symptoms are necessarily present.

[00178] In one specific embodiment, the disease, disorder, or condition is one that responds to inhibition of NLRP3 inflammasome activation.

[00179] In this embodiment, the compound of the first aspect, or a pharmaceutically effective salt, solvate, or prodrug thereof, is a specific inhibitor of NLRP3.

[00180] In an additional embodiment, the disease, disorder, or condition is responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33, and Th17 cells.

[00181] In one embodiment, the modulation is inhibition of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, and IL-33.

[00130] In one embodiment, Th17 cells are modulated by inhibiting the production and/or secretion of IL-17.

[00182] In general embodiments, the disease, disorder, or condition is a disease, disorder, or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, respiratory system, central nervous system, cancer, or other malignant tumor and/or caused by or associated with a pathogenic factor.

[00183] It should be understood that these general implementation options, defined according to the broad categories of diseases, disorders and conditions, are not mutually exclusive. In this regard, any particular disease, disorder, or condition may be classified according to more than one of the aforementioned general implementation options. A non-limiting example is type I diabetes, which is an autoimmune and endocrine disorder.

[00184] In one embodiment, the implementation of the disease, disorder or condition refers to the immune system. In specific embodiments, the disease, disorder, or condition is an inflammatory disease, disorder, or condition, or an autoimmune disease, disorder, or condition.

[00185] In one embodiment, the disease, disorder, or condition is in the skin.

[00186] In one embodiment, the disease, disorder, or condition is related to the cardiovascular system.

[00187] In one embodiment, the disease, disorder, or condition is a cancer, tumor, or other malignancy. As used herein, cancers, tumors, and malignancies refer to diseases, disorders, or conditions, or cells or tissues associated with diseases, disorders, or conditions, characterized by impaired or abnormal cell proliferation, differentiation, and/or migration, often accompanied by impaired or abnormal molecular a phenotype that includes one or more genetic mutations or other genetic changes associated with tumorigenesis, expression of tumor markers, loss of expression or activity of a tumor suppressor expression, and/or impaired or abnormal expression of a cell surface marker. In general embodiments, cancers, tumors, and malignancies may include, but are not limited to, sarcomas, lymphomas, leukemias, solid tumors, blastomas, gliomas, carcinomas, melanomas, and metastatic cancers. A more comprehensive listing of cancers and malignancies can be found on the National Cancer Institute website http://www.cancer.gov/cancertopics/types/alphalist.

[00188] In one embodiment, the disease, disorder, or condition is related to the renal system.

[00189] In one embodiment, the disease, disorder, or condition is of the gastrointestinal tract.

[00190] In one embodiment, the disease, disorder, or condition is related to the respiratory system.

[00191] In an additional embodiment, the disease, disorder or condition refers to the endocrine system.

[00192] In one embodiment, the disease, disorder or condition refers to the central nervous system (CNS).

[00193] In one embodiment, the disease, disorder, or condition is caused by or associated with a pathogen. The pathogen may be a virus, bacterium, protozoan, worm or fungus, or any other organism capable of infecting a mammal, although not limited to them.

[00194] Non-limiting examples of viruses include influenza virus, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus (HIV), alphavirus such as chikungunya and Ross River virus, flaviviruses such as dengue virus, Zika virus and papillomavirus, although not limited to them.

[00195] Non-limiting examples of pathogenic bacteria include Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Corynebactehum dipthehae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida , Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treema pallidum, Chlamydia trachomatis, Vibrio cholerae, Sal monella typhimurium, Salmonella typhi, Borrelia burgdorferi and Yersinia pestis , although not limited to them.

[00196] Non-limiting examples of protozoa include, but are not limited to, Plasmodium, Babesiosis, Giardia, Entameba, Leishmania, and Trypanosomes.

[00197] Non-limiting examples of worms include, but are not limited to, helminths, including schistosomes, roundworms, tapeworms, and flukes.

[00198] Non-limiting examples of fungi include, but are not limited to, Candida and Aspergillus species.

[00199] Additional associated diseases, disorders, or conditions may be selected from the group consisting of those mentioned in the journal article located at:

http://onlinelibrary.wiley.com/store/10.1111/j.1365-2249.2011.04440.x/asset/j.1365-2-249.2011.04440.x.pdf?v=1&t=i60c1phf&s=d26f50a2622926cc6b4bc855bd91 1 ae9dc 9750cf.

[00200] In specific embodiments, the disease, disorder, or condition is selected from the group consisting of constitutive inflammation, including cryopyrin-associated periodic syndromes (CAPS): Mackle-Wales syndrome (MWS), familial cold autoinflammatory syndrome ( CXAS (FCAS)) and multisystem inflammatory disease of neonatal age (MVZNV (NOMID)); including autoinflammatory diseases: periodic disease (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency interleukin 1 receptor antagonist (DARI (DIRA)), Majid syndrome, purulent arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (GA20 (HA20)), pediatric granulomatous arthritis (PGA) associated with PLCG2 antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory disease, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SILZ (SIFD)) ; Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO); autoimmune diseases including multiple sclerosis (PC(MS)), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome and Schnitzler's syndrome; respiratory diseases, including chronic obstructive pulmonary disease (COPD (COPD)), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, and brain damage from pneumococcal meningitis; metabolic diseases including type 2 diabetes, atherosclerosis, obesity, gout, pseudo-gout; eye diseases, including ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy and diabetic nephropathy; liver disease, including non-alcoholic steatohepatitis and alcoholic liver disease; inflammatory reactions on the skin, including contact hypersensitivity and sunburn; inflammatory reactions in the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, acquired Still's disease, relapsing polychondritis; viral infections, including alpha virus (chikungunya, Ross River virus) and flavivirus (Dengue and Zika virus), influenza, HIV; suppurative hidradenitis (HS) and other cyst-causing skin diseases; cancers, including lung cancer metastases, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis; apoplexy; myocardial infarction; graft-versus-host reaction; high blood pressure; colitis; helminth infection; bacterial infection; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis, including Dressler's syndrome, ischemia-reperfusion injury, and any disease in which an individual is determined to carry a non-silent generative or somatic mutation in NLRP3.

[00201] In one non-limiting example of those described, the disease, disorder, or condition being treated is NASH. Activation of the NLRP3 inflammasome is central to inflammatory accumulation in NASH, and inhibition of NLRP3 can both prevent and reverse liver fibrosis. The compounds of the present invention, by disrupting the function of NLRP3 inflammasomes in liver tissue, can cause tissue repair in liver inflammation, reduced accumulation of macrophages and neutrophils, and suppression of NF-κB activation. Inhibition of NLRP3 can reduce hepatic expression of pro-IL-1β and normalize liver and circulating levels of IL-1β, IL-6, and MCP-1, thereby contributing to the treatment of the disease.

[00202] In an additional non-limiting example of those described, the disease, disorder, or condition being treated is severe steroid-resistant asthma (TACP). Respiratory infections induce the NLRP3/caspase-1/IL-1β inflammasome signaling pathway in the lungs, which triggers TACP asthma. The NLRP3 inflammasome recruits and activates procaspase-1 to induce IL-1(3) responses. Therefore, NLRP3 inflammasome-induced IL-1(3) responses are important in the containment of infections, however excessive activation leads to abnormal inflammation and has been associated with the pathogenesis of TACP and COPD asthma. from the first aspect that act on specific disease processes are more therapeutically attractive than non-specific inhibition of inflammatory responses with steroids or IL-1β Therefore, the impact on the NLRP3/caspase-1/IL-1β inflammasome signaling pathway with compounds from the first aspect may be useful in the treatment of TACP asthma and other steroid-resistant inflammatory conditions.

[00203] In one additional non-limiting example of those described, the disease, disorder, or condition being treated is Parkinson's disease. Parkinson's disease is the most common neurodegenerative movement disorder and is characterized by selective loss of dopaminergic neurons accompanied by accumulation of misfolded α-synuclein (Syn) in Lewy bodies, which are the pathological hallmarks of the disease. Chronic microglial neuroinflammation appears early in the disease and has been suggested to cause the pathology.

[00204] Microglial NLRP3 plays a central role in the development of Parkinson's disease. The NLRP3 inflammasome is activated by fibrillar Syn through a Syk-kinase-dependent mechanism, and also occurs in the absence of Syn pathology in the early stages of dopaminergic degeneration and entails neuronal loss. Compounds from the first aspect can block the activation of the NLRP3 inflammasome by Syn fibrillar or mitochondrial dysfunction and thereby provide effective neuroprotection of the nigrostriatal dopaminergic system and contribute to the treatment of Parkinson's disease.

[00205] In a sixth aspect of the invention, there is provided a method for diagnosing a disease, disorder, or condition in a mammal, comprising the step of administering a labeled compound of formula (I)-(VII), or a pharmaceutically effective salt, solvate, or prodrug thereof, to the mammal or into a biological sample derived from the mammal , to aid in the diagnosis of a disease, disorder, or condition in a mammal.

[00206] Activation of the inflammasome, in particular the NLRP3 inflammasome, is known to lead to the triggering, progression, and chronic development of a vast number of inflammatory diseases. Sulfonylureas and related compounds from the first aspect are potent and specific direct inhibitors of NLRP3. Accordingly, a chemical probe specific for NLRP3, which is present in immune cells during inflammation, has potential value in diagnosing inflammatory and other related diseases. An NRLP3 activation probe containing a compound from the first aspect can act as an effective surrogate inflammatory disease biomarker for ex vivo (blood) or in vivo (MPT, PET, etc.) diagnosis.

[00207] The use of the compounds of the first aspect in the diagnosis of inflammatory and other related diseases, such as those listed above, can be achieved by near infrared fluorescence imaging and ex vivo characterization of immune cells by degree of IL-1beta inhibition, procaspase 1 cleavage, and IL- 18. In particular, peripheral blood monocytes (PBMCs), macrophages, dendritic cells, CD4 ⁺ T cells, Th17 cells, Th1 cells and Th2 cells are of importance. Magnetic resonance imaging (MRI) is used in in vivo diagnostics. H2 (deuterium), ¹³ C, ¹⁹ F, ¹⁵ N labeled variants [compound classes] are administered to a patient intravenously, intramuscularly, subcutaneously, orally, topically, intrathecally, etc.

[00208] In vivo diagnostics using positron emission tomography (PET) is also suitable. PET is a molecular imaging technology that requires specific probes labeled with short-lived positron-emitting radionuclides. Representative isotopes include ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁶⁴ Cu, ⁶² Cu, ¹²⁴ I, ⁷⁶ Br, ⁸² Rb and ⁶⁸ Ga, with 18F being the most clinically used. In particular, it is possible in a simple manner to obtain a stable ⁶⁴ Cu or ⁶² Cu salt of one or more compounds of formula (I) by simple ion exchange with a sodium (or other monovalent cation) salt of said compounds. This makes it possible to quickly obtain diagnostic probes for radioimaging, PET, and the like, in which the intensity, location, and accumulation over time of the diagnostic probe allows identification of the extent and/or location of immune cells with activated NLRP3 as a surrogate biomarker of a patient's inflammatory disease, and the site of inflammation within the body. They will also be useful when applied to biological samples taken from the body, i.e. for in vitro diagnostics.

[00209] A seventh aspect of the invention is a method for modulating the activity of a biological target, comprising the step of exposing the biological target to a compound of formula (I)-(VII) or a pharmaceutically effective salt, solvate, or prodrug thereof.

[00210] The biological target can be selected from the group consisting of NLRP3 inflammasome, IL-1β, IL-17, IL-18, IL-1αx, IL-37, IL-33, and Th17 cells.

[00211] The modulation may be as previously described for aspects three through five.

[00212] In common use in this context, a biological sample may include cells, tissues, fluids, molecules, or other biological materials derived from, or that can be derived from, a mammal. Non-limiting examples include urine, blood and fractions thereof such as serum, plasma, lymphocytes and erythrocytes, cerebrospinal fluid, Pap smear, nasal and ocular secretions, amniotic fluid, feces, semen, tissue and/or organ biopsies, and nucleic acid samples (e.g. , DNA, RNA) or protein, although not limited to them.

[00213] In the following experimental part, the characteristics of certain compounds of the present invention and their effectiveness are described in more detail. The purpose is to illustrate certain specific embodiments of the compounds of the present invention and their effectiveness without limiting the invention in any way.

EXPERIMENTAL PART

General synthesis methods

Method A:

A1: To a solution of the amine intermediate R2 (1 eq.) with or without a base, such as, but not exclusively, triethylamine (1.2 eq.) in an anhydrous aprotic solvent, such as, but not exclusively, tetrahydrofuran or dichloromethane, was added triphosgene (from 0.4 to 1.1 eq.). The reaction mixture was stirred at ambient temperature or, if necessary, refluxed until complete, typically 2 to 18 hours.

A2: To di-tert-butyl dicarbonate (1.2-1.4 eq.) in anhydrous acetonitrile or THF was added DMAP (15-100 mol.%), after 5 minutes a solution of the amine intermediate R2 (1.0 eq.) was added. in acetonitrile. The reaction mixture was stirred for 30-60 min at room temperature.

Method B:

B1: The carboxylic acid intermediate R2 (1 eq) was dissolved in an aprotic solvent such as toluene with or without 2 drops of DMF and a chlorinating agent such as thionyl chloride (2 eq) was added. The reaction mixture was heated under reflux until complete, then concentrated under reduced pressure. The corresponding acid chloride intermediate R2 was obtained.

In this case, alternative methods for the formation of the acid chloride are equally suitable, for example, the above procedure can be carried out without toluene and DMF, using thionyl chloride as both solvent and chlorinating agent.

The acid chloride intermediate R2 was dissolved in acetone and added dropwise to a solution of sodium azide (1.5 eq.) in a solution of water:acetone (50:50) at 0°C. Ice water was added to precipitate the resulting acyl azide intermediate R2, which was dissolved in toluene and dried (MgSO ₄ ), followed by addition of the solution dropwise to anhydrous toluene at reflux while maintaining a constant flow of inert gas. The reaction mixture was heated to completion, typically 2 hours, to give isocyanate R2.

B2: Acid chloride R2 (formed as described in method B1) in dry CH2Cl2 was added to NaN ₃ (2.0 eq.) at 0°C. The reaction mixture was stirred at room temperature for 1 hour and extracted into EtOAc. The organic layer was washed with H ₂ O (15 ml), dried (MgSO ₄ ), and carefully evaporated to give the acyl azide. The acyl azide was dissolved in dry toluene and heated to 100° C. for 2 hours. The solvent was removed to give technical isocyanate R2.

Method C:

C1: Sulfonamide intermediate R1 (1 eq) was dissolved in anhydrous THF and treated with NaH (1 eq) under reduced pressure. The mixture was heated at reflux for 2 hours, then cooled to room temperature and the intermediate isocyanate R2 in THF was added under nitrogen atmosphere. The reaction mixture was stirred at reflux until complete.

C2: Sulfonamide intermediate R1 (1 eq) was dissolved in anhydrous THF or anhydrous methanol and treated with NaH (1 eq) under reduced pressure. After gas evolution ceased, isocyanate intermediate R2 was added and the reaction mixture was stirred at ambient temperature overnight.

C3: To sulfonamide intermediate R1 (1 eq) in anhydrous THF (5 ml/mmol) was added NaH (1 eq) at 0°C and stirred for 30 min to 2 h, or until complete, at ambient temperature in a nitrogen atmosphere. Cooled again to 0°C, added isocyanate R2 (1.0 eq) in THF and stirred at ambient temperature until complete, typically 2 to 16 hours.

C4: To industrial isocyanate R2 (1.0 eq.) in anhydrous THF or DCM (5-11 ml/mmol) was added sulfonamide R1 (1.0 eq.), then a base such as triethylamine, DIPEA or DBU (1- 2 eq.), and the reaction mixture was stirred at ambient temperature overnight.

C5: To the intermediate sulfonamide R1 (1 eq.) in anhydrous MeOH (5 ml/mmol) was added NaOMe (1 eq.) [alternatively: a solution of freshly prepared sodium methoxide 1.0 mmol/l (1 eq.) was added to the solution of sulfonamide R1 1.0 mmol/L (1 eq.) in anhydrous methanol]. The solvent was then removed under reduced pressure. The salt was suspended in an anhydrous aprotic solvent such as acetonitrile or THF, isocyanate R2 (1.0 eq.) in an anhydrous aprotic solvent such as acetonitrile or THF was added and the mixture was stirred at ambient temperature overnight. The solution was then refluxed to completion, typically 90 minutes.

C6: Sulfonamide R1 (1.0 eq) was dissolved in anhydrous THF under nitrogen. Solid sodium methoxide (1.0 eq. mmol) was added in one portion. This mixture was stirred at ambient temperature for 3 hours. A solution of isocyanate R2 (1.17 eq.) in THF was added dropwise. The reaction mixture was stirred at room temperature overnight.

Method D:

A solution of the amine (1.0 eq.) in acetonitrile (7-12 ml/mmol) at 0°C was treated with conc. HCl (1.25-2.25 ml/mmol) in H ₂ O (0.5-1.2 ml/mmol) followed by an aqueous solution of NaNO ₂ (1.2 eq.) dissolved in H ₂ O ( 0.3-0.5 ml/mmol NaNO ₂ ). The resulting solution was stirred at 0°C for 45 min. AcOH (0.5-1.2 ml/mmol), CuCl ₂ .2H ₂ O (0.5 eq.) and CuCl (0.05 eq.) were successively added to the above mixture and purged with SO ₂ gas for 20 min. at 0°C. The resulting reaction mixture was stirred at 0°C - 10°C until completion.

Method E:

E1: A solution of sulfonyl chloride (1 equiv.) in THF (10-20 ml/mmol) was cooled to -78°C and gaseous ammonia was passed through the solution for 15 min, stirring continued for another 30 min, then left to warm to ambient temperature and stirred for 2 h or until complete.

E2: A solution of sulfonyl chloride (1 eq.) in acetone (20 ml/mmol) was treated with a solution of NH ₄ HCO ₃ (4 eq.) dissolved in water (1.5 ml/mmol NH ₄ HCO ₃ ) at ambient temperature and stirred within 4 hours or until completed.

E3: A solution of sulfonyl chloride (1 eq.) in acetone (2.5 ml/mmol) was treated with NH ₃ (3.5 ml/mmol, NH ₄ OH in H ₂ O, based on 28% NH ₃ ) at 0°C and stirred for 2 hours or until complete.

Method F

General procedure for the synthesis of triazoles

Alkyne (1 equiv.) and azide (1.2 equiv.), 5 mol.% CuSO ₄ , 10 mol. % NaAsc solution in DMSO (500 µl) was stirred at room temperature until completion, typically 12 h.

Synthesis of sulfonamide intermediates R1:

Cyclohexanesulfonamide

To a solution of cyclohexanesulfonyl chloride (0.1 g, 0.54 mmol) in acetone (1 ml) was added aqueous NH ₃ (2 ml, 28% NH ₄ OH in H ₂ O) at 0°C and the reaction mixture was stirred at room temperature in for ~2 h. The solvent was removed under reduced pressure and MeOH/dichloromethane (1:9) (5 ml) was added, the by-product NH ₄ Cl was removed by filtration and the remaining solution was concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel using 0.2% MeOH-CH ₂ Cl ₂ eluent to give cyclohexanesulfonamide as a white to yellowish solid (30 mg, 34%). ¹ H-NMR (400 MHz, DMSO-d6): δ=6.61 (br s, 2H), 2.76-2.70 (m, 1H), 2.09-2.04 (m, 2H ), 1.80-1.76 (m, 2H), 1.65-1.60 (m, 1H), 1.31-1.19 (m, 4H), 1.16-1.06 (m , 1 H).

Cyclopentansulfonamide

To a solution of cyclopentanesulfonyl chloride (0.1 g, 0.59 mmol) in acetone (1 ml) was added aqueous NH ₃ (1 ml, 28% NH ₄ OH in H ₂ O) at 0°C and the reaction mixture was stirred at room temperature in for ~2 h. The solvent was removed under reduced pressure and MeOH/dichloromethane (1:9) (5 ml) was added, the by-product NH ₄ Cl was removed by filtration and the remaining solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 35% EtOAc-hexanes as eluent to give cyclopentanesulfonamide as a white to yellowish solid (72 mg, 81%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=6.69 (br s, 2H), 3.42-3.32 (m, 1H), 1.89-1.84 (m, 4H ), 1.68-1.64 (m, 2H), 1.61-1.52 (m, 2H).

5-((dimethylamino)methyl)furan-2-sulfonamide

Furan-2-carboxylic acid (5 g, 44.6 mmol) was dissolved in ethanol (100 ml), conc. H ₂ SO ₄ (1.0 ml) and the solution was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, then partitioned between ethyl acetate (100 ml) and saturated NaHCO ₃ (100 ml). The organic phase was washed with water then brine, dried (MgSO ₄ ) and concentrated under reduced pressure to give ethyl furan-2-carboxylate (4.5 g, 80%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.57 (d, J=1.2 Hz, 1H), 7.18 (d, J=3.5 Hz, 1H), 6.51 ( dd, J=3.5, 1.2 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).

Ethylfuran-2-carboxylate (9.0 g, 64.3 mmol) was dissolved in dichloromethane (200 ml) and chlorosulfonic acid (7.5 g, 64.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 6 hours, or until complete, then pyridine (5.6 g, 70.7 mmol) and PCl ₅ (14.7 g, 70.7 mmol) were added portionwise. The reaction mixture was stirred at ambient temperature for 16 hours, then diluted with ice water and stirred for 30 minutes. The mixture was extracted with DCM and the combined organic phases were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product, ethyl 5-(chlorosulfonyl)furan-2-carboxylate (7 g, 46%), was used immediately without further purification. ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.33 (d, J=3.9 Hz, 1H), 7.27 (d, J=3.9 Hz, 1 H), 4.44 ( kv, J=7.1 Hz, 1 H), 1.42 (t, J=7.1 Hz, 2 H).

Commercial grade ethyl 5-(chlorosulfonyl)furan-2-carboxylate (7 g) was converted using General Method E1 to give ethyl 5-sulfamoylfuran-2-carboxylate (5 g, 78%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=8.05 (s, 2H), 7.38 (d, J=3.7 Hz, 1 H), 7.09 (d, J=3 .7 Hz, 1H), 4.32 (kv, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).

Ethyl 5-sulfamoylfuran-2-carboxylate (2 g, 9.13 mmol) in dry THF (40 ml) was cooled to 0°C and lithium aluminum hydride (1.05 g, 27.3 mmol) was added portionwise over 30 minutes. The reaction mixture was heated to 70°C for 4 hours. The reaction mixture was cooled to 0° C. and saturated NH ₄ Cl (20 ml) was added dropwise with great care over 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and filtered through a pad of celite. The organic phase was washed with water (100 ml), brine (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give 5-(hydroxymethyl)furan-2-sulfonamide (1.25 g, 78%) as light -brown liquid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (s, 2H), 6.88 (d, J=3.5 Hz, 1H), 6.44 (d, J=3.4 Hz, 1H), 5.47 (s, 1H), 4.44 (d, J=5.7 Hz, 2H), 3.36 (s, 7H), 2.51 (q, J=1.8 Hz, 5H), 1.36 (s, 1H).

5-(hydroxymethyl)furan-2-sulfonamide (0.3 g, 1.7 mmol) in THF (5 ml) was cooled to 0° C. and POCl ₃ (0.4 g, 2.54 mmol) was added slowly. The reaction mixture was stirred at 75°C for 2 hours, then cooled to ambient temperature. The technical mixture was divided between ethyl acetate (50 ml) and sat. aq. NaHCO ₃ (50 ml) and the organic phase was washed with water (50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 30% EtOAc-hexanes as eluent to give 5-(chloromethyl)furan-2-sulfonamide as a light brown semi-solid (0.25 g, 76%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=7.85 (s, 2H), 6.93 (dd, J=3.5, 1.3 Hz, 1H), 6.69 (dd, J=3.5, 1.3 Hz, 1H), 4.89 (d, J=1.3 Hz, 2H).

5-(chloromethyl)furan-2-sulfonamide (0.4 g, 2.05 mmol) in THF (20 ml) was cooled to 0° C., conc. HCl (7.5 mg, 2.05 mmol) and the solution was stirred for 20 minutes at the same temperature. Added N,N-dimethylamine in ethanol 5.6 mol/l (0.28 g, 6.15 mmol, 3 eq.) at 0°C and sealed the reaction vessel, followed by stirring at room temperature overnight. Solvents were removed under reduced pressure and azeotroped with toluene (×2) to give 5-((dimethylamino)methyl)furan-2-sulfonamide as a gum (0.25 g, 60%). The technical product was used immediately without further purification.

Furan-2-sulfonamide

Furan-2-sulfonyl chloride (0.30 g, 1.8 mmol) was added to aqueous ammonia (1.0 ml) at 0° C. and the mixture was stirred at ambient temperature for 1 hour. After completion of the reaction, excess aqueous ammonia was removed at reduced pressure. The residue was azeotroped with isopropanol and triturated with pentane to give the sub-title compound as a light brown solid (0.21 g, 79%), ¹ H-NMR (400 MHz, DMSO-d ₆ ): 5=7 .91 (s, 1H), 7.45 (br.s, 2H), 6.95 (d, J=3.6 Hz, 1H), 6.63 (dd, J=2.8, 1, 6 Hz, N). LC-MS 97.4% (ELSD (Evaporative Light Scattering Detector)); m/z 146.11 [M-H] ⁺ .

5-methyl furan-2-sulfonamide

To a solution of 2-methylfuran (2.0 g, 24.3 mmol) in anhydrous acetonitrile (4 ml) was added the complex SO ₃ ⋅Py (5.0 g, 31.6 mmol) and the reaction mixture was heated at 40°C under nitrogen throughout the night. The reaction mixture was diluted with EtOAc (5 ml) and stirred for 2 h at 0°C, the resulting precipitates were removed by filtration and dried to give pyridinium 5-methylfuran-2-sulfonate as a white to yellowish solid (2.93 g, 50 %). ¹ H-NMR (400 MHz, DMSO): δ=8.90 (dd, J1=4 Hz, J2=8 Hz, 2H), 8.57 (tt, J=1.5 Hz, J ₂ =8 .1 Hz, 1H), 8.04 (dd, J=4 Hz, J ₂ =8 Hz, 2H), 6.27 (d, J=3.0 Hz, 1H), 5.98-5, 94 (m, 1H), 2.19 (s, 3H).

A suspension of pyridinium 5-methylfuran-2-sulfonate (1.0 g, 4.41 mmol) in anhydrous DME) was treated with oxalyl chloride (0.53 ml, 6.21 mmol) followed by DMF (0.32 ml, 4.41 mmol) at 0°C under argon and the reaction mixture was stirred at room temperature until completion. The reaction mixture was diluted with ice water and extracted with toluene (2×50 ml), the combined organic phases were washed with aqueous saturated NaHCO ₃ (20 ml), brine (20 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to obtain 5-methylfuran -2-sulfonyl chloride as a pale yellow oil (350 mg, 47%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.23-7.21 (m, 1H), 6.27-6.25 (m, 1H), 2.47 (s, 3H).

To a solution of 5-methylfuran-2-sulfonyl chloride (0.2 g, 1.10 mmol) in acetone (1 ml) was added aq. NH ₃ (1 ml, 28% NH ₄ OH in H ₂ O) at 0°C. The reaction mixture was stirred at ambient temperature for ~2 h, then concentrated under reduced pressure. The residue was suspended in dichloromethane (5 ml), the by-product NH ₄ Cl was removed by filtration and the remaining solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 40% EtOAc-hexanes as eluent to give 5-methylfuran-2-sulfonamide as a white to yellowish solid (130 mg, 73%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.60 (s, 2H), 6.83-6.82 (d, J=4.0 Hz, 1H), 6.26-6 .25 (d, J=4.0 Hz, 1H), 2.34 (s, 3H).

5-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide

To a solution of 2-ethylfuran (2.0 g, 20.8 mmol) in anhydrous acetonitrile (3 ml) was added the SO ₃ ⋅Py complex (4.30 g, 27.0 mmol). The resulting reaction mixture was heated at 40° C. under nitrogen for 23 hours or until complete. Added EtOAc (5 ml) and the solution was stirred for 2 h at 0°C. The resulting precipitate was removed by filtration and dried to give pyridin-1-st 5-ethylfuran-2-sulfonate as a brown hygroscopic solid (3.2 g, 60%) which was used immediately in the next step without purification.

To a suspension of pyridinium 5-ethylfuran-2-sulfonate (3.2 g, 12.5 mmol) in DME (15 ml) was added oxalyl chloride (1.62 ml, 27.0 mmol) followed by DMF (0.97 ml, 12 .5 mmol) at 0°C in an argon atmosphere, the resulting reaction mixture was stirred at room temperature until completion. The reaction mixture was diluted with ice water and then extracted with toluene (2×50 ml), the organic layer was washed with aqueous saturated NaHCO ₃ (20 ml) and brine (20 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to obtain 5-ethylfuran -2-sulfonyl chloride as a light brown oil (510 mg, 21%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.23 (d, J=4 Hz, 1H), 6.26 (d, J=8 Hz, 1H), 2.80 (q, J=8 Hz, 2H), 1.33 (t, J=8 Hz, 3H).

Aqueous NH ₃ (1.5 ml, NH ₄ OH in H ₂ O, base 28% NH ₃ ) was added to a solution of 5-ethylfuran-2-sulfonyl chloride in acetone (1 ml) at 0°C, the resulting reaction mixture was stirred at room temperature. temperature for 2 hours or until completed. The solvent was removed under reduced pressure and azeotroped with toluene (×2). The residue was purified by silica gel column chromatography using 1% MeOH/DCM eluent to give 5-ethylfuran-2-sulfonamide as a brown gum (0.36 g, 78%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.63 (brs, 2H), 6.85 (d, J=4 Hz, 1H), 6.28 (d, J=4 Hz, 1H ), 2.70 (kv, J=8 Hz, 2H), 1.21 (t, J=6 Hz, 3H).

4-(prop-1-en-2-yl)furan-2-sulfonamide

Synthesis of 4-(prop-1-en-2-yl)furan-2-sulfonamide was performed from ethylfuran-3-carboxylate using the procedures detailed by Urban et.al. Synth.Commun. 2003, 33(12), 2029-2043, to give the subtitle compound as a white solid with all spectral data corresponding to the referenced reference.

d ₆ -4-(prop-1-en-2-yl)furan-2-sulfonamide

Modification of the methods given in Urban et.al, Synth.Commun. 2003, 33(12), 2029-2043, using methyl-d ₃ -magnesium iodide instead of methylmagnesium chloride leads to the corresponding d ₆ -4-(prop-1-en-2-yl)furan-2-sulfonamide.

4-(prop-1-en-2-yl)furan-2-sulfonamide

To a solution of triphenylphosphine (0.3 g, 1.16 mmol) in anhydrous THF (5.0 ml) was added iodine (1.0 eq) and the mixture was stirred at room temperature for 10 minutes. A solution of 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide in THF (3.0 ml) was added slowly and stirring was continued for 2 hours or until complete. The solution was diluted with EtOAc (20 ml), washed with 10% aq. sodium bisulfite (20 ml), water (20 ml). The organic layer was separated, dried (MgSO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20% EtOAc:hexanes as an eluent to give the sub-title compound as a white solid (0.1 g, 58%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ=7.51 (s, 1H), 7.16 (s, 1H), 5.27 (s, 2H), 2.02 (s, 3H). ¹³ C-NMR (101 MHz, CDCl ₃ ) δ 149.3, 140.7, 140.7, 132.3, 127.8, 112.1, 111.9, 76.0, 7.7, 28, 7, 19.8.

4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

To a solution of 2-methyl-3-furancarboxylic acid ethyl ester (30 g, 0.195 mol) in DCM (300 ml) at -10°C was added chlorosulfonic acid (23.8 g, 0.204 mol) dropwise over ~15 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 72 hours. The solution was cooled to -10° C. and anhydrous pyridine (16.9 g, 0.214 mol) was added dropwise followed by phosphorus pentachloride (44.6 g, 0.214 mol) in ~10 g portions over 10 min. Stirred at <0°C for 30 min, then stirred at ambient temperature overnight. The reaction mixture was added dropwise to water (550 ml) with stirring, and stirring was continued for 2 hours. The organic phase was separated and the aqueous phase was extracted with DCM (150 ml). The combined organic phases were washed with water (300 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 44 g of a dark red oil. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexane as eluent to give ethyl 5-(chlorosulfonyl)-2-methylfuran-3-carboxylate as an orange oil (36 g, 73%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ=7.55 (s, 1H), 4.63 (q, J=7.2 Hz, 2H), 2.75 (s, 3H), 1.38 (t, J=7.2 Hz, 3H).

Ethyl 5-(chlorosulfonyl)-2-methylfuran-3-carboxylate (30 g, 0.12 mol) in acetone (200 ml) was added dropwise over 15 min to a solution of ammonium bicarbonate (37.6 g, 0.475 mol) in water (630 ml). The reaction mixture was stirred at ambient temperature until completion (~3 h). EtOAc (250 ml) was added and the pH was adjusted by dropwise addition of conc. HCl to pH~2. The organic phase was separated and the remaining aqueous phase was saturated with sodium chloride and re-extracted with EtOAc (250 ml). The combined organic phases were washed with brine (300 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a brown oily solid which was recrystallized using EtOAc-hexane to give ethyl-2-methyl-5-sulfamoyl-furan-3 -carboxylate as a beige solid (11.4 g, 41%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.8 (s, 2H), 7.02 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 2 .62 (s, 3H), 1.3 (t, J=7.2 Hz, 3H).

Ethyl 2-methyl-5-sulfamoylfuran-3-carboxylate (10 g, 0.043 mol) in anhydrous THF (400 ml) at -10°C was treated with a solution of methylmagnesium chloride (3.0 mol/l in THF, 64.3 ml ) drop by drop over 5 minutes with vigorous stirring. The solution was then stirred at ambient temperature for 6 hours, then cooled to -5° C. and treated dropwise with a solution of ammonium chloride (51.8 g in 265 ml of water). The aqueous solution was extracted with EtOAc (2×250 ml), the combined organic phases were washed with brine (250 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to an orange oil (10 g). The crude product was purified by silica gel column chromatography using 40% EtOAc-hexane eluent to give the sub-title compound as a white solid (6.1 g, 42%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.54 (br s, 2H), 6.78 (s, 1H), 4.95 (s, 1H), 2.42 (s, 3H), 1.4 (s, 6H).

(d ₆ -4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

Methyl 2-methyl-5-sulfamoylfuran-3-carboxylate can be obtained by modifying the procedures used for the synthesis of ethyl 2-methyl-5-sulfamoylfuran-3-carboxylate, but using methyl-2-methylfuran-3- carboxylate instead of ethyl 2-methylfuran-3-carboxylate.

Methyl 2-methyl-5-sulfamoylfuran-3-carboxylate was obtained as a white solid (3 g, 29%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.89 (s, 2H), 7.03 (s, 1H), 3.79 (s, 3H), 2.61 (s, 3H) .

Methyl 2-methyl-5-sulfamoylfuran-3-carboxylate (0.7 g, 3.2 mmol) in anhydrous THF (20 ml) at -10°C was treated with a solution of c/s-methylmagnesium iodide (1.0 mol/ l in Et ₂ O, 26 ml) dropwise over 10 minutes with vigorous stirring. The solution was then stirred at ambient temperature for 12 hours, then cooled to 0° C. and treated dropwise with a saturated ammonium chloride solution. The aqueous solution was extracted using EtOAc (2×25 ml), the combined organic phases were washed with saline (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a 40-70% EtOAc-hexane gradient eluent to give the sub-title compound as a white solid (0.37 g, 51%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.57 (s, 2H), 6.79 (s, 1H), 4.99 (s, 1H), 2.4 (s, 3H) . ¹³ C-NMR (100 MHz, CD ₃ OD) δ=150.3, 147.3, 128.4, 113.4, 67.3, 28.5 (multiplet), 12.2.

1-benzyl-1Н-1,2,4-triazole-3-sulfonamide

A solution of 1H-1,2,4-triazole-3-thiol (1 g, 9.90 mmol) in DMF (20 ml) was treated with K ₂ CO ₃ (4.8 g, 34.7 mmol), cooled to 0 °C, then benzyl bromide (4.2 g, 24.8 mmol) was added dropwise over 5 min. The resulting reaction mixture was warmed to ambient temperature and stirred for 12 hours. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20% EtOAc-hexanes as eluent to give 1-benzyl-3-(benzylthio)-1H-1,2,4-triazole as a white solid (1.5 g, 54%) . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.67 (s, 1H), 7.39-7.32 (m, 5H), 7.27-7.21 (m, 5H) , 5.36 (s, 2H), 4.29 (s, 2H).

AcOH (3 ml) was added to a solution of 1-benzyl-3-(benzylthio)-1H-1,2,4-triazole, 2 (0.5 g, 1.77 mmol) in acetonitrile (5 ml) at 0°C and then H ₂ O (2 ml) and Cl ₂ gas was bubbled through the solution for 45 minutes. Stirring was continued at 0°C for 30 min, then at 20°C for 1.5 h. The reaction mixture was diluted with water (20 ml) and was extracted with EtOAc (2×20 ml).

The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a colorless liquid. The residue was diluted with THF and cooled to -78°C. Ammonia gas was bubbled through the solution for 20 min and stirring was continued for another 30 min followed by warming to ambient temperature and stirring for 1 h. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was triturated with diethyl ether to give 1-benzyl-1H-1,2,4-triazole-3-sulfonamide as a white to yellowish solid (0.25 g, 60%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.88 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5, 45 (s, 2H).

1-isopropyl-1H-1,2,3-triazole-4-sulfonamide

1H-1,2,3-triazol-5-thiolate sodium (500 mg, 4.06 mmol) was dissolved in EtOH (5 ml) and cooled to 0°C. Benzyl bromide (0.69 g, 4.06 mmol) was added dropwise over 5 minutes. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with saturated NaHCO ₃ solution and extracted with EtOAc (2×20 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was stirred with n-pentane (30 ml), filtered and dried in vacuo to give 4-(benzylthio)-1H-1,2,3-triazole as a white solid (0.7 g, 90%) which used without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.40-7.38 (m, 1H), 7.35-7.21 (m, 5H), 4.12 (s, 2H). LCMS (m/z): 192.0 [M+H] ⁺

A solution of 4-(benzylthio)-1H-1,2,3-triazole (5 g, 26.1 mmol) in DMF (50 ml) was cooled to 0° C. and treated with K ₂ CO ₃ (9.03 g, 65.4 mmol). The reaction mixture was stirred for 5 minutes at the same temperature. Isopropyl iodide (8.89 g, 52.3 mmol) was added dropwise to the above mixture over 5 minutes. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The organic extract was washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The technical product was purified by silica gel column chromatography using 8% EtOAc-hexane eluent to give 5-(benzylthio)-1-isopropyl-1H-1,2,3-triazole A (0.9 g),

4-(benzylthio)-2-isopropyl-2H-1,2,3-triazole B (1 g) and the desired product 4-(benzylthio)-1-isopropyl-1H-1,2,3-triazole C (1, 4 g, 23%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.29-7.18 (m, 5H), 4.78-4.71 (m, 1H), 4.09 (s, 2H) , 1.4 (d, J=6.8 Hz, 6H). LCMS (m/z): 234.30 [M+H] ⁺ .

A solution of 4-(benzylthio)-1-isopropyl-1H-1,2,3-triazole (75 mg, 0.32 mmol) in acetic acid (2.25 ml) and H ₂ O (1.12 ml) was cooled to 0°C. Added N-chlorosuccinamide (170 mg, 1.28 mmol) at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2×10 ml). The combined organic extracts were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 8% EtOAc-hexanes as an eluent to give 1-isopropyl-1H-1,2,3-triazole-4-sulfonyl chloride (0.1 g, 100%) as a light brown liquid, used without further purification. LCMS (m/z): 210.10 [M+H] ⁺ .

A solution of 1-isopropyl-1H-1,2,3-triazole-4-sulfonyl chloride (100 mg) in THF (5 ml) was cooled to -40°C. Ammonia gas was bubbled through the above solution for 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate (25 ml) and water (10 ml). The organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1-isopropyl-1H-1,2,3-triazole-4-sulfonamide (0.07 g, 78%) as brown solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.71 (s, 1H), 7.66 (s, 2H), 4.91-4.87 (m, 1H), 1.5 (d, J=6.8 Hz, 6H). LCMS (m/z): 191.30 [M+H] ⁺ .

1-methyl-1H-pyrazole-3-sulfonamide

1-Methyl-1H-pyrazole-3-amine hydrochloride was converted to 1-methyl-1H-pyrazole-3-sulfonyl chloride, a pale yellow liquid, using General Method D (0.7 g, 38%). 1H-NMR (300 MHz, CDCl ₃ ): δ=7.51-7.50 (d, J=2.1 Hz, 1H), 6.89-6.88 (d, J=2.4 Hz, 1H), 4.06 (s, 3H). LCMS (m/z): 160.9 (M-1) ^- . The sulfonyl chloride was converted using General Method E1 to give the sub-title compound as a white to yellowish solid (0.4 g, 69%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.80 (d, J=2.1 Hz, 1H), 7.36 (s, 2H), 6.53 (d, J=2 .1 Hz, 1H), 3.88 (s, 3H). LCMS (m/z): 162.05 (M+1) ⁺ .

1-(trifluoromethyl)-1H-pyrazole-3-sulfonamide

1-(trifluoromethyl)-1H-pyrazole-3-amine was converted to 1-(trifluoromethyl)-1H-pyrazole-3-sulfonyl chloride, brown liquid using General Method D (0.4 g, 43%). 1 H-NMR (300 MHz, CDCl ₃ ) δ=8.02 (d, J=2.8 Hz, 1H), 7.06 (d, J=2.8 Hz, 1H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-60.46.

The sulfonyl chloride was converted using General Method E1 to give the sub-title compound (0.22 g, 46%). ¹ H-NMR (300 MHz, CDCl ₃ ) 5=7.92 (dd, J=2.8, 0.3 Hz, 1H), 6.91 (dd, J=2.8, 0.7 Hz, 1H), 5.28 (s, 2H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-60.41.

1-isopropyl-1H-pyrazole-3-sulfonamide

1-Isopropyl-1H-pyrazole-3-amine was converted to 1-isopropyl-1H-pyrazole-3-sulfonyl chloride, brown liquid using General Method D (0.5 g, 43%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.55 (s, 1H), 6.88 (s, 1H), 4.66-4.63 (m, 1H), 3.6 (br .s, 2H), 1.59 (d, J=6.8 Hz, 6H). LCMS (m/z): 209.0 (M+1) ⁺ . The sulfonyl chloride was converted using General Method E1 to give the sub-title compound as a yellow solid (0.45 g, 82%). ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=7.9 (d, J=2.4 Hz, 1 H), 7.36 (s, 2H), 6.55 (d, J= 2.1 Hz, 1H), 4.57-4.53 (m, 1H), 1.42 (d, J=6.9 Hz, 6H). LCMS (m/z): 190.0 (M+1) ⁺ .

1-isopropyl-1H-pyrazole-4-sulfonamide

A solution of 4-iodo-1H-pyrazole (1 g, 5.15 mmol) in DMF (20 ml) was treated with K ₂ CO ₃ (1.42 g, 10.30 mmol) and isopropyl iodide (1.05 g, 6. 19 mmol) at ambient temperature under a nitrogen atmosphere. The resulting reaction mixture was heated to 90° C. and stirred for 12 hours. The mixture was cooled, diluted with water (50 ml) and extracted with diethyl ether (2×50 ml). The combined organic phases were washed with water (2×50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexanes as eluent to give 4-iodo-1-isopropyl-1H-pyrazole as a colorless liquid (1.1 g, 92%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.50-7.46 (m, 2H), 4.53-4.47 (m, 1H), 1.50 (d, J=6, 8 Hz, 6H). LCMS (m/z): 237.2 (M+1) ⁺ .

A solution of 4-iodo-1-isopropyl-1H-pyrazole (1 g, 4.24 mmol) in dioxane (20 ml) was treated successively with benzyl mercaptan (0.8 g, 6.35 mmol) and DIPEA (1.1 g, 8.47 mmol) under a nitrogen atmosphere. The solution was degassed by purging with argon gas for 15 minutes. Pd ₂ (dba) ₃ (40 mg, 0.0423 mmol) and Xanthos (50 mg, 0.0847 mmol) were added under argon atmosphere, then the resulting mixture was sealed in the reaction vessel and heated at 75°C for 6 hours. the mixture was cooled, concentrated under reduced pressure, diluted with water (20 ml) and extracted with EtOAc (2×20 ml). The combined organic phases were washed with water (2×50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexanes as an eluent to give 4-(benzylthio)-1-isopropyl-1H-pyrazole as a yellow liquid (650 mg, 66%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.36 (s, 1H), 7.26-7.22 (m, 4H), 7.11-7.09 (m, 2H), 4 .41-4.36 (m, 1H), 3.76 (s, 2H), 1.42 (d, J=6.8 Hz, 6H). LCMS (m/z): 233.3 (M+1) ⁺ .

AcOH (0.7 ml) and H ₂ O (0 .35 mL), then DCDMH (0.6 g, 3.017 mmol) was added portionwise over 5 min. The solution was stirred for 30 min, then warmed to ambient temperature and stirred for another 2 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2×20 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1-isopropyl-1H-pyrazole-4-sulfonyl chloride as a colorless liquid. The sulfonyl chloride was diluted with THF and cooled to -78°C, then gaseous NH ₃ was passed through the solution for 15 minutes. The reaction mixture was stirred at -78°C for 1 h and at ambient temperature for 2 h. The reaction mixture was diluted with water and the compound was extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and dried under reduced pressure to give 1-isopropyl-1H-pyrazole-4-sulfonamide as a light brown solid (0.2 g, 71%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.21 (s, 1H), 7.71 (s, 1H), 7.22 (s, 2H), 4.59-4.53 (m, 1H), 1.4 (d, J=6.8 Hz, 6H). LCMS (m/z): 190.2 (M+1) ⁺ .

1-cyclopropyl-1H-pyrazole-3-sulfonamide

1-Cyclopropyl-1H-pyrazol-3-amine was converted to 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride using General Method D, then converted using General Method E1 to give the sub-title compound as a light brown solid (0.2 g, 33%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ=7.51 (d, J=2.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 5.04 (s , 2H), 3.67 (m, 1H), 1.28-1.05 (m, 4H).

1-(tert-butyl)-1H-pyrazole-3-sulfonamide

1-(tert-Butyl)-1H-pyrazole-3-amine was converted to 1-(tert-butyl)-1H-pyrazole-3-sulfonyl chloride using General Method D, then converted using General Method E1 to give sub-titled compounds as a light brown solid (150 mg, 26%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.56 (d, J=3.6 Hz, 1H), 6.7 (d, J=3.2 Hz, 1H), 4, 75 (br s, 1H), 1.60 (s, 9H). LCMS (m/z): 204.15 (M+1) ⁺ .

1-cyclohexyl-1H-pyrazole-3-sulfonamide

1-Cyclohexyl-1H-pyrazole-3-amine was converted to 1-cyclohexyl-1H-pyrazole-3-sulfonyl chloride using General Method D, then converted using General Method E1 to give the sub-title compound as a white solid (0 .35 mg, 50%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=7.89 (d, J=2.3 Hz, 1H), 7.36 (s, 2H), 6.55 (d, J=2, 3 Hz, 1H), 4.28-4.08(m, 1H), 2.0-1.1(m, 6H).

1-phenyl-1H-pyrazole-3-sulfonamide

1-Phenyl-1H-pyrazole-3-amine was converted to 1-phenyl-1H-pyrazole-3-sulfonyl chloride, a yellow liquid, using General Method D (0.5 g, 47%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=8.04 (d, J=2.4 Hz, 1H), 7.73 (d, J=9.2 Hz, 2H), 7.58 ( t, J=7.6 Hz, 2H), 7.47 (t, J=7.2 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H). The sulfonyl chloride was converted using General Method E1 to give the sub-title compound as a yellow solid (0.4 g, 87%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.62 (d, J=2.7 Hz, 1H), 7.86 (d, J=8.7 Hz, 2H), 7, 61 (br s, 2H), 7.57 (t, J=7.8 Hz, 2H), 7.41 (t, J=7.2 Hz, 1H), 6.85 (d, J=2 .4 Hz, 1H). LCMS (m/z): 224.1 (M+1) ⁺ .

1-benzyl-1H-pyrazole -3-sulfonyl chloride

1-Benzyl-1H-pyrazole-3-amine was converted to 1-benzyl-1H-pyrazole-3-sulfonyl chloride, a light brown liquid using General Method D (0.2 g, 45%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.42-7.38 (m, 3H), 7.33-7.28 (m, 3H), 6.8 (d, J=2.4 Hz, 1H), 5.42 (s, 2H). The sulfonyl chloride was converted using General Method E1 to give the sub-title compound as a light brown liquid (0.15 g, 81%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.42-7.36 (m, 4H), 7.24 (d, J=1.6 Hz, 2H), 6.7 (d, J =2.4 Hz, 1H), 5.35 (s, 2H), 5.10 (s, 2H). LCMS (m/z): 238.10 (M+1) ⁺ .

1-(1-phenylethyl)-1H-pyrazole-3-sulfonamide

1-(1-phenylethyl)-1H-pyrazole--amine was converted to 1-(1-phenylethyl)-1H-pyrazole-3-sulfonyl chloride using General Method D, then converted using General Method E1 to give the sub-title compound as a white solid (0.25 mg, 68%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.43-7.18 (m, 6H), 6.72 (d, J=2.4 Hz, 1H), 5.57 (q, J= 7.1 Hz, 1H), 5.02 (s, 2H), 1.92 (d, J=7.1 Hz, 3H).

1-(2-(piperidin-1-yl)ethyl)-1H-pyrazole-3-sulfonamide

1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-3-amine was converted to 1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-3-sulfonyl chloride, light brown the liquid using General Method D was then converted using General Method E1 to give the sub-title compound as a white to yellowish solid (0.3 g, 46%). ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=7.84 (d, J=2.1 Hz, 1H), 7.36 (s, 2H), 6.54 (s, J=2 .4 Hz, 1H), 4.26 (t, J=6.9 Hz, 2H), 2.66 (t, J=6.6 Hz, 2H), 2.36 (s, 4H), 1, 46-1.34 (m, 6H). LCMS (m/z): 259.10 (M+1) ⁺ .

1,5-dimethyl-1H-pyrazole-3-sulfonamide

1,5-Dimethyl-1H-pyrazole-3-amine was converted to 1,5-dimethyl-1H-pyrazole-3-sulfonyl chloride, a yellow liquid, using General Method D (0.45 g, 26%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=5.92 (s, 1H), 3.71 (s, 3H), 2.23 (s, 3H). LCMS (m/z): 217 (M+Na) ⁺ . The sulfonyl chloride was converted using General Method E1 to give the sub-title compound as a white to yellowish solid (0.25 g, 55%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.30 (s, 2H), 6.36 (s, 1H), 3.76 (s, 3H), 2.27 (s, 3H ). LCMS (m/z): 175.9 (M+1) ⁺ .

1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonamide

1-Methyl-5-(trifluoromethyl)-1H-pyrazole-3-amine was converted to 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl chloride, a light brown liquid using General Method D (1, 1 g, 37%). ¹ H-NMR (300 MHz, CDCl ₃ ): 5=7.21 (s, 1H), 4.16 (s, 3H). The sulfonyl chloride was converted using General Method E1 to give the sub-title compound as a yellow solid (0.45 mg, 82%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.06 (s, 1H), 5.02 (br s, 2H), 4.03 (s, 3H).

1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonamide

A mixture of NaH (2.14 g, 89.3 mmol) in DMF (20 ml) was cooled to -10°C. To this mixture was added a solution of 1,1,1-trifluoropropan-2-one (5 g, 44.6 mmol) in DMF (80 ml) very carefully and stirred at -10° C. for 5 minutes. CS ₂ (10.2 g, 133.9 mmol) was added dropwise to the above mixture over 30 min, then the reaction mixture was warmed to ambient temperature and stirred for 1 h. The reaction mixture was cooled to 0° C. and CH ₃ (7.5 ml) for 10 min. The resulting reaction mixture was warmed to ambient temperature and stirred for 12 hours. The reaction mixture was diluted with cold water (50 ml) and extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 5% EtOAc-hexanes as an eluent to give 1,1,1-trifluoro-4,4-bis(methylthio)but-3-en-2-one as a light brown solid ( 3.5 g, 36%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=6.24 (s, 1H), 2.57 (m, 6H). LCMS (m/z): 217.20 (M+1) ⁺ .

A solution of 1,1,1-trifluoro-4,4-bis(methylthio)but-3-en-2-one (2.5 g, 11.6 mmol) in EtOH (25 ml) was treated with isopropylhydrazine hydrochloride (2 g , 13.9 mmol) at 0° C., Et ₃ N (2.4 g, 40.98 mmol) was added and the mixture was heated at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure, diluted with sat. aq. NaHCO ₃ solution and extracted with EtOAc (2×250 ml). The combined organic phases were washed with water (200 ml), brine (200 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% EtOAc eluent to give 1-isopropyl-3-(methylthio)-5-(trifluoromethyl)-1H-pyrazole as a light brown liquid (1.5 g, 58%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=6.47 (s, 1H), 4.58-4.53 (m, 1H), 2.49 (s, 3H), 1.50 (d , J=6.8 Hz, 6H). LCMS (m/z): 225.20 (M+1) ⁺ .

A solution of 1-isopropyl-3-(methylthio)-5-(trifluoromethyl)-1H-pyrazole (0.5 g, 2.23 mmol) in chloroform (10 ml) was treated with mCPBA (0.38 g, 2.23 mmol) and stirred at 10° C. for 1 h. The reaction mixture was diluted with saturated NaHCO ₃ solution (10 ml) and extracted with CHCl ₃ (2×30 ml). The combined organic phases were washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was dissolved in CHCl ₃ (10 ml) and treated with trifluoroacetic anhydride (1.4 g, 6.7 mmol), the reaction mixture was heated at 50°C for 3 h, cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was diluted with MeOH (5 ml)-THF (5 ml)-H ₂ O (5 ml), cooled to 0°C, acted on Na ₂ CO ₃ (0.7 g, 6.7 mmol) and stirred for 3 hours The solution was diluted with water (30 ml) and was extracted with CHCl ₃ (2×50 ml). The combined organic phases were washed with water (50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical residue (0.2 g) containing 1-isopropyl-3-((1-isopropyl-5-(trifluoromethyl)-1H-imidazol-4-yl)disulfanyl)-5-(trifluoromethyl)-1H-pyrazole was used in the next step without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ): δ=6.85 (s, 2H), 6.70 (s, 1H), 6.60 (s, 1H), 4.6 (m, 2H), 1.53 (m, 6H). LCMS (m/z): 416.75 (M-1) ^- .

Technical 1-isopropyl-3-((1-isopropyl-5-(trifluoromethyl)-1H-imidazol-4-yl) disulfanyl)-5-(trifluoromethyl)-1H-pyrazole solution (0.2 g technical, 0.478 mmol) in acetonitrile (10 ml) was cooled to 0°C and acted on it AcOH (1 ml) and H ₂ O (1.5 ml). DCDMH (0.19 g, 0.956 mmol) was added portionwise over 5 minutes and stirred for 2 hours. The mixture was diluted with water (20 ml) and extracted with DCM (2×20 ml). The combined organic phases were washed with water (50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl chloride as colorless liquid.

(1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl chloride) was diluted with THF, cooled to -78°C and gaseous NH ₃ was passed through the solution for 10 min, then stirred for 1 h, followed by heating to ambient temperature and stirring for another 1 h. The reaction mixture was diluted with water and was extracted with ethyl acetate (2×25 ml). The combined organic phases were washed with water (50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and n-pentane to give 1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonamide as a white solid (75 mg, 61%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.01 (s, 1H), 5.06 (s, 2H), 4.73-4.70 (m, 1H), 1.5 (d , J=6.8 Hz, 6H). LCMS (m/z): 256.0 (M-1) ^- .

5-isopropyl -1-methyl -1H-pyrazole -3-sulfonamide

A solution of 1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-amine (0.25 g, 1.824 mmol) in acetonitrile (10 ml) at 0°C was treated with conc. HCl (1.2 ml) in H ₂ O (0.5 ml) followed by an aqueous solution of NaNO ₂ (0.15 g, 2.19 mmol) dissolved in H ₂ O (2 ml). The resulting solution was stirred at 0°C for 45 min. AcOH (0.25 ml), CuCl ₂ ⋅2H ₂ O (0.15 g, 0.91 mmol) and CuCl (10 mg, 0.091 mmol) were successively added to the mixture described above and purged with SO ₂ gas for 20 min at 0°C. The resulting reaction mixture was stirred at 0°C - 10°C for 60 minutes. Upon completion, the reaction mixture was diluted with water (20 ml) and was extracted with EtOAc (2×20 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel using 20% EtOAc-hexanes eluent to give 1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-sulfonyl chloride as a colorless liquid (0.15 d, 38%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=6.77 (s, 1H), 5.51 (s, 1H), 5.28 (s, 1H), 4.02 (s, 3H), 2.11 (s, 3H).

A solution of 1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-sulfonyl chloride (0.075 g, 0.34 mmol) in THF (7 ml) was cooled to -78°C and through the solution bubbling ammonia gas for 15 minutes, stirring continued for another 30 minutes, then allowed to warm to ambient temperature and stirred for 2 hours or until complete. The reaction mixture was diluted with ethyl acetate (25 ml) and filtered through a pad of celite. The filtrate was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 0.04 g (technical) 1-methyl-5-(prop-1-en-2-yl)-1H-pyrazole-3-sulfonamide as white yellowish solid, used without purification.

To a solution of technical 1-methyl-5- (prop-1-en-2-yl) -1H-pyrazole-3-sulfonamide (0.12 g, 0.6 mmol) in MeOH (10 ml) - EtOAc (4 ml ) were treated with 10% palladium on charcoal (30 mg) under a nitrogen atmosphere. The reaction flask was evacuated, filled with hydrogen (balloon) and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (25 ml), filtered through a pad of celite, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solid was further washed with diethyl ether to give 5-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide as a white to yellowish solid (0.11 g, 91%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=6.50 (s, 1 H), 5.00 (b.s., 2H), 3.87 (s, 3H), 2.97-2 .93 (m, 1H), 1.28 (d, J=7.2 Hz, 6H).

5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

Ethyl 3-amino-1-methyl-1H-pyrazole-5-carboxylate was converted to ethyl 3-(chlorosulfonyl)-1-methyl-1H-pyrazole-5-carboxylate, a light yellow liquid, using General Method D (0 .35 g, 47%). ¹ H-NMR (300 MHz, chloroform-d) δ 7.39 (s, 1 H), 4.40 (q, J=7.1 Hz, 2H), 4.32 (s, 3H), 1, 40 (t, J=7.1 Hz, 3H). The sulfonyl chloride was converted using General Method E2 to give ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate as a white to yellowish solid (0.3 g, 94%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=7.59 (s, 2H), 7.09 (s, 1H), 4.33 (q, J=7.1 Hz, 2H), 4 .14 (s, 3H), 1.31 (t, J=7.1 Hz, 3H).

Methyl magnesium chloride (3 mol/l) was added dropwise in THF, 5 equivalents). The resulting reaction mixture was gradually warmed to ambient temperature and stirred for 6 hours or until complete. The solution was cooled to 0°C, diluted with sat. aq. NH ₄ Cl (2.0 ml) then diluted with cold water (20 ml) and extracted with EtOAc (2×25 ml). The combined organic phases were washed with brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient eluent of 50% EtOAc in hexanes to give the sub-title compound as a white solid. (0.2 g, 87%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.34 (s, 2H), 6.40 (s, 1H), 5.48 (s, 1H), 4.0 (s, 3H) , 1.50 (s, 6H).

1-benzyl-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

Ethyl 3-amino-1-benzyl-1H-pyrazole-5-carboxylate was converted to ethyl 1-benzyl-3-(chlorosulfonyl)-1H-pyrazole-5-carboxylate, light brown liquid using method D (0 .35 g, 47%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.41 (s, 1H), 7.34-7.26 (m, 5H), 5.87 (s, 2H), 4.37 (q , J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H). The sulfonyl chloride was converted using General Method E2 to give ethyl 1-benzyl-3-sulfamoyl-1H-pyrazole-5-carboxylate as a white solid (0.7 g, 88%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.66 (s, 2H), 7.39-7.27 (m, H), 7.2-7.18 (m, 3H) , 5.77 (s, 2H), 4.33 (kv, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H). LCMS (m/z): 310.05 (M+1) ⁺ .

Methylmagnesium chloride (3 mol/l) was added dropwise in THF, 2.77 ml, 8.1 mmol). The resulting reaction mixture was gradually warmed to ambient temperature and stirred for 4 hours or until complete. The solution was cooled to 0°C, diluted with sat. aq. NH ₄ Cl (2.0 ml) then diluted with cold water (20 ml) and extracted with EtOAc (2×25 ml). The combined organic phases were washed with brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient eluent of 70-100% EtOAc in hexanes to give the sub-title compound as a white solid. (0.27 g, 57%). ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=7.37 (s, 2H), 7.39-7.27 (m, 3H), 7.2-7.18 (m, 2H) , 6.45 (s, 1H), 5.66 (s, 2H), 5.60 (s, 1H), 1.44 (s, 6H). LCMS (m/z): 296.1 (M+1) ⁺ .

5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

2-(3-Amino-1-phenyl-1H-pyrazol-5-yl)propan-2-ol was converted to 5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonyl chloride, yellow liquid using method D (0.4 g, 36%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.55-7.45 (m, 5H), 6.91 (s, 1H), 1.51 (s, 6H). The sulfonyl chloride was converted using General Method E2 to give the sub-title compound as a yellow solid (0.32 g, 87%). ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=7.5 (s, 5H), 7.47 (s, 2H), 6.65 (s, 1H), 5.41 (s, 1H ), 1.30 (s, 6H).

5-(dimethylamino)naphthalene-1-sulfonamide

5-(dimethylamino)naphthalene-1-sulfonamide 3-azidobenzenesulfonamide was synthesized according to the procedures described in Satish K. Nair, Daniel Elbaum and David W. Christianson. J Biol. Chem. 1996, 2711003-100 and Lixuan Mu, Wensheng Shi, Guangwei She, Jack C. Chang, and Shuit-Tong Lee. Angew. Chem. Int. Ed. 2009, 48, 3469-3472.

A solution of 5-(dimethylamino)naphthalene-1-sulfonyl chloride (0.12 g, 0.44 mmol) in acetone (5 ml) was added dropwise to a solution of ammonium bicarbonate (0.17 g, 1.76 mmol) in water (1 0 ml) and the reaction mixture was stirred at ambient temperature for 2 hours or until complete. pH with conc. HCl was adjusted to pH 2.0. The organic phase was separated and the aqueous phase was saturated with NaCl and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure to give the sub-title compound as a white solid (0.075 g, 67% yield). ¹ H-NMR (600 MHz, CD ₃ OD) δ=8.54 (d, J=8.5 Hz, OH), 8.36 (d, J=8.7 Hz, 1 H), 8.23 (d, J=7.3 Hz, 1H), 7.58 (ddd, J=17.0, 8.6, 7.4 Hz, 2H), 7.28 (d, J=7.6 Hz, 1H), 2.89 (s, 6H). ¹³ C-NMR (151 MHz, CD ₃ OD) δ=151.6, 138.9, 129.7, 129.4, 129.2, 127.4, 126.6, 122.9, 119.5, 114.8, 44.4.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydrobenzo[b]thiophene-6-sulfonamide-1,1-dioxide

m-Chloroperbenzoic acid (77%, 6.35 g, 27.9 mmol) was added in portions to a solution of benzo[b]thiophene (1.50 g, 11.1 mmol) in anhydrous dichloromethane (100 ml) at room temperature under vigorous stirring, the resulting reaction mixture was stirred for 16 hours at the same temperature. Saturated aqueous NaHCO ₃ (250 ml) was added and the aqueous layer was extracted with dichloromethane (2×100 ml), the organic layer was separated, the combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure. Crystallization from ethanol gave benzo[b]thiophene-1,1-dioxide (1.56 g, 84%) as a white to yellowish solid. ¹ H-NMR (600 MHz, CDCl ₃ ): δ=7.73 (d, J=6 Hz, 1H), 7.58-7.53 (m, 2H), 7.38 (d, J=12 Hz, 1H), 7.23 (d, J=6 Hz, 1 H), 6.73 (d, J=6 Hz, 1H). LCMS (m/z): 167 [M+H] ⁺

A solution of benzo[b]thiophene-1,1-dioxide (0.75 g, 4.51 mmol) in ethanol (55 ml) was degassed with nitrogen for 10 minutes, then 10% Pd/C (10 mg) was added and the mixture was stirred under a hydrogen atmosphere (1 atm) for 24 hours. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated to give 2,3-dihydrobenzo[b]thiophene-1,1-dioxide (0.74 g, 97%) in as a white to yellowish solid. ¹ H-NMR (600 MHz, CDCl ₃ ): δ=7.75 (d, J=6 Hz, 1H), 7.59 (t, J=9 Hz, 1H), 7.49 (t, J= 6 Hz, 1H), 7.40 (d, J=6 Hz, 1H), 3.51 (t, J=6 Hz, 2H), 3.41 (t, J=6 Hz, 2H). LCMS (m/z): 169 [M+H] ⁺

2,3-dihydrobenzo[b]thiophene-1,1-dioxide (0.75 g, 4.45 mmol) was heated in chlorosulfonic acid (1.5 ml, 22.2 mmol) at 80°C for 4 h. The reaction mixture was poured onto crushed ice and stirred for 5 minutes. The aqueous solution was extracted with dichloromethane (2×50 ml) and the combined organic phases were dried (MgSO ₄ ) and concentrated under reduced pressure to obtain

2,3-dihydrobenzo[b]thiophene-6-sulfonyl chloride-1,1-dioxide (0.45 g, 38%) as light brown oil. The technical product was used immediately in the next step without purification. ¹ H-NMR (600 MHz, CDCl ₃ ): δ=8.42 (s, 1H), 8.25 (d, J=12 Hz, 1H), 7.69 (d, J=6 Hz, 1H) , 3.64 (t, J=9 Hz, 2H), 3.55 (t, J=6 Hz, 2H).

Aqueous NH ₃ (2 ml, 28% NH ₄ OH in H ₂ O) at 0°C, the resulting reaction mixture was stirred at room temperature for 2 h or until completion. The solvent was removed under reduced pressure and azeotroped with toluene (×2). The technical residue was purified by silica gel column chromatography using 4% MeOH/CH ₂ Cl ₂ eluent to give 2,3-dihydrobenzo[b]thiophene-6-sulfonamide-1,1-dioxide (0.16 mg, 39%) as white to yellowish solid. ¹ H-NMR (DMSO-d ₆ ): δ=8.09 (s, 1H), 8.06 (d, J=12 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.60 (brs, 2H) 3.70 (t, J=6 Hz, 2H), 3.44 (t, J=9 Hz, 2H).

3-azidobenzenesulfonamide

Synthesized according to the method given in Pawan Kumar, Navneet Chandak, Poul Nielsen, Pawan K. Sharma. Bioorg. Med. Chem. 2012, 20, 3843-3849. A solution of 3-aminobenzenesulfonamide (0.3 g, 1.7 mmol) in CH ₃ CN (8 ml) was cooled to 0°C. To this stirred mixture was added tert-BuONO (250 μl, 2.1 mmol) followed by TMSN ₃ (276 μl, 2.1 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using 100% hexanes as an eluent to give the sub-title compound as a pale yellow solid (0.31 g, 91%). ¹ H-NMR (600 MHz, CD ₃ OD) δ 7.68-7.62 (m, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.47 (d, J= 7.8 Hz, 1H), 7.19-7.15 (m, 1H). ¹³ C-NMR (151 MHz, DMSO-d ₆ ) δ 146.2, 140.8, 131.2, 122.9, 122.4, 116.5.

N-(3-Sulfamoylphenyl)pent-4-ynamide

HBTU (0.46 g , 1.22 mmol) followed by DIPEA (212 µl, 1.22 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, or until complete. The mixture was diluted with EtOAc (30 ml), washed with H ₂ O (20 ml), brine (20 ml), then the organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% hexanes as an eluent to give the sub-title compound as a pale yellow solid (0.2 g, 79%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=8.22 (dd, J=2.2, 1.7 Hz, 1 H), 7.75-7.68 (m, 1H), 7, 65-7.58 (m, 1H), 7.51-7.42 (m, 2H), 2.64-2.59 (m, 2H), 2.58-2.54 (m, 2H), 2.32-2.25 (m, 1H). ¹³ C-NMR (101 MHz, CD ₃ OD) δ=171.3, 143.8, 138.9, 129.2, 122.9, 121.0, 117.1, 82.1, 69.1, 35.4, 14.0.

Benzene-1,3-disulfonamide

Benzene-1,3-disulfonyl dichloride (0.50 g, 0.726 mmol) was dissolved in tetrahydrofuran (4 ml) and the solution was cooled to 0°C. Aqueous ammonia (0.4 ml) was added at 0° C. and the mixture was stirred at ambient temperature for 1 hour. After completion of the reaction, the mixture was poured into chilled water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solid was triturated with pentane to give the sub-title compound as a light brown solid (0.16 g, 87%), ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.27 (t , J=2.0 Hz, 1H), 8.06 (dd, J=2.0, 8.0 Hz, 2H), 7.81 (t, J=8.0 Hz, 1H), 7.64 (s, 4H).

N ¹ ,N ¹ -dimethyl benzene-1,3-disulfonamide

3-Amino-N,N-dimethylbenzenesulfonamide was converted to 3-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (0.45 g, 80%) using method D. ¹ H-NMR (300 MHz, CDCl ₃ ) δ=8, 42 (t, J=2.0 Hz, 1H), 8.27 (d, J=7.9 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.85 ( t, J=7.9 Hz, 1H), 2.79 (s, 6H). The sulfonyl chloride was converted using General Method E1 to give the sub-title compound as a yellow solid (0.45 g, 93%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.13 (m, 2H), 7.98 (d, J=7.9 Hz, 1H), 7.87 (t, J=7, 9 Hz, 1H), 7.65 (s, 2H), 2.65 (s, 6H).

Methyl 3-sulfamoylbenzoate

Methyl 3-(chlorosulfonyl)benzoate (1.00 g, 4.26 mmol) was dissolved in anhydrous tetrahydrofuran (15 ml) and the solution was cooled to 0°C. Aqueous ammonia (5.0 ml) was added dropwise and the mixture was stirred at ambient temperature for 2 hours. Upon completion, the reaction mixture was poured into chilled water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solid was triturated with pentane to give the sub-title compound as a light brown solid (0.75 g, 82%), ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.40 (s , 1H), 8.19 (d, J=8 Hz, 1H), 8.1 (d, J=8 Hz, 1H), 7.77 (t, J=8 Hz, 1H), 7.6 ( s, 2H), 3.92 (s, 3H); m/z 214.0 [M-H+] ^-

3-(4-phenyl-1H-1,2,3-triazol-1-yl)benzenesulfonamide

Ethinylbenzene (1 eq.) and 3-azidobenzenesulfonamide (1.2 eq.), 5 mol. % CuSO ₄ , 10 mol. A % solution of NaAsc in DMSO (500 µl) was stirred at room temperature for 12 h. The technical product was purified directly from the reaction mixture by reverse phase column chromatography (Reveleris flash column chromatography system, 4 g, 18 ml/min. ) and freeze-dried to give the product as a white solid (32 mg, 70%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=9.57-9.36 (m, 1H), 8.46 (d, J=5.7 Hz, 1H), 8.20 (s, 1H), 7.98 (d, J=8.1 Hz, 3H), 7.88 (d, J=7.6 Hz, 1H), 7.62 (s, 2H), 7.53 (d, J=7.4 Hz, 2H), 7.42 (d, J=7.5 Hz, 1H).

N-(prop-2-yn-1-yl)-3-(4-sulfamoylphenyl)propanamide

HBTU (0.74 g, 1.5 mmol) followed by DIPEA (342 µl, 1.22 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and after completion of the reaction, the mixture was diluted with EtOAc (30 ml), washed with H ₂ O (20 ml), brine (20 ml). The organic layer was separated; dried (MgSO ₄ ) and evaporated to obtain a technical product. The crude product was purified by silica gel column chromatography (1:1, EtOAc:Hexane) to isolate the sub-title compound as a white solid (0.22 g, 63%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=7.85 (d, J=7.9 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 3.97 ( t, J=2.4 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.33 (d, J=2.8 Hz, 1H).

benzo[d][1,3]dioxol-5-sulfonamide

Sulfuryl chloride (2.18 ml, 26.7 mmol) was added to anhydrous DMF (2.10 ml, 26.7 mmol) at 0° C. under nitrogen, then the ice bath was removed and the solution was stirred for 15 minutes. The solution was cooled again to 0° C. and benzo[d][1,3]dioxol was added. The reaction mixture was left to reach room temperature, then heated at 100° C. for 2 hours. The reaction mixture was poured onto crushed ice, stirred for 5 minutes, then extracted with dichloromethane (100 ml, then 2×50 ml). The combined organic phases were dried (MgSO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 15% DCM-hexane eluent to give benzo[d][1,3]dioxol-5-sulfonyl chloride as a white to yellowish solid (1.78 g, 33%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.64 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 6.95 (d, J=8 .0 Hz, 1H), 6.16 (s, 2H).

To a solution of benzo[d][1,3]dioxol-5-sulfonyl chloride (0.30 g, 1.35 mmol) in acetone (1 ml) was added aq. NH ₃ (1.5 ml, 28% NH ₄ OH in H ₂ O) at 0°C, the reaction mixture was stirred at room temperature until completion, usually 2 h, then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% MeOH-DCM eluent to give the sub-title compound as a white to yellowish solid (210 mg, 77%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.32 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 7.21 (br.s, 2H ), 7.02 (d, J=8.0 Hz, 1H), 6.11 (s, 2H).

Pyridine-4-sulfonamide

Pyridine-4-sulfonyl chloride was converted using General Method E3 to give the sub-title compound as a pale yellow solid (50 mg, 56%), ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=8, 56 (d, J=4.5 Hz, 1H), 7.49 (d, J=4.5 Hz, 1H), 7.24 (br.s, 2H).

Pyridine-3-sulfonamide

Pyridine-3-sulfonyl chloride was converted using General Method E3 to give the sub-title compound as a pale yellow solid (0.7 g, 79%), ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=8 .96 (dd, J=2.5, 0.9 Hz, 1H), 8.77 (dd, J=4.8, 1.6 Hz, 1H), 8.17 (dd, J=8.0 , 2.4, 1.6 Hz, 1H), 7.67 -7.56 (m, 3H).

Pyridine-2-sulfonamide

A solution of HCl 1.0 mol/l (45 ml) and DCM (45 ml) was cooled to -10°C and pyridine-2-thiol (1.0 g, 9.0 mmol) was added. After 10 minutes, NaOCl (6% solution, 47 ml, 3.3 eq.) was added dropwise over 5 minutes and stirring was continued at -10°C for 10 minutes. The organic phase was separated, dried with Na ₂ SO ₄ and filtered. The resulting solution was added dropwise to a pre-cooled saturated solution of ammonia in methanol and DCM (1:1, 40 ml) at 0°C, then allowed to warm to ambient temperature and stirred until complete, typically 2 h. The solvent was removed at reduced pressure to give a white solid which was dissolved in hot EtOAc and filtered to remove solids. The solvent was removed under reduced pressure and recrystallized from EtOAc-hexanes to give the sub-title compound as a yellow solid (0.5 g, 35%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=8.70 (ddd, J=4.7, 1.7, 0.9 Hz, 1H), 8.05 (td, J=7.7 , 1.7 Hz, 1H), 7.91 (dt, J=7.9, 1.1 Hz, 1H), 7.62 (ddd, J=7.6, 4.7, 1.2 Hz, 1H), 7.45 (s, 2H).

4-(trifluoromethyl)pyridine-2-sulfonamide

4-(trifluoromethyl)pyridine-2-sulfonamide was synthesized according to the procedures used for the synthesis of pyridine-2-sulfonamide, but using 4-(trifluoromethyl)pyridine-2-thiol instead of pyridine-2-thiol. The product 4-(trifluoromethyl)pyridine-2-sulfonamide was obtained as a solid (0.7 g, 56%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=9.02 (d, J=5.0 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J=5, 0 Hz, 1H), 7.68 (s, 2H).

3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide

3-(3-(trifluoromethyl)-3H-diazirin-3-yl)aniline was converted using General Method D to 3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonyl chloride, yellow liquid (1.1 d, 52%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=8.15-8.08 (m, 1H), 7.82-7.77 (m, 1H), 7.76-7.68 (m, 1 H), 7.68-7.61 (m, 1H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ -65.06.

3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonyl chloride was converted using General Method E2 to the sub-title compound as a white solid (0.6 g, 60%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.99 (dt, J=7.9.1.5 Hz, 1H), 7.71 (t, J=2.0 Hz, 1H), 7 .60 (t, J=7.9 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 4.87 (s, 2H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ-65.13.

2-(methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-N-(4-sulfamoylphenethyl)acetamide

2-(methylamino)acetic acid (0.24 g, 2.75 mmol) and sodium hydrogen carbonate (0.694 g, 8.26 mmol) were dissolved in a mixture of water (10 ml) and MeOH (20 ml). Then 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (0.50 g, 2.50 mmol) was added and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the volatiles were removed at reduced pressure and the resulting technical residue was purified by silica gel column chromatography using a gradient of 0-5% methanol in dichloromethane to give 2-(methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)acetic acid as a brick red solid (1.10 g, 87%).

2-(Methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)acetic acid (1.00 g, 3.96 mmol) was dissolved in anhydrous tetrahydrofuran (25 ml) under nitrogen atmosphere and the solution was cooled to 0°C. Diisopropylethylamine (0.76 g, 5.55 mmol) and 1,1'-carbonyldiimidazole (0.90 g, 4.75 mmol) were added and the mixture was stirred at 50° C. until all 2-(methyl (7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)acetic acid. The reaction mixture was then cooled to 0°C, 4-(2-aminoethyl)benzenesulfonamide (0.95 g, 4.75 mmol) was added and stirred at ambient temperature until completion, typically 6 h. The solvents were removed under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the sub-title compound as a brick red solid (1.20 g, 70%). LCMS (m/z): 435.4 (M+1) ⁺ .

4-(2-(7-Nitrobenzo[c][1,2,5]oxadiazol4-ylamino)ethyl)benzenesulfonamide

4-(2-aminoethyl)benzenesulfonamide (0.55 g, 2.75 mmol) and diisopropylethylamine (0.64 g, 2.75 mmol) were dissolved in ethanol (20 ml) and the solution was cooled to 0°C. 4-Chloro-7-nitrobenzo[c][1,2,5]oxadiazole (0.50 g, 2.50 mmol) was added at 0° C. and the mixture was stirred at ambient temperature for 16 h. the masses were poured into brine and extracted with ethyl acetate. The solvents were evaporated from the combined organic extract under reduced pressure and the resulting crude product was purified by reverse phase preparative HPLC to give the sub-title product as a dark yellow solid (0.250 g, 7%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=8.5 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H). 7.47 (d, J=8.4 Hz, 2H), 6.35 (d, J=8.8 Hz, 1H), 3.83 (m, 2H), 3.15 (t, J=7 .6 Hz, 2H).

2-(7-(Dimethylamino)-2-oxo-2H-chromen-4-yl)-N-(4-sulfamoylphenethyl)acetamide (171):

2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)acetic acid (0.50 g, 2.02 mmol), EDCHCl (0.47 g, 3.03 mmol), HOBt ( 0.464 g, 3.03 mmol) and N-methylmorpholine (0.409 g, 4.04 mmol) were mixed in anhydrous tetrahydrofuran (5 ml) and stirred at 0° C. for 30 minutes. 4-(2-Aminoethyl)benzenesulfonamide (0.445 g, 2.224 mmol) was added and stirring was continued at ambient temperature for 18 hours. Upon completion, the reaction mixture was poured into chilled water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-5% methanol in dichloromethane to give 2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)-N-(4 -sulfamoylphenethyl)acetamide as a greenish yellow solid (0.25 g, 29%). LCMS (m/z): 430.2 (M+1) ⁺ .

6,7-Dihydro-5H-pyrrolo[1,2-а]imidazole-2-sulfonamide

A solution of 3-chlorobutanenitrile (20 g, 193.1 mmol) in diethyl ether (100 ml) was treated with MeOH (7.41 g, 231.7 mmol) and cooled to 0°C. HCl gas was bubbled into the reaction mixture for 4 hours at 0°C. The reaction mixture was stirred at -20°C for 24 h and the reaction mixture was concentrated under reduced pressure. The resulting solid residue was washed with diethyl ether (3×100 ml), n-pentane (2×100 ml) and dried in vacuo at 45° C. to give methyl 4-chlorobutanimidate hydrochloride as a white solid. Methyl 4-chlorobutanimidate hydrochloride (25 g, 146.1 mmol) was dissolved in DCM (250 ml) and treated with Et ₃ N (44.3 g, 4.38 mmol) and the resulting solution was cooled to 0°C. To the above mixture was added 2,2-dimethoxyethane-1-amine (12.2 g, 116.9 mmol) dropwise over 5 minutes. The resulting reaction mixture was warmed to 60°C and stirred for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was treated with formic acid (150 ml) and heated at 80°C for 24 h. Upon completion, the reaction mixture was concentrated under reduced pressure. pressure and the resulting residue was subjected to azeotropic distillation with toluene (2×100 ml). Raised the basicity of the technical mixture with a saturated solution of NaHCO ₃ and was extracted with DCM (3×200 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (8 g, 39% over 3 steps) as a low melting dark solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.0 (s, 1H), 6.83 (s, 1H), 3.95 (t, J=7.2 Hz, 2H), 2, 84 (t, J=7.2 Hz, 2H), 2.61-2.51 (m, 2H).

A solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (4 g, 37.0 mmol) in acetonitrile (120 ml) was cooled to 0°C. N- _{iodosuccinimide} (9.16 _g , _40.7 mmol) was added in portions at 0°C. ethyl acetate (2×50 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by silica gel column chromatography using 4-40% EtOAc-hexanes eluent to give 2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (1.0 g, 19%) in form of a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.03 (s, 1H), 3.89 (t, J=7.2 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H), 2.65-2.55 (m, 2H). LCMS (m/z): 235 [M+H] ⁺

In a 50 mL sealed reaction vessel, to a solution of 2-iodo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (0.3 g, 1.28 mmol) and phenylmethanethiol (0.24 g, 1.92 mmol) in 1,4-dioxane (10 mL) reacted with DIPEA (0.41 g, 3.20 mmol) at room temperature under nitrogen. Nitrogen gas was bubbled through the solution for 5 minutes. Xanthos (74 mg, 0.128 mmol) and Pd ₂ (dba) ₃ (60 mg, 0.064 mmol) were successively added to the above solution, and the vessel was purged with nitrogen gas for 5 minutes. The resulting mixture was stirred at 110° C. for 12 hours. Upon completion, the mixture was cooled to room temperature, diluted with EtOAc (25 ml) and filtered through celite. The filtrate was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 50-70% EtOAc-hexanes eluent to give 2-(benzylthio)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, ( 0.15 g, 51%) as a brown liquid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.26-7.22 (m, 3H), 7.12 (s, 1H), 7.05-7.02 (m, 2H), 3 .73 (s, 2H), 3.14 (t, J=6.9 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 2.32-2.27 (m, 2H). LCMS (m/z): 231.3 [M+H] ⁺ .

Solution of 2-(benzylthio)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (250 mg, 1.08 mmol) in acetonitrile (2.5 ml), acetic acid (0.5 ml) and H ₂ O (1.2 ml) cooled to 0°C. DCDMH (170 mg, 0.869 mmol) was added at 0° C. and the resulting reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2×20 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-sulfonyl chloride as a light brown liquid used immediately in the next step.

A solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-sulfonyl chloride (300 mg) in THF (15 ml) was cooled to -40°C. Ammonia gas was bubbled through the above solution for 15 minutes and the solution was stirred at -40°C for 1 hour. The reaction mixture was warmed to room temperature, stirred for 1 hour, then, when complete, concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 10% MeOH-CHCl ₃ eluent to give 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-sulfonamide (117 mg, 88 %) as a white solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=7.54 (s, 2H), 7.26 (s, 1H), 4.06 (s, 2H), 2.80 (s, 2H ), 2.32 (s, 2H). LCMS (m/z): 187.95 [M+H] ⁺ .

4-Nitrobenzenesulfonamide

4-Nitrobenzenesulfonyl chloride (1.0 eq.) dissolved in acetone (0.8 ml/mmol) was added dropwise to ammonium bicarbonate (4.0 eq.) dissolved in water (0.8 ml/mmol). The reaction mixture was stirred at room temperature for 2 h followed by acidification with 1 M HCl (pH~2). The mixture was extracted with ethyl acetate (3×10 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give the sub-title compound as a pale orange solid (157 mg, 57%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=8.42 (d, J=8.8 Hz, 2H), 8.06 (d, J=8.8 Hz, 2H), 7.74 (s, 2H). HRMS calculated for C ₆ H ₅ N ₂ O ₄ S ₁ [M-H] ^- 200.9976, found 200.9984.

5-Methyl-N-(4-sulfamoylphenethyl)isoxazole-3-carboxamide

5-Methylisoxazole-3-carbonyl chloride (1.0 eq.) (prepared using general method B1) was dissolved in anhydrous THF (4 ml/mmol) and treated with triethylamine (1.0 eq.). After stirring for 5 minutes, 4-(2-aminoethyl)benzenesulfonamide (1.0 eq.) was added to the acid chloride solution. The reaction mixture was stirred at room temperature under argon overnight. The solvent was removed under reduced pressure and the residue was purified by reverse phase column chromatography using acetonitrile/10 mmol/L ammonium bicarbonate (aqueous) as mobile phase to give the sub-title compound as a white solid (205 mg, 48%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=8.79 (t, J=5.8 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.30 (s, 2H), 6.50 (q, J=0.6 Hz, 1H), 3.52-3.46 (m, 2H) , 2.91 (t, J=7.2 Hz, 2H), 2.45 (d, J=0.6 Hz, 3H). HRMS calculated for C ₁₃ H ₁₄ N ₃ O ₄ S ₁ [M-H] ^- 308.0711, found 308.0708.

4-(2-(7-Methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide

N-(cyclohexylcarbamoyl)-4-(2-(7-methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide (1.0 eq. ) was dissolved in anhydrous pyridine (8 ml/mmol), treated with phthalic anhydride (1 eq.) and DMAP (0.1 eq.) and heated under reflux under an inert atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue was purified by reverse phase column chromatography using acetonitrile/10 mmol/L ammonium bicarbonate (aqueous) as mobile phase to give the sub-title compound as a white solid (291 mg, 75%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=7.72 (d, J=8.4 Hz, 2H), 7.61 (d, J f=8.7 Hz, 1H), 7, 53 (d, J=2.8 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.33-7.25 (m, 3H), 4.13 (d, J =7.5 Hz, 2H), 3.83 (s, 3H), 2.93 (t, J=7.3 Hz, 2H), 1.45 (s, 6H). HRMS calculated for C ₂₀ H ₂₁ N ₂ O ₅ S ₁ [M-H] ^- 401.1177, found 401.1174.

Synthesis of amine intermediates R1 and R2:

1-methyl-1H-pyrazole-3-amine HCl

In a 20 ml microwave vial, a solution of 2-chloroacrylonitrile (2 g, 22.85 mmol) in EtOH (10 ml) was treated with methylhydrazine (1.93 g, 41.13 mmol). The resulting reaction mixture was heated at 100° C. for 10 minutes in a Biotage microwave synthesizer. The reaction mixture was left at <5°C for 12 h, during which time a solid precipitated. The precipitate was removed by filtration and dried in vacuo to give the sub-title compound as a white solid (0.12 g, 55%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.76 (s, 1H), 6.13 (s, 1H), 3.80 (s, 3H), 2.58 (s, 2H) . LCMS (m/z): 98.3 (M+1) ⁺ .

1-(trifluoromethyl)-1H-pyrazole-3-amine

3-Nitro-1H-pyrazole (5 g, 44 mmol) was dissolved in N,N-dimethylformamide (100 ml), cooled to -5° C. and NaH (3.8 g, 93.6 mmol) was added in portions. The reaction mixture was stirred for 15 min followed by the addition of dibromodifluoromethane (8.6 g, 44 mmol) and warming to ambient temperature overnight. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 3-nitro-1-(trifluoromethyl)-1H-pyrazole (2.1 g, 22%) which was used without further purification . ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-34.20.

1-(Bromodifluoromethyl)-3-nitro-1H-pyrazole (2.1 g, 9.76 mmol) was dissolved in DCM (50 ml) and cooled to -78°C followed by the addition of AgBF ₄ (5.7 g, 28 ,3, 3 equivalents). The reaction mixture was left to warm to ambient temperature overnight, then cooled to 0°C and stopped the reaction by adding saturated. aq. NaHCO ₃ (50 ml). The aqueous phase was extracted with DCM and the combined organic phases were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 3-nitro-1-(trifluoromethyl)-1H-pyrazole (0.9 g, 51 %). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-60.96.

3-nitro-1-(trifluoromethyl)-1H-pyrazole (1.0 g) was dissolved in THF:EtOAc (1:1, 50 ml), Pd/C (200 mg) was added and the mixture was stirred under a hydrogen atmosphere (inflatable ball) throughout the night. The mixture was filtered through celite and washed with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using 40% EtOAc in hexanes as an eluent to give the sub-title product (0.75 g, 87%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.54 (d, J=2.7 Hz, 1H), 5.84 (d, J=2.7 Hz, 1H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-61.13.

1-isopropyl-1 H-pyrazole-3-amine

Isopropylhydrazine hydrochloride (5 g, 45.45 mmol) in water (40 ml) was treated successively with K ₂ CO ₃ (12.5 g, 91 mmol) and 2-chloroacrylonitrile (4 g, 45.45 mmol). The resulting reaction mixture was stirred at 50°C for 1 h, cooled to room temperature and was extracted with ethyl acetate (50 ml). The organic extract was washed with water (40 ml), brine (40 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the sub-title compound as a yellow solid (3.5 g, 62%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.15 (s, 1H), 5.56 (s, 1H), 4.27-4.23 (m, 1H), 3.6 (br .s, 2H), 1.43 (d, J=6.4 Hz, 6H). LCMS (m/z): 126.0 (M+1) ⁺ .

1-cyclopropyl-1H-pyrazole-3-amine

A solution of 1H-pyrazol-3-amine (2 g, 24.1 mmol) in AcOH (20 ml) was treated with 2,5-hexanedione (5.7 g, 50.6 mmol) at ambient temperature under nitrogen. The resulting reaction mixture was heated to 100°C for 6 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The crude product was purified by silica gel column chromatography using a gradient eluent of 50-100% EtOAc-hexanes to give 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole as a red solid (2.25 d, 59%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 7.85 (t, J=1.8 Hz, 1H), 6.28 (t, J=2.1 Hz, 1H), 5.75 (s, 2H), 2.00 (s, 6H). Copper (II) acetate (0.56 g, 3.1 mmol), 2,2'-bipyridine (0.48 g, 3.1 mmol) and dichloroethane (10 ml) were heated to 75°C for 20 min. 5 ml of this pre-prepared solution was added to a mixture of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (0.5 g, 3.1 mmol), potassium cyclopropyl trifluoroborate (2 eq) and sodium carbonate (2 eq.) in dichloroethane (5 ml), then the reaction mixture was stirred at 75°C for 6 hours. The reaction mixture was diluted with DCM, washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure . The technical product was purified by column chromatography on silica gel using 10% EtOAc-hexanes eluent to give 1-cyclopropyl-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole as a yellow liquid (0.2 d, 32%). ¹ H-NMR (300 MHz, Chloroform-d) δ 7.48 (dd, J=2.3, 0.5 Hz, 1H), 6.12 (d, J=2.3 Hz, 1H), 5 .84 (s, 2H), 3.61 (tt, J=7.3, 3.6 Hz, 1H), 2.09 (s, 6H), 1.22-0.95 (m, 4H).

To a solution of ammonium hydroxide (1.64 g, 11.8 mmol) in ethanol ((10 ml) was added a solution of potassium hydroxide (0.66 g) in water (10 ml) at 0°C. After 10 min stirring, a solution of 1-cyclopropyl-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (0.95 g) in ethanol (10 ml) and the reaction mixture was heated at 100°C for 20 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water The organic phase was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure The crude product was purified by silica gel column chromatography using a gradient eluent of 70-100% EtOAc -hexanes to give the sub-title product as a brown solid (0.4 g, 69%) ¹ H-NMR (400 MHz, CDCl ₃ ) δ=7.51 (d, J=2.4 Hz, 1H ), 6.69 (d, J=2.4 Hz, 1H), 5.04 (s, 2H), 3.67 (m, 1H), 1.19 (m, 2H), 1.12 (m , 2H).

1-(tert-butyl)-1H-pyrazole-3-amine

Isopropylhydrazine hydrochloride (1.42 g, 11.4 mmol) in water (25 ml) at 0°C was treated successively with K ₂ CO ₃ (1.57 g, 11.4 mmol), NaHCO ₃ (1.91 g, 22.9 mmol) and 2-chloroacrylonitrile (1 g, 11.4 mmol), then warmed to ambient temperature and stirred for 12 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×25 ml). The combined organic phases were washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the sub-title compound as a brown liquid (0.9 g, 60%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.34 (s, 1H), 5.35 (s, 1H), 4.51 (br.s, 2H), 1.40 (s , 9H). LCMS (m/z): 140.10 (M+1) ⁺ .

1-cyclohexyl-1H-pyrazole-3-amine

3-nitro-1H-pyrazole (1 g, 8.85 mmol) was dissolved in N,N-dimethylformamide (20 mL) and treated with potassium carbonate (1.47 g, 10.62 mmol) and bromocyclohexane (1.8 g, 10.62 mmol). The mixture was heated at 100° C. for 16 hours (or until complete), then cooled to ambient temperature, diluted with water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a 10% EtOAc-hexanes gradient eluent to give 1-cyclohexyl-p-nitro-1H-pyrazole as a colorless liquid (1.3 g, 76%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.47 (d, J=2.5 Hz, 1H), 6.88 (d, J=2.5 Hz, 1H), 4.26-4 .11 (m, 1H), 2.18 (m, 2H), 1.93 (m, 2H), 1.82-1.20 (m, 6H).

In a 100 ml Parr reaction vessel, a solution of 1,5-dimethyl-3-nitro-1H-pyrazole (0.65 g, 3.3 mmol) in MeOH (4 ml) and EtOAc (20 ml) was treated with 10% palladium on carbon (200 mg) in a nitrogen atmosphere. The flask was evacuated, then filled with hydrogen gas (60 psi (414 kPa)) and stirred at ambient temperature for 12 hours.

The reaction mixture was diluted with ethyl acetate (50 ml) and filtered through a pad of celite. The filtrate was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1-cyclohexyl-1H-pyrazol-3-amine as a light brown solid (0.3 g, 55%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.15 (d, J=2.3 Hz, 1H), 5.56 (d, J=2.3 Hz, 1H), 3.85 (m , 1H), 3.62 (s, 1H), 2.1 (m, 2H), 1.8 (m, 2H), 1.77-1.10 (m, 6H).

1-phenyl-1H-pyrazole-3-amine

Potassium tert-butoxide (11.9 g, 106.3 mmol) was dissolved in tert-BuOH (100 ml) and the solution heated to 100°C. Phenylhydrazine (5 g, 46.2 mmol) and 3-ethoxyacrylonitrile (4.5 g, 46.2 mmol) were added successively and heating was continued for 16 h. The mixture was concentrated under reduced pressure. The resulting residue was partitioned between water (500 ml) and ethyl acetate (500 ml). The organic extract was washed with water (250 ml), brine (250 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 25% EtOAc-hexanes as eluent to give 1-phenyl-1H-pyrazole-3-amine as a light brown solid (3.5 g, 48%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.69 (s, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.2 (t, J=7.6 Hz, 1H), 5.85 (s, 1H), 3.83 (br.s, 2H). LCMS (m/z): 160.3 (M+1) ⁺ .

1-benzyl-1H-pyrazole-3-amine

A solution of 3-nitro-1H-pyrazole (1 g, 8.85 mmol) in THF (20 ml) was cooled to 0° C. and NaH (0.53 g, 13.27 mmol) was added. The suspension was stirred for 20 minutes, then benzyl bromide (1.5 g, 8.85 mmol) was added dropwise. The reaction mixture was stirred to completion ~6 h, diluted with saturated NaHCO ₃ solution (20 ml) and extracted with EtOAc (2×50 ml). The organic phases were washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1-benzyl-3-nitro-1H-pyrazole as a white solid (1.5 d, 84%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.40-7.36 (m, 4H), 7.31-7.27 (m, 2H), 6.90 (d, J=2, 7 Hz, 1H), 5.37 (s, 2H). LCMS (m/z): 204.20 (M+1) ⁺

A solution of 1-benzyl-3-nitro-1H-pyrazole (1.5 g, 7.39 mmol) in THF (20 ml) and MeOH (5 ml) was cooled to 0°C. Zinc powder (2.4 g, 36.9 mmol) and a solution of NH ₄ Cl (1.97 g, 36.94 mmol; in 5 ml water) were added. The resulting reaction mixture was heated at 70° C. for 12 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (50 ml) and filtered through a pad of celite. The filtrate was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 50% EtOAc-hexanes as eluent to give 1-benzyl-1H-pyrazole-3-amine as a light brown liquid (0.85 g, 67%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.34-7.26 (m, 3H), 7.14-7.11 (m, 2H), 7.05 (d, J=2, 4 Hz, 1H), 5.59 (d, J=2.4 Hz, 1H), 5.14 (s, 2H). LCMS (m/z): 174.10 (M+1) ⁺

1-(1-phenylethyl)-1H-pyrazole-3-amine

A solution of 3-nitro-1H-pyrazole (1 g, 8.85 mmol) in THF (20 ml) was cooled to 0° C. and NaH (0.7 g, 17.7 mmol) was added. The suspension was stirred for 30 minutes, then (1-bromoethyl)benzene (1.96 g, 10.6 mmol) was added dropwise. The reaction mixture was heated at 80° C. overnight or until complete, cooled to ambient temperature, diluted with water (40 ml) and extracted with EtOAc (2×50 ml). The organic phases were washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20% EtOAc-hexanes as eluent to give 3-nitro-1-(1-phenylethyl)-1H-pyrazole as a yellow liquid (1.2 g, 63%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.46-7.18 (m, 6H), 6.88 (d, J=2.5 Hz, 1H), 5.59 (q, J=7 .1 Hz, 1H), 1.96 (d, J=7.1 Hz, 3H).

A solution of 3-nitro-1-(1-phenylethyl)-1H-pyrazole (1 g, 4.6 mmol) in THF (20 ml) and MeOH (5 ml) was cooled to 0°C. Zinc powder (1.49 g, 23.04 mmol) and a solution of NH ₄ Cl (1.23 g, 23.04 mmol; in 5 ml water) were added. The resulting reaction mixture was stirred for 30 min, then heated at 80° C. for 6 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (50 ml) and filtered through a pad of celite. The organic phase was washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 50% EtOAc-hexanes as eluent to give 1-(1-phenylethyl)-1H-pyrazole-3-amine as a yellow liquid (0.85 g, 67%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.39-7.04 (m, 6H), 5.59 (d, J=2.4 Hz, 1H), 5.35 (q, J= 7.1 Hz, 1H), 3.83 (s, 2H), 1.78 (d, J=7.1 Hz, 3H).

1-(2-(piperidin-1-yl)ethyl)-1H-pyrazole-3-amine

A solution of 3-nitro-1H-pyrazole (2 g, 17.7 mmol) in DMF (20 mL) was treated with 1-(2-chloroethyl)piperidine hydrochloride (4.8 g, 26.5 mmol) at ambient temperature. The solution was cooled to 0° C. and treated with K ₂ CO ₃ (6.1 g, 44.27 mmol) portionwise over 5 minutes. The resulting reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2×40 ml). The combined organic phases were washed with water (40 ml), brine (40 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 25% EtOAc-hexanes as eluent to give 1-(2-(3-nitro-1H-pyrazol-1-yl)ethyl)piperidine as a pale yellow solid (2.5 g , 64%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.60 (d, J=2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 4.29 ( t, J=6.4 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.41 (s, 4H), 1.57-1.53 (m, 4H), 1.45 (t, J=6 Hz, 2H). LCMS (m/z): 225.10 (M+1) ⁺ .

A solution of 1-(2-(3-nitro-1H-pyrazol-1-yl)ethyl)piperidine 3 (2.5 g, 11.16 mmol) in THF (20 ml) and MeOH (5 ml) was cooled to 0° WITH. The solution was treated successively with zinc powder (3.6 g, 55.8 mmol) and aqueous NH ₄ Cl (3 g, 55.8 mmol), then the solution was warmed to ambient temperature and stirred for 5 h. The reaction mixture was diluted with ethyl acetate (50 ml), filtered through a pad of celite and concentrated under reduced pressure. The residue was diluted with ethyl acetate (60 ml) and washed with water (40 ml), brine (40 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1-(2-(piperidin-1-yl)ethyl) -1H-pyrazole-3-amine as a light yellow liquid (1.75 g, 81%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.28 (d, J=2 Hz, 1H), 5.30 (s, J=2 Hz, 1H), 4.50 (s, 2H), 3.90 (t, J=6.8 Hz, 2H), 2.5-2.53 (m, 4H), 2.39-2.33 (m, 6H), 1.2 (s , 2H). LCMS (m/z): 195.10 (M+1) ⁺ .

1,5-dimethyl-1H-pyrazole-3-amine

A solution of 5-methyl-3-nitro-1H-pyrazole (2 g, 15.7 mmol) in THF (20 ml) was cooled to 0°C. NaH (0.7 g, 17.32 mmol) was added portionwise over 10 minutes under nitrogen. The resulting suspension was stirred for 10 min, then treated with Mel (2.2 g, 15.7 mmol), warmed to ambient temperature and stirred for 4 h. The reaction mixture was diluted with a saturated solution of NH ₄ Cl (20 ml) and was extracted with EtOAc (2 × 30 ml). The organic phases were washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1,5-dimethyl-3-nitro-1H-pyrazole as a white solid (2 g, 91%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=6.71 (s, 1H), 3.87 (s, 3H), 2.34 (s, 3H).

In a 100 ml Parr reaction vessel, a solution of 1,5-dimethyl-3-nitro-1H-pyrazole (2 g, 14.18 mmol) in MeOH (4 ml) and EtOAc (20 ml) was treated with 10% palladium per coal (400 mg) in a nitrogen atmosphere. The flask was evacuated, then filled with hydrogen gas (60 psi (414 kPa)) and stirred at ambient temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered through a pad of celite. The filtrate was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1,5-dimethyl-1H-pyrazole-3-amine as a light brown solid (1.36 g, 87%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=5.19 (s, 1H), 4.33 (b.s, 2H), 3.43 (s, 3H), 2.07 (s , 3H). LCMS (m/z): 112.3 (M+1) ⁺

1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-amine

A solution of 1,1,1-triethoxyethane (20 g, 123 mmol) in DCM (250 ml) and pyridine (20.5 g, 259 mmol) was cooled to 0°C. A solution of trifluoroacetic anhydride (52 g, 246 mmol) in DCM (50 ml) was added dropwise over 30 minutes. The reaction mixture was warmed to ambient temperature, stirred for 12 h, then diluted with sat. aq. NaHCO ₃ solution and extracted with DCM (2×250 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 4,4-diethoxy-1,1,1-trifluorobut-3-ene-2 -one in the form of a light brown liquid (20 g, 76%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=4.93 (s, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 4H), 1.46-1.40 (m, 6H).

A solution of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (10 g, 47.16 mmol) in acetonitrile (100 ml) was treated with an aqueous solution of NH ₃ (15 ml) at 0° C, then stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, then the residue was treated with water (250 ml) and extracted with DCM (2×250 ml). The combined organic phases were washed with water (250 ml), brine (250 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give (E)-4-amino-4-ethoxy-1,1,1-trifluorobut -3-en-2-one as a white to yellowish solid (7.5 g, 87%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=5.6 (br s, 1H), 4.17 (q, J=7.2 Hz, 2H), 1.42 (t, J=7 .2 Hz, 3H).

A solution of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (5 g, 27.3 mmol) in EtOH (30 ml) was treated with methylhydrazine sulfate (4, 72 g, 32.8 mmol) and Et ₃ N (4.1 g, 41.0 mmol) at ambient temperature. The resulting reaction mixture was heated at 85°C for 12 h, then cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was diluted with sat. aq. NaHCO ₃ solution (250 ml) and extracted with EtOAc (2 × 250 ml). The combined organic phases were washed with water (250 ml), brine (250 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20% EtOAc-hexanes as an eluent to give 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine as a light brown liquid (0.17 g, 38%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=5.93 (s, 1H), 3.79 (s, 3H), 3.68 (br s, 2H).

1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-amine

A solution of 1-methyl-1H-pyrazol-3-amine (2 g, 20.6 mmol) in AcOH (50 ml) was treated with 2,5-hexanedione (4.9 g, 43.29 mmol) at ambient temperature of nitrogen atmosphere. The resulting reaction mixture was heated to 100° C. for 1 hour, then stirred at ambient temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexanes as an eluent to give 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole as a liquid (2.5 g , 69%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.39 (d, J=2.1 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 5.84 ( s, 2H), 3.92 (s, 3H), 2.10 (s, 6H).

A solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole (1 g, 5.71 mmol) in dry THF (10 ml) was cooled to -78° C. under atmospheric nitrogen, H-BuLi (1.6 mol/l in hexanes, 4.4 ml, 6.86 mmol) was added dropwise to this solution over 10 minutes, then stirred at -78°C for 1 hour, followed by exposure solution of I ₂ (1.54 g, 5.71 mmol) in THF (5 ml) at -78°C, stirring was continued at this temperature until completion (2 h). The reaction mixture was diluted with sat. aq. NH ₄ Cl solution and extracted with ethyl acetate (2×25 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel using 50% EtOAc-hexanes eluent to give 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-1-methyl-1H-pyrazole as white with yellowish solid (0.75d, 43.6%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=6.33 (s, 1H), 5.84 (s, 2H), 3.95 (s, 3H), 2.09 (s, 6H).

To a solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-1-methyl-1H-pyrazole (1 g, 3.32 mmol) in DME:water (8:2, 10 ml) acted 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.67 g, 3.98 mmol) and Na ₂ CO ₃ (0.52 g, 4.98 mmol) at ambient temperature under nitrogen atmosphere. The resulting solution was degassed by purging with argon for 15 min, followed by exposure to Pd(PPh ₃ ) ₄ (190 mg, 0.166 mmol) under argon. The resulting mixture was heated at 90°C for 24 h, then cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was diluted with cold water (20 ml) and extracted with EtOAc (2×20 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by silica gel column chromatography using 5% EtOAc-hexanes as eluent to give 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(prop-1-en-2- yl)-1H-pyrazole as a pale yellow liquid (0.765 g, 92%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=6.08 (s, 1H), 5.84 (s, 2H), 5.39 (s, 1H), 5.23 (s, 1H), 3.92 (s, 3H), 2.12 (s, 9H).

To a solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(prop-1-en-2-yl)-1H-pyrazole (0.7 g, 3.25 mmol) in EtOH-H ₂ O (8:2, 12 ml) was treated with NH ₂ OH.HCl (2.26 g, 32.55 mmol) and KOH (1.8 g, 32.55 mmol). The resulting reaction mixture was heated at 100° C. for 48 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with saturated NaHCO ₃ to give a pH~8 solution, then extracted with EtOAc (2 x 50 ml). The combined organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by silica gel column chromatography using 100% EtOAc eluent to give 1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-amine as a light brown liquid (0.4 g, 91%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=5.54 (s, 1H), 5.27 (s, 1H), 5.08 (s, 1H), 3.71 (s, 3H), 2.41 (s, 2H), 1.92 (s, 3H).

Ethyl 1-benzyl-3-nitro-1H-pyrazole-5-carboxylate

A solution of 3-nitro-1H-pyrazole-5-carboxylic acid (5 g, 31.8 mmol) in ethanol (50 ml) was treated with thionyl chloride (4.5 g, 38.2 mmol) dropwise over 10 min at 0 °C in a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 6 h, then cooled to ambient temperature and concentrated under reduced pressure. Raise the basicity of the obtained residue to pH 8 with saturated NaHCO ₃ solution, followed by extraction with ethyl acetate (2×100 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was triturated with diethyl ether, filtered and dried under reduced pressure to give ethyl 3-nitro-1H-pyrazole-5-carboxylate as a white solid (5 g, 85%). ¹ H-NMR (400 MHz, -d ₆ ): δ=7.44 (s, 1H), 4.36 (q, J=6.8 Hz, 2H), 1.33 (t, J=7, 2 Hz, 3H). LCMS (m/z): 184 (M-1) ^- .

Ethyl 3-nitro-1H-pyrazole-5-carboxylate (1 g, 5.4 mmol) was dissolved in DMF (10 mL) at ambient temperature and treated (1.34 g, 9.7 mmol). The resulting mixture was cooled to 0°C and methyl iodide (1.15 g, 8.1 mmol) was added dropwise, the reaction mixture was sealed, left to warm to ambient temperature and stirred for 12 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2×30 ml).

The combined organic phases were washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 5% EtOAc-hexanes as an eluent to give ethyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate as a white solid (0.65 g, 61%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.54 (s, J=1.1 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 4.19 (d, J=1.2 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H).

Ethyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate (0.65 g, 3.3 mmol) was dissolved in THF (20 ml) and MeOH (5 ml) at 0°C. Zinc powder (1.0 g, 16.3 mmol) and aqueous NH ₄ Cl (0.87 g, 16.3 mmol) were added successively. The resulting reaction mixture was stirred at ambient temperature for 4 hours, then heated to 70°C for 1 hour. The solvents were removed under reduced pressure. The resulting residue was dissolved in EtOAc (30 ml) and filtered through a pad of celite. The filtrate was washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give ethyl 3-amino-1-methyl-1H-pyrazole-5-carboxylate as a white solid substances (0.5 g, 91%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 5.95 (s, 1H), 4.24 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3, 41 (s, 2H), 1.27 (t, J=7.1 Hz, 4H).

Ethyl 1-benzyl-3-nitro-1H-pyrazole-5-carboxylate

A solution of 3-nitro-1H-pyrazole-5-carboxylic acid (5 g, 31.8 mmol) in ethanol (50 ml) was treated with thionyl chloride (4.5 g, 38.2 mmol) dropwise over 10 min at 0 °C in a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 6 h, then cooled to ambient temperature and concentrated under reduced pressure. Raise the basicity of the resulting residue to pH 8 with saturated NaHCO ₃ solution, followed by extraction with ethyl acetate (2×100 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was triturated with diethyl ether, filtered and dried under reduced pressure to give ethyl 3-nitro-1H-pyrazole-5-carboxylate as a white solid (5 g, 85%). ¹ H-NMR (400 MHz, -d ₆ ): δ=7.44 (s, 1H), 4.36 (q, J=6.8 Hz, 2H), 1.33 (t, J=7, 2 Hz, 3H). LCMS (m/z): 184 (M-1) ^- .

Ethyl 3-nitro-1H-pyrazole-5-carboxylate (2 g, 10.8 mmol) was dissolved in DMF (10 ml) at ambient temperature and worked (3 g, 21.6 mmol). The resulting mixture was cooled to 0° C. and benzyl bromide (2.7 g, 16.2 mmol) was added dropwise, the reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2 × 30 ml). The combined organic phases were washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 5% EtOAc-hexanes as an eluent to give ethyl 1-benzyl-3-nitro-1H-pyrazole-5-carboxylate as a white solid (1.2 g, 40%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.44 (s, 1H), 7.34-7.31 (m, 5H), 5.83 (s, 2H), 4.39 (q , J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H). LCMS (m/z): 276.15 (M

Ethyl 1-benzyl-3-nitro-1H-pyrazole-5-carboxylate (1.2 g, 4.36 mmol) was dissolved in THF (20 ml) and MeOH (5 ml) at 0°C. Zinc powder (1.4 g, 21.8 mmol) and aqueous NH ₄ Cl (1.16 g, 21.8 mmol) were added successively. The resulting reaction mixture was stirred at ambient temperature for 4 h, then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (30 ml) and filtered through a pad of celite. The filtrate was washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give ethyl 3-amino-1-benzyl-1H-pyrazole-5-carboxylate as a white solid substances (1 g, 94%). ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=7.30-7.19 (m, 3H), 7.11-7.08 (m, 2H), 6.00 (s, 1H) , 5.43 (s, 2H), 4.91 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H) . LCMS (m/z): 245.9 (M+1) ⁺ .

3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenyl-1H-pyrazole

A solution of 1-phenyl-1H-pyrazole-3-amine (3.5 g, 21.9 mmol) in acetic acid (20 ml) was treated with 2,5-hexanedione (5.2 g, 45.9 mmol) and heated at 100° C. for 4 hours. The mixture was cooled and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel using 5% EtOAc-hexanes eluent to give 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenyl-1H-pyrazole as a colorless liquid (2.8 d, 54%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.98 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.32 (t, J=7.6 Hz, 1H), 6.39 (s, 1H), 5.9 (s, 2H), 2.19 (s, 6H).

A solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenyl-1H-pyrazole (2.7 g, 11.4 mmol) in THF (70 ml) at -78°C was treated with dropwise n-BuLi (1.6 mol/l in THF, 10 ml, 23.91 mmol) over 10 min. The reaction mixture was stirred at -78°C for 1.5 h, then treated with freshly dried acetone (1 g, 17.0 mmol) and stirring continued at -78°C for 1.5 h. The reaction mixture was diluted with saturated ammonium chloride ( 2 ml), concentrated under reduced pressure, then partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extract was washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20% EtOAc-hexanes as eluent to give 2-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenyl-1H-pyrazol-5-yl) propan-2-ol as a white to yellowish solid (1.4 g, 42%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.57-7.56 (m, 2H), 7.47-7.46 (m, 3H), 6.23 (s, 1H), 5 .85 (s, 2H), 2.19 (s, 6H), 1.52 (s, 6H). LCMS (m/z): 296.1 (M+1) ⁺ .

In a 100 ml sealed reaction vessel, 2-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenyl-1H-pyrazol-5-yl)propan-2-ol , 4.74 mmol) was dissolved in - (1:1, 50 ml) at ambient temperature. Hydroxylamine hydrochloride (3.3 g, 47.45 mmol) and KOH (2.6 g, 47.45 mmol) were added successively and the resulting reaction mixture was heated at 120° C. for 16 h. The reaction mixture was concentrated under reduced pressure, diluted water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic extracts were washed with water (50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 50% EtOAc-hexanes as an eluent to give 2-(3-amino-1-phenyl-1H-pyrazol-5-yl)propan-2-ol as a colorless liquid (0.8 g , 78%). LCMS (m/z): 218.1 (M+1) ⁺ .

8-bromo-1,2,3,5,6,7-hexahydro-5-indacene-4-amine

N-Bromosuccinimide (1.02 g, 5.78 mmol) was added in portions to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (1 g, 5.78 mmol) in DCM (20 ml) at 0°C. The solution was gradually warmed to ambient temperature and stirred for 12 hours. The reaction mixture was diluted with saturated aqueous Na ₂ S ₂ O ₃ (50 ml) and extracted with DCM (2×25 ml). The combined organic extracts were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 5% EtOAc-hexane eluent to give 8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine as a brown solid (1. 2 g, 83%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=3.45 (br s, 2H), 2.92-2.88 (m, 4H), 2.81-2.77 (m, 4H) , 2.16-2.09 (m, 4H); LC-MS 94% (210 nm); m/z 252.15 [M+H] ⁺ .

8-chloro-1,2,3,5,6,7-hexahydro-5-indacene-4-amine

N-Chlorosuccinimide (0.46 g, 3.46 mmol) was added in portions to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine, 1 (0.6 g, 3.46 mmol) in CHCl ₃ (10 ml) at 0°C. The solution was gradually warmed to ambient temperature and stirred for 10 h. The reaction mixture was diluted with saturated aqueous Na ₂ S ₂ O ₃ (50 ml) and extracted with DCM (2×25 ml). The combined organic extracts were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10%-hexane eluent to give 8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine as a brown solid (0.45 d, 63%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ=2.94 (t, J=7.2 Hz, 4H), 2.77 (t, J=8.1 Hz, 4H), 2.18 ( m, 4H); m/z 207.8 [M+H] ⁺ .

8-methyl 1,2,3,5,6 7-hexahydro-s-indacene-4-amine

8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (400 mg, 1.59 mmol) was dissolved in 1,4-dioxane-water (8:2, 10 ml) and the reaction flask was purged with argon for 15 min. Sequentially added (650 mg, 4.78 mmol), methylboronic acid (100 mg, 1.75 mmol) and Pd(PPh ₃ ) ₄ (100 mg, 0.079 mmol) under argon. The resulting mixture was sealed and heated at 100°C for 2 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (2×20 ml). The combined organic extracts were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by silica gel column chromatography using 5% hexane as eluent to give 8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine as a colorless liquid (0.220 g, 76 %). ¹ H-NMR (400 MHz, CDCl ₃ ): 5=3.41 (br s, 2H), 2.88-2.8 (m, J=7.5 Hz, 4H), 2.75-2 .67 (m, 4H), 2.18-2.09 (m, 7H); m/z 188.2 [M+H] ⁺ .

3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine

A solution of 2,3-dihydrobenzofuran-5-carbaldehyde, (10 g, 67.6 mmol), malonic acid (10.5 g, 101.35 mmol) and piperidine (0.47 ml, 4.73 mmol, 0.07 equiv.) was heated in pyridine (60 ml) at 100°C for 5 h. The reaction mixture was acidified to ~pH 3 with 1N HCl and the product was extracted with a mixture of 10% IPA/chloroform (2 × 250 ml). The combined organic extracts were washed with water (250 ml), brine (250 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was triturated with diethyl ether to obtain

(E)-3-(2,3-dihydrobenzofuran-5-yl)acrylic acid as a yellow solid (10 g, 78%). ¹ H-NMR (300 MHz, Chloroform-d) δ=7.73 (d, J=15.9 Hz, 1H), 7.43 (s, 1H), 7.33 (dd, J=8.1 , 1.8 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.29 (d, J=15.9 Hz, 1H), 4.64 (t, J=8 .7 Hz, 2H), 3.24 (t, J=8.7 Hz, 2H).

A solution of (E)-3-(2,3-dihydrobenzofuran-5-yl)acrylic acid (8.0 g, 42.1 mmol) in acetic acid (80 ml) and water (1.0 ml) was treated with 10% palladium on carbon (1.0 g) in two portions. The reaction mixture was stirred under hydrogen gas (balloon) until completion, typically 4 hours. The mixture was diluted with ethyl acetate (100 ml) and filtered through a pad of celite, washing with additional ethyl acetate. The solvents were removed under reduced pressure and the technical residue was azeotroped with toluene (2 x 50 ml) to give a white to yellowish solid which was triturated with diethyl ether (50 ml) to give 3-(2,3-dihydrobenzofuran-5- yl) propionic acid as a white solid (6.5 g, 80%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ=7.04 (s, 1H), 6.93 (d, J=8.4, 1H), 6.7 (d, J=8.4 Hz, 1H), 4.55 (t, J=8.4 Hz, 2H), 3.18 (t, J=8.4 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H) , 2.64 (t, J=7.6 Hz, 2H).

A solution of 3-(2,3-dihydrobenzofuran-5-yl)propionic acid (6.0 g, 31 mmol) in thionyl chloride (8 ml) was heated at 80° C. for 1 h. After the reaction was complete, the thionyl chloride was removed under reduced pressure and technical 3-(2,3-dihydrobenzofuran-5-yl)propanoyl chloride was dissolved in anhydrous 1,2-dichloroethane (30 ml). In a separate flask, aluminum trichloride (2 g, 15 mmol) was added to anhydrous 1,2-dichloroethane (40 ml) at 0°C, followed by an acid chloride solution (10 ml) dropwise over 5 min, and the resulting solution was stirred for 30 min at 0°C. Added an additional portion of aluminum trichloride (3 g, 22.5 mmol), followed by dropwise addition of the remaining acid chloride solution (20 ml) at 0°C. The reaction mixture was stirred at room temperature for 1 h or until complete, diluted with water and extracted with (2×50 ml). The combined organic extracts were washed with 1N HCl (50 ml), 1N NaOH (50 ml), water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexanes eluent to give 2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one as a white solid (3. 8 g, 70%). ¹ H-NMR (300 MHz, CD ₃ OD) δ=7.36 (s, 1H), 6.91 (s, 1H), 4.61 (t, J=8.6 Hz, 3H), 3, 26 (t, J=8.6 Hz, 2H), 3.05 (t, J=5.5 Hz, 3H), 2.68 (t, J=5.5 Hz, 2H).

2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (1.5 g, 8.61 mmol) was dissolved in conc. H ₂ SO ₄ (6.0 ml) at 0°C followed by smoke dropwise addition. HNO3: conc. H ₂ SO ₄ , 1:1 (1.2 ml), stirring was continued at 0°C for 1 h. The reaction mixture was added to ice water (60 ml) and stirred for 10 min, the resulting light brown precipitate was removed by filtration , washed with ice water (20 ml) and dried in vacuo to give 8-nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (1.2 g, 64 %). ¹ H-NMR (300 MHz, CD ₃ OD) δ=7.54 (s, 1H), 4.80 (t, J=8.6 Hz, 2H), 3.42 (t, J=8.6 Hz, 2H), 3.09 (t, J=5.6 Hz, 2H), 2.74 (t, J=5.6 Hz, 2H).

To a solution of 8-nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (1.0 g, 4.57 mmol) in methanol (20 ml) 0° C was treated with methanesulfonic acid (0.2 ml) followed by 20% palladium hydroxide (0.5 g). The reaction mixture was stirred under a hydrogen atmosphere at 60 psi. inch (414 kPa) to completion. The reaction mixture was filtered through a pad of celite, rinsing with methanol (50 ml) and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 ml) and washed with sat. aq. NaHCO ₃ (50 ml), water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10%-hexanes as eluent to give 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine as a white solid (0.5 d, 63%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=6.54 (s, 1H), 5.30 (s, 2H), 4.61 (t, J=8.7 Hz, 2H), 3.21 (t, J=8.7 Hz, 2H), 2.95 (t, J=5.5 Hz, 2H), 2.66 (t, J=5.5 Hz, 2H).

4-bromo-3,5,6,7-tetrahydro-2Н-indeno[5,6-b]furan-8-amine

For 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine (0.5 g, 2.86 mmol) and triethylamine (0.51 ml, 3.71 mmol) in dichloromethane (6.0 ml) at 0° C. was treated dropwise with a solution of pivalic acid chloride (0.41 g, 3.43 mmol) in DCM (4.0 ml). The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was added to sat. aq. NaHCO ₃ (30 ml) and extracted with DCM (2×25 ml). The combined organic phases were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give N-(3,5,6,7-tetrahydro-2H-indeno[5, 6-b]furan-8-yl)pivalamide as a white solid (0.55 g, 74%). ¹ H-NMR (300 MHz, Chloroform-d) δ=6.91 (s, 1H), 4.56 (t, J=8.6 Hz, 2H), 3.17 (t, J=8.6 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.04 (n, J=7.4 Hz, 2H), 1.32 (s, 9H).

N-(3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)pivalamide (0.55 g, 2.12 mmol) in acetic acid (10 mL) was treated with with a solution of bromine (0.4 g, 2.55 mmol) in acetic acid (2.0 ml) dropwise, and the reaction mixture was stirred at ambient temperature for 3 hours. Ice water was added to the reaction mixture and stirred for 10 minutes. The resulting precipitate was removed by filtration, washed with water (20 ml) and dried in vacuo to give

N-(4-bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)pivalamide as a light brown solid (0.65 g, 91%) . ¹ H-NMR (300 MHz, Chloroform-d) δ=6.94 (s, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.18 (t, J=8.7 Hz, 2H), 2.92-2.80 (m, 4H), 2.06 (n, J=7.4 Hz, 2H), 1.31 (s, 9H).

N-(4-bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)pivalamide (0.6 g, 1.78 mmol) in EtOH (10 ml ) and conc. HCI (15 ml) was heated at 90° C. for 36 hours. The solution was concentrated under reduced pressure, then made basic with aqueous NH ₄ OH. The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 4-bromo-3,5,6,7-tetrahydro-2H-indeno[5, 6-b]furan-8-amine as a brown solid (0.3 g, 67%). ¹ H-NMR (400 MHz, Chloroform-d) δ=4.61 (t, J=8.6 Hz, 2H), 3.49 (s, 2H), 3.17 (t, J=8.6 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.12(n, J=7.4 Hz, 2H).

3,5,6,7-tetrahydro-2Н-indeno[5,6-b]furan-4-amine

On 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine (0.5 g, 1.98 mmol) in ethanol (10 ml) and acetic acid (1.5 ml) was treated with a solution of sodium nitrate (1.3 g, 19.8 mmol) in water (3.0 ml) and the reaction mixture was stirred at ambient temperature for 4 hours. Ethanol was removed under reduced pressure, then the residue was diluted with water (30 ml), extracted with 10% IPA/chloroform (2×25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 5% EtOAc-hexanes eluent to give 4-bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan as a yellow solid (0. 28 g, 60%).

Copper iodide (0.22 g, 1.18 mmol), L-proline (0.21 g, 1.88 mmol) and sodium azide (0.19 g, 2.94 mmol). The reaction mixture was heated in a sealed vessel at 135°C for 36 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (2×25 ml). The combined organic extracts were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexanes eluent to give 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-amine as a gray solid (0. 17 g, 85%), 1H-NMR (300 MHz, Chloroform-d) δ=6.21 (s, 1H), 4.59 (t, J=8.5 Hz, 2H), 3.51 (s , 1H), 2.98 (t, J=8.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H ), 2.10 (n, J=7.5 Hz, 2H).

benzo[1,2-b:4,5-b']difuran-4-amine

2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-carboxylic acid (0.8 g, 3.88 mmol), 2,3-dichloro-5,6 -dicyanobenzoquinone (2.64 g, 11.65 mmol) in anhydrous dioxane (20 ml) was heated in a sealed vessel at 120° C. for 18 h. The reaction mixture was cooled to room temperature and sat. aq. Na ₂ S ₂ O ₃ (30 ml) followed by extraction with ethyl acetate (2×25 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give commercial benzo[1,2-b:4,5-b']difuran-4-carboxylic acid (1.5 g). Technical acid (1.5 g), triethylamine (2.05 ml) and diphenylphosphoryl azide (4.08 g, 14.85 mmol) in tertiary butanol (20 ml) were heated in a sealed vessel at 90°C for 12 hours. cooled to room temperature, diluted with water (50 ml) and extracted with (2 × 50 ml). The combined organic extracts were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel using 10% EtOAc-hexanes as an eluent to give tert-butylbenzo[1,2-b:4,5-b']difuran-4-ylcarbamate (0.75 g) with minor impurities from phosphine reagent, the product was dissolved in DCM (10 ml) and TFA (3.0 ml) was added dropwise over 5 min at 0°C. The reaction mixture was stirred at ambient temperature for 2 h, then added carefully to sat. aq. NaHCO ₃ (50 ml). The aqueous phase was extracted with DCM (2×30 ml) and the combined organic extracts were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexanes eluent to give benzo[1,2-b:4,5-b']difuran-4-amine as a white to yellowish solid (0.2 g , 30% in three stages). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.6 (d, J=2.2 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.12 ( s, 1H), 6.78 (m, 2H), 4.17 (br.s, 1H).

3-(3-(trifluoromethyl)-3H-diazirin-3-yl)aniline

To a solution of 2,2,2-trifluoro-1-phenylethan-1-one (5 g, 28.7 mmol) in conc. H ₂ SO ₄ (10 ml) at -5°C was added a solution of conc. H ₂ SO ₄ and smoke. HNO ₃ (1:1, 16 ml) and the reaction mixture was stirred for 3 hours. The resulting solution was poured into ice-water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20% EtOAc-hexanes as eluent to give 2,2,2-trifluoro-1-(3-nitrophenyl)ethan-1-one as a yellow liquid (4.2 g, 67%) .

¹ H-NMR (400 MHz, CDCl ₃ ) δ=8.92 (s, 1H), 8.59 (dd, J=8.1, 1.4 Hz, 1H), 8.41 (d, J= 7.8 Hz, 1H), 7.82 (t, J=8.1 Hz, 1H). ¹⁹ F-NMR (233.33 MHz, CDCl ₃ ): -71.82 (s, 3F).

A solution of 2,2,2-trifluoro-1-(3-nitrophenyl)ethan-1-one (4.2 g, 19.2 mmol), hydroxylamine hydrochloride (4.0 g, 57.5 mmol) and pyridine (25 ml) in ethanol (25 ml) was heated under reflux for 3 hours or until complete. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography using 40% hexanes as an eluent to give 2,2,2-trifluoro-1-(3-nitrophenyl)ethan-1-one oxime as a colorless liquid (4, 0 g, 89%). ¹⁹ F-NMR (233.33 MHz, CDCl ₃ ): -66.42 and 62.28 (E- and Z-oxime).

A solution of 2,2,2-trifluoro-1-(3-nitrophenyl)ethan-1-one oxime (4.0 g, 17.1 mmol) in dichloromethane (20 ml) was cooled to 0°C, treated with triethylamine ( 1.5 eq.), N,N-dimethylaminepyridine (0.5 eq.), tosyl chloride (1.1 eq.) and stirred at ambient temperature until complete, typically 16 hours. The reaction mixture was diluted with dichloromethane (50 ml ), washed with saturated aq. NH ₄ Cl (100 ml), water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 5%-hexanes as an eluent to give 2,2,2-trifluoro-1-(3-nitrophenyl)ethan-1-on-O-tosyloxime as a white solid (4.0 g , 60%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=8.41 (ddd, J=5.6, 3.5, 2.2 Hz, 1H), 8.21 (t, J=1.5 Hz, 1H), 7.89 (d, J=8.3 Hz, 2H), 7.81 - 7.65 (m, 2H), 7.42 (d, J=7.8 Hz, 2H), 2, 50 (s, 3H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ -61.55, -66.90.

A solution of 2,2,2-trifluoro-1-(3-nitrophenyl)ethan-1-on-O-tosyloxime (4.0 g, 10.3 mmol) in diethyl ether was cooled to -78°C and the solution was passed through it ammonia for 30 min. The reaction mixture was sealed, allowed to warm to ambient temperature, then stirred for 16 hours. The mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 7%-hexanes as eluent to give 3-(3-nitrophenyl)-3-(trifluoromethyl)diazirine as a colorless liquid (2.4 g, 100%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=8.52 (t, J=2.0 Hz, 1H), 8.33 (ddd, J=8.3, 2.3, 1.1 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.65 (tt, J=7.8, 0.4 Hz, 1H), 2.95 (d, J=8.8 Hz, 1H), 2.31 (d, J=8.9 Hz, 1H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-75.10.

A solution of 3-(3-nitrophenyl)-3-(trifluoromethyl)diazirine (2.4 g, 10.3 mmol) in methanol (30 ml) was treated with triethylamine (2 eq.) and iodine (1 eq.) and the reaction mixture stirred to completion, typically 2 hours. The solution was diluted with diethyl ether, washed with 10% aqueous citric acid, water, aqueous sodium thiosulfate, brine, then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% hexanes as an eluent to give 3-(3-nitrophenyl)-3-(trifluoromethyl)-3H-diazirine as a colorless liquid (2.1 g, 88%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.30 (ddd, J=7.9, 2.2, 1.4 Hz, 1H), 8.09-8.01 (m, 1H), 7 .70-7.54 (m, 2H). ¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-65.14.

3-(3-nitrophenyl)-3-(trifluoromethyl)-3H-diazirine (3.0 g, 13 mmol) in THF (70 ml) was treated with a solution of sodium dithionate (10 eq.) in water (30 ml) and a mixture of stirred at ambient temperature until complete, usually overnight. The solution was diluted with water, extracted with ethyl acetate (x2), washed with water, brine, then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 40% hexanes as an eluent to give the sub-title compound, 3-(3-(trifluoromethyl)-3H-diazirin-3-yl)aniline, as a yellow solid (1.5 g , 58%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ=7.16 (t, J=7.9 Hz, 1H), 6.70 (ddd, J=8.1, 2.3, 0.9 Hz, 1H), 6.52 (ddt, J=7.9, 1.9, 0.9 Hz, 1H), 6.45 (br, 1H), 3.77 (s, 2H). ¹⁹ P-NMR (282 MHz, CDCl ₃ ) 5 -65.07.

4,6-di-tert-butylpyrimidin-2-amine

2,4,6-Trichloropyrimidine (2.7 g, 14.7 mmol) was dissolved in anhydrous THF (30 ml) at 0°C under nitrogen atmosphere. Cul (280 mg, 1.47 mmol) was added to the above solution and then treated with 2 mol/L tert-butyl magnesium chloride in THF (3.78 g, 16.15 ml, 32.3 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution and extracted with EtOAc (2×50 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using 100% hexane eluent to give 4,6-di-tert-butyl-2-chloropyrimidine (1.3 g, 39%) as a light brown liquid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.20 (s, 1H), 1.33 (s, 18H). LCMS (m/z): 227.3 [M+H] ⁺

In a 100 ml sealed reaction vessel, a solution of 4,6-di-tert-butyl-2-chloropyrimidine (1.3 g) in EtOH (15 ml) was cooled to -50°C. Ammonia gas was bubbled through the above solution for 15 minutes. The reaction mixture was heated to 70° C. and stirred for 12 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water and extracted with ethyl acetate (50 ml). The organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 4,6-di-tert-butylpyrimidin-2-amine (0.7 g, 59%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=6.64 (s, 1H), 4.83 (s, 2H), 1.26 (s, 18H). LCMS (m/z): 208.4 [M+H] ⁺

4-chloro-2,6-diisopropylaniline

2,6-Diisopropylaniline (5.0 g, 28.2 mmol) in DMF (100 ml) was treated with N-chlorosuccinimide (3.97 g, 29.7 mmol) and the reaction mixture was stirred at room temperature overnight. The solution was poured into water (500 ml) and extracted with diethyl ether (2×150 ml). The combined organic phases were washed with water (2×200 ml), brine (200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The product was purified by short path distillation to give the sub-title compound as a red oil (3.0 g, 50%). ¹ H-NMR (600 MHz, DMSO-d ₆ ): δ=6.84 (s, 2H), 4.75 (s, 2H), 3.01 (hept, J=6.8 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H). ¹³ C-NMR (151 MHz, DMSO-d ₆ ): δ=141.1, 133.8, 122.5, 120.5, 27.2, 22.8.

4-chloro-2,6-dicyclopropylaniline

In a 50 ml sealed reaction vessel, a solution of 2,6-dibromo-4-chloroaniline (0.25 g, 0.88 mmol) and cyclopropylboronic acid (0.22 g, 2.62 mmol) together with K ₃ PO ₄ (0 .74 g, 3.50 mmol) was dissolved in toluene:water (10 ml:1 ml). The resulting solution was degassed by purging with nitrogen for 5 minutes. Pd(OAc) ₂ (20 mg, 0.087 mmol) and tricyclohexylphosphine (25 mg, 0.087 mmol) were added and the solution was purged with nitrogen gas for another 5 minutes. The resulting mixture was stirred at 100° C. for 12 h. After completion of the reaction, the mixture was diluted with water (25 ml), extracted with EtOAc (2×25 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 5% EtOAc-hexanes as an eluent to give 4-chloro-2,6-dicyclopropaniline (150 mg, 83%) as a brown liquid. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=6.69 (s, 2H), 4.98 (s, 2H), 1.74-1.64 (m, 2H), 0.90 -0.84 (m, 4H), 0.52 -0.47 (m, 4H). LCMS (m/z): 208.30 [M+H] ⁺ .

Synthesis of 4-chloro-2-methyl-6-(trifluoromethyl)aniline

A solution of 2-methyl-6-(trifluoromethyl)aniline (0.4 g, 2.20 mmol) in acetonitrile (4 ml) and AcOH (0.3 ml) was cooled to 0°C. N-chlorosuccinimide (0.36 g, 2.70 mmol) was added at 0° C. and the solution was then allowed to warm to room temperature and stirred for 12 h. Upon completion of the reaction, the reaction mixture was diluted with ice water and the resulting precipitate was removed by filtration and washed successively saturated NaHCO ₃ , Na ₂ S ₂ O ₃ solution, n-pentane and dried in vacuo to give 4-chloro-2-methyl-6-(trifluoromethyl)aniline (0.25 g, 52%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.30 (d, J=2.4 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 2.17 ( s, 3H). ¹⁹ F-NMR (400 MHz, CDCl ₃ ): δ=-63.03

4-chloro-2,6-diethyl aniline

A solution of 2,6-dibromo-4-chloroaniline (0.5 g, 1.75 mmol) and ethylboronic acid (0.4 g, 5.25 mmol) in toluene (15 mL) and water (4 mL) was treated with ( 1.5 g, 7.0 mmol) at room temperature under argon. The solution was purged with argon for 5 minutes followed by exposure to Pd(OAc) ₂ (40 mg, 0.175 mmol) and tricyclohexylphosphine (50 mg, 0.175 mmol). The reaction mixture was again purged with argon for 5 minutes. The resulting mixture was stirred at 100° C. for 12 hours. Upon completion, the reaction mixture was diluted with water, extracted with EtOAc (2×25 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 8% EtOAc-hexanes as an eluent to give 4-chloro-2,6-dicyclopropylaniline (100 mg, 31%) as a yellow liquid. ¹ H-NMR (300 MHz, ) : δ=6.94 (s, 2H), 3.61 (s, 2H), 2.53 (q, J=7.5 Hz, 4H), 1.27 ( t, J=7.5 Hz, 6H). LCMS (m/z): 184.00 [M+H] ⁺ .

4-chloro-2,6-dimethoxyaniline

2,6-dibromo-4-chloroaniline (4 g, 14.0 mmol) was dissolved in 25% NaOMe in MeOH (48 ml) and treated with Cul (2.9 g, 15.4 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70° C. for 12 hours under nitrogen. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2×50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 1% EtOAc-hexanes to give 4-chloro-2,6-dimethoxyaniline (1.0 g, 38%) as a light brown liquid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=6.52 (s, 2H), 3.83 (s, 6H). LCMS (m/z): 187.9 [M+H] ⁺

2-amino-5-chloro-3-cyclopropyl-N,N-dimethylbenzamide

In a 50 ml sealed reaction vessel, 2-amino-3-bromobenzoic acid (2.0 g, 9.25 mmol) was dissolved in DMF (20 ml) and cooled to 0°C. EDC-HCl (2.1 g, 11.0 mmol), HOBt (1.49 g, 11.0 mmol), DIPEA (2.8 ml, 27.7 mmol) and dimethylamine hydrochloride (1.13 g , 13.8 mmol) at 0°C. The reaction mixture was heated to 70°C and stirred for 12 h. Upon completion, the reaction mixture was diluted with water, extracted (2×50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 2-amino-3-bromo-N,N-dimethylbenzamide (2.0 g, 89%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.44 (dd, J=7.8, 1.5 Hz, 1H), 7.06 (dd, J=7.8, 1.5 Hz , 1H), 6.61 (t, J=7.8 Hz, 1H), 4.82 (br s, 2H), 3.05 (s, 6H). LCMS (m/z): 243.10, 245.10 [M+H] ⁺ .

In a 50 mL sealable reaction vessel, a solution of 2-amino-3-bromo-N,N-dimethylbenzamide (2 g, 8.23 mmol), cyclopropylboronic acid (850 mg, 9.87 mmol) and (5.23 g, 24 .06 mmol) was dissolved in toluene (30 ml) and water (3 ml). The solution was degassed by purging with nitrogen for 5 minutes, then Pd(OAc) ₂ (184 mg, 0.823 mmol) and tricyclohexylphosphine (230 mg, 0.823 mmol) were added and the solution was again purged with nitrogen for 5 minutes. The resulting mixture was stirred at 100° C. for 12 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted (2×50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated at reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 20%-hexanes to give 2-amino-3-cyclopropyl-N,N-dimethylbenzamide (1.0 g, 60%) as a light brown solid colors. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.06 (d, J=7.5 Hz, 1H), 6.99 (dd, J=7.8, 1.5 Hz, 1H), 6.66 (t, J=7.8 Hz, 1H), 4.70 (brs, 2H), 3.05 (s, 6H), 1.68-1.61 (m, 1H), 0.94 -0.88 (m, 2H), 0.62-0.57 (m, 2H). LCMS (m/z): 205.3 [M+H] ⁺ .

A solution of 2-amino-3-cyclopropyl-N,N-dimethylbenzamide (0.5 g, 2.44 mmol) in acetonitrile (10 ml) and AcOH (0.3 ml) was cooled to 0°C. N-chlorosuccinimide (0.5 g, 3.67 mmol) was added at 0° C. and the resulting reaction mixture was warmed to room temperature and stirred for 12 h. Upon completion, the reaction mixture was diluted with saturated Na ₂ S ₂ O ₃ solution and extracted with ethyl acetate (2 × 50 ml). The combined organic extracts were washed with NaHCO ₃ solution, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 25%-hexanes eluent to give 2-amino-5-chloro-3-cyclopropyl-N,N-dimethylbenzamide (0.2 g, 34%) as brown solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.02 (d, J=1.5 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 4.66 ( brs, 2H), 3.05 (s, 6H), 1.68-1.61 (m, 1H), 0.94-0.88 (m, 2H), 0.62-0.57 (m, 2H). LCMS (m/z): 239.0 [M+H] ⁺ .

4-chloro-2-methoxy-6-(trifluoromethyl)aniline

In a 50 mL sealed reaction vessel, a solution of 2-bromo-4-chloro-6-(trifluoromethyl)aniline (0.5 g, 1.82 mmol), bis(pinacolato)diboron (0.92 g, 3.64 mmol) and KOAc (0.44 g, 4.55 mmol) in 1,4-dioxane (10 ml) were degassed by purging with nitrogen for 5 minutes. Pd(dppf)Cl ₂ (015 g, 0.182 mmol) was added and the solution was again purged with nitrogen gas for 5 minutes. The resulting mixture was stirred at 110° C. for 12 hours. Upon completion, the reaction mixture was diluted with water, extracted (2×50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 2% EtOAc-hexanes eluent to give 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-6-(trifluoromethyl)aniline (0.5 g, 85%). LCMS (m/z): 324.10 [M+H] ⁺ .

4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)aniline (500 mg, 1.55 mmol) was dissolved in THF (5 ml) and H ₂ O (2 ml) at room temperature. NaBO ₃ .H ₂ O (0.62 g, 6.23 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 4 h. Upon completion, the reaction mixture was diluted with water, extracted (2×50 ml) and the combined organic extract was washed water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 15% EtOAc-hexanes eluent to give 2-amino-5-chloro-3-(trifluoromethyl)phenol (0.5 g, 100%) as a yellow liquid . ¹ H-NMR (300 MHz, -d ₆ ): δ=10.50 (s, 1H), 6.85 (s, 2H), 5.12 (br s, 2H). ¹⁹ F-NMR (300 MHz, DMSO-d ₆ ): δ=-61.46. LCMS (m/z): 211.6 [M+H] ⁺ .

2-amino-5-chloro-3-(trifluoromethyl)phenol (250 mg, 1.18 mmol) was dissolved in anhydrous DMF (5 ml) and worked (240 mg, 1.77 mmol).

The resulting mixture was stirred at room temperature for 30 minutes. Methyl iodide (185 mg, 1.303 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was diluted with water, extracted (2 x 50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc-hexanes eluent to give 4-chloro-2-methoxy-6-(trifluoromethyl)aniline (0.2 g, 75%) as light brown solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.10 (d, J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 5, 34 (br s, 2H) 3.85 (s, 3H). ¹⁹ F-(400 MHz, DMSO-d ₆ ): δ=-61.45.

7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-amine

A solution of 2,3-dihydro-1H-inden-4-amine, 1 (500 mg, 3.75 mmol) in EtOH (5 ml) was cooled to 0°C and treated dropwise with acetic anhydride (0.95 g, 9. 37 mmol) under a nitrogen atmosphere. The resulting reaction mixture was warmed to room temperature and stirred for 3 h. Upon completion of the reaction (TLC, 30% ethyl acetate-hexanes, R _f , 0.2), the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, filtered and dried in vacuo to give N-(2,3-dihydro-1H-inden-4-yl)acetamide (0.3 g, 45%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=9.29 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.08 (t, J=7 .6 Hz, 1H), 6.99 (d, J=6.8 Hz, 1H), 2.87 (t, J=7.2 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.04 (s, 3H), 1.99-1.95 (m, 2H). LCMS (m/z): 176.40 [M+H] ⁺

N-(2,3-dihydro-1H-inden-4-yl)acetamide (200 mg, 1.11 mmol) was dissolved in AcOH (5 ml) and cooled to 0°C. N-chlorosuccinimide (220 mg, 1.69 mmol) was added, then the reaction mixture was warmed to room temperature and stirred overnight. Upon completion, the reaction mixture was diluted with ice water and the resulting solid was removed by filtration, washed with saturated NaHCO ₃ , Na ₂ S ₂ O ₃ solution and dried in vacuo to give N-(7-chloro-2,3-dihydro-1H-indene-4 -yl)acetamide (0.12 g, 50%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.73 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.86 ( s, 1H), 3.02-2.85 (m, 4H), 2.19 (s, 3H), 1.99 (m, 2H). LCMS (m/z): 209.80 [M+H] ⁺

N-(7-chloro-2,3-dihydro-1H-inden-4-yl)acetamide (120 mg, 0.57 mmol) was dissolved in 3 M HCl (5 ml) and heated at 90°C for 4 h Upon completion, the reaction mixture was cooled to room temperature and made basic (pH ~8) with saturated NaHCO ₃ followed by extraction with EtOAc (2 x 20 ml). The combined organic extracts were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 7-chloro-2,3-dihydro-1H-inden-4-amine (70 mg, 74%) as white solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=6.85 (d, J=8.4 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4, 97 (s, 2H), 2.82 (t, J=8.1 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.01-1.96 (m, 2H ). LCMS (m/z): 168.20 [M+H] ⁺ .

A solution of 7-chloro-2,3-dihydro-1H-inden-4-amine (0.8 g, 4.79 mmol) in acetonitrile (10 ml) was cooled to 0°C and treated with N-iodosuccinimide (1.61 g , 7.18 mmol) at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 12 h. Upon completion, the reaction mixture was diluted with saturated Na ₂ S ₂ O ₃ solution and extracted with ethyl acetate (2×50 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 4-5% hexanes as eluent to give 7-chloro-5-iodo-2,3-dihydro-1H-inden-4-amine (0.45 g , 32%) as a light brown solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ=7.36 (s, 1H), 5.04 (s, 2H), 2.82-2.72 (m, 4H), 2.03 -1.98 (m, 2H). LCMS (m/z): 293.7 [M+H] ⁺ .

In a 50 ml sealed reaction vessel, a solution of 7-chloro-5-iodo-2,3-dihydro-1H-inden-4-amine (0.35 g, 1.19 mmol) and cyclopropylboronic acid (0.41 g, 4.77 mmol) in 1,4-dioxane (14 ml) and water (4 ml) was treated with Cs ₂ CO ₃ (1.16 g, 3.57 mmol) at room temperature under nitrogen atmosphere. Nitrogen was bubbled through the solution for 5 minutes and Pd(OAc) ₂ (26 mg, 0.119 mmol) and Catacxium-A (42 mg, 0.119 mmol) were exposed under nitrogen. The resulting mixture was again degassed with nitrogen for another 5 minutes. The resulting mixture was stirred at 100° C. for 24 h. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc (2×25 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 5% EtOAc-hexanes eluent to give 7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-amine (70 mg, 28% ) as a light brown solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=6.86 (s, 1H), 2.94 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.15-2.10 (m, 2H), 1.44-1.43 (m, 1H), 0.91-0.88 (m, 2H), 0.58-0, 55 (m, 2H). LCMS (m/z): 208.3 [M+H] ⁺ .

Synthesis of acid intermediates R2:

2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-carboxylic acid

The synthesis of 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-carboxylic acid was carried out from hydroquinone using the procedures detailed by Monte et al. J.Med.Chem. 1996, 39, 2953-2961 to give 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-carbaldehyde as a light yellow solid; ¹ H-NMR (400 MHz, CDCl ₃ ): δ=10.27 (s, 1H), 6.87 (s, 1H), 4.67 (t, J=8.8 Hz, 2H), 4, 59 (t, J=8.8 Hz, 2H), 4.59 (t, J=8.8 Hz, 2H), 3.46 (t, J=8.8 Hz, 2H), 3.18 ( t, J=8.8 Hz, 2H).

The aldehyde (0.68 g, 3.58 mmol) was oxidized with silver (I) oxide (1.5 eq.) in 5% aqueous sodium hydroxide at room temperature for 20 days. The technical reaction mixture was filtered through celite, extracted with diethyl ether (2×50 ml) to remove unreacted aldehyde, then the aqueous phase was acidified to pH 1 with 3.0 mol/l aqueous HCl dropwise at 0°C. The product was extracted with dichloromethane (2 x 50 ml) and the combined organic phases were washed with brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give 2,3,6,7-tetrahydrobenzo[1,2-b :4,5-b']difuran-4-carboxylic acid as a white solid (0.44 g; 60%).

Alternatively, the aldehyde (0.5 g, 2.77 mmol) in acetone (5.0 ml) was treated with aminosulfonic acid (0.4 g, 4.17 mmol) in two portions at 0°C. After 2 minutes, a solution of sodium chlorite (0.32 g, 3.6 mmol) in water (1.0 ml) was added dropwise and stirring was continued at 0° C. for 4 hours. The reaction mixture was diluted with water (20 ml) and extracted with a mixture of 10% IPA/chloroform (2 x 20 ml). The combined organic phases were washed with water (25 ml), brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical solid was triturated with diethyl ether to give 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-carboxylic acid (0.4 g, 70%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=6.86 (s, 1H), 4.52 (t, J=8.8 Hz, 2H), 4.47 (t, J=8 .8 Hz, 2H), 3.30 (t, J=8.8 Hz, 2H), 3.10 (t, J=8.8 Hz, 2H). ¹³ C (100 MHz, DMSO-d ₆ ): δ=166.4, 154.2, 153.9, 128.9, 127.2, 111.4, 110.43, 71.9, 71.6, 31.5, 29.5.

Benzo[d][1,3]dioxole-4-carboxylic acid

Synthesized using modified techniques from Pie et.al. J.Med.Chem. 2004, 47, 871-887 as follows:

2,3-dihydroxybenzoic acid (5.0 g, 32.4 mmol) in anhydrous methanol (50 ml) was treated with concentrated sulfuric acid (10 drops) and refluxed overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 ml), washed with sat. aq NaHCO ₃ (2×50 mL), brine (50 mL), then dried (MgSO ₄ ) and concentrated under reduced pressure to give methyl 2,3-dihydroxybenzoate (2.92 g, 54%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ=10.9 (s, 1H), 7.32 (dd, J=8.0, 1.2 Hz, 1H), 7.09 (m, 1H ), 6.78 (t, J=8.0 Hz, 1H), 5.65 (s, 3H). ¹³ C-NMR (100 Hz, CDCl ₃ ) 170.7, 148.8, 145.0, 120.5, 119.8, 119.2, 112.4, 52.4.

Methyl 2,3-dihydroxybenzoate (1.0 g, 5.95 mmol) in DMF (16 mL) was treated with KF (1.79 g, 30.9 mmol) and stirred at ambient temperature for 30 minutes. Diiodomethane (1.79 g, 6.7 mmol) was added and the reaction mixture was heated at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into water (100 ml) and extracted with diethyl ether (2×50 ml). The combined organic phases were washed with water (50 ml), brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel using 10% petroleum ether as eluent to give methylbenzo[d][1,3]dioxol-4-carboxylate as a white crystalline solid (0.56 g, 52%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.41 (dd, J=8.0, 1.2 Hz, 1H), 6.97 (dd, J=8.0, 1.2 Hz , 1H), 6.86 (t, J=8.0 Hz, 1H), 6.1 (s, 2H), 3.93 (s, 3H).

A solution of methyl benzo[d][1,3]dioxol-4-carboxylate (0.4 g, 2.22 mmol) in methanol (8.0 ml) was treated with 2.0 M aq KOH (2.2 ml) and the solution was stirred at room temperature for 3 hours. The mixture was concentrated to a volume of ~3 ml, diluted with water (5 ml) and acidified to pH ~3 with 2.0 mol/l HCl. The resulting precipitate was removed by filtration, washed with water then diethyl ether and dried in vacuo to give benzo[d][1,3]dioxole-4-carboxylic acid as a beige solid (0.38 g, 97%). ¹ H-NMR (400 MHz, -d ₆ ): δ=7.28 (dd, J=8.0, 1.2 Hz, 1H), 6.97 (dd, J=8.0, 1.2 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 6.12 (s, 2H); ¹³ C-NMR (100 Hz, DMSO-d ₆ ) 165.5, 148.9, 148.5, 122.9, 121.6, 113.8, 112.5, 102.1.

Synthesized compounds by substituent class

Aliphatic substituents

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)cyclohexanesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and cyclohexanesulfonamide were used in General Method C3 to give the sub-title compound as a white solid (12 mg , 41%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=6.97 (s, 1H), 3.50-3.43 (m, 1H), 2.87 (t, 4H, J=8.0 Hz), 2.78 (t, 4H, J=8.0 Hz), 2.22-2.18 (m, 2H), 2.10-2.02 (m, 4H), 1.94-1 .71 (m, 2H), 1.63-1.59 (m, 1H), 1.64-1.53 (m, 2H); 1.41-1.21 (m, 3H); ¹³ C-NMR (100 MHz, CD ₃ OD): δ=143.7, 137.8, 126.4, 118.4, 110.2, 59.9, 35.5, 30.0, 28.5 , 25.8, 25.1, 24.8; Purity by LCMS: >95%; LCMS (m/z): 363 [M+H] ⁺ ; HRMS calculated for C ₁₉ H ₂₆ N ₂ O ₃ S [M+H] ⁺ :363.1737, found 363.1729.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)cyclopentanesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and cyclopentanesulfonamide were used in General Method C3 to give the sub-title compound as a white solid (26 mg , 42%) ¹ H-NMR (400 MHz, CD ₃ OD): δ=6.97 (s, 1H), 4.08-4.02 (m, 1H), 2.83 (t, J=8 .0 Hz, 4H), 2.80 (t, J=8.0 Hz, 4H), 2.13-2.01 (m, 8H), 1.84-1.77 (m, 2H), 1 .71-1.65 (m, 2H); ¹³ C-NMR (100 MHz, CD ₃ OD): δ=145.1, 139.2, 127.8, 119.8, 111.7, 62.2, 33.9, 31.4, 29.9 , 28.6, 26.9; Purity by LCMS: >95%; LCMS (m/z): 349 [M+H] ⁺ ; HRMS calculated for C ₁₈ H ₂₄ N ₂ O ₃ S: 349.1580, found 349.1588.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)tetrahydro-2H-pyran-4-sulfonamide.

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and tetrahydro-2H-pyran-4-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (12 mg, 57%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=7.00 (s, 1H), 4.09 (dd, J ₁ =4 Hz, J ₂ =12 Hz, 2H), 3.82-3 .76 (m, 1H), 3.49-3.43, (m, 2H), 2.89 (t, J=8 Hz, 4H), 2.81 (t, J=8 Hz, 4H), 2.12-2.05 (m, 6H), 1.98-1.87 (m, 2H); ¹³ C-NMR (100 MHz, CD ₃ OD): δ=154.0, 143.1, 137.7, 126.5, 110.4, 66.0, 57.0, 32.5, 28.5 , 25.9, 25.1; Purity by LCMS: >95%; LCMS (m/z): 365 [M+H] ⁺ ; HRMS calculated for C ₁₈ H ₂₄ N ₂ O ₄ S, 365.1530, found 365.1541.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)tetrahydrofuran-3-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and tetrahydrofuran-3-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid substances (12 mg, 60%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.04 (s, 1H), 6.93 (s, 1H), 4.33-4.27 (m, 1H), 4.04 -4.00 (m, 1H), 3.91-3.89 (m, 1H), 3.85-3.79 (m, 1H), 3.72-3.66 (m, 1H), 2 .80 (t, J=16.0 Hz, 4H), 2.70 (t, J=16.0 Hz, 4H), 2.24-2.17 (m, 2H), 1.99 -1, 95 (m, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=142.4, 139.6, 136.6, 124.7, 108.2, 68.7, 61.7, 32.5, 30, 3, 28.8, 28.1, 24.9; Purity by LCMS: >95%; LCMS (m/z): 351 [M+H] ⁺ ; HRMS calculated for C ₁₇ H ₂₂ N ₂ O ₄ S 351.1373, found 351.1389.

FURANS

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and furan-2-sulfonamide were used in General Method C4 to give the sub-title compound as a white solid substances (75 mg, 16%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.08 (br s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.22 (q , J=2.0 Hz, 1H), 6.94 (s, 1H), 6.71 (kv, J=2.0 Hz, 1H), 2.78 (t, J=7.2 Hz, 4H ), 2.59 (t, J=7.2 Hz, 4H), 1.94 (quint, J=7.2 Hz, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=148.9, 147.9, 147.3, 143.1, 137.3, 128.7, 118.0, 117.5, 111, 7, 54.9, 32.5, 30.1, 25.1. LCMS, Purity: 96.26%; m/z 345.1 (M-H ⁺ ). HRMS (FAB ^- (fast atom bombardment)) calculated for C ₁₇ H ₁₈ N ₂ O ₄ S [M-H] ^- : 345.0987, found: 345.0866.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methylfuran-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 5-methylfuran-2-sulfonamide were used in General Method C2 to give the sub-title compound as white solid (28 mg, 53%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.96 (s, 1H), 7.00-6.99 (d, J=4.0 Hz, 1H), 6.91 (s , 1H), 6.29-6.28 (d, J=4.0 Hz, 1H), 1H), 2.78 (t, J=8.0 Hz, 4H), 2.61 (t, J = 8.0 Hz, 4H), 2.34 (s, 3H), 2 (t, J=8.0 Hz, 4H), 1.98-1.90 (m, 4H); ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=143.3, 137.6, 129.9, 125.2, 118.0, 114.6, 108.7, 108.2, 107, 8, 32.9, 30.6, 25.4, 13.8; Purity by LCMS: >95%; LCMS (m/z): 361 [M+H] ⁺ ; HRMS calculated for C ₁₈ H ₂₀ N ₂ O ₄ S [M+H] ⁺ 361.1216, found 361.1217.

5-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 5-ethylfuran-2-sulfonamide were used in General Method C2 to give the sub-title compound as white solid (51 mg, 47%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.97 (br, 1H), 7.02 (s, 1H), 6.91 (d, J=4.0 Hz, 1H), 6.31 (d, J=4.0 Hz, 1H), 2.78 (t, J=8.0 Hz, 4H), 2.68 (q, J=8.0 Hz, 2H), 2. 59 (t, J=6.0 Hz, 4H), 1.97-1.90 (m, 4H), 1.19 (t, J=8.0 Hz, 3H). ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=143.5, 143.3, 142.9, 137.6, 129.8, 118.0, 108.7, 106.8, 106, 3, 32.9, 30.5, 25.4, 21.3, 12.1; Purity by LCMS: >95%; LCMS (m/z): 375 [M+H] ⁺ ; HRMS calculated for C ₁₉ H ₂₂ N ₂ O ₄ S [M+H] ⁺ 375.13730, found 375.13910.

5-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 5-((dimethylamino)methyl)furan-2-sulfonamide were used in General Method C2 to give sub-title compound as white solid (25 mg, 6%), ¹ H-NMR (400 MHz, CD ₃ OD) δ=7.17 (d, J=3.5 Hz, 1H), 6.96 (s, 1H), 6.86 (d, J=3.5 Hz, 1H), 4.43 (s, 2H), 2.86 (s, 3H), 2.86 (t, J=7, 4 Hz, 4H), 2.73 (t, J=7.4 Hz, 4H), 2.04 (n, J=7.4 Hz, 4H).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C5 to give the sub-title compound as a white solid (2.5 g, 63%). ¹ H-NMR (600 MHz, DMSO-d ₆ ): δ=7.61 (br s, 1H), 7.37 (d, J=0.9 Hz, 1H), 6.77 (s, 1H ), 6.58 (d, J=0.9 Hz, 1H), 2.74 (t, J=7.3 Hz, 4H), 2.65 (t, J=7.3 Hz, 4H), 1.89 (tt, J=7.3, 7.3 Hz, 4H), 1.34 (s, 6H). ¹³ C-NMR (101 Hz, DMSO-d ₆ ): δ=157.4, 155.7, 142.2, 137.3, 136.7, 135.7, 132.4, 115.7, 109, 3, 66.6, 32.6, 31.1, 30.6, 25.1.

N-((8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-Bromo-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide used in General Method C1 to give the sub-title compound as a white solid (40 mg, 7%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=7.68 (s, 1H), 7.23 (s, 1H), 2.91 (t, J=7.6 Hz, 4H), 2 .85 (t, J=7.6 Hz, 4H), 2.11 (m, 4H), 1.51 (s, 6H). LCMS (m/z): 482.9 [M-H] ^- ; 97.64% (210 nm), 99% (254 nm). HPLC: 96.70% (210 nm), 97.22% (254 nm).

N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-Chloro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide used in General Method C1 to give the sub-title compound as a white solid (50 mg, 16%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=7.55 (s, 1H), 7.02 (s, 1H), 2.91 (t, J=7.2 Hz, 4H), 2, 85 (t, J=7.2 Hz, 4H), 2.09 (m, 4H), 1.5 (s, 6H). LCMS (m/z): 460.9 (M+Na) ^- ; 95.16% (210 nm), 95.07% (254 nm). HPLC: 97.91% (210 nm), 98.04% (254 nm).

4-(2-hydroxypropan-2-yl)-N-((8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide used in General Method C1 to give the sub-title compound as a white solid (15 mg, 3%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=7.58 (s, 1H), 7.07 (s, 1H), 6.46 (s, 1H), 2.82-2.73 ( m, J=7.5 Hz, 8H), 2.12 (s, 3H), 2.05-2.02 (m, 4H), 1.508 (s, 6H). LCMS(m/z): 417.10(M-1) ^- ; 99.59% (210 nm), 99.33% (254 nm). HPLC: 97.92% (210 nm), 97.53% (254 nm).

5-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)furan-3-carboxylic acid

On ethyl 5-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)furan-3-carboxylate (0.1 g, 0.24 mmol) in THF (8 ml) at 0° C. was treated with a solution of LiOH (0.1 g, 2.4 mmol) in water (2 ml). The cooling bath was removed and the reaction mixture was stirred for 3 h. The solution was acidified with 10% citric acid and immediately extracted with ethyl acetate (2×25 ml). The organic phases were washed with water (20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase HPLC to give the sub-title compound as a white solid (5.0 mg, 5%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=8.14 (s, 1H), 7.28 (s, 1H), 6.93 (s, 1H), 2.85 (t, J= 7.6 Hz, 4H), 2.74 (t, J=7.6 Hz, 4H), 2.04 (quint, J=7.6 Hz, 4H).

Ethyl 5-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)furan-3-carboxylate

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and ethyl 5-sulfamoylfuran-3-carboxylate were used in General Method C3. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2×25 ml) and the organic phases were washed with brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 50% hexanes as an eluent to give the sub-title compound as a white solid (0.45 g, 63%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ=8.31 (s, 1H), 7.59 (s, 1H), 6.77 (s, 1H), 4.22 (q, J= 7.2 Hz, 2H), 2.75 (t, J=7.3 Hz, 4H), 2.65 (t, J=7.3 Hz, 4H) 1.90 (pent, J=7.6 Hz, 4H), 1.26 (t, J=7.2 Hz, 3H).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4-(prop-1-en-2-yl)furan-2-sulfonamide were used in General Method C6 to give the sub-title compound as a white solid (85 mg, 51%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.54 (s, 1H), 7.28 (s, 1H), 7.00 (s, 1H), 5.26 (s, 1H), 5, 05 (s, 1H), 2.86 (t, J=7.4 Hz, 4H), 2.69 (t, J=7.5 Hz, 4H), 2.09-1.98 (m, 7H ). ¹³ C-NMR (101 MHz, CDCl ₃ ) δ 144.4, 142.8, 137.8, 132.8, 129.2, 127.2, 119.4, 115.4, 113.6, 32, 9, 30.5, 25.5, 20.9. HRMS (ESI (Electric Field Sputter Ionization)) calculated for C ₂₀ H ₂₃ N ₂ O ₄ S [M+H] 387.1373, found 387.1379.

4-(2-hydroxypropan-2-yl)-N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)carbamoyl)furan-2-sulfonamide

8-isocyanato-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan (prepared using General Method A1) and ethyl 5-sulfamoylfuran-3-carboxylate were used in General Method C3 to give ethyl 5-(N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)carbamoyl)sulfamoyl)furan-3-carboxylate as light brown solid substances (0.25 g, 50%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.17 (s, 1H), 6.77 (d, J=5.2 Hz, 1H), 4, 43 (t, J=8.6 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.07 (t, J=8.6 Hz, 2H), 2.71 ( t, J=7.3 Hz, 2H), 2.63 (t, J=7.3 Hz, 2H), 1.89 (p, J=7.4 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H).

On ethyl 5-(N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)carbamoyl)sulfamoyl)furan-3-carboxylate (0.25 g , 0.6 mmol) in anhydrous THF (10 ml) at 0° C. was treated with a solution of methylmagnesium chloride (3.0 mol/l in Et ₂ O, 6 eq.) dropwise over 5 minutes with vigorous stirring. The solution was then stirred at 0° C. for 30 minutes, then at ambient temperature for 4 hours, followed by stopping the reaction by dropwise addition of a saturated ammonium chloride solution. The aqueous solution was extracted using (2×25 ml), the combined organic phases were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was triturated with diethyl ether, then purified by reverse phase preparative HPLC to give the sub-title compound as a white solid (32 mg, 13%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.58 (s, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 5.02 (s, 1H), 4.47 (t, J=8.6 Hz, 2H), 3.10 (t, J=8.6 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H), 2. 59 (t, J=7.5 Hz, 2H), 1.90 (d, J=7.4 Hz, 2H), 1.36 (s, 6H).

N-((4-bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan- 2-sulfonamide

4-bromo-8-isocyanato-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan (prepared using General Method A1) and 4-(prop-1-en-2-yl )furan-2-sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (20 mg, 9%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=7.48 (d, J=1.2 Hz, 1H), 6.93 (d, J=1.2 Hz, 1H), 4.60 ( t, J=8.7 Hz, 2H), 3.16 (t, J=8.6 Hz, 2H), 2.85 (m, 4H), 2.03 (n, J=7.5 Hz, 2H), 1.50 (s, 6H).

4-(2-hydroxypropan-2-yl)-N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)furan-2-sulfonamide

4-isocyanato-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan (prepared using General Method A1) and 4-(prop-1-en-2-yl)furan-2 The α-sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (20 mg, 9%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=7.58 (s, 1H), 7.07 (s, 1H), 6.46 (s, 1H), 4.49 (d, J=8 .9 Hz, 2H), 3.05 (t, J=8.7 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 2.04 (n, J=7.4 Hz, 2H), 1.51 (d, J=1.9 Hz, 6H).

4-(2-hydroxypropan-2-yl)-N-((2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)carbamoyl)furan-2 -sulfonamide

4-isocyanato-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan- 2-sulfonamide was used in General Method C6 to give the sub-title compound as a white solid (285 mg, 96%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 7.76 (s, 1H), 7.66 (s, 1H), 7.01 (s, 1H), 6.45 (s, 1H), 5.04 (s, 1H), 4.46 (t, J=8.6 Hz, 2H), 4.39 (t, J=8.6 Hz, 2H), 3.08 (t, J=8 .6 Hz, 2H), 2.94 (t, J=8.6 Hz, 2H), 1.37 (s, 6H).

N-(benzo[1,2-b:4,5-b']difuran-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-Isocyanatobenzo[1,2-b:4,5-b']difuran (prepared using General Method A1) and ethyl 5-sulfamoylfuran-3-carboxylate were used in General Method C3 to give ethyl 5-(N- (benzo[1,2-b:4,5-b']difuran-4-ylcarbamoyl)sulfamoyl)furan-3-carboxylate as a white solid (0.05 g, 53%). ¹ H-NMR (300 MHz, CD ₃ OD) δ=8.25 (s, 1H), 7.72 (d, J 2.1 Hz, 1H), 7.63 (d, J 2.1 Hz, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 6.93 (s, 1H), 6.89 (d, J 2.1 Hz, 1H), 6.86 (d , J 2.1 Hz, 1H), 4.30 (q, J 6.9 Hz, 2H), 1.4 (t, J 6.9 Hz, 3H).

On ethyl 5-(N-(benzo[1,2-b:4,5-b']difuran-4-ylcarbamoyl)sulfamoyl)furan-3-carboxylate (0.25 g, 0.6 mmol) in anhydrous THF (10 ml) at 0° C. was reacted with a solution of methylmagnesium chloride (3.0 mol/l in Et ₂ O, 10 eq.) dropwise over 10 minutes with vigorous stirring. The solution was then stirred at 0-10° C. for 3 hours, then the reaction was stopped by dropwise addition of a saturated ammonium chloride solution. The aqueous solution was extracted using EtOAc (2×20 ml), the combined organic phases were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was triturated with diethyl ether, then purified by reverse phase preparative HPLC to give the sub-title compound as a white solid (15 mg, 6%), ¹ H-MP (400 MHz, CD ₃ OD) δ = 7.76 (d, J=2.0 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.05 (s, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 1.5 (s, 6H).

N-(anthracen-9-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

9-isocyanatoanthracene (prepared using General Method B2) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C6 to give the sub-title compound as a white solid (24 mg, 23% ). ¹ H-NMR (400 MHz, CD ₃ OD) δ = 8.49 (s, 1H), 8.07-7.98 (m, 4H), 7.75 (s, 1H), 7.55-7 .44 (m, 4H), 7.27-7.22 (m, 1H), 1.49 (s, 6H). ¹³ C-NMR (101 MHz, CD ₃ OD) δ = 153.8, 149.4, 141.4, 136.6, 131.7, 128.8, 128.2, 127.4, 126.4, 125.9, 124.9, 122.8, 115.2, 111.1, 67.2, 29.6.

4-(2-hydroxypropan-2-yl)-N-(quinolin-8-ylcarbamoyl)furan-2-sulfonamide

To a solution of quinoline-8-amine (1 g, 6.9 mmol) in THF (10 ml) and triethylamine (2 eq.) was slowly added phenyl chloroformate (1.5 eq.) at 0°C. The solution was stirred at room temperature for 2 hours or until complete. The solution was diluted with saturated aq. NaHCO ₃ solution, extracted with ethyl acetate (2 x 50 ml), washed with water, brine, then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EtOAc-hexanes to give phenylquinolin-8-ylcarbamate (1.5 g, 83%) as a white solid which was used immediately in the next reaction step.

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (0.2 g, 0.98 mmol) in THF (5 ml) at 0°C was treated with sodium hydride (3 eq.) in portions and the suspension was stirred at ambient temperature for 45 minutes (until gas evolution stops). Commercial phenylquinolin-8-ylcarbamate was dissolved in THF (5 ml), then slowly added to the reaction mixture and the solution was stirred at ambient temperature until completion, typically 4 hours. The reaction mixture was diluted with saturated aqueous NH ₄ Cl, extracted with ethyl acetate (x2) , washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the sub-title compound, 4-(2-hydroxypropan-2-yl)-N-(quinolin-8-ylcarbamoyl)furan-2-sulfonamide, as a white solid (40 mg, eleven%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.63 (s, 1H), 8.89 (d, J=4.3 Hz, 1H), 8.37 (m, 2H), 7, 80-6.76 (m, 5H), 5.09 (s, 1H), 1.38 (s, 6H).

4-(2-hydroxypropan-2-yl)-N-((6-methoxyquinolin-8-yl)carbamoyl)furan-2-sulfonamide

4-(2-hydroxypropan-2-yl)-N-((6-methoxyquinolin-8-yl)carbamoyl)furan-2-sulfonamide was synthesized using a modification of the procedures used to obtain 4-(2-hydroxypropan-2-yl )-N-(quinolin-8-ylcarbamoyl)furan-2-sulfonamide, but using 6-methoxyquinoline-8-amine instead of quinoline-8-amine. The sub-title compound was obtained as a white to yellowish solid (75 mg, 38%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H), 8.63 (m, 1H), 8.17 (m, 1H), 8.09 (d, J=2 .7 Hz, 1H), 7.49 (dd, J=8.3, 4.2 Hz, 1H), 7.40 (s, 1H), 6.79 (d, J=2.8 Hz, 1H ), 6.69 (s, 1H), 4.96 (s, 1H), 3.84 (s, 3H), 1.36 (s, 6H).

N-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

5-Isocyanato-2,3-dihydrobenzo[b][1,4]dioxin (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C6 to give the sub-title compound as a white solid (49 mg, 39%). ¹ H-NMR (600 MHz, Acetonitrile-d ₃ ) δ = 7.56 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (d, J=1.0 Hz, 1H) , 6.98 (d, J=1.0 Hz, 1H), 6.7 (t, J=8.4 Hz, 1H), 6.48 (dd, J=8.4, 1.5 Hz, 1H), 4.22 (m, 4H), 1.43 (s, 6H).

N-((2,3-dihydrobenzofuran-7-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

7-Isocyanato-2,3-dihydrobenzofuran (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C6 to give the sub-title compound as a white solid (32 mg, 39%). ¹ H-NMR (600 MHz, Acetonitrile-d ₃ ) δ 7.64 (d, J=7.7 Hz, 1H), 7.48 (d, J=1.1 Hz, 1H), 7.00 ( e, J=1.1 Hz, 1H), 6.89 (m, 1H), 6.74 (t, J=7.7 Hz, 1H), 4.56 (t, J=8.7 Hz, 1H), 3.2 (t, J=8.7 Hz, 1H), 1.43 (s, 6H).

N-((2,4-bis(trifluoromethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

1-Isocyanato-2,4-bis(trifluoromethyl)benzene (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C4 to give the sub-title compound in as a white to yellowish solid (0.12 g, 33%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.59 (d, J=8.8 Hz, 1H), 7.87 (d, J=9.2 Hz, 1H), 7, 81 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 6.68 (s, 1H), 4.94 (s, 1H), 1.36 (s, 6H ). ¹³ C-NMR (100 MHz, DMSO-d ₆ : δ = 156.0, 154.4, 142.5, 138.1, 135.8, 129.9, 125.2, 124.9, 123.0 , 122.5, 121.3, 120.7, 120.4, 115.5, 115.2, 110.2, 66.5, 31.0 LCMS, Purity: 90.47%, tr=3, 84 min, m/z 459.25 (MH ⁺ ) MCBP (FAB ^- ) calculated for C ₁₆ H ₁₄ F ₆ N ₂ O ₅ S [MH] ^- : 459.0528, found: 459.0512.

N-((2,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

2-Isocyanato-1,4-bis(trifluoromethyl)benzene (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C4 to give the sub-title compound in as a white to yellowish solid (55 mg, 12%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 8.61 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 7 .37 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 1.41 (s, 6H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ 156.4, 154.5, 139.7, 138.1, 132.9, 127.2, 124.9, 122.3, 118.9 , 117.6, 117.0, 110.0, 66.5, 31.0. LCMS, Purity: 95.02%, tr=2.09 min, m/z 558.94 (MH ⁺ ). MCBP (FAB ^- ) calculated for C ₁₆ H ₁₄ F ₆ N ₂ O ₅ S [MH] ^- : 459.0528, found: 459.0224.

4-(2-hydroxypropan-2-yl)-N-((2-methoxyphenyl)carbamoyl)furan-2-sulfonamide

1-Isocyanato-2-methoxybenzene (prepared using General Method A2) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C2 to give the sub-title compound as a white to yellowish solid substances (30 mg, 38%).

N-((2,5-dimethoxyphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

2-isocyanato-1,4-dimethoxybenzene and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C2 to give the sub-title compound as a white to yellowish solid (52 mg, 55 %).

N-((4-chloro-2,6-dimethylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-chloro-2,6-dimethylaniline, 1 (300 mg, 1.92 mmol) was dissolved in THF (50 ml) and cooled to 0°C. NaH (100 mg, 2.49 mmol) was added portionwise to the above solution under nitrogen atmosphere and the mixture was stirred for 15 minutes. Phenyl chloroformate (0.33 ml, 0.72 mmol) was added dropwise to the above solution at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with EtOAc, filtered through Celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 30% EtOAc-hexanes eluent to give phenyl (4-chloro-2,6-dimethylphenyl)carbamate (0.2 g, 85%) as a white solid . ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.41-7.36 (m, 2H), 7.21-7.19 (m, 2H), 7.11-7.10 (m, 3H), 6.30 (brc, 1H), 2.33 (s, 6H).

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (133mg, 0.64mmol) was dissolved in anhydrous THF (5mL) and treated gently with NaH (65mg, 1.63mmol) at 0°C in a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 45 min, then reacted with a solution of phenyl (4-chloro-2,6-dimethylphenyl)carbamate (200 mg, 0.73 mmol) in THF (3 ml) under nitrogen at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes eluent to give

N-((4-chloro-2,6-dimethylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (20 mg, 31%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.83 (s, 1H), 7.56 (s, 1H), 7.19 (s, 1H), 7.10-7.05 (m , 2H), 2.16 (s, 6H), 1.55 (s, 6H). LCMS (m/z): 385.05 [MH] ^- , 94.12% (210 nm). HPLC: 92.60% (210 nm). HRMS calculated for C ₁₆ H ₁₈ Cl ₁ N ₂ O ₅ S ₁ [MH] ^- 385.0630, found 365.0621.

N-((2,4-dimethyl-6-(trifluoromethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-Chloro-2-methyl-6-(trifluoromethyl)aniline (230 mg, 1.1 mmol) was dissolved in anhydrous THF (20 ml) and treated with Et ₃ N (0.17 ml, 1.32 mmol) at room temperature . The solution was treated with triphosgene (130 mg, 0.44 mmol) and the resulting mixture was stirred at 60° C. for 4 h, then concentrated under reduced pressure. The resulting residue was stirred with n-pentane (20 ml) for 10 min, filtered through a pad of celite and concentrated under reduced pressure to give 5-chloro-2-isocyanato-1-methyl-3-(trifluoromethyl)benzene (0.2 g ) as a white solid. The product was used in the next step without further purification.

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide, 3 (150mg, 0.731mmol) was dissolved in anhydrous THF (50mL) and treated gently with NaH (44mg, 1.096mmol) at 0°C under atmospheric nitrogen. The resulting reaction mixture was stirred at room temperature for 30 minutes and reacted with a solution of 5-chloro-2-isocyanato-1-methyl-3-(trifluoromethyl)benzene (0.2 g) in THF (30 ml) under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes as an eluent. The product was then triturated with diethyl ether and n-pentane to give N-((2,4-dimethyl-6-(trifluoromethyl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (15 mg, 5%) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.52-7.48 (m, 3H), 6.99 (s, 1H), 2.19 (s, 3H), 1.47 ( s, 6H). ¹⁹ F-NMR (400 MHz, CD ₃ OD): δ = -63.09. LCMS (m/z): 439.05 [M-H] ^- ; 94.86% (210 nm), 96.92% (254 nm). HPLC: 98.90% (210 nm). HRMS calculated for C ₁₆ H ₁₅ Cl ₁ F ₃ N ₂ O ₅ S ₁ [MH] - 439.0348, found 439.0339. N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide were used in General Method C2 to give the sub-title compound in as a white solid (161 mg, 34%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ = 7.82 (s, 1H), 7.61 (s, 1H), 7.09 (s, 2H), 6.93 (s, 1H) , 5.04 (s, 1H), 3.05-2.99 (m, 2H), 1.35 (s, 6H), 1.05 (d, J=6.9 Hz, 12H). HRMS calculated for C ₂₀ H ₂₆ Cl ₁ N ₂ O ₅ S ₁ [MH] ^- 441.1256, found 441.1264.

N-((4-chloro-2,6-dicyclopropylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-Chloro-2,6-dicyclopropylaniline, 1 (250 mg, 1.20 mmol) was dissolved in THF (50 ml) and cooled to 0°C. NaH (72 mg, 1.80 mmol) was added portionwise and the resulting mixture was stirred for 20 minutes under nitrogen. Phenyl chloroformate (370 mg, 2.40 mmol) was added dropwise at 0°C, then the reaction mixture was warmed to room temperature and stirred for 12 h. When complete, the reaction mixture was diluted with EtOAc, filtered through celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 8% EtOAc-hexanes as an eluent to give phenyl (4-chloro-2,6-dicyclopropylphenyl)carbamate (0.2 g, 51%) as a white solid . ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.38-7.35 (m, 2H), 7.21-7.19 (m, 3H), 6.84-6.83 (m, 2H), 2.06-2.04 (m, 2H), 1.04-1.02 (m, 4H), 0.69-0.68 (m, 4H).

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (75mg, 0.365mmol) was dissolved in anhydrous THF (50mL) and treated gently with NaH (36mg, 0.914mmol) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 30 min, then reacted with a solution of phenyl (4-chloro-2,6-dicyclopropylphenyl)carbamate (135 mg, 0.402 mmol) in THF (3 ml) under nitrogen at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 4 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by silica gel column chromatography (60-120 mesh) using 50-100% EtOAc-hexanes to give

N-((4-chloro-2,6-dicyclopropylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (10 mg, 6%) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.59 (s, 1H), 7.13 (s, 1H), 6.76 (s, 2H), 1.88-1.86 ( m, 2H), 1.47 (s, 6H), 0.89-0.84 (m, 4H), 0.55-0.54 (m, 4H). LCMS (m/z): 436.95 [M-H] ^- ; 96.29% (210 nm). HPLC: 98.29% (210 nm). HRMS calculated for C ₂₀ H ₂₂ Cl ₁ N ₂ O ₅ S ₁ [M-H] ^- 437.0943, found 437.0945. HRMS calculated for C ₂₀ H ₂₂ Cl ₁ N ₂ O ₅ S ₁ [M-H] ^- 437.0943, found 437.0945.

4-(2-hydroxypropan-2-yl)-N-((5-methoxy-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide

5-methoxy-2,3-dihydro-1H-inden-4-amine (150 mg, 0.59 mmol) was dissolved in THF (15 ml) and cooled to 0°C. NaH (35 mg, 0.89 mmol) was added to the above solution and stirred for 20 minutes. Phenyl chloroformate (150 mg, 0.932 mmol) was added dropwise at 0° C., then the solution was allowed to warm to room temperature overnight. Upon completion, the reaction mixture was diluted with saturated NaHCO ₃ and extracted with EtOAc (30 ml), the organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to obtain phenyl (5-methoxy-2,3-dihydro- 1H-inden-4-yl)carbamate (100 mg, 59%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.40-7.35 (m, 2H), 7.22-7.18 (m, 3H), 7.06 (d, J=8, 1 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 2.98-2.84 (m, 4H), 2.08 (t, J=7.5 Hz, 2H). LCMS (m/z): 284.3 [M+H] ⁺

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (87 mg, 0.424 mmol) was dissolved in anhydrous THF (5 mL) and treated gently with NaH (44 mg, 1.097 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 1 h, then reacted with a solution of phenyl (5-methoxy-2,3-dihydro-1H-inden-4-yl)carbamate (120 mg, 0.424 mmol) in THF (5 ml) under atmosphere nitrogen at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 6 h. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution and extracted with EtOAc (2 x 30 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: X bridge (150 mm x 19 mm, particle size 5 µm); flow rate: 15 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: 17% B=0/10, 2/10, 9/70]. Fractions were freeze-dried to give 4-(2-hydroxypropan-2-yl)-N-((5-methoxy-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (45 mg, 17%) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.67 (s, 1H), 7.21 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 3.79 (s, 3H), 2.84 (t, J=7.2 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H ), 2.01-1.97 (m, 2H), 1.49 (s, 6H). LCMS (m/z): 393.10 [M-H] ^- ; 98.97% (210 nm), 99.47% (254 nm). HPLC: 92.07% (210 nm), 93.87% (254 nm). HRMS calculated for C ₁₈ H ₂₁ N ₂ O ₆ S ₁ [M-H] ⁺ 393.1126, found 392.1113.

N-((7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-amine, 6 (70 mg, 0.33 mmol) was dissolved in THF (5 ml) and cooled to 0°C. NaH (20 mg, 0.505 mmol) was added to the above solution under nitrogen atmosphere and stirred for 15 min, followed by the addition of phenyl chloroformate (100 mg, 0.674 mmol) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with EtOAc, filtered through Celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc-hexanes eluent to give phenyl(7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamate (80 mg, 73%) as a brown solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.39-7.37 (m, 3H), 7.25-7.24 (m, 2H), 6.85 (s, 1H), 3 0-2.94 (m, 4H), 2.12-2.10 (m, 2H), 1.34 (m, 1H), 0.96-0.95 (m, 2H), 0.59 -0.57 (m, 2H). LCMS (m/z): 328.30 [M+H] ⁺ .

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (56mg, 0.274mmol) was dissolved in anhydrous THF (5mL) and treated gently with NaH (27mg, 0.685mmol) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 15 min and reacted with a solution of phenyl (7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamate (100 mg, 0.244 mmol) in THF (2 ml ) in a nitrogen atmosphere at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 3 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 30 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: Gemini NX C18 (21.2 mm x 150 mm, particle size 5 µm); flow rate: 18 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: T/% B=0/20, 2/30, 10/50]. The fractions were freeze-dried to give

N-((7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (45mg, 38 %) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.95 (d, J=2.4 Hz, 1H), 6.74 (s, 1H), 6.69 (d, J=2 .4 Hz, 1H), 4.49 (m, 1H), 2.84 (t, J=7.6 Hz, 2H), 2.66 (t, J=7.6 Hz, 2H), 1, 95 (m, 2H), 1.78 (m, 1H), 1.41 (d, J=6.4 Hz, 6H), 0.82 (m, 2H), 0.54 (m, 2H). LCMS (m/z): 437.0 [M-H] ^- , 97.99% (210 nm). HPLC: 98.26% (210 nm). HRMS calculated for C ₂₀ H ₂₂ Cl ₁ N ₂ O ₅ S ₁ [MH] ⁺ 437.0943, found 437.0927.

4-(2-hydroxypropan-2-yl)-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide

A solution of 8-nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (200 mg, 0.92 mmol) in MeOH (5 ml) was degassed with nitrogen for 5 minutes, added 10% Pd/C (20 mg, 10% w/w) and the mixture was stirred under hydrogen atmosphere at room temperature for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 8-amino-3.5, 6,7-tetrahydro-s-indacen-1(2H)-one as a white to yellowish solid (160 mg, 93%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 6.49 (s, 1H), 6.34 (s, 2H), 2.90-2.84 (m, 2H), 2.80 (t , J=7.5 Hz, 2H), 2.62 (t, J=7.4 Hz, 2H), 2.56-2.51 (m, 2H), 2.04-1.99 (m, 2H). ¹³ C-NMR (150 MHz, DMSO-d ₆ ): 206.6, 155.4, 153.7, 144.1, 125.3, 118.6, 109.4, 36.8, 33.7, 28.6, 25.0, 24.9. LCMS (m/z): 188 [M+H] ⁺ . MCBP calculated for C ₂ H ₁₄ N ₁ O ₁ [M+H] ⁺ 188.1070, found 188.1077.

To di-tert-butyl dicarbonate (163 mg, 0.74 mmol) in anhydrous acetonitrile (1 ml) was added DMAP (26.1 mg, 0.21 mmol) at room temperature, stirred for 5 minutes, 8-amino solution was added -3,5,6,7-tetrahydro-s-indacen-1(2H)-one (100 mg, 0.53 mmol) in acetonitrile. The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was used directly in the next step without isolation.

NaH (18.3 mg, 0.48 mmol) was added to the intermediate 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (100 mg, 0.48 mmol) in anhydrous THF (1 ml) at 0° C and stirred for 30 minutes at ambient temperature under nitrogen. Cooled again to 0°C, added 8-isocyanato-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (reaction mixture from previous step) and stirred at ambient temperature for 16 hours. 0.5 ml H ₂ O was added to the reaction mixture, loaded directly into the C18 column for purification using an aqueous solution of (NH ₄ )HCO ₃ 10 mmol/l and acetonitrile as the mobile phase, to obtain

4-(2-hydroxypropan-2-yl)-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide in as white solid (150 mg, 67%), ¹ H-NMR (600 MHz, DMSO-d ₆ ): δ 8.79 (s, 1H), 7.37 (s, 1H), 6.94 (s , 1H), 6.61 (s, 1H), 4.92 (s, 1H), 2.92 (t, J=5.6 Hz, 2H), 2.82 (t, J=7.5 Hz , 2H), 2.75 (t, J=7.5 Hz, 2H), 2.63-2.57 (m, 2H), 1.97-1.80 (m, 2H), 1.34 ( s, 6H); LCMS (m/z): 417 [M-H] ^- . HRMS calculated for C ₂₀ H ₂₃ N ₂ O ₆ S ₁ [M+H] ⁺ 419.1271, found 419.1291

To a solution of 4-(2-hydroxypropan-2-yl)-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2- sulfonamide (70 mg, 0.16 mmol) in MeOH (2 ml) NaBH ₄ (63 mg, 1.67 mmol) was added at 0°C under nitrogen atmosphere, the resulting reaction mixture was stirred at room temperature for 3 hours. diluted with H ₂ O (2 ml, MeOH was distilled off, the aqueous layer was loaded directly into a C18 column for purification using an aqueous solution of (NH ₄ )HCO ₃ 10 mmol/l and acetonitrile as a mobile phase, obtaining

N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide in as a white to yellowish solid (60 mg, 86%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 7.73 (br s, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.60 (s, 1H ), 5.63 (br.s, 1H), 4.92 (br.s, 1H), 4.87 (d, J=6.0 Hz, 1H), 3.00-2.84 (m, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.64-2.53 (m, 2H), 2.07-2.00 (m, 1H), 1.97-1 .92 (m, 1H), 1.91-1.81 (m, 2H), 1.35 (s, 6H); 13C-NMR (150 MHz, DMSO-d ₆ ): 159.5, 156.0, 144.9, 143.3, 138.3, 137.7, 136.8, 136.0, 133.0, 72 .6, 67.0, 35.4, 33.1, 31.5, 31.4, 31.0, 30.4, 25.5; LCMS (m/z): 419 [M-H] ^- ; HRMS calculated for C ₂₀ H ₂₃ N ₂ O ₆ S ₁ [M-H] ^- 419.1282, found 419.1263.

N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

A solution of 4-nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (110 mg, 0.50 mmol) in MeOH (5 ml) was degassed with nitrogen for 5 minutes, added 10% Pd/C (11 mg, 10% w/w), stirred under hydrogen atmosphere at room temperature for about 2 h. 7-tetrahydro-s-indacen-1(2H)-one as a white to yellowish solid (75 mg, 80%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 6.72 (s, 1H), 5.11 (s, 2H), 2.87-2.74 (m, 4H), 2.70 (t , J=7.4 Hz, 2H), 2.62-2.54 (m, 2H), 2.06-1.99 (m, 2H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ) δ 206.7, 144.6, 141.7, 139.9, 136.9, 136.8, 104.2, 39.9, 36.7, 30.6, 30.5, 24.5, 23.7. LCMS (m/z): 188 [M+H] ^- ; HRMS calculated for C ₁₂ H ₁₄ N ₁ O ₁ [M+H] ⁺ 188.1070, found 188.1074.

To di-tert-butyl dicarbonate (81.6 mg, 0.37 mmol) in anhydrous acetonitrile (1 ml) was added DMAP (13.0 mg, 0.04 mmol) at room temperature, stirred for 5 minutes, a solution of 4 was added -amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (50 mg, 0.26 mmol) in acetonitrile (1 ml). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was used directly in the next step without isolation.

NaH (9.3 mg, 0.24 mmol) was added to the intermediate 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (50 mg, 0.24 mmol) in anhydrous THF (1 ml) at 0° C and stirred for 30 minutes at ambient temperature under nitrogen. Cooled again to 0°C, 4-isocyanato-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (reaction mixture from previous step) was added and stirred at ambient temperature for 16 h. 0.5 ml H ₂ O was added to the reaction mixture, loaded directly into the C18 column for purification using an aqueous solution of (NH ₄ )HCO ₃ 10 mmol/l and acetonitrile as the mobile phase, to obtain

4-(2-hydroxypropan-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2-sulfonamide ( 70 mg, 63%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 7.94 (s, 1H), 7.38 (s, 1H), 7.17 (s, 1H), 6.60 (s, 1H), 4.92 (s, 1H), 2.94-2.89 (m, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.4 Hz , 2H), 2.56-2.52 (m, 2H), 2.00-1.94 (m, 2H), 1.35 (s, 6H); LCMS (m/z): 417 [M-H] ^- ; HRMS calculated for C ₂₀ H ₂₁ N ₂ O ₆ S ₁ [M-H] ^- 417.1126, found 417.1113.

To a solution of 4-(2-hydroxypropan-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2- sulfonamide (50 mg, 0.11 mmol) in MeOH (2 ml) NaBH ₄ (45 mg, 1.19 mmol) was added at 0°C under nitrogen atmosphere, the resulting reaction mixture was stirred at room temperature for 3 hours. diluted with H ₂ O (1 ml), MeOH was distilled off, the aqueous layer was loaded directly into a C18 column for purification using an aqueous solution of (NH ₄ )HCO ₃ 10 mmol/l and acetonitrile as a mobile phase, obtaining

N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide ( 20 mg, 40%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 7.77 (s, 1H), 7.51 (s, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 5.05 (d, J=5.8 Hz, 1H), 4.99 (s, 1H), 4.94 (q, J=6.4 Hz, 1H), 2.79 (t, J=7.5 Hz, 2H), 2.70-2.61 (m, 3H), 2.52-2.49 (m, 1H), 2.2-2.21 ( m, 1H), 1.95-1.90 (m, 2H), 1.74-1.59 (m, 1H), 1.36 (s, 6H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): 163.5, 146.0, 143.1, 140.6, 138.5, 136.5, 136.2, 122.0, 116.5, 112.5, 108.5, 74.9, 67.0, 36.0, 33.0, 31.5, 30.9, 27.8, 25.6; LCMS (m/z): 419 [M-H] ^- . HRMS calculated for C ₂₀ H ₂₃ N ₂ O ₆ S ₁ [M-H] ^- 419.1282, found 419.1265.

N-((4,6-dimethylpyrimidin-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

A solution of 4,6-dimethylpyrimidine-2-amine (200 mg, 1.62 mmol) in THF (5 ml) was cooled to 0° C. and treated with NaH (130 mg, 3.24 mmol) under nitrogen. The reaction mixture was stirred for 15 min and treated with phenyl chloroformate (380 mg, 2.43 mmol) at 0° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with EtOAc, filtered through Celite and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes as an eluent to give phenyl (4,6-dimethylpyrimidin-2-yl)carbamate (200 mg, 51%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.91 (s, 1H), 7.40-7.35 (m, 2H), 7.24-7.19 (m, 3H), 6 .78 (s, 1H), 2.41 (s, 6H). LCMS (m/z): 244.20 [M+H] ⁺ .

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (150mg, 0.731mmol) was dissolved in anhydrous THF (5mL) and treated gently with NaH (75mg, 1.83mmol) at 0°C under atmospheric nitrogen. The resulting mixture was heated to 60°C and stirred for 2 h. The solution was cooled to 0°C and reacted with a solution of phenyl (4,6-dimethylpyrimidin-2-yl)carbamate (195 mg, 0.804 mmol) in THF (5 ml) in nitrogen atmosphere at 0°C. The reaction mixture was heated to 50°C for 4 h and then stirred at room temperature for 4 h. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 30 ml) and the combined organic extract was washed with water, brine , dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: X-bridge (150 mm x 19 mm, particle size 5 µm);

flow rate: 15 ml/min; eluent: 10 mmol/l ammonium acetate in 0.1% AcOH in water (A) & MeCN (B); gradient: T/% B=0/15, 2/25, 8/40]. The fractions were freeze-dried to give

N-((4,6-dimethylpyrimidin-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (25 mg, 7%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 8.18 (s, 1H), 7.51 (d, J=0.8 Hz, 1H), 7.40 (d, J=1.2 Hz, 1H), 6.78 (s, 1H), 2.48 (s, 6H), 1.57 (s, 6H). LCMS (m/z): 355.0 [M+H] ⁺ , 100% (210 nm), 100% (254 nm). HPLC: 96.49% (210 nm), 98.76% (254 nm). HRMS calculated for C ₁₄ H ₁₇ N ₄ O ₅ S ₁ [MH] ^- 353.0925, found 353.0921.

N-((4-cyclopropyl-6-methylpyrimidin-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4-cyclopropyl-6-methylpyrimidin-2-amine (50 mg, 0.33 mmol) was dissolved in THF (2 ml) and cooled to 0°C. NaH (16 mg, 0.40 mmol) was carefully added to the above solution and stirred for 20 minutes. Phenyl chloroformate (80 mg, 0.503 mmol) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. Upon completion of the reaction (TLC, 50% ethyl acetate-hexanes, R _f , 0.4), the reaction mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (60-120 mesh) using 30% EtOAc-hexanes eluent to give phenyl (4-cyclopropyl-6-methylpyrimidin-2-yl)carbamate (40 mg, 44% ) as a white to yellowish solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.06 (s, 1H), 7.40-7.37 (m, 2H), 7.24-7.15 (m, 3H), 6 .73 (s, 1H), 2.4 (s, 3H), 1.94-1.86 (m, 1H), 1.15-1.1 (m, 2H), 1.0-0.99 (m, 2H). LCMS (m/z): 270.3 [M+H] ⁺

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (150mg, 0.731mmol) was dissolved in anhydrous THF (5mL) and treated gently with NaH (73mg, 1.829mmol) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 1 h and reacted with a solution of phenyl (4-cyclopropyl-6-methylpyrimidin-2-yl)carbamate (190 mg, 0.731 mmol) in THF (5 ml) under nitrogen at 0°C. The resulting reaction mixture was warmed to room temperature and stirred at room temperature for 6 h. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution and extracted with EtOAc (2 x 30 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: X bridge (150 mm x 19 mm, particle size 5 µm);

flow rate: 15 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: 17% B=0/15, 2/25, 8/40]. The fractions were freeze-dried to give

N-((4-cyclopropyl-6-methylpyrimidin-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (30 mg, 11%) as a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.53 (s, 1H), 7.07 (s, 1H), 6.80 (s, 1H), 2.35 (s, 3H) , 1.97-1.93 (m, 1H), 1.42 (s, 6H), 1.08-1.02 (m, 4H). LCMS (m/z): 381.00 [M+H] ⁺ ; 98.60% (210 nm), 99.49% (254 nm). HPLC: 98.05% (210 nm), 99.01% (254 nm). HRMS calculated for C ₁₆ H ₁₉ N ₄ O ₅ S ₁ [MH] ⁺ 379.1082, found 379.1082.

N-((4,6-di-tert-butylpyrimidin-2-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

4,6-di-tert-butylpyrimidin-2-amine (0.15 g, 0.72 mmol) was dissolved in THF (5 ml) and cooled to 0°C. NaH (37 mg, 0.93 mmol) was added to the above solution, and the resulting mixture was stirred for 15 minutes under nitrogen. Phenyl chloroformate (0.16 g, 1.08 mmol) was added dropwise to the above solution at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 h. Upon completion of the reaction (TLC, 10% ethyl acetate-hexanes, R _f , 0.5), the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with 10% IPA/CHCl ₃ , filtered through a pad of celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 4% EtOAc-hexanes eluent to give phenyl(4,6-di-tert-butylpyrimidin-2-yl)carbamate (0.1 g, 43%) in form of a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.65 (s, 1H), 7.38 (m, 2H), 7.22 (m, 3H), 7.01 (s, 1H), 1.32 (s, 18H). LCMS (m/z): 327.80 [M+H] ⁺

4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide (65mg, 0.305mmol) was dissolved in anhydrous THF (8mL) and treated gently with NaH (30mg, 0.764mmol) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 45 minutes and treated with a solution of phenyl (4,6-di-tert-butylpyrimidin-2-yl)carbamate (100 mg, 0.305 mmol) in THF (5 ml) dropwise under nitrogen at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 3 hours. After completion of the reaction (TLC, 50% ethyl acetate-hexanes, R _f , 0.5), the reaction mixture was diluted with saturated NH4CI solution and extracted with EtOAc (2 x 20 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes eluent to give N-((4,6-di-tert-butylpyrimidin-2-yl)carbamoyl)-4-(2-hydroxypropane -2-yl)furan-2-sulfonamide (0.07 g, 52%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.75 (s, 1H), 10.71 (s, 1H), 7.83 (s, 1H), 7.37 (s, 1H ), 7.20 (s, 1H), 5.17 (s, 1H), 1.39 (s, 6H), 1.31 (s, 18H). LCMS (m/z): 439.55 [M+H] ⁺ ; 94.58% (210 nm), 97.94% (254 nm). HPLC: 98.51% (210 nm), 99.27% (254 nm). HRMS calculated for C ₂₀ H ₂₉ N ₄ O ₅ S ₁ [MH] ⁺ 437.1864, found 437.1846.

METHYLFURANS

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

4-isocyanato-1,2,3,5,6,7-hexahydro-8-indacene (prepared using General Method A2) and 4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (52 mg, 51%).

N-((2,6-diisopropylphenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

2-Isocyanato-1,3-diisopropylbenzene (prepared using General Method A1) and 4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide were used in General Method C1 to give the sub-title compound as white to yellowish solid (14 mg, 4%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.24 (t, J=7.6 Hz, 1H), 7.15 (d, J=7.6 Hz, 2H), 7.04 (s, 1H), 3.10 (sept, J=6.8 Hz, 2H), 2.50 (s, 3H), 1.50 (s, 6H), 1.17 (d, J=6, 8 Hz, 12H).

DEUTERATED FURANS

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl-1,1,1,3,3, 3-d ₆ )furan-2-sulfonamide

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide can be synthesized using 4 -isocyanato-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A1) and d ₆ -4-(2-hydroxypropan-2-yl)-5-methylfuran-2- sulfonamide in General Method C1.

Alternatively, ethyl 2-methyl-5-sulfamoylfuran-3-carboxylate (0.4 g, 0.96 mmol) in anhydrous THF (30 ml) at -10° C. was treated with a solution of d ₃ -methylmagnesium iodide (1.0 mol /l in Et ₂ O, 10 eq.) dropwise over 10 minutes with vigorous stirring. The solution was then stirred at ambient temperature for 12 hours, then cooled to 0°C and the reaction was stopped by dropwise addition of a saturated ammonium chloride solution. The aqueous solution was extracted with EtOAc (2 x 20 ml), the combined organic phases were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC to give the sub-title compound as a white solid (5 mg, 1%). ¹ H-NMR (300 MHz, CD ₃ OD): δ = 7.50 (d, J=1.2 Hz, 1H), 6.95 (d, J=1.2 Hz, 1H), 6.89 (s, 1H), 2.83 (t, J=7.2 Hz, 4H), 2.75 (t, J=7.2 Hz, 4H), 2.02 (quint, J=7.2 Hz , 4H).

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl-1,1,1,3,3, 3-d ₆ )-5-methylfuran-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and d ₆ -4-(2-hydroxypropan-2-yl)-5-methylfuran-2 -sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (10 mg, 3%), ¹ H-NMR (400 MHz, CD ₃ OD) δ = 7.03 (s, 1H), 6 .95 (s, 1H), 2.86 (t, J=7.4 Hz, 4H), 2.73 (t, J=7.4 Hz, 4H), 2.48 (s, 3H), 2 .04 (n, J=7.4 Hz, 4H).

4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d ₆ )-5-methyl-N-((3,5,6,7-tetrahydro-2H-indeno[5 ,6-b]furan-4-yl)carbamoyl)furan-2-sulfonamide

4-isocyanato-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan (prepared using General Method A1) and d ₆ -4-(2-hydroxypropan-2-yl)-5 -methylfuran-2-sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (20 mg, 5%). ¹ H-NMR (400 MHz, CD ₃ OD) δ = 7.13 (s, 1H), 6.52 (s, 1H), 4.51 (t, J=8.6 Hz, 2H), 3, 03 (t, J=8.6 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.50 ( s, 3H), 2.05 (n, J=7.4 Hz, 2H).

N-((4-bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl-1, 1,1,3,3,3-d ₆ )-5-methylfuran-2-sulfonamide

4-bromo-8-isocyanato-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan (prepared using General Method A1) and d ₆ -4-(2-hydroxypropane-2- yl)-5-methylfuran-2-sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (32 mg, 39%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 8.01 (s, 1H), 7.07 (s, 1H), 5.04 (s, 1H), 4.59 (t, J= 8.7 Hz, 2H), 3.14 (t, J=8.7 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.69 (t, J=7, 4 Hz, 2H), 2.43 (s, 3H), 1.98 (q, J=7.4 Hz, 2H).

THIOPHENE

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)thiophene-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A2) and thiophene-2-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid substances (11 mg, 11%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.79 (d, J=4.0 Hz, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.73 (t, J=4.0 Hz, 1H), 6.93 (s, 1H), 2.83 (t, J=12 Hz, 4H), 2.66 (t, J=12 Hz, 4H), 2.04-1.96 (m, 4H). ¹³ C-NMR (100 MHz, CD ₃ OD): δ 143.5, 143.2, 137.8, 132.7, 132.2, 126.6, 126.4, 118.2, 110.3, 32.5, 29.9, 25.1; Purity by LCMS C: >95%; LCMS (m/z): 363 [M+H] ⁺ ; HRMS calculated for C ₁₇ H ₁₈ N ₂ O ₃ S ₂ (M+H) ⁺ , 363.0832, found 363.0819.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methylthiophene-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A2) and 5-methylthiophene-2-sulfonamide were used in General Method C2 to give the sub-title compound as white solid (12 mg, 18%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.88 (s, 1H), 7.43 (d, J=4.0 Hz, 1H), 6.89 (s, 1H), 6.82 (d, J=4.0 Hz, 1H), 2.78 (t, J=12 Hz, 4H), 2.61 (t, J=12 Hz, 4H), 2.47 (s, 3H), 1.97-1.89 (m, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ = 143.2, 142.9, 137.3, 130.6, 126.0, 125.6, 125.2, 117.5, 108, 7, 32.69, 30.7, 25.5, 15.4; Purity by LCMS: >95%; LCMS (m/z): 377 [M+H] ⁺ ; HRMS calculated for C ₁₈ H ₂₀ N ₂ O ₃ S ₂ , (M+H) ⁺ 377.0988, found 377.0994.

THIAZOLS

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)thiazole-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-8-indacene (prepared using General Method A2) and thiazole-2-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid substances (8 mg, 20%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.02 (d, 1H, J=4.0 Hz), 6.99 (s, 1H), 6.60 (d, 1H, J= 4.0 Hz), 2.88 (t, 4H, J=8.0 Hz), 2.76 (t, 4H, J=8.0 Hz), 2.08-2.02 (m, 4H) ; ¹³ C-NMR (100 MHz, CD ₃ OD): δ = 169.6, 144.2, 144.1, 137.7, 137.5, 132.4, 118.1, 106.9, 32.4 , 29.9, 25.2.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-methylthiazole-5-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 2-methylthiazole-5-sulfonamide were used in General Method C3 to give the sub-title compound as white solid (35 mg, 65%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ = 7.73 (s, 1H), 7.53 (s, 1H), 6.78 (s, 1H), 2.75 (t, J= 7.4 Hz, 4H), 2.66 (t, J=7.4 Hz, 4H), 2.59 (s, 3H), 1.93-1.88 (m, 4H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): 166.8, 158.3, 143.9, 142.0, 141.4, 136.6, 132.3, 115.5, 32.5, 30.4, 25.0, 18.6; Purity by LCMS: >95%; LCMS (m/z): 378 [M+H] ⁺ ; MCBP calculated for C ₁₇ H ₁₈ N ₃ O ₃ S ₂ [M-H] ⁺ 376.0795, found 376.0791.

TRIAZOLS

1-benzyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-1,2,4-triazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-benzyl-1H-1,2,4-triazole-3- the sulfonamide was used in General Method C3 to give the sub-title compound as a white solid (40 mg, 15%) ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.9 (s, 1H), 8 0 (s, 1H), 7.35-7.28 (m, 5H), 6.90 (s, 1H), 5.48 (s, 2H), 2.77 (t, J=7.2 Hz, 4H), 2.59 (t, J=7.2 Hz, 4H), 1.95-1.90 (m, 4H). LCMS (m/z): 438.10 (M+1) ⁺ 95.84% (210 nm), 97.84% (254 nm). HPLC: 95.99% (210 nm), 95.31% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4H-1,2,4-triazole-3-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4H-1,2,4-triazole-3-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid (31 mg, 62%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ = 9.83 (s, 1H), 7.99 (s, 1H), 7.62 (s, 1H), 6.77 (s, 1H) , 2.73 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 1.91-1.86 (m, 4H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): 159.2, 149.8, 148.7, 142.5, 137.2, 132.8, 116.1, 33.0, 30.9, 25.6; Purity by LCMS: >95%; LCMS (m/z): 348 [M+H] ⁺ ;

MCBP calculated for C ₁₅ H ₁₆ N ₅ O ₃ S ₁ [MH] ^- 346.0979, found 346.0983.

N((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-1,2,3-triazole-4-sulfonamide

1,2,3,5,6,7-hexahydro-s-indacen-4-amine, 7 (100 mg, 0.578 mmol) was dissolved in anhydrous THF (5 ml) and treated with Et ₃ N (70 mg, 0.693 mmol) at room temperature. The solution was treated with triphosgene (70 mg, 0.231 mmol) and the resulting mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was stirred with n-pentane (20 ml) for 10 min and filtered through celite. The filtrate was concentrated under reduced pressure to give the isocyanate as a white solid. In another 50 ml round bottom flask, 1-isopropyl-1H-1,2,3-triazole-4-sulfonamide (95 mg, 0.50 mmol) was dissolved in anhydrous THF (5 ml) and NaH (42 mg, 1 .05 mmol) at 0°C under nitrogen. Stirred at room temperature for 45 minutes and reacted with the above isocyanate solution in THF under nitrogen.

The resulting reaction mixture was stirred at room temperature for 5 hours. Upon completion (TLC, 70% ethyl acetate-hexanes, R _f , 0.3), the reaction mixture was diluted with saturated NH ₄ Cl solution and extracted with EtOAc (2 x 25 ml). The combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: Gemini NX C18 (21.5 mm x 150 mm, particle size 5 µm); flow rate: 15 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: T/% B=0/10, 2/20, 8/65]. Fractions were freeze-dried to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-1,2,3-triazole-4- sulfonamide (25 mg, 12%), as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.75 (s, 1H), 7.91 (s, 1H), 6.89 (s, 1H), 4.9 (m, 1H ), 2.79 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.96-1.89 (m, 4H), 1.5 (d, J=6.8 Hz, 6H). LCMS (m/z): 390.10 [M+H] ⁺ ; 100% (210 nm), 100% (254 nm). HPLC: 96.05% (210 nm), 96.13% (254 nm). HRMS calculated for C ₁₈ H ₂₂ N ₅ O ₃ S ₁ [M-H] ^- 388.1449, found 388.1457.

PYRAZOLES

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-5-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 1-methyl-1H-pyrazole-5-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (8 mg) 20%. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.95 (s, 1H), 7.45 (s, 1H), 6.88 (s, 1H), 6.66 (s, 1H ), 4.02 (s, 3H), 2.77 (t, J=16 Hz, 4H), 2.60 (t, J=16 Hz, 4H), 1.96-1.88 (m, 4H ). ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ = 143.1, 142.9, 137.2, 125.2, 117.4, 110.0, 109.0, 108.7, 38, 6, 33.0, 30.7, 25.5; Purity by LCMS: >95%; LCMS (m/z): 361 [M+H] ⁺ ; HRMS calculated for C ₁₇ H ₂₀ N ₄ O ₃ S (M+H) ⁺ , 361.13289, found 361.13213.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-methyl-1H-pyrazole-3-sulfonamide were used in General Method C1 to give the sub-title compound as a white solid (40 mg, 8%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.8 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 6.92 (s, 1H ), 6.69 (s, 1H), 3.91 (s, 3H), 2.80 (t, J=7.2 Hz, 4H), 2.62 (t, J=7.2 Hz, 4H ), 1.96 (t, J=7.2 Hz, 4H). LCMS (m/z): 383.10 (M+Na) ⁺ ; 96.00% (210 nm), 93.44% (254 nm). HPLC: 97.86% (210 nm), 97.44% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(trifluoromethyl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A1) and 1-(trifluoromethyl)-1H-pyrazole-3-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (5 mg, 1%). ¹ H-NMR (400 MHz, CD ₃ OD) δ = 8.28 (d, J=2.8 Hz, 1H), 6.96 (d, J=2.8, 1H), 6.91 (s , 1H), 2.84 (t, J=7.4 Hz, 4H), 2.75 (t, J=7.4 Hz, 4H), 2.03 (m, J=7.4 Hz, 4H ).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-isopropyl-1H-pyrazole-3-sulfonamide were used in General Method C1 to give the sub-title compound as a white to yellowish solid (40 mg, 9%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.92 (s, 1H), 8.02 (s, 1H), 8.0 (s, 1H), 6.94 (s, 1H ), 6.74 (s, 1H), 4.67-4.59 (m, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.58 (t, J=7, 2 Hz, 4H), 1.95-1.91 (m, 4H), 1.44 (d, J=6.8 Hz, 6H). LCMS (m/z): 387.1 (M -1) ^- ; 97.14% (210 nm), 95.11% (254 nm). HPLC: 95.57% (210 nm), 93.53% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-4-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A1) and 1-isopropyl-1H-pyrazole-4-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid (40 mg, 10%) ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.6 (s, 1H), 8.44 (s, 1H ), 8.05 (s, 1H), 7.86 (s, 1H), 6.94 (s, 1H), 4.63-4.57 (m, 1H), 2.80 (t, J= 7.2 Hz, 4H), 2.57 (t, J=7.6 Hz, 4H), 1.94-1.89 (m, 4H), 1.42 (d, J=6.8 Hz 6H ). LCMS (m/z): 389.20 (M+1) ⁺ ; 97.25% (210 nm), 94.22% (254 nm). HPLC: 97.13% (210 nm), 95.06% (254 nm).

1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and N-cyclopropyl-1H-pyrazole-3-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid (20 mg, 6%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 7.83 (s, 1H), 7.8 (s, 1H), 6.84 (s, 1H), 6.48 (s, 1H) , 3.81-3.71 (m, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.02- 1.86 (m, 4H), 1.09-0.93 (m, 4H).

1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A1) and 1-(t-butyl)-1H-pyrazole-3-sulfonamide were used in General Method C3 to give the sub-title compound as a pale yellow solid (120 mg, 51%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.85 (br.s., 1H), 7.95 (s. 1H), 7.88 (br.s., 1H), 6 .88 (s, 1H), 6.63 (s, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.61 (t, J=7.2 Hz, 4H), 1 .96 (m, 4H), 1.55 (s, 9H). LCMS (m/z): 403.15 (M +1) ⁺ ; 97.86% (210 nm), 96.50% (254 nm). HPLC: 96.45% (210 nm), 95.89% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-cyclohexyl-1H-pyrazole-3-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid (20 mg, 6%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 10.8 (s, 1H), 8.03 (s, 1H), 7.99 (d, J=2.4, 1H), 6, 95 (s, 1H), 6.75 (d, J=2.4 Hz, 1H), 4.33-4.20 (m, 1H), 2.79 (t, J=7.4 Hz, 4H ), 2.58 (t, J=7.4 Hz, 4H), 2.05-1.88 (m, 6H), 1.86-1.63 (m, 6H), 1.48-1, 33 (m, 2H).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenyl-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-phenyl-1H-pyrazole-3-sulfonamide were used in General Method C1 to give the sub-title compound as a white to yellowish solid (110 mg, 27%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.92 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 7.95 (br s, 1H ), 7.86 (d, J=8.4 Hz, 2H), 7.56 (t, J=7.6 Hz, 2H), 7.41 (t, J=7.2 Hz, 1H), 6.9 (d, J=2.0 Hz, 1H), 6.86 (s, 1H), 2.77 (t, J=7.2 Hz, 4H), 2.62 (t, J=7 .2 Hz, 4H), 1.91-1.83 (m, 4H). LCMS (m/z): 421.05 (M -1) ^- ; 96.62% (210 nm), 95.12% (254 nm). HPLC: 95.2% (210 nm), 95.77% (254 nm).

1-benzyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A1) and 1-benzyl-1H-pyrazole-3-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid (85 mg, 34%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.85 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.99 (s, 1H), 7.32-7.31(m, 3H), 7.24-7.22(m, 2H), 6.93(s, 1H), 6.78(d, J=2.4Hz, 1H) , 5.44 (s, 2H), 2.80 (t, J=7.6 Hz, 4H), 2.57 (t, J=7.2 Hz, 4H), 1.96 (m, 4H) . LCMS (m/z): 437.15 (M+1)+; 97.70% (210 nm), 96.86% (254 nm). HPLC: 98.05% (210 nm), 97.56% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-phenylethyl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-(1-phenylethyl)-1H-pyrazole-3-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid (0.13 g, 38%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 7.94 (d, J=2.4 Hz, 1H), 7.80 (s, 1H), 7.34-7.18 (m, 5H), 6.85 (s, 1H), 6.62 (d, J=2.3 Hz, 1H), 5.68 (q, J=7.0 Hz, 1H), 2.76 (t, J=7.4Hz, 4H), 2.58(t, J=7.4Hz, 4H), 1.90(p, J=7.4Hz, 4H), 1.8(d, J= 7.1 Hz, 3H).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazole-3- sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-(2-(piperidin-1-yl)ethyl)-1H -pyrazole-3-sulfonamide was used in General Method C3 to give the sub-title compound as a white solid (110 mg, 25%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.76 (d, J=2.4 Hz, 1H), 6.91 (s, 1H), 6.73 (d, J=2, 4 Hz 1H), 4.55 (t, J=6.4 Hz, 2H), 3.41 (t, J=6.0 Hz, 2H), 3.02 (s, 4H), 2.86 ( t, J=7.2 Hz, 4H), 2.78 (t, J=7.2 Hz, 4H), 2.06-1.99 (m, 4H), 1.74-1.70 (m , 4H), 1.51 (d, J=5.2 Hz, 2H). LCMS (m/z): 458.20 (M +1) ⁺ ; 100% (210 nm), 100% (254 nm). HPLC: 98.70% (210 nm), 98.31% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1,5-dimethyl-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1,5-dimethyl-1H-pyrazole-3-sulfonamide were used in general Method C1 to give the sub-title compound as a white solid (15 mg, 4%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.7 (br.s., 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.52 ( s, 1H), 3.79 (s, 3H), 2.80 (t, J=7.2 Hz, 4H), 2.62 (t, J=7.6 Hz, 4H), 2.28 ( s, 3H), 1.98-1.93 (m, 4H). LCMS (m/z): 397.10 (M+Na) ⁺ ; 97.75% (210 nm), 88.23% (254 nm). HPLC: 94.42% (210 nm), 95.19% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3- the sulfonamide was used in General Method C3 to give the sub-title compound as a white solid (200 mg, 48%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.10 (s, 1H), 6.87 (s, 1H), 4.03 (s, 3H), 2.83 (t, J= 7.2 Hz, 4H), 2.74 (t, J=7.2 Hz, 4H), 2.03-1.99 (m, 4H). LCMS(m/z): 429.10 (M +1) ⁺ ; 97.73% (210 nm), 95.71% (254 nm). HPLC: 94.95% (210 nm), 93.52% (254 nm).

N-((2,6-diisopropylphenyl)carbamoyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonamide

2-Isocyanato-1,3-diisopropylbenzene (prepared using General Method A1) and 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid substances (70 mg, 39%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.18-7.16 (m, 1H), 7.10-7.08 (m, 3H), 4.03 (s, 3H), 3.17-3.13 (m, 2H), 1.03 (d, J=6.0 Hz, 12H). LCMS (m/z): 433.15 (M +1) ⁺ ; 99.73% (210 nm), 98.16% (254 nm). HPLC: 97.51% (210 nm), 95.47% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-3- the sulfonamide was used in General Method C3 to give the sub-title compound as a white solid (15 mg, 12%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.54 (s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 4.62-4.56 (m, 1H), 2.76 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.6 Hz, 4H), 1.92-1.84 (m, 4H) , 1.44 (d, J=6.4 Hz, 6H). LCMS (m/z): 455.05 (M -1) ^- ; 96.13% (210 nm), 95.41% (254 nm). HPLC: 95.71% (210 nm), 95.12% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-isopropyl-1-methyl-1H-pyrazole-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and

5-Isopropyl-1-methyl-1H-pyrazole-3-sulfonamide was used in General Method C3 to give the sub-title compound as a white solid (10 mg, 17%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 6.88 (s, 1H), 6.50 (s, 1H), 3.82 (s, 3H), 3.08-3.03 ( m, 1H), 2.83 (t, J=7.2 Hz, 4H), 2.71 (t, J=7.2 Hz, 4H), 2.04-1.96 (m, 4H), 1.21 (d, J=6.8 Hz, 6H). LCMS(m/z): 403.20 (M+1) ⁺ ; 98.39% (210 nm), 94.19% (254 nm). HPLC: 95.62% (210 nm), 93.00% (254 nm).

N-((2,6-diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

2-Isocyanato-1,3-diisopropylbenzene (obtained using General Method A1) and 5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide were used in General Method C1 to obtain the indicated in subtitle compound as a white solid (90 mg, 26%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.25-7.24 (m, 1H), 7.16-7.14 (m, 2H), 6.67 (s, 1H), 4.13 (s, 3H), 3.11-3.08 (m, 2H), 1.61 (s, 6H), 1.16 (d, J=6.8 Hz, 12H). LCMS (m/z): 423.20 (M +1) ⁺ ; 99.16% (210 nm), 97.19% (254 nm). HPLC: 98.16% (210 nm), 97.09% (254 nm).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3 -sulfonamide.

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and

5-(2-Hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (70 mg, 15%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (s, 1H), 6.92 (s, 1H), 6.53 (s, 1H), 5.51 (s, 1H), 4.02 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 1.95 (n, J=7 .4 Hz, 4H), 1.50 (s, 6H).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3 -sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and

5-(2-Hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (10 mg, 2%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.54 (s, 5H), 6.59 (s, 1H), 6.91 (s, 1H), 2.86 (t, J= 7.2 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H), 2.05-1.96 (m, 4H), 1.44 (s, 6H). LCMS (m/z): 481.20 (M -1) ^- ; 93.76% (210 nm), 93.24% (254 nm). HPLC: 95.86% (210 nm), 93.93% (254 nm).

1-benzyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazol-3 -sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-5-indacene (prepared using General Method A1) and 1-benzyl-5-(2-hydroxypropan-2-yl)- 1H-pyrazole-3-sulfonamide was used in General Method C1 to give the sub-title compound as a white solid (40 mg, 7%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 7.20-7.14 (m, 5H), 6.95 (s, 2H), 6.73 (s, 1H), 5.77 ( s, 2H), 2.86 (t, J=7.2 Hz, 4H), 2.68 (t, J=7.6 Hz, 4H), 2.01-1.94 (m, 4H), 1.51 (s, 6H). LCMS (m/z): 494.7 (M+1)+; 98.74% (210 nm), 96.05% (254 nm). HPLC: 95.11% (210 nm), 95.08% (254 nm).

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and 5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (83 mg, 17%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ = 7.81 (s, 1H), 7.10 (s, 2H), 6.42 (s, 1H), 5.45 (s, 1H) , 3.99 (s, 3H), 3.03 (hept, J=7.0 Hz, 2H), 1.47 (s, 6H), 1.05 (d, J=1.8 Hz, 12H) . HRMS calculated for C ₂₀ H ₂₈ Cl ₁ N ₄ O ₄ S ₁ [MH] ^- 455.1525, found 455.1515.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and 5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (168 mg, 31%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ = 7.87 (s, 1H), 7.52 (s, 5H), 7.10 (s, 2H), 6.71 (s, 1H) , 5.42 (s, 1H), 3.10-2.92 (m, 2H), 1.31 (s, 6H), 1.02 (d, J=7.0 Hz, 12H). HRMS calculated for C ₂₅ H ₃₀ Cl ₁ N ₄ O ₄ S ₁ [M-H] ^- 517.1682, found 517.1671.

N-((4-chloro-2,6-dimethylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

A solution of 4-chloro-2,6-dimethylaniline (50 mg, 0.321 mmol) in DCM (5 ml) was treated with Et ₃ N (50 mg, 0.48 mmol) and cooled to 0°C. Phenyl chloroformate (60 mg, 0.39 mmol) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 _h . Upon completion, the reaction mixture was diluted with sat. the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was washed with n-pentane and dried in vacuo to give phenyl(4-chloro-2,6-dimethylphenyl)carbamate (75 mg, 85%) as a brown solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.46-7.37 (m, 4H), 7.26-7.20 (m, 2H), 7.12-7.11 (m, 2H), 2.33 (s, 6H). LCMS (m/z): 275.9 [M+H] ⁺ .

1-isopropyl-1H-pyrazole-3-sulfonamide (150 mg, 0.79 mmol) was dissolved in anhydrous THF (5 ml) and treated gently with NaH (80 mg, 1.98 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 30 min, then reacted with a solution of phenyl (4-chloro-2,6-dimethylphenyl)carbamate (240 mg, 0.87 mmol) in THF (3 ml) under nitrogen at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 3 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 30 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes eluent to give

N-((4-chloro-2,6-dimethylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (90 mg, 31%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 11.05 (s, 1H), 7.99 (d, J=2.8 Hz, 1H), 7.93 (s, 1H), 7.13 (s, 2H), 6.73 (d, J=2.4 Hz, 1H), 4.64-4.57 (m, 1H), 2.03 (s, 6H), 1.43 (d, J=6.8 Hz, 6H). LCMS (m/z): 370.95 [M+H] ⁺ .; 97.62% (210 nm), 97.48% (254 nm). HPLC: 97.20% (210 nm). HRMS calculated for C ₁₅ H ₁₈ Cl ₁ N ₄ O ₃ S ₁ [M-H] ^- 369.0794, found 369.0785.

N-((4-chloro-2,6-dimethoxyphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

A solution of 4-chloro-2,6-dimethoxyaniline (200 mg, 1.06 mmol) in THF (8 mL) was cooled to 0° C. and treated with NaH (62 mg, 1.59 mmol) under nitrogen. The resulting mixture was stirred for 15 minutes. followed by the addition of phenyl chloroformate (330 mg, 2.13 mmol) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with EtOAc and filtered through a pad of celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc-hexanes eluent to give phenyl (4-chloro-2,6-dimethoxyphenyl)carbamate (0.2 g, 61%) as a white solid . ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.35-7.33 (m, 2H), 7.20-7.19 (m, 3H), 6.61 (s, 2H), 3 .83 (s, 6H).

1-Isopropyl-1H-pyrazole-3-sulfonamide (100 mg, 0.53 mmol) was dissolved in anhydrous THF (5 mL) and treated gently with NaH (52 mg, 1.32 mmol) at 0°C under nitrogen.) . The resulting mixture was stirred at room temperature for 40 min, then reacted with a solution of phenyl (4-chloro-2,6-dimethoxyphenyl)carbamate (180 mg, 0.58 mmol) in THF (3 ml) under nitrogen at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The combined organic extract was washed with water, brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: Gemini NX C18 (21.2 mm x 150 mm, particle size 5 µm); flow rate: 20 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: T/% B=0/20, 2/20, 8/70]. The fractions were freeze-dried to give

N-((4-chloro-2,6-dimethoxyphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (20 mg, 9%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.90 (d, J=2.0 Hz, 1H), 7.28 (s, 1H), 6.72 (s, 2H), 6.63 (d, J=2.0 Hz, 1H), 4.60-4.54 (m, 1H), 3.70 (s, 6H), 1.43 (d, J=6.8 Hz , 6H). LCMS (m/z): 403.0 [M+H] ⁺ .; 90.61% (210 nm). HPLC: 91.63% (210 nm). HRMS calculated for C ₁₅ H ₁₈ Cl ₁ N ₄ O ₅ S ₁ [MH] ^- 401.0692, found 401.0684.

N-((4-chloro-2-methyl-6-(trifluoromethyl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

4-Chloro-2-methyl-6-(trifluoromethyl)aniline (50 mg, 0.24 mmol) was dissolved in anhydrous THF (5 mL) and treated with Et ₃ N (30 mg, 0.29 mmol) at room temperature. The solution was treated with triphosgene (30 mg, 0.095 mmol) and the resulting mixture was stirred at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was stirred with n-pentane (20 ml) for 10 min, filtered through a pad of celite and concentrated under reduced pressure to give the corresponding isocyanate as a white solid. In another 50 ml round bottom flask, 1-isopropyl-1H-pyrazole-3-sulfonamide (40 mg, 0.212 mmol) was dissolved in anhydrous THF (5 ml) and NaH (22 mg, 0.529 mmol) was gently treated at 0°C in nitrogen atmosphere. Stirred at room temperature for 30 minutes. The above isocyanate solution was added to THF under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 25 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes eluent to give N-((4-chloro-2-methyl-6-(trifluoromethyl)phenyl)carbamoyl)-1-isopropyl-1H -pyrazole-3-sulfonamide. It was triturated with diethyl ether and n-pentane to give

N-((4-chloro-2-methyl-6-(trifluoromethyl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (35 mg, 35%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 11.05 (s, 1H), 8.09 (s, 1H), 7.6 (s, 1H), 7.70 (s, 1H ), 7.61 (s, 1H), 6.67 (d, J=0.4 Hz, 1H), 4.62 (m, 1H), 2.05 (s, 3H), 1.43 (d , J=6.8 Hz, 6H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ): δ = -60.82. LCMS (m/z): 425.00 [M+H] ⁺ ; 94.05% (210 nm).

HPLC 98.03% (210 nm). HRMS calculated for C ₁ H ₁₅ Cl ₁ F ₃ N ₄ O ₃ S ₁ [MH] ^- 423.0511, found 423.0513.

N-((4-chloro-2-methoxy-6-(trifluoromethyl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

4-Chloro-2-methoxy-6-(trifluoromethyl)aniline (50 mg, 0.22 mmol) was dissolved in anhydrous THF (2 ml) and treated with Et ₃ N (27 mg, 0.27 mmol) at room temperature. The solution was treated with triphosgene (32 mg, 0.11 mmol) and the resulting mixture was stirred at 70°C for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was stirred with 5% EtOAc-hexanes (20 ml) for 10 min , filtered through celite and concentrated under reduced pressure to give the title isocyanate as a white solid. In another 50 ml round bottom flask, 1-isopropyl-1H-pyrazole-3-sulfonamide (42 mg, 0.22 mmol) was dissolved in anhydrous THF (5 ml) and NaH (18 mg, 0.44 mmol) was gently treated at 0 °C in a nitrogen atmosphere. The mixture was stirred at 0° C. for 20 minutes and treated with the above isocyanate solution in THF under a nitrogen atmosphere. The resulting reaction mixture was stirred at 0-10° C. for 2 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 50% EtOAc-hexanes eluent to give N-((4-chloro-2-methoxy-6-(trifluoromethyl)phenyl)carbamoyl)-1-isopropyl-1H -pyra zol-3-sulfonamide (10 mg, 10%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.81 (s, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.10 (s, 1H), 6.82 (d, J=2.0 Hz, 1H), 4.64-4.57 (m, 1H), 3.84 (s, 3H ), 1.54 (d, J=6.8 Hz, 6H). ¹⁹ F-NMR (400 MHz, CDCl ₃ ): δ = -61.55. LCMS (m/z): 441.05 [M+H] ⁺ .; 94.58% (210 nm). HPLC: 92.16% (210 nm). HRMS calculated for C ₁₅ H ₁₅ Cl ₁ F ₃ N ₄ O ₄ S ₁ [MH] ^- 439.0460, found 439.0478.

N-((4-chloro-2,6-diethylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

A solution of 4-chloro-2,6-dicyclopropaniline (100 mg, 0.546 mmol) in THF (5 mL) was cooled to 0°C and treated with NaH (30 mg, 0.66 mmol) under nitrogen and stirred for 15 min. Phenyl chloroformate (130 mg, 0.819 mmol) was added dropwise to the above solution at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the mixture was diluted with EtOAc, filtered through a pad of celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc-hexanes to give phenyl(4-chloro-2,6-diethylphenyl)carbamate (0.15 g, 91%) as a white solid . ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.38-7.33 (m, 2H), 7.23-7.18 (m, 3H), 7.13 (m, 2H), 6 .27 (s, 1H), 2.75-2.64 (m, 4H), 1.28-1.22 (m, 6H).

1-isopropyl-1H-pyrazole-3-sulfonamide (75 mg, 0.40 mmol) was dissolved in anhydrous THF (5 ml) and NaH (40 mg, 0.99 mmol) was treated carefully at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 30 min, then reacted with a solution of phenyl(4-chloro-2,6-diethylphenyl)carbamate (130 mg, 0.44 mmol) in THF (3 ml) under nitrogen at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 4 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2 x 30 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 30-40% EtOAc-hexanes as an eluent, followed by trituration with diethyl ether and n-pentane to give N-((4-chloro-2,6-diethylphenyl)carbamoyl )-1-isopropyl-1H-pyrazole-3-sulfonamide (40 mg, 24%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.05 (s, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.89 (s, 1H), 7.12 (s, 2H), 6.72 (d, J=2.4 Hz, 1H), 4.62-4.59 (m, 1H), 2.42 (q, J=7.6 Hz , 4H), 1.43 (d, J=6.8 Hz, 6H), 1.02 (t, J=7.6 Hz, 6H). LCMS (m/z): 399.0 [M+H] ⁺ , 96.72% (210 nm). HPLC: 97.13% (210 nm). HRMS calculated for C ₁₇ H ₂₂ Cl ₁ N ₄ O ₃ S ₁ [M-H] ^- 397.1107, found 397.1090.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and 1-isopropyl-1H-pyrazole-3-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid ( 221 mg, 49%). ¹ H-NMR (600 MHz, DMSO-d6) δ=7.70 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.00 (s, 2H), 6, 36 (s, 1H), 4.62-4.29 (m, 1H), 3.11 (d, J=6.4 Hz, 2H), 1.38 (d, J=6.8 Hz, 6H ), 1.01 (d, J=6.8 Hz, 12H). ¹³ C-NMR (151 MHz, DMSO) δ=160.96, 156.43, 150.19, 135.25, 131.49, 128.53, 123.27, 105.21, 54.23, 28, 80, 24.15, 23.55. HRMS calculated for C ₁₉ H ₂₆ Cl ₁ N ₄ O ₃ S ₁ [M-H] ^- 425.1420, found 425.1409.

N-((4-chloro-2,6-dicyclopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

A solution of 4-chloro-2,6-dicyclopropylaniline (150 mg, 0.724 mmol) in THF (5 ml) was cooled to 0°C. NaH (35 mg, 0.87 mmol) was added portionwise to the above solution and stirred for 20 minutes. Phenyl chloroformate (170 mg, 1.08 mmol) was added dropwise to the above solution at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the mixture was diluted with EtOAc, filtered through celite and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using 15% EtOAc-hexanes as an eluent to give phenyl(4-chloro-2,6-dicyclopropylphenyl)carbamate (195 mg, 83%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.37-7.35 (m, 2H), 7.21-7.19 (m, 3H), 6.84-6.83 (m, 2H), 2.08-2.04 (m, 2H), 1.04-1.02 (m, 4H), 0.69-0.68 (m, 4H). LCMS (m/z): 328.2 [M+H] ⁺ .

1-Isopropyl-1H-pyrazole-3-sulfonamide (100 mg, 0.53 mmol) was dissolved in anhydrous THF (5 ml) and treated gently with NaH (53 mg, 1.32 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 30 min, then reacted with a solution of phenyl(4-chloro-2,6-dicyclopropylphenyl)carbamate (190 mg, 0.582 mmol) in THF (3 ml) under nitrogen at 0°C. The reaction mixture was warmed to room temperature and stirred for 4 h. Upon completion of the reaction, the reaction mixture was diluted with a saturated solution of NH ₄ Cl, was extracted with EtOAc (2×30 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes eluent to give N-((4-chloro-2,6-dicyclopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3- sulfonamide. This was triturated with diethyl ether and n-pentane to give a white solid (25 mg, 11%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.05 (s, 1H), 8.01-7.98 (m, 2H), 6.74 (s, 3H), 4.59 -4.56 (m, 1H), 1.77-1.76 (m, 2H), 1.41 (d, J=6.8 Hz, 6H), 0.77-0.75 (m, 4H ), 0.56-0.55 (m, 4H). LCMS (m/z): 423.00 [M+H]+.; 93.58% (210 nm). HPLC: 92.87% (210 nm). HRMS calculated for C ₁₉ H ₂₂ Cl ₁ N ₄ O ₃ S ₁ [M-H] ^- 421.1107, found 421.1107.

N-((7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-amine, 6 (70 mg, 0.33 mmol) was dissolved in THF (5 ml) and cooled to 0°C. NaH (20 mg, 0.505 mmol) was added to the above solution under nitrogen atmosphere and stirred for 15 min, followed by the addition of phenyl chloroformate (100 mg, 0.674 mmol) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with EtOAc, filtered through Celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc-hexanes eluent to give phenyl(7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamate (80 mg, 73%) as a brown solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.39-7.37 (m, 3H), 7.25-7.24 (m, 2H), 6.85 (s, 1H), 3 0-2.94 (m, 4H), 2.12-2.10 (m, 2H), 1.34 (m, 1H), 0.96-0.95 (m, 2H), 0.59 -0.57 (m, 2H). LCMS (m/z): 328.30 [M+H] ⁺ .

1-Isopropyl-1H-pyrazole-3-sulfonamide (41 mg, 0.219 mmol) was dissolved in anhydrous THF (3 ml) and treated gently with NaH (21 mg, 0.549 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 30 min and reacted with a solution of phenyl (7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamate (80 mg, 0.244 mmol) in THF (2 ml ) in a nitrogen atmosphere at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 4 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2×30 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: Gemini NX C18 (21.2 mm×150 mm, particle size 5 μm); flow rate: 20 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: T/% B=0/20, 2/30, 8/70]. The fractions were freeze-dried to give N-((7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (20 mg, 20 %) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.95 (d, J=2.4 Hz, 1H), 6.74 (s, 1H), 6.69 (d, J=2 .4 Hz, 1H), 4.60-4.55 (m, 1H), 2.84 (t, J=7.6 Hz, 2H), 2.66 (t, J=7.6 Hz, 2H ), 1.95-1.92 (m, 2H), 1.79-1.76 (m, 1H), 1.41 (d, J=6.4 Hz, 6H), 0.82-0, 78 (m, 2H), 0.54-0.50 (m, 2H). LCMS (m/z): 421.15 [M-H] ^- ; 94.19% (210 nm). HPLC: 95.46% (210 nm). HRMS calculated for C ₁₉ H ₂₂ Cl ₁ N ₄ O ₃ S ₁ [M-H] ^- 421.1107, found 421.1110.

5-chloro-3-cyclopropyl-2-(3-((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)ureido)-N,N-dimethylbenzamide

2-Amino-5-chloro-3-cyclopropyl-N,N-dimethylbenzamide (200 mg, 0.84 mmol) was dissolved in anhydrous THF (5 ml) and treated with NaH (50 mg, 1.26 mmol) at 0°C. C in a nitrogen atmosphere. The resulting reaction mixture was stirred for 15 minutes, then phenyl chloroformate (262 mg, 1.68 mmol) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with EtOAc, filtered through Celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 15% EtOAc-hexanes eluent to give phenyl(4-chloro-2-cyclopropyl-6-(dimethylcarbamoyl)phenyl)carbamate (0.14, 47%) in dark brown liquid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=7.39-7.34 (m, 2H), 7.23-7.15 (m, 3H), 7.08-7.02 (m, 2H), 3.09 (s, 3H), 2.96 (s, 3H), 2.05-2.0 (m, 1H), 1.05-1.02 (m, 2H), 0.71 -0.69 (m, 2H). LCMS (m/z): 358.60 [M+H] ⁺ .

1-Isopropyl-1H-pyrazole-3-sulfonamide (57 mg, 0.30 mmol) was dissolved in anhydrous THF (5 ml) and treated gently with NaH (18 mg, 0.451 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 45 min, then reacted with a solution of phenyl (4-chloro-2-cyclopropyl-6-(dimethylcarbamoyl)phenyl)carbamate (120 mg, 0.335 mmol) in THF (3 ml) under nitrogen at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2×30 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: Gemini NX C18 110A AXIA (21.2 mm×150 mm, particle size 5 μm); flow rate: 18 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: T/% B=0/20, 2/20, 10/60]. The fractions were freeze-dried to give 5-chloro-3-cyclopropyl-2-(3-((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)ureido)-N,N-dimethylbenzamide (10 mg, 7%) in form of a white solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ=7.77 (s, 1H), 7.11 (d, J=2.4 Hz, 1H), 7.05 (d, J=2, 0 Hz, 1H), 6.76 (s, 1H), 4.62-4.53 (m, 1H), 2.96 (s, 3H), 2.84 (s, 3H), 1.88- 1.87(m, 1H), 1.50(d, J=6.8Hz, 6H), 0.90-0.88(m, 2H), 0.63-0.61(m, 2H) . LCMS (m/z): 454.0 [M+H] ⁺ .; 97.52% (210 nm). HPLC: 92.05% (210 nm). HRMS calculated for C ₁₉ H ₂₃ Cl ₁ N ₅ O ₄ S ₁ [M-H] ^- 452.1165, found 452.1180.

N-((4,6-dimethylpyrimidin-2-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

A solution of 4,6-dimethylpyrimidine-2-amine (300 mg, 2.43 mmol) in THF (10 mL) was cooled to 0° C. and treated with NaH (140 mg, 3.64 mmol) under nitrogen. The resulting mixture was stirred for 15 min, then treated with phenyl chloroformate (0.6 ml, 4.87 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was diluted with EtOAc (30 ml), filtered through celite and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using 30% EtOAc-hexanes as an eluent to give phenyl(4,6-dimethylpyrimidin-2-yl)carbamate (250 mg, 42%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ=8.14 (s, 1H), 7.45-7.34 (m, 2H), 7.25-7.18 (m, 3H), 6 .78 (s, 1H), 2.46 (s, 6H). LCMS (m/z): 244.30 [M+H] ⁺ .

1-isopropyl-1H-pyrazole-3-sulfonamide (75 mg, 0.396 mmol) was dissolved in anhydrous THF (50 ml) and treated gently with NaH (40 mg, 0.99 mmol) at 0° C. under nitrogen. The resulting mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0°C, then reacted with a solution of phenyl (4,6-dimethylpyrimidin-2-yl)carbamate (100 mg, 0.436 mmol) in THF (5 ml) under a nitrogen atmosphere at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2×50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by reverse phase preparative HPLC [column: Gemini NX-bridge (150 mm×21.2 mm, particle size 5 μm); flow rate: 15 ml/min; eluent: 10 mmol/l ammonium bicarbonate in water (A) & MeCN (B); gradient: T/% B=0/10, 2/20, 10/60]. Fractions were freeze-dried to give N-((4,6-dimethylpyrimidin-2-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (10 mg, 13%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ=13.0 (s, 1H), 7.49-7.46 (m, 2H), 7.02 (d, J=2.4 Hz, 1H ), 6.74 (s, 1H), 4.62-4.57 (m, 1H), 2.45 (s, 6H), 1.53 (d, J=6.8 Hz, 6H). LCMS (m/z): 339.10 [M+H] ⁺ . 99.70% (210 nm), 100% (254 nm). HPLC: 97.22% (210 nm). HRMS calculated for C ₁₃ H ₁₇ N ₆ O ₃ S ₁ [M-H] ^- 337.1088, found 337.1099.

N-((4,6-di-tert-butylpyrimidin-2-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

A solution of 4,6-di-tert-butylpyrimidin-2-amine (0.15 g, 0.72 mmol) in THF (5 ml) was cooled to 0°C and treated with NaH (35 mg, 0.86 mmol) in an atmosphere nitrogen. The resulting mixture was stirred for 15 minutes and phenyl chloroformate (0.17 g, 1.08 mmol) was added dropwise to the above solution at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate, filtered through Celite and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 15% EtOAc-hexanes eluent to give phenyl (4,6-di-tert-butylpyrimidin-2-yl)carbamate (140 mg, 59%) as white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ=7.95 (s, 1H), 7.65-7.61 (m, 2H), 7.50-7.45 (m, 4H), 1 .32 (s, 18H). LCMS (m/z): 328.40 [M+H] ⁺ ;

1-Isopropyl-1H-pyrazole-3-sulfonamide (50 mg, 0.264 mmol) was dissolved in anhydrous THF (40 ml) and treated gently with NaH (27 mg, 0.661 mmol) at 0° C. under nitrogen. The resulting mixture was stirred for 30 minutes, then reacted with a solution of phenyl(4,6-di-tert-butylpyrimidin-2-yl)carbamate (95 mg, 0.29 mmol) in THF (5 ml) under nitrogen at 0°C . The resulting reaction mixture was warmed to room temperature and stirred for 4 hours. Upon completion, the reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc (2×50 ml) and the combined organic extract was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical product was purified by column chromatography on silica gel (60-120 mesh) using 40% EtOAc-hexanes eluent to give N-((4,6-di-tert-butylpyrimidin-2-yl)carbamoyl)-1-isopropyl-1H- pyrazole-3-sulfonamide (38 mg, 25%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=13.75 (s, 1H), 10.71 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.18 (s, 1H), 6.81 (d, J=2.4 Hz, 1H), 4.61-4.54 (m, 1H), 1.38 (d, J=6.8 Hz , 6H), 1.31 (s, 18H). LCMS (m/z): 423.50 [M+H] ⁺ ; 99.88% (210 nm). HPLC: 98.49% (210 nm). HRMS calculated for C ₁₉ H ₂₉ N ₆ O ₃ S ₁ [M-H] ^- 421.2027, found 421.2008.

PHENYL/BICYCLES

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and phenylsulfonamide were used in General Method C1 to give the sub-title compound as a white solid substances (50 mg, 13%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=8.05 (d, J=7.6 Hz, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 2H), 6.96 (s, 1H), 2.84 (t, J=7.2 Hz, 4H), 2.59 (t, J=7.2 Hz , 4H), 2.00 (quint, J=7.2 Hz, 4H).

5-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)naphthalene-1-sulfonamide

A solution of 5-(dimethylamino)naphthalene-1-sulfonamide (20 mg, 0.08 mmol) in THF (5.0 mL) was treated with DIPEA (17 μL, 0.09 mmol), stirred at ambient temperature for 15 min , then added dropwise a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) (19 mg, 0.09 mmol) in THF (1.0 ml). The reaction mixture was stirred at ambient temperature overnight, then concentrated under reduced pressure. The technical product was purified by HPLC to give the sub-title compound as a pale yellow solid (24 mg, 66%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=8.62 (d, J=8.4 Hz, 1H), 8.36 (dd, J=9.5, 8.1 Hz, 2H), 7.67-7.56 (m, 2H), 7.26 (d, J=7.8 Hz, 1H), 6.91 (s, 1H), 2.91 (s, 6H), 2.79 (t, J=7.4 Hz, 4H), 2.40 (t, J=7.4 Hz, 4H), 1.92 (quint, J=7.4 Hz, 4H). ¹³ C-NMR (101 MHz, CD ₃ OD) δ=152.5, 150.3, 144.4, 138.3, 131.9, 131.7, 131.1, 130.3, 130.1, 129.9, 128.9, 127.2, 123.6, 119.4, 119.1, 118.9, 115.7, 78.4, 78.0, 77.7, 49.6, 48, 3, 45.6, 33.4, 33.2, 30.5, 29.3, 25.9, 25.8; HRMS (ESI) calculated for C ₂₅ H ₂₇ N ₃ O ₃ S [M+H] 450.1846, found 450.1859.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydro benzo[b]thiophene-6-sulfonamide-1,1-dioxide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 2,3-dihydrobenzo[b]thiophene-6-sulfonamide-1,1-dioxide were used in General Method C2 to give the sub-title compound as a white solid (33 mg, 28%). ¹ H-NMR (600 MHz, DMSO-d ₆ ): δ=8.17 (brs, 1H), 8.15 (s, 1H), 8.13 (d, J=9 Hz, 1H), 7, 73 (d, J=12 Hz, 1H), 6.89 (s, 1H), 3.68 (t, J=9 Hz, 2H), 3.43 (t, J=6 Hz, 2H), 2 .75 (t, J=6 Hz, 4H), 2.55 (t, J=6 Hz, 4H), 1.93-1.88 (m, 4H). ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=151.6, 143.3, 143.0, 142.7, 139.6, 137.6, 137.5, 132.2, 128, 9, 120.1, 117.9, 50.9, 32.9, 30.6, 25.6, 25.4 LCMS (m/z): 447 [M+H] ⁺

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-methoxybenzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 2-methoxybenzenesulfonamide were used in General Method C6 to give the sub-title compound as a white solid ( 30 mg, 48%). ¹ H-NMR (400 MHz, CD ₃ OD) δ 7.96 (d, J=7.9 Hz, 1H), 7.62 (t, J=8.3 Hz, 1H), 7.14-7 .05 (m, 2H), 6.97 (s, 1H), 4.00 (s, 3H), 2.83 (t, J=7.3 Hz, 4H), 2.56 (t, J= 7.3 Hz, 4H), 2.09-1.90 (m, 4H). ¹³ C-NMR (101 MHz, CD ₃ OD) δ 155.9, 143.2, 136.6, 134.7, 129.5, 127.2, 126.6, 125.9, 119.5, 118 .0, 111.6, 111.2, 55.3, 31.9, 29.3, 24.5. HRMS (ESI) calculated for C ₂₀ H ₂₃ N ₂ O ₄ S [M+H] 387.1373, found 387.1378.

N-(1,2,3,5,6,7-Hexahydro-s-indacen-4-ylcarbamoyl)-3-(trifluoromethyl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 3-(trifluoromethyl)benzenesulfonamide were used in General Method C4 to give the sub-title compound as white solid (0.015 g, 12%); white color with a yellowish tint, viscous. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.01 (br s, 1H), 8.34 (s, 1H), 8.25-8.23 (m, 2H), 8 .11 (d, J=7.6 Hz, 1H), 7.90 (t, J=8.0 Hz, 1H), 6.93 (s, 1H), 2.77 (t, J=7, 2 Hz, 4H), 2.50 (m, 4H), 1.90 (quint, J=7.6 Hz, 4H). LCMS, Purity: 96.69%, m/z 425.1 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₀ H ₁₉ F ₃ N ₂ O ₃ S [M+H] ⁺ : 425.1068, found: 425.1009.

N-(1,2,3,5,6,7-hexahydro-5-indacen-4-ylcarbamoyl)-3-methoxybenzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 3-methoxybenzenesulfonamide were used in General Method C4 to give the sub-title compound as white with a yellowish tint solids (0.025 g, 23%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.77 (br s, 1H), 8.15 (s, 1H), 7.56-7.45 (m, 3H), 7 .27 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 3.82 (s, 3H), 2.77 (t, J=7.2 Hz, 4H), 2 .53 (t, J=7.6 Hz, 4H), 1.92 (quint, J=7.2 Hz, 4H). LCMS, Purity: 95.02%, tr=3.77 min, m/z 387.28 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₀ H ₂₂ N ₂ O ₄ S [M+H] ⁺ : 387.1300, found: 387.1301.

N-(1,2,3,5,6,7-Hexahydro-s-indacen-4-ylcarbamoyl)-3-(trifluoromethoxy)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 3-(trifluoromethoxy)benzenesulfonamide were used in General Method C4 to give the sub-title compound as white with a yellowish solid (0.045 g, 43%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.04 (d, J=8.0 Hz, 1H), 7.95 (s, 1H), 7.72 (t, J=8 .4 HZ, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 2.82 (t, J=7.6 Hz, 4H), 2, 59 (t, J=7.6 Hz, 4H), 1.99 (quint, J=7.6 Hz, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=149.2, 147.9, 143.1, 142.2, 137.3, 131.5, 128.5, 126.4, 125, 9, 121.2, 119.7, 118.6, 118.1, 32.5, 29.4, 25.0. ¹⁹ F-NMR (233.33 MHz, DMSO-d ₆ ): -57.10 (s, 3F). LCMS, Purity: 95.56%, m/z 441.20 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₀ H ₁₉ F ₃ N ₂ O ₄ S [M+H] ⁺ : 441.1018, found: 441.1015.

3-(difluoromethoxy)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 3-(difluoromethoxy)benzenesulfonamide were used in General Method C5 to give the sub-title compound as white with a yellowish solid (0.056 g, 50%). ¹ H-NMR (600 MHz, Acetonitrile-d ₃ ) δ=7.85 (d, J=8.0 Hz, 1H), 7.75 (t, J=2.1 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.43 (dd, J=8.0, 2.1 Hz, 1H), 6.95 (s, 1H) , 2.81 (t, J=7.5 Hz, 4H), 2.55 (t, J=7.5 Hz, 4H), 1.95 (quint, J=7.5 Hz, 4H).

N ¹ -(1,2,3,5,6,7-Hexahydro-s-indacen-4-ylcarbamoyl)benzene-1,3-disulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and benzene-1,3-disulfonamide were used in General Method C4 to give the sub-title compound as white solid (0.080 g, 12%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.02 (br s, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 8.15 (d , J=7.8 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.63 (s, 2H ), 6.93 (s, 1H), 2.77 (t, J=7.2 Hz, 4H), 2.54 (t, J=7.6 Hz, 4H), 1.92 (quint, J =7.2 Hz, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=149.0, 144.9, 143.1, 140.9, 137.3, 130.4, 130.2, 128.5, 124, 4, 118.1, 32.4, 30.0, 25.0. LCMS, Purity: 98.63%, m/z 436.03 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₁₉ H ₂₁ N ₃ O ₅ S ₂ [M+H] ⁺ : 436.0923, found: 436.0919.

N ¹ - ((1,2,3,5,6,7-hexahydro-5-indacen-4-yl) carbamoyl) -N ³ , N ³ -dimethylbenzene-1,3-disulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and N ¹ ,N ¹ -dimethylbenzene-1,3-disulfonamide were used in General Method C1 to give the sub-title compound as a white solid (0.019 g, 5%). ¹ H-NMR (400 MHz, CD ₃ OD) δ 8.41 (t, J=1.4 Hz, 1H), 8.32 (dt, J=7.9, 1.4 Hz, 1H), 8 .08 (dt, J=7.9, 1.4 Hz, 1H), 7.87 (t, J=7.9 Hz, 1H), 6.95 (s, 1H), 2.84 (t, J=7.4Hz, 4H), 2.73(s, 6H), 2.61(t, J=7.4Hz, 4H), 2.00(p, J=7.4Hz, 4H) .

3-(N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)sulfamoyl)benzoic acid

Methyl 3-(N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)sulfamoyl)benzoate (0.25 g, 0.603 mmol) was dissolved in tetrahydrofuran:methanol:water (9 ml, 1:1:1) and the mixture was cooled to 0°C. Lithium hydroxide monohydrate (0.75 g, 1.81 mmol, 3 eq.) was added and the mixture was stirred at ambient temperature for 3 hours. Upon completion, the reaction mixture was poured into chilled water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give the sub-title compound as a white solid (0.017 g, 3%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=13.26 (br s, 1H), 8.43 (s, 1H), 8.13-8.08 (m, 2H), 7 .99 (brs, 1H), 7.67 (t, J=8.0 Hz, 1H), 6.87 (s, 1H), 6.52 (s, 1H), 2.75 (t, J=7.2 Hz, 4H), 2.55 (t, J=7.6 Hz, 4H), 1.89 (quint, J=7.6 Hz, 4H). LCMS, Purity: 96%, m/z 400.98 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₀ H ₂₀ N ₂ O ₅ S [M+H] ⁺ : 401.1093, found: 401.4514.

3-(N-(1,2,3,5,6,7-Hexahydro-s-indacen-4-ylcarbamoyl)sulfamoyl)benzamide

3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)benzoic acid (0.06 g, 0.074 mmol) was dissolved in anhydrous N,N -dimethylformamide (4 ml) and the solution was cooled to 0°C. Diisopropylethylamine (3.0 eq.) and HATU (2.0 eq.) were added and the mixture was stirred at 0° C. for 15 minutes. Ammonium chloride (3.0 eq.) was added and the mixture was stirred at ambient temperature for 5 hours. When complete, the reaction mixture was poured into brine (20 ml) and extracted with ethyl acetate (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical residue was purified by reverse phase preparative HPLC to give the sub-title compound as a white solid (0.011 g, 37%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.23 (d, J=9.2 Hz, 2H), 8.02 (s, 1H), 7.89 (d, J=7 .6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.38 (s, 1H), 7, 33 (s, 1H). 6.74 (s, 1H), 2.73 (t, J=6.8 Hz, 4H), 2.62 (t, J=6.8 Hz, 4H), 1.87 (quint, J=7 .6 Hz, 4H). LCMS, Purity: 93%, m/z 400.05 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₀ H ₂₁ N ₃ O ₄ S [M+H] ⁺ : 400.1253, found: 400.1378.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) was added directly to methyl 3-sulfamoylbenzoate (0.447 g, 2.07 mmol, 1.20 eq. ) at ambient temperature and the mixture was stirred overnight. The reaction mixture was poured into chilled water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a 0-10% methanol in dichloromethane gradient to give methyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)benzoate as a light brown solid (0.36 g, 50%).

Methyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)benzoate (0.06 g, 0.144 mmol) was dissolved in anhydrous THF and the solution was cooled to 0°C. Methylmagnesium bromide (3 mol/l diethyl ether solution, 0.14 ml, 0.42 mmol, 3.0 eq.) was added and the mixture was stirred at ambient temperature for 4 h. Upon completion, saturated aqueous ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification of the technical residue by reverse phase preparative HPLC gave the sub-title compound as a white to yellowish solid (0.015 g, 25%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.16 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.59-7.48 (m, 2H), 7.32 (t, J=7.6 Hz, 1H), 6.78 (s, 1H), 5.10 (s, 1H), 2.74 (t, J=7.2 Hz, 4H), 2.60 (t, J=6.8 Hz, 4H), 1.88 (quint, J=7.6 Hz, 4H), 1.42 (s , 6H). LCMS, Purity: 91%, m/z 415.05 (M+H ⁺ ).

3-Azido-N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 3-azidobenzenesulfonamide were used in General Method C6 to give the sub-title compound as white with a yellowish tinge solids (70 mg, 50%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=8.22 (s, 1H), 7.72 (m, J=5.2 Hz, H), 7.65 (t, J=8, 0 Hz, 1H), 7.59 (s, 1H), 7.46-7.42 (m, 1H), 6.93 (s, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.53 (t, J=7.4 Hz, 4H), 1.92 (m, 4H). ¹³ C-NMR (101 MHz, CD ₃ OD) δ 151.2, 144.9, 144.6, 142.9, 142.5, 138.9, 131.5, 131.4, 128.6, 124 .9, 124.6, 124.6, 119.8, 119.2, 118.9, 111.9, 33.7, 33.6, 31.1, 29.7, 26.3. HRMS (ESI) calculated for C ₁₉ H ₂₀ N ₅ O ₃ S [M+H] 398.1281, found 398.1272.

N-((1,2,3,5,6,7-Hexahydro-5-indacen-4-yl)carbamoyl)-3-(4-phenyl-1H-1,2,3-tr iazol-1-yl )benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 3-(4-phenyl-1H-1,2,3-triazol-1-yl )benzenesulfonamide was used in General Method C6 to give the sub-title compound as a pale yellow solid (10 mg, 49%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=8.89 (s, 1H), 8.55 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 8, 13 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.6 Hz, 2H), 7.79 (t, J=8.0 Hz, 1H), 7.68 ( s, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 6.92 (s, 1H), 2.82 ( t, J=7.4 Hz, 4H), 2.70-2.63 (m, 4H), 1.98 (m, 4H). ¹³ C-NMR (151 MHz, CD ₃ OD) δ=148.8, 143.9, 143.6, 137.7, 137.2, 137.0, 130.6, 130.3, 129.7, 129.6, 128.8, 128.5, 127.6, 127.4, 126.7, 125.6, 124.5, 124.0, 119.3, 118.7, 110.8, 32, 7, 32.6, 30.2, 28.7, 25.3. HRMS (ESI) calculated for C ₂₇ H ₂₆ N ₅ O ₃ S [M+H] 500.1751, found 500.1735.

N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)pent-4-ynamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and N-(3-sulfamoylphenyl)pent-4-ynamide were used in General Method C6 to give the indicated in the subtitle compound as a white solid (116 mg, 61%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=8.18 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.43 (dd, J=8.3, 7.8 Hz, 1H), 6.87 (s, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.67-2.60 (m, 4H), 2.60-2.48 (m, 4H), 2.28-2.22 (m, 1H), 2.04-1.89 (m, 4H ). ¹³ C-NMR (101 MHz, CD ₃ OD) δ=170.9, 143.3, 143.0, 138.8, 137.7, 128.7, 128.3, 126.4, 122.8, 122.0, 117.9, 117.7, 82.0, 68.9, 35.4, 32.4, 29.9, 25.1, 13.9. HRMS (ESI) calculated for C ₂₄ H ₂₆ N ₃ O ₄ S [M+H] 452.1639, found 452.1658.

3-(1-(3-aminopropyl)-1Н-1,2,3-triazol-4-yl)-N-(3-(N-((1,2,3,5,6,7-hexahydro- 5-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)propanamide

N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)pent-4-ynamide and 3-azidopropan-1- the amine was used in General Method F to give the sub-title compound as a white solid (6 mg, 43%). ¹ H-NMR (600 MHz, CD ₃ OD) δ=7.85 (s, 1H), 7.55 (t, J=3.8 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.29 (t, J=7.9 Hz, 1H), 6.78 (s, 1H), 4.26 (t, J=6.4 Hz, 2H), 3.00 ( t, J=6.6 Hz, 2H), 2.71 (t, J=7.3 Hz, 4H), 2.64-2.50 (m, 8H), 1.94-2.02 (m , 2H), 1.92-1.83 (m, 4H). ¹³ C-NMR (151 MHz, CD ₃ OD) δ=173.0, 147.4, 146.8, 144.7, 144.6, 139.5, 139.2, 131.6, 130.0, 129.8, 124.2, 123.9, 123.2, 119.5, 118.6, 48.3, 37.7, 34.0, 31.6, 26.7, 26.6, 22, 9. HRMS (ESI) calculated for C ₂₇ H ₃₄ N ₇ O ₄ S [M+H] 552.2387, found 552.2368.

N-(3-(N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)-3-(1-(3-((7 -nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)propyl)-1H-1,2,3-triazol-4-yl)propanamide

N-(2-Azidopropyl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine was synthesized by the methods given in Chun Li, Etienne Henry, Naresh Kumar Mani, Jie Tang, Jean-Claude Brochon, Eric Deprez, and Juan Xie Eur. J. Org. Chem. 2010, 2395-2405. To a solution of 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (300 mg, 1.5 mmol) in THF (10 ml) was added 3-azidopropylamine (160 mg, 1.65 mmol) and Cs ₂ CO ₃ (480 mg, 1.5 mmol). The reaction mixture was stirred at 50° C. for 4 hours. The reaction mixture was partitioned between EtOAc (50 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30% EtOAc-petroleum ether as eluent to give N-(2-azidopropyl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine (240 mg, 76%) . ¹ H-NMR (400 MHz, CDCl ₃ ): δ=8.50 (d, J=8.8 Hz, 1H), 6.57 (s, 1H, NH), 6.23 (d, J=8 .8 Hz, 1H), 3.66 (q, J=6.8 Hz, 2H), 3.59 (J=6.0 Hz, 2H), 2.00-2.16 (m, 2H). ¹³ C-NMR (101 MHz, CDCl ₃ ) δ 144.2, 144.0, 143.8, 136.7, 123.7, 98.8, 49.1, 41.6, 27.6. HRMS (ESI): calculated for C ₉ H ₁₀ N ₇ O ₃ 264.0840; found 264,0711.

N-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)pent-4-ynamide (10 mg, 0.022 mmol) and N-(2-azidopropyl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine (7.0 mg, 0.026 mmol), 10 mol. % TNRTA, 5 mol. % CuSO ₄ , 10 mol. % sodium ascorbate in DMSO (500 µl) was stirred at room temperature for 12 h. NH ₄ CO ₃ , MeCN) and freeze-dried to give the product as a white solid (7.0 mg, 44%). ¹ H-NMR (600 MHz, CD ₃ OD) δ=8.46 (d, J=8.7 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.61 (s, 1H), 6.94 (s, 1H), 6.15 (d, J=9.0 Hz, 1H), 4.46 (t, J=6.7 Hz, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.4 Hz, 4H), 2.77 (t, J=7.0 Hz, 2H), 2.70-2.56 (m, 6H), 2.37-2.26 (m, 2H), 1.99 (q , J=7.3 Hz, 4H). ¹³ C-NMR (151 MHz, CD ₃ OD) δ=172.9, 147.9, 145.4, 140.5, 139.0, 138.4, 130.6, 129.1, 128.0, 125.6, 124.2, 123.6, 120.3, 119.6, 112.4, 70.6, 48.9, 37.2, 34.3, 34.2, 31.7, 30, 2, 26.8, 22.3; HRMS (ESI) calculated for C ₃₃ H ₃₄ N ₁₀ O ₇ S [M-H] 713.2260, found 713.2290.

N-(3-(4-(3-((3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)amino) -3-oxopropyl)-1H-1,2,3-triazol-1-yl)propyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol- 4-yl)pentanamide

To a solution of biotin (0.4 g, 1.63 mmol) and 3-azidopropylamine (0.2 g, 1.96 mmol) in dry DMF (10.0 ml) was added HBTU (0.93 g, 2.45 mmol ) followed by DIPEA (428 µl, 2.45 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by LCMS and after completion of the reaction was diluted with EtOAc (50 ml), washed with H ₂ O (25 ml), brine (25 ml). The organic layer was separated; dried (MgSO ₄ ) and evaporated to obtain a technical product. The technical product was purified by silica gel column chromatography using 50% EtOAc-hexane eluent to give N-(3-azidopropyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamide as a white solid (0.13 g, 24%). H-NMR (400 MHz, CD ₃ OD) δ=4.52 (dd, J=7.9, 5.0 Hz, 1H), 4.32 (dd, J=7.9, 4.5 Hz, 1H), 3.36 (t, J=6.7 Hz, 2H), 3.28 (d, J=6.8 Hz, 2H), 3.21-3.14 (m, 1H), 2, 93 (dd, J=12.8, 5.0 Hz, 1H), 2.75 (d, J=12.8 Hz, 1H), 2.20 (t, J=7.3 Hz, 2H), 1.78 (q, J=6.8 Hz, 2H), 1.74-1.57 (m, 4H), 1.45 (q, J=7.5 Hz, 2H). ¹³ C-NMR (101 MHz, CD ₃ OD) δ=173.5, 163.4, 61.0, 59.3, 54.7, 48.2, 39.4, 35.8, 34.8, 27.7, 27.5, 27.2, 24.6.

N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)pent-4-ynamide (1.0 mmol) and N-(3-azidopropyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (2.0 mmol), 10 mol. % TNRTA, 5 mol. % CuSO ₄ , 10 mol. % sodium ascorbate in DMSO was stirred at room temperature for 12 hours. The reaction mixture was purified by reverse phase column chromatography to give the sub-title compound as a white solid (8.0 mg, 31%); ¹ H-NMR (600 MHz, CD ₃ OD) δ=8.26 (s, 1H), 7.83-7.68 (m, 3H), 7.50-7.43 (m, 1H), 6 .92 (s, 1H), 4.48 (dd, J=8.0, 4.8 Hz, 1H), 4.41-4.22 (m, 3H), 3.18 (dd, J=6 .9, 3.5 Hz, 1H), 3.14 (td, J=6.7, 1.7 Hz, 2H), 3.12-3.06 (m, 2H), 2.90 (dd, J=12.8, 4.9 Hz, 1H), 2.81 (t, J=7.7 Hz, 4H), 2.77 (d, J=7.1 Hz, 1H), 2.71 ( s, 1H), 2.62 (t, J=7.3 Hz, 4H), 2.19 (td, J=7.4, 1.7 Hz, 2H), 2.05-2.01 (m , 2H), 2.00-1.95 (m, 4H), 1.76-1.57 (m, 4H), 1.43 (q, J=7.6, 7.1 Hz, 2H). ¹³ C-NMR (151 MHz, CD ₃ OD) δ=174.8, 174.8, 171.6, 171.5, 164.5, 146.2, 143.6, 139.1, 137.7, 129.1, 129.1, 128.7, 128.1, 126.5, 123.7, 122.9, 122.4, 122.2, 120.9, 118.4, 118.4, 118, 3, 118.2, 118.2, 117.2, 110.5, 69.0, 61.9, 60.2, 55.6, 39.8, 36.1, 36.0, 35.8, 35.4, 35.4, 32.6, 32.6, 30.0, 29.7, 29.7, 28.6, 28.3, 28.0, 25.3, 25.2, 25, 2, 20.9. HRMS (ESI) calculated for C ₃₇ H ₄₈ N ₉ O ₆ S ₂ [M+H] 778.3163, found 778.3145.

N-((1-(3-(N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)-1H-1,2,3 -triazol-4-yl)methyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide

5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-N-((1-(3-sulfamoylphenyl)-1H-1,2, 3-triazol-4-yl)methyl)pentanamide was synthesized using 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-N-(prop -2-yn-1-yl)pentanamide (1.0 mmol) and 3-azidobenzenesulfonamide (2.0 mmol), 10 mol. % TNRTA, 5 mol. % CuSO ₄ , 10 mol. % NaAsc in DMSO, stirred at room temperature for 12 hours. Product formation was monitored by LCMS. After completion of the reaction, the reaction mixture was purified by HPLC (Reveleris flash column chromatography system, 4 g, 18 ml/min, mobile phase; 10 mmol aq. NH ₄ CO ₃ , MeCN) to isolate 5-((3aS, 4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-N-((1-(3-sulfamoylphenyl)-1H-1,2,3-triazol-4- yl)methyl)pentanamide as a white solid (24 mg, 47%) which was used immediately.

To a solution of 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-N-((1-(3-sulfamoylphenyl)-1H-1, 2,3-triazol-4-yl)methyl)pentanamide (15 mg, 0.031 mmol) in THF (5.0 ml) DIPEA (605 μl, 0.037 mmol) was added under nitrogen. This mixture was stirred at room temperature for 15 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) (705 mg, 0.037 mmol) in THF was added dropwise. The reaction mixture was stirred at room temperature overnight, then the solvent was removed under reduced pressure to give a technical compound, which was purified by reverse phase column chromatography using aq. (NH ₄ ) ₂ CO ₃ 10 mmol/L and MeCN to isolate the sub-title compound as a white solid (5.2 mg, 24%). ¹ H-NMR (600 MHz, CD ₃ OD) δ=8.53 (d, J=2.4 Hz, 1H), 8.50 (d, J=7.5 Hz, 1H), 8.22- 8.11 (m, 2H), 7.86-7.78 (m, 1H), 6.99 (s, 1H), 4.62 (s, 2H), 4.57-4.49 (m, 1H), 4.38-4.31 (m, 1H), 3.27-3.20 (m, 1H), 3.00-2.84 (m, 4H), 2.78-2.70 ( m, 4H), 2.36 (t, J=7.2 Hz, 2H), 2.06 (q, J=7.4 Hz, 4H), 1.83-1.73 (m, 3H), 1.71-1.63 (m, 1H), 1.54-1.43 (m, 3H). ¹³ C-NMR (151 MHz, CD ₃ OD) δ=174.6, 164.5, 146.1, 145.4, 143.6, 137.7, 137.2, 130.5, 125.9, 123.4, 121.1, 117.8, 110.6, 61.8, 60.2, 55.5, 47.7, 47.6, 39.8, 3.2, 34.3, 32, 6, 30.14, 28.2, 27.9, 25.3, 25.2. HRMS (ESI) calculated for C ₃₂ H ₃₉ N ₈ O ₅ S ₂ [M+H] 679.2479, found 679.2456.

N-(quinolin-6-ylcarbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide

To a solution of quinoline-6-amine (0.1 g, 0.69 mmol) in THF (50 ml) and triethylamine (1.5 eq.) was added phenyl chloroformate (1 eq.) at 0°C. The solution was diluted with water, extracted with ethyl acetate (×2), washed with water, brine, then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was triturated with pentane to give phenylquinolin-6-ylcarbamate as a white to yellowish solid, which was used immediately in the next reaction step.

3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide (0.185 g, 0.69 mmol) in THF (30 ml) at 0°C was treated with sodium hydride (3 eq.) in portions and the suspension was stirred for 30 minutes (until gas evolution stops). Commercial grade phenylquinolin-6-ylcarbamate was dissolved in THF (20 mL) then added slowly to the reaction mixture and stirring continued at ambient temperature until complete, typically 2 hours. The reaction mixture was diluted with saturated aq. NH ₄ Cl, extracted with ethyl acetate (×2), washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was triturated with diethyl ether then pentane to give the sub-title compound, N-(quinolin-6-ylcarbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide, as a white solid substances (10 mg, 3%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.88 (s, 1H), 8.59 (d, J=3.5 Hz, 1H), 8.11 (s, 1H), 8 .04 (d, J=8.3 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.74 (d, J=9.1 Hz, 1H), 7.70 -7.60 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 7.34 (dd, J=8.3, 4.2 Hz, 1H), 7.30 ( e, J=8.0 Hz, 1H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ) δ -64.49.

N-(quinolin-5-ylcarbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide

N-(quinolin-5-ylcarbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide was synthesized using a modification of the procedures used to prepare N-(quinolin-6-ylcarbamoyl)-3-( 3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide, but using quinoline-5-amine instead of quinoline-6-amine. The sub-title compound was obtained as a white to yellowish solid (10 mg, 3%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.79 (d, J=4.1 Hz, 1H), 8.61 (s, 1H), 8.57 (d, J=8, 7 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.2 Hz, 1H), 7.70 (s, 1H), 7.59 -7.50 (m, 2H), 7.40 (dd, J=8.7, 4.1 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ) δ -64.51.

N-((6-methoxyquinolin-8-yl)carbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide

N-((6-methoxyquinolin-8-yl)carbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide was synthesized using a modification of the procedures used to prepare N-(quinolin-6-ylcarbamoyl )-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide, but using 6-methoxyquinoline-8-amine instead of quinoline-6-amine. The sub-title compound was obtained as a white to yellowish solid (35 mg, 20%). ¹ H-NMR (400 MHz, CD ₃ OD) δ 8.64 (dd, J=4.2, 1.6 Hz, 1H), 8.18-8.02 (m, 3H), 7.88 ( s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.50-7.36 (m, 2H), 6.79 (d, J=2.6 Hz, 1H), 3.88 (s, 3H). ¹⁹ F-NMR (376 MHz, CD ₃ OD) δ -67.04.

N-(quinolin-8-ylcarbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide

N-(Quinolin-8-ylcarbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide was synthesized using a modification of the procedures used to prepare N-(quinolin-6-ylcarbamoyl)-3-( 3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide, but using quinoline-8-amine instead of quinoline-6-amine. The sub-title compound was obtained as a white solid (20 mg, 16%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=8.82 (dd, J=4.3, 1.6 Hz, 1H), 8.35 (dd, J=7.4, 1.8 Hz , 1H), 8.21 (dd, J=8.3, 1.7 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.88 (s, 1H), 7 .59 (t, J=7.9 Hz, 1H), 7.52-7.38 (m, 4H).

N-((2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)carbamoyl)-3-(3-(trifluoromethyl)-3H-diazirin-3 -yl)benzenesulfonamide

4-isocyanato-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (prepared using General Method A1) and 3-(3-(trifluoromethyl)-3H-diazirin- 3-yl)benzenesulfonamide was used in General Method C1 to give the sub-title compound as a white solid (0.01 g, 2%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=8.06 (dt, J=7.9, 1.3 Hz, 1H), 7.80 (s, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 6.39 (s, 1H), 4.49 (t, J=8.6 Hz, 2H), 4.42 (t, J=8.6 Hz, 2H), 3.09 (t, J=8.4 Hz, 2H), 3.02 (t, J=8.6 Hz, 2H). ¹⁹ F-NMR (376 MHz, CD ₃ OD) δ -67.06.

4-chloro-N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4-chlorobenzenesulfonamide were used in General Method C2 to give the sub-title compound as a white solid ( 48 mg, 43%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.13 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.68 (d, J=12 Hz, 2H), 6.92 (s, 1H), 2.77 (t, J=8.0 Hz, 4H), 2.54 (t, J=8.0 Hz, 4H), 1.95- 1.88 (m, 4H); ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=150.1, 143.4, 139.9, 138.1, 137.6, 129.6, 129.4, 129.2, 32, 8, 30.5, 25.9; Purity by LCMS: >95%; LCMS (m/z): 391 [M+H] ⁺ ; HRMS calculated for C ₁₉ H ₁₉ ClN ₂ O ₃ S [M+H] ⁺ : 391.0878, found: 391.0895.

N-(1,2,3,5,6,7-hexahydro-5-indacen-4-ylcarbamoyl)-4-methylbenzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 4-methylbenzenesulfonamide were used in General Method C4 to give the sub-title compound as a white solid ( 0.045 g, 27%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.70 (br s, 1H), 8.08 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 6.92 (s, 1H), 2.79-2.68 (m, 4H), 2.58-2.50 (m, 4H) , 2.39 (s, 3H), 1.97-1.87 (m, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=149.0, 143.6, 143.0, 137.1, 129.4, 128.6, 127.3, 117.9, 32, 4, 30.0, 25.0, 21.0. LCMS, Purity: 95.08%, m/z 371.07 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₀ H ₂₂ N ₂ O ₃ S [M+H] ⁺ : 371.1351, found: 371.1419.

5-Chloro-N-(4-(N-(1,2,3,5,6,7-hexahydro-5-indacen-4-ylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 5-Chloro-2-methoxy-N-(4-sulfamoylphenethyl)benzamide were used in General Method C4 to give the sub-title compound as a white solid (45 mg, 10%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.73 (s, 1H), 8.27 (t, J=5.2 Hz, 1H), 8.09 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.65 (d, J=2.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7. 49 (d, J=2.4 Hz, 1H), 7.13 (d, J=9.2 Hz, 1H), 6.92 (s, 1H), 3.78 (s, 3H), 3. 54 (q, J=6.4 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H), 2.75 (t, J=7.2 Hz, 4H), 2.50 ( m, 4H), 1.89 (quint, J=7.6 Hz, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=163.6, 155.7, 145.3, 143.6, 143.0, 142.4, 142.1, 139.6, 137, 1, 131.5, 129.5, 129.2, 127.4, 125.7, 124.8, 124.3, 117.9, 114.1, 108.3, 56.2, 34.7, 32.6, 32.4, 30.0, 28.9, 24.9. LCMS, Purity: 90.06%, tr=3.38 min, m/z 566.37 (M-H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₉ H ₃₀ ClN ₃ O ₅ S [M+H] ⁺ : 568.1595, found: 568.1589.

N-(4-(N-(1,2,3,5,6,7-Hexahydro-s-indacen-4-ylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 5-methyl-N-(4-sulfamoylphenethyl)pyrazine-2-carboxamide were used in General Method C4 to give the sub-title compound as a white to yellowish solid (0.02 g, 4%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.71 (s, 1H), 9.02 (s, 1H), 8.96 (t, J=6 Hz, 1H), 8, 59 (s, 1H), 8.07 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 6, 92 (s, 1H), 3.57 (kv, J=6.8 Hz, 2H), 2.97 (t, J=7.4 Hz, 2H), 2.82-2.73 (m, 4H ), 2.53 (s, 3H), 2.57-2.50 (m, 4H), 1.97-1.84 (m, 4H). LCMS, Purity: 88.15%, m/z 520.28 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₇ H ₂₉ N ₅ O ₄ S [M+H] ⁺ : 520.1940, found: 520.1977.

3-(4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenyl)-N-(prop-2-yn-1- silt) propanamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and N-(prop-2-yn-1-yl)-3-(4-sulfamoylphenyl) )propanamide was used in General Method C6 to give the sub-title compound as a white solid (120 mg, 68%). ¹ H-NMR (400 MHz, CD ₃ OD) δ=7.91 (d, J=7.8 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 6.98 ( s, 1H), 3.95 (d, J=2.9 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 2.85 (t, J=7.4 Hz, 4H), 2.62 (t, J=6.9 Hz, 4H), 2.55-2.46 (m, 2H), 2.25 (t, J=2.6 Hz, 1H), 2, 02 (m, 4H). ¹³ C-NMR (101 MHz, CD ₃ OD) δ=172.0, 147.2, 144.1, 143.8, 137.5, 129.0, 128.8, 128.1, 127.4, 126.5, 118.9, 79.2, 71.0, 36.8, 32.8, 32.8, 31.2, 30.7, 28.8, 28.7, 25.4, 25, 3. HRMS (ESI) calculated for C ₂₅ H ₂₈ N ₃ O ₄ S [M+H] 466.1795, found 466.1794.

N-(4-(N-(1,2,3,5,6,7-Hexahydro-s-indacen-4-ylcarbamoyl)sulfamoyl)phenethyl)-2-(methyl(7-nitrobenzo[c][1, 2,5]oxadiazol-4-yl)amino)acetamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 2-(methyl(7-nitrobenzo[c][1,2,5]oxadiazol- 4-yl)amino)-N-(4-sulfamoylphenethyl)acetamide was used in General Method C4 to give the sub-title compound as an orange solid (0.003 g, 1%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.74 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.31 (t, J=7 .6 Hz, 1H), 8.09-7.96 (m, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.41 (d, J=7.6 Hz, 2H ), 6.89 (s, 1H), 6.42-6.32 (m, 1H), 4.74 (brs, 2H), 3.44-3.30 (m, 5H), 2.80 ( t, J=7.6 Hz, 2H), 2.73-2.69 (m, 4H), 2.61-2.50 (m, 4H), 1.92-1.88 (m, 4H) . LCMS, Purity: 92.20%, m/z 632.35 (M-H ⁺ ).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazole -4-yl)amino)ethyl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 4-(2-((7-nitrobenzo[c][1,2,5] oxadiazol-4-yl)amino)ethyl)benzenesulfonamide was used in General Method C4 to give the sub-title compound as a yellow solid (0.047 g, 15%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.69 (br s, 1H), 9.55 (s, 1H), 8.50 (d, J=8.8 Hz, 1H ), 8.09 (s, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 6.92 (s, 1H ), 6.50 (d, J=8.8 Hz, 1H), 3.76 (w s, 2H), 3.11 (t, J=6.8 Hz, 2H), 2.76 (t, J=7.6 Hz, 4H), 2.53 (t, J=6.8 Hz, 4H), 1.90 (quint, J=7.6 Hz, 4H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=149.1, 144.8, 144.3, 142.4, 138.3, 137.8, 137.1, 129.3, 128, 6, 127.3, 125.7, 121.0, 117.9, 108.3, 99.5, 44.1, 33.2, 32.5, 30.1, 28.9, 25.0. LCMS, Purity: 96.50%, tr=2.29 min, m/z 563.20 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₇ H ₂₆ N ₆ O ₆ S [M+H] ⁺ : 563.1635, found: 563.1641.

2-(7-(Dimethylamino)-2-oxo-2H-chromen-4-yl)-N-(4-(N-(1,2,3,5,6,7-hexahydro-5-indacene-4 -ylcarbamoyl)sulfamoyl)phenethyl)acetamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl )-N-(4-sulfamoylphenethyl)acetamide was used in General Method C4 to give the sub-title compound as a pale yellow solid (0.008 g, 0.44%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=9.53 (s, 1H), 8.29 (t, J=4.8 Hz, 1H), 8.22 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.8 Hz, 1H), 8.42 (s, 1H), 7.16 (d, J=8 .0 Hz, 2H), 6.74-6.70 (m, 2H), 6.54 (d, J=2.4 Hz, 1H), 5.99 (s, 1H), 3.56-3 .52 (m, 2H), 3.48 (t, J=6.0 Hz, 2H), 3.31-3.24 (m, 2H), 2.76-2.70 (m, 4H), 3.02 (s, 6H), 2.63 (t, J=7.2 Hz, 4H), 1.88 (quint, J=7.6 Hz, 4H). LCMS, Purity: 92.26%, m/z 629.40 (MH ⁺ ).

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)benzo[d][1,3]dioxol-5-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and benzo[d][1,3]dioxol-5-sulfonamide were used in General Method C2 with yielding the sub-title compound as a white solid (28 mg, 27%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.04 (b.s., 1H), 7.47 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.09 (d, J=4.0 Hz, 1H), 6.91 (s, 1H), 6.16 (s, 2H) 2.77 (t, J=8.0 Hz, 4H ), 2.56 (t, J=8.0 Hz, 4H), 1.96-1.89 (m, 4H); Purity by LCMS: >95%; LCMS (m/z): 401 [M+H] ⁺ ; HRMS calculated for C ₂₀ H ₂₀ N ₂ O ₅ S [M+H] ⁺ 401.1166, found 401.1182.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-sulfonamide

1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (70 mg, 0.40 mmol) was dissolved in anhydrous THF (5 mL) and treated with Et ₃ N (49 mg, 0.49 mmol) at room temperature. The solution was treated with triphosgene (48 mg, 0.161 mmol) and the resulting mixture was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was stirred with 5% EtOAc-hexanes (20 mL) for 10 min, filtered through a pad of celite, and concentrated under reduced pressure to give the corresponding isocyanate as a white solid. In a separate flask, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-sulfonamide (115 mg, 0.61 mmol) was dissolved in anhydrous THF (5 ml) and NaH (25 mg, 0 .61 mmol) at 0° C. under nitrogen and stirred for 20 minutes. The above isocyanate in THF was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was warmed to room temperature, stirred for 4 h, then concentrated under reduced pressure. The resulting residue was diluted with ammonium bicarbonate in water 10 mmol/l (20 ml), acetonitrile (20 ml), ethyl acetate (10 ml) and the resulting solid was removed by filtration and washed with diethyl ether to give N-((1,2,3,5 ,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-sulfonamide (50 mg, 32%) as a white solid substances. ¹ H-NMR (400 MHz, CD ₃ OD): δ=7.29 (s, 1H), 6.85 (s, 1H), 4.23 (t, J=7.2 Hz, 1H), 2 .86-2.79 (m, 6H), 2.72 (t, J=7.2 Hz, 4H), 2.65-2.60 (m, 2H), 2.02-1.95 (m , 4H). LCMS (m/z): 387.10 [M+H] ⁺ ; 95.53% (210 nm). HPLC: 94.43% (210 nm). HRMS calculated for C ₁₉ H ₂₁ N ₄ O ₃ S ₁ [M-H] ^- 385.1340, found 385.1331.

4-Acetyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4-acetylbenzenesulfonamide were used in General Method C2 to give the sub-title compound as a white solid ( 31 mg, 16%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=11.03 (br, 1H) 8.08 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 7.03 (br.s, 1H), 6.87 (s, 1H), 2.75 (t, J=7.4 Hz, 4H), 2.62 (s, 3H), 2.56 (t, J=7.4 Hz, 4H), 1.90 (n, J=7.4 Hz, 4H). HRMS calculated for C ₂₁ H ₂₁ N ₂ O ₄ S ₁ [M-H] ^- 397.1128, found 397.1225.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-nitrobenzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4-nitrobenzenesulfonamide were used in General Method C2 to give the sub-title compound as a pale yellow solid substances (148 mg, 60%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=10.00 (br s, 1H), 8.21 (d, J=9.0 Hz, 2H), 7.97 (d, J= 9.0 Hz, 2H), 7.45 (s, 1H), 6.75 (s, 1H), 2.73 (t, J=7.4 Hz, 4H), 2.61 (t, J= 7.4 Hz, 4H), 1.87 (n, J=7.4 Hz, 4H). HRMS calculated for C ₁₉ H ₁₈ N ₃ O ₅ S ₁ [M-H] ^- 400.0973, found 400.0979.

4-Amino-N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)benzenesulfonamide

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-nitrobenzenesulfonamide dissolved in ethyl acetate/DMF solution (4:1, 25 ml/mmol), stirred at room temperature for 1 hour under a hydrogen atmosphere with a catalytic amount of Pd/C (0.1 mol %) to give the sub-title compound as a white solid (16 mg, 43%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=7.95 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 6.91 (s, 1H), 6 .59 (d, J=8.8 Hz, 2H), 6.05 (s, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.55 (t, J=7, 4 Hz, 4H), 1.93 (kv, J=7.4 Hz, 4H). HRMS calculated for C ₁₉ H ₂₀ N ₃ O ₃ S ₁ [M-H] ^- 370.1231, found 370.1225.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydro-1H-inden-5-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 2,3-dihydro-1H-indene-5-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (48 mg, 12%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=10.68 (br s, 1H), 8.02 (s, 1H), 7.75 (d, J=1.7 Hz, 1H) , 7.68 (dd, J=7.9, 1.7 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 6.90 (s, 1H), 2.91 ( t, J=7.5 Hz, 4H), 2.76 (t, J=7.4 Hz, 4H), 2.53 (t, J=7.4 Hz, 4H), 2.05 (n, J=7.5 Hz, 2H), 1.91 (n, J=7.4 Hz, 4H). HRMS calculated for C ₂₂ H ₂₃ N ₂ O ₃ S ₁ [M-H] ^- 395.1435, found 395.1430.

N-((4-chlorophenyl)carbamoyl)-2,3-dihydro-1H-indene-5-sulfonamide

1-Chloro-4-isocyanatobenzene (prepared using General Method B1) and 2,3-dihydro-1H-indene-5-sulfonamide were used in General Method C2 to give the sub-title compound as a white solid (60 mg, 32 %). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 10.90 (br s, 1H), 8.90 (s, 1H), 7.74 (d, J=1.8 Hz, 1H) 7 .68 (dd, J=7.9, 1.7 Hz, 1H), 7.41-7.35 (m, 3H), 7.26 (dt, 2H), 2.91 (m, 4H), 2.05 (n, J=7.5 Hz, 2H). HRMS calculated for C ₁₆ H ₁₄ Cl ₁ N ₂ O ₃ S ₁ [M-H] ^- 349.0419, found HRMS 349.0418.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)quinoline-8-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and quinoline-8-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid (75 mg, 71%) . ¹ H-NMR (600 MHz, CD ₃ OD): δ=9.13 (dd, J=4.2, 1.6 Hz, 1H), 8.57-8.49 (m, 2H), 8, 26 (d, J=8.2 Hz, 1H), 7.77-7.67 (m, 2H), 6.99 (s, 2H), 2.65-2.60, (m, 2H), 0.85 (d, 12H); ¹³ C-NMR (150 MHz, CD ₃ OD) δ=151.2, 149.0, 143.3, 136.8, 136.7, 133.8, 133.5, 132.3, 129.4, 129.1, 125.3, 123.0, 122.1, 109.1, 28.3, 22.5; Purity by LCMS: >95%; LCMS (m/z): 446 [M+H] ⁺ ; HRMS calculated for C ₂₂ H ₂₅ Cl ₁ N ₃ O ₃ S ₁ [M+H] ⁺ 446.1300, found 446.1314.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)isoquinoline-5-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and isoquinoline-5-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as a white solid substances (70 mg, 67%). ¹ H-NMR (600 MHz, CD ₃ OD): δ=9.41 (s, 1H), 8.82 (s, 1H), 8.59 (d, J=7.3 Hz, 2H), 8 .35 (d, J=8.2 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 6.96 (s, 2H), 2.74-2.70 (m, 2H), 0.96 (s, 6H), 0.85 (d, 12H); ¹³ C-NMR (150 MHz, CD ₃ OD) δ=156.3, 152.5, 149.1, 143.8, 137.2, 133.9, 133.1, 132.6, 131.5, 130.4, 126.3, 124.8, 122.8, 122.1, 28.3, 22.4; Purity by LCMS: >95%; LCMS (m/z): 446 [M+H] ⁺ ; HRMS calculated for C ₂₂ H ₂₅ Cl ₁ N ₃ O ₃ S ₁ [M+H] ⁺ 446.1300, found 446.1319.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)quinoline-5-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and quinoline-5-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as a white solid substances (31 mg, 60%). ¹ H-NMR (600 MHz, CD ₃ OD): δ=9.53 (d, J=8.9 Hz, 1H), 8.94 (d, J=3.8 Hz, 1H), 8.35 (dd, J=7.3, 1.2 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.79 (dd, J=8.5, 7.3 Hz, 1H), 7.69 (dd, J=8.7, 4.3 Hz, 1H), 2.81-2.76 (m, 2H), 0.85 (d, 12H); ¹³ C-NMR (150 MHz, CD ₃ OD) δ=161.4, 151.3, 150.7, 149.1, 142.2, 137.4, 134.0, 133.0, 132.8, 129.9, 129.4, 126.0, 124.1, 122.9, 29.6, 24.0; Purity by LCMS: >95%; LCMS (m/z): 446 [M+H] ⁺ ; HRMS calculated for C ₂₂ H ₂₅ Cl ₁ N ₃ O ₃ S ₁ [M+H] ⁺ 446.1300, found 446.1317.

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)quinoline-8-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4H-quinoline-8-sulfonamide were used in General Method C3 to give the sub-title compound as white solid (60 mg, 51%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=9.11 (d, J=2.7 Hz, 1H), 8.56 (d, J=8.3 Hz, 1H), 8.40 (d, J=7.4 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.76 (t, J=7.7 Hz , 1H), 7.73 (dd, J=8.4, 4.2 Hz, 1H), 6.82 (s, 1H), 2.67 (t, J=7.4 Hz, 4H), 2 .26 (t, J=7.4 Hz, 4H), 1.79 (n, J=7.5 Hz, 4H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=151.8, 151.7, 143.3, 143.2, 137.5, 137.1, 134.5, 133.4, 132, 8, 129.9, 126.0, 122.8, 118.0, 108.7, 32.7, 30.2, 25.3. LCMS (m/z): 408 [M+H] ⁺ . HRMS calculated for C ₂₂ H ₂₂ N ₃ O ₃ S ₁ [M+H] ⁺ 408.1376, found 408.1371.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)quinoline-3-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and quinoline-3-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as a white solid substances (30 mg, 57%). ¹ H-NMR (600 MHz, DMSO-d ₆ ): δ=9.24 (s, 1H), 8.92 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.12 (d, J=8.5 Hz, 1H), 7.98 (s, 1H), 7.93 (t, J=7.7 Hz, 1H), 7.74 (t, J=7 .6 Hz, 1H), 7.02 (s, 2H), 2.81-2.78 (m, 2H), 0.84 (d, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=153.7, 149.3, 148.7, 147.6, 141.5, 136.8, 132.6, 132.4, 131, 5, 129.9, 129.2, 128.4, 126.4, 123.3, 28.5, 23.5; Purity by LCMS: >95%; LCMS (m/z): 446 [M+H] ⁺ ; HRMS calculated for C ₂₂ H ₂₅ Cl ₁ N ₃ O ₃ S ₁ [M+H] ⁺ 446.1300, found 446.1315.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)quinoxaline-5-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and quinoxaline-5-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as a white solid substances (39 mg, 75%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=9.18 (d, J=3.7 Hz, 2H), 8.46 (d, J=7.3 Hz, 1H), 8.38 (dd, J=8.1, 2.7 Hz, 1H), 8.04-7.95 (m, 1H), 7.83 (s, 1H), 6.99 (s, 2H), 2, 55-2.49 (m, 2H), 0.74 (d, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): 149.2, 147.1, 146.8, 146.2, 142.7, 140.5, 138.5, 138.2, 134.2, 133.4, 132.6, 129.6, 123.4, 28.4, 22.7; Purity by LCMS: >95%; LCMS (m/z): 447 [M+H] ⁺ ; HRMS calculated for C ₂₁ H ₂₄ Cl ₁ N ₄ O ₃ S ₁ [M+H] ⁺ 447.1252, found 447.1266.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)naphthalene-2-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and naphthalene-2-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as a white solid substances (35 mg, 67%). ¹ H-NMR (600 MHz, CD ₃ OD): δ=8.55 (s, 1H), 8.05-7.92 (m, 4H), 7.64-7.58 (m, 2H), 6.99 (s, 2H), 2.94-2.89 (m, 2H), 0.94 (br, 12H); ¹³ C-NMR (150 MHz, CD ₃ OD) δ 159.9, 150.6, 142.2, 135.9, 134.0, 133.7, 132.6, 130.2, 129.5, 129 .1, 128.8, 128.6, 128.1, 124.3, 124.2, 29.7, 24.0; Purity by LCMS: >95%; LCMS (m/z): 445 [M+H] ⁺ ; HRMS calculated for C ₂₃ H ₂₆ Cl ₁ N ₂ O ₃ S ₁ [M+H] ⁺ 445.1347, found 445.1349.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-6-methoxynaphthalene-2-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and 6-methoxynaphthalene-2-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as white solid (39 mg, 70%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=8.23 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.78 (dd, J=9, 1, 6.4 Hz, 2H), 7.49 (s, 1H), 7.35 (d, J=2.6 Hz, 1H), 7.20 (dd, J=8.9, 2.6 Hz, 1H), 6.96 (s, 2H), 3.08-2.98 (m, 2H), 0.93 (br.s, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=158.0, 149.6, 135.2, 134.4, 131.0, 130.5, 128.1, 127.5, 127, 3, 126.5, 124.7, 124.6, 122.7, 119.4, 106.2, 55.7, 28.3, 23.4; Purity by LCMS: >95%; LCMS (m/z): 475 [M+H] ⁺ ; HRMS calculated for C ₂₄ H ₂₈ Cl ₁ N ₂ O ₄ S ₁ [M+H] ⁺ 475.1453, found 475.1474.

6-chloro-N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)naphthalene-2-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and 6-chloronaphthalene-2-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as white solid (34 mg, 61%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=8.30 (s, 1H), 8.06 (d, J=2.2 Hz, 1H), 8.01 (d, J=8, 8 Hz, 1H), 7.93-7.85 (m, 2H), 7.55 (dd, J=8.7, 2.2 Hz, 1H), 7.40 (s, 1H), 6, 95 (s, 2H), 3.09-2.97 (m, 2H), 0.92 (br s, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=160.2, 149.6, 145.8, 134.8, 134.2, 131.7, 131.1, 130.8, 130, 7, 127.2, 126.8, 126.6, 125.8, 125.7, 122.7, 28.3, 23.6; Purity by LCMS: >95%; LCMS (m/z): 479 [M+H] ⁺ ; HRMS calculated for C ₂₃ H ₂₅ Cl ₂ N ₂ O ₃ S ₁ [M+H] ⁺ 479.0957, found 479.0937.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-5,6,7,8-tetrahydronaphthalene-2-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and 5,6,7,8-tetrahydronaphthalene-2-sulfonamide (prepared using General Method E3) were used in General Method C1 to give the sub-title compound as a white solid (8 mg, 38%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=7.85 (s, 1H), 7.58 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7 .22 (d, J=7.2 Hz, 1H), 7.08 (s, 2H), 2.85-2.81 (m, 2H), 2.78-2.74 (m, 4H), 1.74 (t, J=3.3 Hz, 4H), 0.98 (br.s, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=149.3, 137.7, 137.5, 132.4, 129.8, 129.5, 129.7, 126.3, 124, 3, 123.4, 122.9, 29.3, 29.2, 28.5, 23.4, 22.8, 22.7; Purity by LCMS: >95%; LCMS (m/z): 449 [M+H] ⁺ ; HRMS calculated for C ₂₃ H ₃₀ Cl ₁ N ₂ O ₃ S ₁ [M+H] ⁺ 449.1660, found 449.1664.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)thieno[3,2-b]pyridine-6-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and thieno[3,2-b]pyridine-6-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid substances (35 mg, 66%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=9.07 (d, J=2.0 Hz, 1H), 9.05 (s, 1H), 8.45 (d, J=5, 5 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J=5.5 Hz, 1H), 7.05 (s, 2H), 2.79-2.75 (m, 2H), 0.87 (d, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=158.2, 152.7, 149.3, 145.8, 138.2, 132.7, 132.3, 132.2, 131, 6, 131.1, 124.7, 123.4, 28.5, 22.9; Purity by LCMS: >95%; LCMS (m/z): 452 [M+H] ⁺ ; HRMS calculated for C ₂₀ H ₂₃ Cl ₁ N ₃ O ₃ S ₂ [M+H] ⁺ 452.0864, found 452.0884.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-3-ethylisoxazolo[5,4-b]pyridine-5-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and thieno[3,2-b]pyridine-6-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid substances (38 mg, 64%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=9.11 (s, 1H), 8.98 (s, 1H), 8.14 (s, 1H), 7.08 (s, 2H) , 3.09 (q, J=7.5 Hz, 2H), 2.82-2.77 (m, 2H), 1.34 (t, J=7.5 Hz, 3H), 1.02- 0.90 (d, 12H). ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=170.2, 161.9, 150.5, 149.3, 134.3, 134.2, 132.8, 131.0, 123, 5, 112.7, 109.9, 28.5, 23.0, 19.2, 11.9; Purity by LCMS: >95%; LCMS (m/z): 465 [M+H] ⁺ ; HRMS calculated for C ₂₁ H ₂₆ Cl ₁ N ₄ O ₄ S ₁ [M+H] ⁺ 465.1358, found 465.1354.

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)benzofuran-2-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and benzofuran-2-sulfonamide were used in General Method C3 to give the sub-title compound as a white solid substances (60 mg, 52%); ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.00 (br s, 1H), 7.77 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 7.51 (s, 1H), 7.49 (d, J=8 Hz, 1H), 7.36 (t, J=8 Hz, 1H), 7.08 (br.s, 1H), 6.87 (s, 1H), 2.75 (t, J=8 Hz, 4H), 2.59 (t, J=8 Hz, 4H), 1.92-1.85 (m, 4H). ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=154.9, 143.2, 137.6, 130.3, 127.5, 126.7, 124.4, 123.3, 117, 7, 112.3, 110.0, 109.4, 107.4, 32.9, 30.6, 25.5. LCMS (m/z): 397 [M+H] ⁺ . HRMS calculated for C ₂₁ H ₂₁ N ₂ O ₄ S ₁ [M+H] ⁺ 397.1217, found 397.1215.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)benzofuran-2-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and benzofuran-2-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as a white solid substances (25 mg, 49%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=7.85 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.66 (d, J=8, 4 Hz, 1H), 7.47 (s, 1H), 7.34 (t, J=7.5 Hz, 1H), 7.17 (s, 1H), 7.04 (s, 2H), 2 .99-2.95 (m, 2H), 0.94 (br, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ=154.9, 149.5, 132.6, 132.3, 132.0, 127.2, 126.9, 126.8, 123, 3, 123.2, 112.1, 112.0, 109.8, 28.5, 23.3; Purity by LCMS: >95%; LCMS (m/z): 435 [M+H] ⁺ ; HRMS calculated for C ₂₁ H ₂₄ Cl ₁ N ₂ O ₄ S ₁ [M+H] ⁺ 435.1140, found 435.1140.

N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)benzo[b]thiophene-2-sulfonamide

5-Chloro-2-isocyanato-1,3-diisopropylbenzene (prepared using General Method A2) and benzo[b]thiophene-2-sulfonamide (prepared using General Method E3) were used in General Method C3 to give the sub-title compound as a white solid (38 mg, 72%); ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 8.03 (d, J=7.9 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.80 ( s, 1H), 7.46 (dt, J=15.4, 7.0 Hz, 2H), 7.04 (s, 2H), 3.05-2.83 (m, 2H), 0.94 (shs, 12H); ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ 155.3, 149.5, 141.1, 138.0, 132.4, 132.0, 126.8, 125.7, 125.4 , 123.1, 123.0, 122.9, 109.7, 28.5, 23.3; Purity by LCMS: >95%; LCMS (m/z): 451 [M+H] ⁺ ; HRMS calculated for C ₂₁ H ₂₄ Cl ₁ N ₂ O ₃ S ₂ [M+H] ⁺ 451.0911, found 451.0900.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-(7-methoxy-4,4-dimethyl-1,3-dioxo -3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 4-(2-(7-methoxy-4,4-dimethyl-1,3- dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide was used in General Method C2 to give the sub-title compound as a white solid (85 mg, 52%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=10.72 (brs, 1H), 7.91 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7 .58 (d, J=8.7 Hz, 1H), 7.53 (d, J=2.9 Hz, 1H), 7.39 (d, J=7.9 Hz, 2H), 7.29 (dd, J=8.7, 2.9 Hz, 1H), 6.88 (s, 1H), 4.13 (t, J=7.5 Hz, 2H), 3.83 (s, 3H) , 2.93 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H), 2.55 (t, J=7.4 Hz, 4H), 1 .90 (n, J=7.4 Hz, 4H), 1.42 (s, 6H). HRMS calculated for C ₃₃ H ₃₄ N ₃ O ₆ S ₁ [M-H] ^- 600.2174, found 600.2183.

N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenethyl)-5-methylisoxazole-3-carboxamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 5-methyl-N-(4-sulfamoylphenethyl)isoxazole-3-carboxamide were used in General Method C2 to give the sub-title compound as a white solid (14 mg, 62%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 8.78 (t, J=5.8 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 6.85 (s, 1H), 6.50 (q, J=1.0 Hz, 1H), 3.49 ( m, 2H), 2.91 (t, J=7.0 Hz, 2H), 2.75 (t, J=7.4 Hz, 4H), 2.56 (t, J=7.4 Hz, 4H), 2.45 (d, J=0.9 Hz, 3H), 1.89 (n, J=7.4 Hz, 4H). HRMS calculated for C ₂₆ H ₂₇ N ₄ O ₅ S ₁ [M-H] ^- 507.1708, found 507.1709.

3-Ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)sulfamoyl)phenethyl)-4-methyl-2-oxo -2,5-dihydro-1H-pyrrole-1-carboxamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 3-ethyl-4-methyl-2-oxo-N-(4-sulfamoylphenethyl)- 2,5-dihydro-1H-pyrrole-1-carboxamide was used in General Method C2 to give the sub-title compound as a white solid (78 mg, 50%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=10.78 (brs, 1H), 8.38 (t, J=7.6 Hz, 1H), 7.97 (s, 1H), 7 .82 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 6.88 (s, 1H), 4.16 (s, 2H), 3 .48 (kv, J=6.7 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.75 (t, J=7.4 Hz, 4H), 2.53 (t, J=7.4 Hz, 4H), 2.18 (q, J=7.5 Hz, 2H), 2.01 (s, 3H), 1.90 (p, J=7.4 Hz , 4H), 0.97 (t, J=7.5 Hz, 3H). HRMS calculated for C ₂₉ H ₃₃ N ₄ O ₅ S ₁ [M-H] ^- 549.2177, found 549.2169.

5-Chloro-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 5-Chloro-2-methoxy-N-(4-sulfamoylphenethyl)benzamide were used in General Method C2 to give the sub-title compound as a white solid (325 mg, 70%). ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ=10.83 (brs, 1H), 8.27 (t, J=6.0 Hz, 1H), 7.96 (s, 1H), 7 .84 (d, J=8.0 Hz, 2H), 7.66 (d, J=2.8 Hz, 1H), 7.50 (dd, J=8.9 Hz, 2.8 Hz, 1H , 7.44 (t, J=8.0 Hz, 2H), 7.13 (d, J=8.9 Hz, 1H), 6.87 (s, 1H), 3.78 (s, 3H) , 3.53 (q, J=6.6 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.4 Hz, 4H), 2 .53 (t, J=7.4 Hz, 4H), 1.88 (n, J=7.3 Hz, 4H) HRMS calculated for C ₂₉ H ₂₉ Cl ₁ N ₃ O ₅ S ₁ [M-H ] ^- 566.1522, found 566.1543 ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=163.6, 155.7, 145.3, 143.6, 143.0, 142.4 , 142.1, 139.6, 137.1, 131.5, 129.5, 129.2, 127.4, 125.7, 124.8, 124.3, 117.9, 114.1, 108 .3, 56.2, 34.7, 32.6, 32.4, 30.0, 28.9, 24.9 LCMS, Purity: 90.06%, tr=3.38 min, m/z 566.37 (M-H ⁺ ) HRMS (FAB ⁺ ) calculated for C ₂₉ H ₃₀ ClN ₃ O ₅ S [M+H] ⁺ : 568.1595, found: 568.1589.

PYRIDINES

N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)pyridine-2-sulfonamide

Triethylamine (0.35 g, 3 .47 mmol, 3.0 eq.) and then triphosgene (0.265 g, 0.86 mmol, 0.5 eq.) at 0°C and the mixture was stirred at ambient temperature for 3 hours. The mixture was cooled to 0° C, methyl 2-sulfamoylisonicotinate (0.27 g, 1.27 mmol, 1.1 eq) was added and stirring was continued at ambient temperature overnight. Upon completion, the reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a 20-50% EtOAc-hexanes gradient eluent to give methyl 2-(N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl) sulfamoyl)isonicotinate as a light brown solid (0.31 g, 65%).

Methyl 2-(N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)sulfamoyl)isonicotinate (0.30 g, 0.72 mmol) was dissolved in anhydrous THF (8 ml) and the solution was cooled to 0°C. Methylmagnesium bromide (3 mol/l diethyl ether solution, 0.96 ml, 2.88 mmol, 4.0 eq.) was added at 0° C. under nitrogen atmosphere and stirring was continued at ambient temperature for 3 h. the mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The technical residue was purified by reverse phase preparative HPLC to give the sub-title compound as a white solid (0.016 g, 5%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=8.45 (br s, 1H), 8.16 (s, 1H), 7.55 (br s, 1H), 6.87 ( s, 1H), 2.80 (t, J=7.2 Hz, 4H), 2.66 (t, J=7.2 Hz, 4H), 1.96 (quint, J=7.6 Hz, 4H), 1.53 (s, 6H). LCMS, Purity: 98%, m/z 416.09 (M+H ⁺ ). HRMS (FAB ⁺ ) calculated for C ₂₁ H ₂₅ N ₃ O ₄ S [M+H] ⁺ : 416.1566, found: 416.1556.

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-sulfonamide

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A2) and 6,7-dihydro-5H-cyclopenta[b]pyridine-3-sulfonamide were used in general Method C2 to give the sub-title compound as a white solid (12 mg, 27%). ¹ H-NMR (600 MHz, DMSO-d ₆ ): δ=8.71 (s, 1H), 8.01 (s, 1H), 7.96 (brisk, 1H), 6.87 (s, 1H ), 2.97-2.93 (m, 4H), 2.75 (t, J=6 Hz, 4H), 2.55 (t, J=6 Hz, 4H), 2.11-2.07 (m, 2H), 1.93-1.88 (m, 4H). ¹³ C-NMR (150 MHz, DMSO-d ₆ ): δ 169.6, 146.4, 144.9, 143.2, 137.4, 137.2, 131.0, 129.6, 117.7 , 108.7, 34.0, 32.9, 30.6, 30.3, 25.4, 23.2. LCMS (m/z): 398 [M+H] ⁺ .

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-2-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and pyridine-2-sulfonamide were used in General Method C1 to give the sub-title compound as a white solid (40 mg, 10%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.5 (d, J=4.0 Hz, 1H), 7.88 (t, J=7.6 Hz, 1H), 7, 81 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.4 (t, J=5.8 Hz, 1H), 6.76 (s, 1H), 2, 73 (t, J=7.2 Hz, 4H), 2.61 (t, J=7.2 Hz, 4H), 1.88 (quint, J=7.2 Hz, 4H).

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)pyridine-3-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and pyridine-3-sulfonamide were used in General Method C1 to give the sub-title compound as a white solid (12 mg, 3%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=9.08 (s, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.36 (d, J=8, 0 Hz, 1H), 7.56 (dd, J=8.0, 4.8 Hz, 1H), 6.88 (s, 1H), 2.82 (t, J=7.2 Hz, 4H) , 2.69 (t, J=7.2 Hz, 4H), 2.0 (quint, J=7.2 Hz, 4H).

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(trifluoromethyl)pyridine-2-sulfonamide

4-Isocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (prepared using General Method A1) and 4-(trifluoromethyl)pyridine-2-sulfonamide were used in General Method C1 with yielding the sub-title compound as a white solid (16 mg, 3%). ¹ H-NMR (400 MHz, CD ₃ OD): δ=8.47 (s, 1H), 8.22 (s, 1H), 7.42 (s, 1 H), 6.98 (s, 1 H), 2.82 (t, J=7.2 Hz, 4H), 2.66 (t, J=7.2 Hz, 4H), 1.95 (quint, J=7.2 Hz, 4H) ; ¹⁹ P-NMR (233.33 MHz, DMSO-d6): -63.48 (s, 3F).

LINKER

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamothioyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide

To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (0.10 g, 0.58 mmol) in anhydrous DCM (2.0 ml) was added 1,1'-thiocarbonyldiimidazole (1.1 eq.) and the reaction mixture was stirred for 4 h at ambient temperature. The solvent was removed under reduced pressure, then the residue was taken up in acetone (2.0 ml) and potassium carbonate (2.5 eq.) was added, followed by 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (1, 2 eq.). The reaction mixture was heated at reflux overnight, concentrated under reduced pressure, then neutralized with 10% citric acid (10 ml) and immediately extracted with ethyl acetate (2×10 ml), dried (MgSO ₄ ) and concentrated under reduced pressure . The crude product was purified by silica gel column chromatography eluting with MeOH/DCM followed by HPLC to give the sub-title compound as a white to yellowish solid (13 mg, 4%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=12.0 (brc, 1H), 9.72 (s, 1 H), 7.88 (s, 1 H), 7.43 (s , 1H), 7.01 (s, 1H), 5.15 (br.s., 1H), 2.81 (t, J=6.8 Hz, 4H), 2.59 (t, J= 6.8 Hz, 4H), 1.95 (quint, J=7.6 Hz, 4H), 1.39 (s, 6H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ=176.9, 143.1, 142.7, 138.7, 137.1, 130.4, 119.3, 117.7, 66, 6, 32.4, 30.9, 29.9, 24.9. LCMS: Purity=95.08%, tr=3.45 min, m/z 421.30 (M+H ⁺ ).

Biological testing methodology

NLRP3 inhibition assays

To determine the inhibitory activity of test compounds on the NLRP3 inflammasome, the following assays can be used using conventional stimuli such as adenosine triphosphate, nigericin, LeuLeu-OMe, or sodium monourate (MSU) crystals.

Cell culture

Human monocytes were isolated from buffy coat blood using Ficoll-Plaque Plus (GE Healthcare) and density centrifugation for production of MMPs. The selection of CD14 ⁺ cells was carried out using magnetic beads MACS (Miltenyl Biotec). Isolated CD14 ⁺ monocytes were differentiated in culture for 7 days with human CSF-1 (colony stimulating factor) 10 ng/ml (Miltenyl Biotec) in Iscove's Modified Dulbecco's Medium (IMDM) containing L-glutamine supplemented with 10% FBS (fetal bovine serum) and 1% penicillin/streptomycin (Life Technologies) as described in Croker et al 2013 Immunol Cell Biol 91:625.

Mouse bone marrow macrophages (BMDM) were obtained from bone marrow progenitor cells isolated from the femurs and tibias of C57BL/6 mice. The bones were washed with medium, and the bone marrow cells were cultured for 7 days in RPMI 1640 medium supplemented with 10% heat-inactivated FCS (fetal bovine serum), 2 mmol/l GlutaMAX (Life Technologies), 50 μmol/ml penicillin-streptomycin (Life Technologies) and 150 ng/ml recombinant human M-CSF (macrophage colony stimulating factor) (without endotoxins, expressed and purified on the University of Queensland protein expression facility).

NLRP3 inflammas activation tests

Produced sowing MMCH at 1×10 ⁵ /ml. The next day, medium was changed after overnight and the cells were stimulated with Escherichia coli 0111:B4 serotype (Sigma Aldrich) for 3 h. The medium was removed and replaced with serum-free medium (SFM) containing test compound 30 min before NLRP3 stimulation. Cells were then stimulated with: adenosine 5'-triphosphate disodium hydrate (5 mmol/L 1 h), nigericin (10 µmol/L 1 h), LeuLeu-OMe (1 mmol/L 2 h) or MSU (200 µg /ml 15 h). ATP is available from Sigma Aldrich, nigericin and MSU from Invivogen, and LeuLeu-Ome from Chem-Impex International.

Produced seeding BMDM at 1×10 ⁵ /ml. The next day, medium was changed overnight and cells were stimulated with Ultrapure lipopolysaccharide from Escherichia coli strain K12 (InvivoGen) for 3 hours. The medium was removed and replaced with serum-free medium (SFM) containing test compound 30 min before NLRP3 stimulation. Cells were then stimulated with: adenosine-5'-triphosphate disodium hydrate (1.25-5 mmol/L 1 h), nigericin (5 µmol/L 1 h), LeuLeu-OMe (1 mmol/L 2 h) or MSU (200 μg/ml 15 h). ATP is available from Sigma Aldrich, nigericin and MSU from Invivogen, and LeuLeu-Ome from Chem-lmpex International.

Measurement of IL-1β, IL-18, TNFα and cell death

For ELISA and cell death tests, cells were seeded in 96-well plates. Supernatants were removed and analyzed using ELISA kits according to the manufacturer's instructions (DuoSet® R&D Systems, ReadySetGo!® eBioscience, BD OptEIA™, or Perkin Elmer AlphaLISA®). Cell death was assessed by measuring LDH release versus a 100% cell lysis control using the CytoTox96® non-radioactive cytotoxicity assay (Promega).

Studies of compound levels in blood plasma and brain in mice

General Experimental: Carbutamide was purchased from Sigma Aldrich (Cat. No. 381578). Acetonitrile was HPLC grade Chromasolv® (Sigma Aldrich, Sydney, Australia), formic acid was AR (analytical grade) 99%-100% Normapur (VWR International Pty Ltd, Brisbane, Australia), DMSO was ReagentPlus® grade (D5879, Sigma Aldrich, Sydney, Australia) and H ₂ O Milli-Q was filtered. HPLC vials and polypropylene inserts were from Agilent Technologies (Melbourne, Australia) and Eppendorf 1.5 ml Protein LoBind Tubes were from VWR International Pty Ltd (Brisbane, Australia).

Precipitation solution preparation: 100 ml acetonitrile and 5 µl carbutamide in DMSO 10 mmol/l (MS internal standard acetonitrile with 135 ng/ml carbutamide).

Plasma Calibration Curve Preparation: Prepare 1 mg/mL of test compound in NH ₄ HCO ₃ 10 mmol/L and dilute 10-fold to give a stock solution of 100,000 ng/mL. A 10-fold dilution sequence of a 100,000 ng/mL stock solution with 10 mmol/L NH ₄ HCO ₃ gave concentrations of 10,000, 1000, 100, and 10 ng/mL. The 100,000 ng/ml stock solution was diluted 3:7 with NH ₄ HCO ₃ 10 mmol/l to give a concentration of 30,000 ng/ml and a 10-fold dilution sequence gave concentrations of 3000, 300, 30 and 3 ng/ml.

20 µl of test compound containing solution and 160 µl of precipitation solution were added to 20 µl of mouse plasma in a low retention Eppendorf tube. Samples were vortexed, left to stand at 4°C for 10 min, and centrifuged at 14,000 x g for 8 min. 150 µl of the supernatant was transferred to an HPLC vial insert. Samples were stored at 4°C until analysis.

Preparation of the calibration curve in brain homogenate: The test solutions prepared for the plasma calibration curve were used for the calibration curve of the brain homogenate.

The brain homogenate of mice from the control group treated with saline was thawed and vortexed for 3 min or until homogeneous, sonicated for 1 min. After the foam had settled, 50 µl of the mouse brain homogenate was transferred to an Eppendorf tube, followed by 50 µl of the test compound in NH ₄ HCO ₃ 10 mmol/l, 150 µl of H ₂ O and 500 µl of ice-cold vortex precipitation solution after each addition. The standard solutions were left to stand at 4°C for 10 min and then centrifuged at 14,000 x g for 8 min. 200 µl of the supernatant was transferred to an HPLC vial insert, ensuring that no air bubbles were present, and the samples were stored at 4° C. until analysis.

Mice dosing and transcardial perfusion

Dosage: Oral forced feeding at a dose of 20 mg/kg

Point in time: 2 hours

Prepared basic compounds for dosing at 4 mg/ml in sterile PBS (phosphate buffered saline). Mice were weighed and dosed by forced oral feeding at a dose of 20 mg/kg for each compound. After 2 hours, mice were anesthetized with a combination of Zoletil (50 mg/kg) and Xylazine (10 mg/kg) and blood was collected by cardiac puncture into tubes containing 20 μl of 100 mmol/l EDTA. Blood was centrifuged at 2000×g for 15 minutes at 4°C to collect plasma.

Preparation of plasma samples for analysis: 20 µl of NH ₄ HCO ₃ and 160 µl of precipitation solution were added to 20 µl of mouse plasma in a low retention Eppendorf tube. The samples were mixed by vortexing, left to stand at 4°C for 10 min and centrifuged at 14,000 x g for 8 min. 150 µl of the supernatant was transferred to the HPLC vial insert, ensuring that no air bubbles were present. Samples were stored at 4°C until analysis.

Brain homogenate preparation: Mouse brains were perfused with PBS for 5 minutes, then cut and weighed. A brain homogenate was prepared by homogenizing the whole brain (0.5 g) with 4 volumes (2 ml) of deionized water and stored at -20°C until analysis. The homogenate was thawed, vortexed for 3 min or until homogeneous, and sonicated for 1 min. After the foam settled, 50 µl of the mouse brain homogenate was transferred to an Eppendorf tube, followed by 50 µl of NH ₄ HCO ₃ 10 mmol/l, 150 µl of H ₂ O and 500 µl of ice-cold precipitation solution with vortex mixing after each addition. 200 µl of the supernatant was transferred to an HPLC vial insert, ensuring that no air bubbles were present, and the samples were stored at 4° C. until analysis.

Preparation of brain samples for analysis: 50 μl of mouse brain was transferred to an Eppendorf tube, followed by 50 μl of NH ₄ HCO ₃ 10 mmol/l, 150 μl of H ₂ O and 500 μl of ice-cold vortex precipitation solution after each addition. The solutions were left to stand at 4°C for 10 min and then centrifuged at 14,000 x g for 8 min. 200 µl of the supernatant was transferred to an HPLC vial insert, ensuring that no air bubbles were present, and the samples were stored at 4° C. until analysis.

LC-MS/MS: samples were analyzed on a Sciex 4000QTrap MS AB with 2 Shimadzu Nexera LC-30AD solvent feeders, Shimadzu Nexera SIL-30AC autosampler, Shimadzu Prominence DGU-20A5 degasser, Shimadzu Prominence CBM-20A system controller, and Shimadzu Prominence column oven CTO-20A. The column thermostat was set to 40°C, while the autosampler was set to 15°C. 2 μl injections were made and selective reaction monitoring (SRM) MS analyzes were performed using Turbo Spray (-)-ESI (Electric Field Spray Ionization) with Q1 low resolution and Q3 low resolution. MS parameters: CUR: 30.00, IS: -4300.00, TEM: 500.00, GS1: 50.00, GS2: 50.00, ihe: ON, CAD: High, DP -60.00, EP - 10.00, SHR -15.00. MCC950 SRM: Q1 403.2 to Q3 204.3 Da, measurement time per point 150 ms, SRM CE -27 and carbutamide (IS): Q1 270.0 to Q3 171.0 Da, measurement time per point 100 ms, CE -25. HPLC column: Waters Atlantis® T3 5 µm 2.1 x 50 mm with guard column Atlantis® T3 5 µm 2.1 x 10 mm. Flow rates and solvents: 0.35 ml/min, solvent A: 0.1% formic acid in H ₂ O, solvent B: 0.1% formic acid in acetonitrile; isocratic 2% V from 0→2 min, gradient 2%→100% V from 2→5 min, isocratic 100% from 5→9 min, gradient 100%→2% V from 9→9.1 min and isocratic 2% B from 9.1→13 min. Peak areas from SRM data for carbutamide and test compound were analyzed with AB Sciex's Analyst software using the Quantitation Wizard. The peak area was plotted as a function of concentration in ng/ml in 20 μl test compound solutions from 3 to 30,000 ng/ml, and the lower and upper limits of the linear response were determined. These data were then plotted in Microsoft Excel and a linear reaction equation was used to determine the concentration of test compound in 20 µl plasma solutions. Similarly, for brain homogenate samples, 50 µl peak areas from 3 to 3000 ng/ml test compound solutions were used to determine the concentration of test compound in 50 µl brain homogenate solutions.

RESULTS

Full tPSA series and biological results are shown in the tables below, however, individual data for certain compounds of the present invention are presented below.

Plasma concentration after dosing

Single dose pharmacokinetic study

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (MCC7840 and being the compound of the first aspect) according to compared to

N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl) furan-2-sulfonamide (MCC950) using The intravenous dose of 4 mg/kg and the oral dose of 20 mg/kg clearly showed a longer half-life, increased maximum concentration (C max ) and area under the curve (AUC) for the pyrazole derivative compared to furan. This is an advantage resulting in relatively lower doses or less frequent administration.

The procedure followed was as follows: Male C57BL/6 mice aged 7-9 weeks were used with 3 animals per group. Mice were dosed with test compound via a single intravenous bolus or forced oral feeding. Blood samples were taken from the submandibular or saphenous vein for analysis of plasma compound concentrations by LC-MS/MS at the following time points: IV (3 mice): 0.083, 0.25, 0.5, 1, 2, 4 , 8 and 24 hours after dosing, orally (PO) (3 mice): 0.25, 0.5.1, 2, 4, 8 and 24 hours after dosing. An LC-MS/MS method was developed to quantify a test compound in an appropriate biological matrix. Pharmacokinetic (PK) parameters were calculated using Phoenix WinNonlin 6.3. The results are presented graphically in FIG. 1A to 1C (MCC950) and FIG. from 2A to 2C (MCC7840).

The corresponding compound structures are shown below, and tables 5-8 contain the relevant data:

Claims (56)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

where W is selected from O, S and Se; J is selected from S and Se; R ₁ is selected from the group consisting of 5-membered and 6-membered heterocyclyl, each of which contains from 1 to 4 heteroatoms selected from N, O and S, and each of which may be optionally substituted, where any optional substituent is independently selected from the group consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C _1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl; R ₂ is selected from 2,6-dialkylphenyl, 2,6-dialkyl-4-halophenyl, 2,6-dicycloalkylphenyl, 2,6-dicycloalkyl-4-halophenyl, and

where each occurrence of Y is independently selected from C, N, S and O, which may be optionally substituted, where any optional substituent is independently selected from the group consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C _1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl; R ₅ is selected from the group consisting of hydrogen, halo, cyano, amide, sulfonamide, acyl, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₅ cycloalkyl and C ₁ -C ₆ alkoxy, all of which may be optionally substituted with halo, cyano or C ₁ -C ₆ alkoxy; And as R ₁ is directly connected to J, so R ₂ is directly connected to the adjacent nitrogen atom, through a carbon atom; provided that when W is O, J is S, and R ₁ is a 5-membered heterocyclyl, then said 5-membered heterocyclyl does not contain any ring nitrogen atoms. 2. The compound of claim 1 wherein R ₁ is a 6-membered heterocyclyl which contains 1 to 4 heteroatoms selected from N, O and S and which may be optionally substituted, wherein any optional substituent is independently selected from the group , consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C _1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl. 3. A compound according to any one of the preceding claims, wherein R ₁ is a fully saturated heterocyclyl which contains from 1 to 4 heteroatoms selected from N, O and S and which may be optionally substituted, wherein any optional substituent is independently selected from the group , consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C _1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl. 4. The compound according to any one of the preceding claims, wherein R ₁ is a nitrogen heterocyclyl which contains from 1 to 4 heteroatoms selected from N, O and S and which may be optionally substituted, wherein any optional substituent is independently selected from the group, consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C _1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl. 5. A compound according to any one of the preceding claims, wherein R ₁ is selected from the group consisting of tetrahydrofuran, tetrahydropyran, pyran, pyrrolidine, morpholine, piperazine, and piperidine, all of which may be optionally substituted as necessary, wherein any optional substituent is independently selected from a group consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂ 5; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C _1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl. 6. A compound according to any one of the preceding claims, wherein R ₁ is selected from the group consisting of tetrahydrofuran, tetrahydropyran, pyrrolidine, morpholine, piperazine and piperidine, all of which may be optionally substituted, wherein any optional substituent is independently selected from the group consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; C _1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl. 7. A compound according to any one of the preceding claims, wherein R₁ is selected from the group consisting of pyrrolidine, piperazine and piperidine, all of which may be optionally substituted, where any optional substituent is independently selected from the group consisting of C_1-10 alkyl; WITH_3-6 cycloalkyl; C_1-9 hydroxyalkyl; WITH_1-10 alkoxy; WITH_2-10 alkenyl; WITH_2-10 alkynyl; WITH₆-WITH₁₂ aryla; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C_1-9 alkyl; amino; WITH_1-9 alkylamino; acyl; amido; CN; NO₂; N₃; CH₂HE; CONH₂; CONR₂₄R₂5; CO₂R₂₄; CH₂OR₂₄; NHCOR₂₄; NHCO₂R₂₄; C_1-3 alkylthio; sulfonic acid; trityl; monomethoxytrityl; R₂₄SO; R₂₄SO₂; CF₃S; CF₃SO₂; and trialkylsilyl; where R₂₄ and R₂₅ each independently selected from H or C_1-10 alkyl. 8. The compound according to any one of the preceding paragraphs, in which R ₁ represents piperidine, which may be optionally substituted, where any optional substituent is independently selected from the group consisting of C _1-10 alkyl; C _3-6 cycloalkyl; C _1-9 hydroxyalkyl; C _1-10 alkoxy; C _2-10 alkenyl; C _2-10 alkynyl; C ₆ -C ₁₂ aryl; a heterocyclyl containing 5 to 8 ring atoms and of these atoms, 1 to 4 are heteroatoms selected from N, O and S; halo; hydroxyl; halogenated C _1-9 alkyl; amino; C _1-9 alkylamino; acyl; amido; CN; _NO2 ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₂₄ R ₂₅ ; CO ₂ R ₂₄ ; CH ₂ OR ₂₄ ; NHCOR ₂₄ ; NHCO ₂ R ₂₄ ; d. ₃ alkylthio; sulfonic acid; trityl; monomethoxytrityl; R ₂₄ SO; R ₂₄ SO ₂ ; _CF3S ; CF ₃ SO ₂ ; and trialkylsilyl; where R ₂₄ and R ₂₅ are each independently selected from H or C _1-10 alkyl. 9. Connection according to any one of paragraphs. 1, 2, 3, 5, or 6, wherein R ₁ is selected from the group consisting of

and in combination with each such group, R ₁ , R ₂ is independently selected from the group consisting of:

10. A compound according to any one of the preceding claims, wherein R ₂ is selected from

where Y and R ₅ have the meanings specified in any of the preceding paragraphs. 11. A compound according to any one of the preceding claims, wherein R ₂ is selected from

where each occurrence of Y is carbon and R ₅ is hydrogen or halo. 12. A compound according to any one of the preceding claims, wherein R ₂ is selected from substituted or hydrogenated indacene, 2,6-dialkylphenyl, 2,6-dialkyl-4-halophenyl, 2,6-dicycloalkylphenyl and 2,6-dicycloalkyl-4- halophenyl. 13. A compound according to any one of the preceding claims, wherein R ₂ is selected from hexahydroindacene, 2,6-diisopropylphenyl, 2,6-diisopropyl-4-chlorophenyl, 2,6-dicyclopropylphenyl and 2,6-dicyclopropyl-4-chlorophenyl. 14. A compound according to any one of the preceding claims, wherein J is a sulfur atom. 15. A compound according to any of the preceding claims, wherein W is an oxygen atom. 16. A compound according to any of the preceding claims, which is a compound of formula (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof:

where R ₁ is as defined in any of the preceding paragraphs. 17. Connection according to any one of paragraphs. 1-3, 5, 6 or 9-16, wherein the compound is selected from the group consisting of:

and their pharmaceutically acceptable salts. 18. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein the compound, or a pharmaceutically acceptable salt thereof, is an NLRP3 inflammasome inhibitor. 19. A pharmaceutical composition having the activity of inhibiting the activation of the NLRP3 inflammasome and containing an effective amount of a compound according to any one of paragraphs. 1-18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient. 20. A method of treating or preventing a disease, disorder or condition, comprising the step of administering an effective amount of a compound according to any one of paragraphs. 1-18 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 for the treatment or prevention of that disease, disorder, or condition, wherein the disease, disorder, or condition is one that responds to inhibition of NLRP3 inflammasome activation. 21. The method of claim 20, wherein the disease, disorder, or condition is responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33, and Th17 cells. 22. The method of claim 20 or 21, wherein the disease, disorder, or condition is selected from the group consisting of constitutive inflammation, including cryopyrin-associated periodic syndromes (CAPS): Mackle-Wales syndrome (MWS), familial cold auto-inflammatory syndrome (CXAS (FCAS)) and multisystem inflammatory disease of neonatal age (MVZNV (NOMID)); including autoinflammatory diseases: periodic illness (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency interleukin 1 receptor antagonist (DARI (DIRA)), Majid syndrome, purulent arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (GA20 (HA20)), pediatric granulomatous arthritis (PGA) associated with PLCG2 antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory disease, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SILZ (SIFD)) ; Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO); autoimmune diseases including multiple sclerosis (PC(MS)), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome and Schnitzler's syndrome; respiratory diseases, including chronic obstructive pulmonary disease (COPD (COPD)), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, and brain damage from pneumococcal meningitis; metabolic diseases including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout; eye diseases, including ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy and diabetic nephropathy; liver disease, including non-alcoholic steatohepatitis and alcoholic liver disease; inflammatory reactions on the skin, including contact hypersensitivity and sunburn; inflammatory reactions in the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, acquired Still's disease, relapsing polychondritis; viral infections, including alpha virus, including chikungunya and Ross River virus, and flavivirus, including dengue and Zika viruses, influenza, HIV; suppurative hidradenitis (HS) and other cyst-causing skin diseases; cancers, including lung cancer metastases, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis; apoplexy; myocardial infarction; graft-versus-host reaction; high blood pressure; colitis; helminth infection; bacterial infection; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis, including Dressler's syndrome, ischemia-reperfusion injury, and any disease in which an individual is determined to carry a non-silent generative or somatic mutation in NLRP3. 23. The method according to any one of paragraphs. 20-22, wherein the treatment or prevention of a disease, disorder, or condition is carried out in a mammal. 24. The method of claim 23 wherein the mammal is a human subject. 25. A method of inhibiting the activity of a biological target, comprising the step of influencing the biological target with a compound according to any one of paragraphs. 1-18 or a pharmaceutically acceptable salt thereof, wherein the biological target is selected from the group consisting of NLRP3 inflammasome, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33 and Th17 cells. 26. Connection or pharmaceutically acceptable salt according to any one of paragraphs. 1-18, where the compound or a pharmaceutically acceptable salt thereof is used in: (a) treating or preventing a disease, disorder or condition responsive to inhibition of NLRP3 inflammasome activation; and/or (b) treating or preventing a disease, disorder or condition responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33 and Th17 cells; and/or (c) treating or preventing a disease, disorder, or condition selected from the group consisting of constitutive inflammation, including cryopyrin-associated periodic syndromes (CAPS): Mackle-Wales syndrome (MWS), familial cold autoinflammatory syndrome ( CXAS (FCAS)) and multisystem inflammatory disease of neonatal age (MVZNV (NOMID)); including autoinflammatory diseases: periodic illness (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency interleukin 1 receptor antagonist (DARI (DIRA)), Majid syndrome, purulent arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (GA20 (HA20)), pediatric granulomatous arthritis (PGA) associated with PLCG2 antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory disease, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SILZ (SIFD)) ; Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO); autoimmune diseases including multiple sclerosis (PC(MS)), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome and Schnitzler's syndrome; respiratory diseases, including chronic obstructive pulmonary disease (COPD (COPD)), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, and brain damage from pneumococcal meningitis; metabolic diseases including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout; eye diseases, including ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy and diabetic nephropathy; liver disease, including non-alcoholic steatohepatitis and alcoholic liver disease; inflammatory reactions on the skin, including contact hypersensitivity and sunburn; inflammatory reactions in the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, acquired Still's disease, relapsing polychondritis; viral infections, including alpha virus, including chikungunya and Ross River virus, and flavivirus, including dengue and Zika viruses, influenza, HIV; suppurative hidradenitis (HS) and other cyst-causing skin diseases; cancers, including lung cancer metastases, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis; apoplexy; myocardial infarction; graft-versus-host reaction; high blood pressure; colitis; helminth infection; bacterial infection; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis, including Dressler's syndrome, ischemia-reperfusion injury, and any disease in which an individual is determined to carry a non-silent generative or somatic mutation in NLRP3. 27. Connection or pharmaceutically acceptable salt according to any one of paragraphs. 1-18, where the compound or a pharmaceutically acceptable salt thereof is used in inhibiting the activity of a biological target selected from the group consisting of inflammasome NLRP3, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33 and Th17 cells. 28. The use of a compound or pharmaceutically acceptable salt according to any one of paragraphs. 1-18 for the manufacture of a medicinal product for: (a) treating or preventing a disease, disorder or condition responsive to inhibition of NLRP3 inflammasome activation; and/or (b) treating or preventing a disease, disorder or condition responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33 and Th17 cells; and/or (c) treating or preventing a disease, disorder, or condition selected from the group consisting of constitutive inflammation, including cryopyrin-associated periodic syndromes (CAPS): Mackle-Wales syndrome (MWS), familial cold autoinflammatory syndrome ( CXAS (FCAS)) and multisystem inflammatory disease of neonatal age (MVZNV (NOMID)); including autoinflammatory diseases: periodic illness (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency interleukin 1 receptor antagonist (DARI (DIRA)), Majid syndrome, purulent arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (GA20 (HA20)), pediatric granulomatous arthritis (PGA) associated with PLCG2 antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory disease, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SILZ (SIFD)) ; Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO); autoimmune diseases including multiple sclerosis (PC(MS)), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome and Schnitzler's syndrome; respiratory diseases, including chronic obstructive pulmonary disease (COPD (COPD)), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, and brain damage from pneumococcal meningitis; metabolic diseases including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout; eye diseases, including ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy and diabetic nephropathy; liver disease, including non-alcoholic steatohepatitis and alcoholic liver disease; inflammatory reactions on the skin, including contact hypersensitivity and sunburn; inflammatory reactions in the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, acquired Still's disease, relapsing polychondritis; viral infections, including alpha virus, including chikungunya and Ross River virus, and flavivirus, including dengue and Zika viruses, influenza, HIV; suppurative hidradenitis (HS) and other cyst-causing skin diseases; cancers, including lung cancer metastases, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis; apoplexy; myocardial infarction; graft-versus-host reaction; high blood pressure; colitis; helminth infection; bacterial infection; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis, including Dressler's syndrome, ischemia-reperfusion injury, and any disease in which an individual is determined to carry a non-silent generative or somatic mutation in NLRP3. 29. The use of a compound or pharmaceutically acceptable salt according to any one of paragraphs. 1-18 for the manufacture of a pharmaceutical composition for inhibiting the activity of a biological target selected from the group consisting of NLRP3 inflammasome, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33 and Th17 cells.

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